Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
PE PEER-REVIEWD OPEN ACCESS HIV/AIDS JOURNAL ONLINE ONLINE HIV/AIDS JOURNAL HIV/AIDS JOURNAL PEER-REVIEWD HIV/AIDS JOURNAL PO ONLI ONLINE HIV/AIDS JOURNAL ONLI OPEN ACCESS PEER-REVIEWDHIV/AIDS JOURNAL N ACCESS ACCESS ONLINE PEER-REVIEWD AIDS JOURNAL EN ACCESS OPEN A ONLINE R-REVIEWD PEER-REVIEWD ONLINE PEER-REVIEWD DS JOURNAL OPEN ACCESS HIV/AIDS JOURNAL HIV/AIDS JOUR ONLINE HIV/A HIV/AIDS JOURN OPEN ACCE HIV/AIDS JOURN -REVIEWD PEER-REVIEW URNAL HIV/AIDS JOURNAL HIV/AIDS JOURNAL PEER-REVIEW OPEN ACCESS OPEN ACCESS PEER-REVIEWD ONLINE Perinatally HIV-infected adolescents PERINATAL INFECTION HEART METABOLISM HIV/AIDS ADOLESCENTS EPIDEMIOLOGY NEURODEVELOPMENT BONE DENSITY Volume 16, Special Issue June 2013 REVIEWS MENTAL HEALTH LUNG LUNG TREATMENT EPIDEMIOLOGY KIDNEYS BONE DENSITY PERINATAL INFECTION MENTAL HEALTH EPIDEMIOLOGY TREATMENT Guest Editors: Lynne M Mofenson and Mark F Cotton Scan this QR code with your mobile device to view the special issue online Support The publication of this special issue was supported by the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), which is funded through an unrestricted grant from ViiV Healthcare’s Paediatric Innovation Seed Fund. Perinatally HIV-infected adolescents Guest Editors: Lynne M Mofenson and Mark F Cotton Contents Editorial: The challenges of success: adolescents with perinatal HIV infection Lynne M Mofenson and Mark F Cotton The changing epidemiology of the global paediatric HIV epidemic: keeping track of perinatally HIV-infected adolescents Annette H Sohn and Rohan Hazra Antiretroviral treatment, management challenges and outcomes in perinatally HIV-infected adolescents Allison L Agwu and Lee Fairlie Understanding the mental health of youth living with perinatal HIV infection: lessons learned and current challenges Claude A Mellins and Kathleen M Malee Neurodevelopment in perinatally HIV-infected children: a concern for adolescence Barbara Laughton, Morna Cornell, Michael Boivin and Annelies Van Rie Cardiac effects in perinatally HIV-infected and HIV-exposed but uninfected children and adolescents: a view from the United States of America Steven E Lipshultz, Tracie L Miller, James D Wilkinson, Gwendolyn B Scott, Gabriel Somarriba, Thomas R Cochran and Stacy D Fisher Metabolic complications and treatment of perinatally HIV-infected children and adolescents Linda Barlow-Mosha, Allison Ross Eckard, Grace A McComsey and Philippa M Musoke Bone health in children and adolescents with perinatal HIV infection Thanyawee Puthanakit and George K Siberry Kidney disease in children and adolescents with perinatal HIV-1 infection Rajendra Bhimma, Murli Udharam Purswani and Udai Kala The challenge of chronic lung disease in HIV-infected children and adolescents Heinrich C Weber, Robert P Gie and Mark F Cotton Volume 16, Special Issue June 2013 http://www.jiasociety.org/index.php/jias/pages/view/thematicadolescents http://www.jiasociety.org/index.php/jias/article/view/18778 | http://dx.doi.org/10.7448/IAS.16.1.18778 Mofenson LM and Cotton MF. Journal of the International AIDS Society 2013, 16:18650 http://www.jiasociety.org/index.php/jias/article/view/18650 | http://dx.doi.org/10.7448/IAS.16.1.18650 Editorial The challenges of success: adolescents with perinatal HIV infection Lynne M Mofenson§,1 and Mark F Cotton2 § Corresponding author: Lynne M Mofenson, Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Boulevard, Room 4B11 Rockville, MD 20852, USA This article is part of the special issue Perinatally HIV-infected adolescents - more articles from this issue can be found at http://www.jiasociety.org Abstract The great success in the prevention and treatment of pediatric HIV in high resource countries, and now in low resource countries, has changed the face of the HIV epidemic in children from one of near certain mortality to that of a chronic disease. However, these successes pose new challenges as perinatally HIV-infected youth survive into adulthood. Increased survival of HIV-infected children is associated with challenges in maintaining adherence to what is likely life-long therapy, and in selecting successive antiretroviral drug regimens, given the limited availability of pediatric formulations, limitations in pharmacokinetic and safety data of drugs in children, and the development of extensive drug resistance in multi-drug-experienced children. Pediatric HIV care must now focus on morbidity related to long-term HIV infection and its treatment. Survival into adulthood of perinatally HIV-infected youth in high resource countries provides important lessons about how the epidemic will change with increasing access to antiretroviral therapy for children in low resource countries. This series of papers will focus on issues related to management of perinatally infected youth and young adults. Keywords: perinatal HIV infection; adolescents; HIV care. Published 18 June 2013 Copyright: – 2013 Mofenson LM and Cotton MF; licensee International AIDS Society. This is an open access article distributed under the terms of the Creative Commons Attribution 3.0 Unported (CC BY 3.0) Licence (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The remarkable success in the prevention and treatment of paediatric HIV infection in high-resource countries has changed the face of the HIV epidemic in children from a fatal disease to that of a chronic illness. With widespread access to antiretroviral therapy in high-resource settings, many perinatally infected children are surviving into adolescence, young adulthood and beyond [1]. With increasing access to antiretroviral therapy in resource-limited settings, a similar population of perinatally infected youth is emerging [2]. Important lessons gained in high-resource settings about how the epidemic changes with increasing access to antiretroviral therapy for children will help to inform management in resource-limited settings [3]. These successes pose new management challenges as perinatally infected youth survive into adulthood. There have been significant difficulties in maintaining adherence to lifelong therapy, and in selecting successive antiretroviral drug regimens, given the limited availability of paediatric formulations, pharmacokinetic, and safety data in children and development of extensive drug resistance in multi-drugexperienced children. Long-term survival of youth with perinatal HIV infection has been accompanied by unanticipated needs. These include management of long-term complications of therapy, sexual and reproductive health, mental health needs, and issues of higher education and career training [4,5]. How to transition from complete dependence on adult caregivers and health services provided in paediatric HIV care settings, which are often multidisciplinary, family-centred and include extensive support services, to adult HIV care systems and assuming responsibility for their own care has received little attention [6]. These young adolescents may fall through the cracks and suffer from a sense of abandonment as they lose the familiar and dependable environment and staff of the paediatric HIV clinic (clinicians, social workers, nursing staff) and its support services. To optimize the psychosocial well-being and treatment outcomes of perinatally infected adolescents and young adults as well as enabling them to lead long, meaningful and productive lives, there is an urgent need to understand the factors that either facilitate or serve as a barrier to the health and well-being of HIV-infected children and youth, and the complications of HIV and therapy as they age. The articles in this series provide a comprehensive evaluation of the issues related to perinatal HIV infection in both high- and lowresource settings. One common theme is the paucity of research in the area of adolescent perinatal HIV infection, including a lack of epidemiologic data to better define this population of youth on a global basis, and the general lack of data regarding potential impacts of gender on HIV disease in this population. Sohn and Hazra discuss the changes in the global paediatric HIV epidemic as children receiving antiretroviral therapy age into adolescence, highlighting our lack of knowledge regarding the global numbers of perinatally infected youth over 15 years of age because global reporting does not differentiate 1 Mofenson LM and Cotton MF. Journal of the International AIDS Society 2013, 16:18650 http://www.jiasociety.org/index.php/jias/article/view/18650 | http://dx.doi.org/10.7448/IAS.16.1.18650 between perinatal and behaviourally infected youth [7]. They discuss treatment challenges in multi-drug-experienced children and available data on regional outcomes of treatment and long-term complications in perinatally infected youth in Africa, Asia, the US, Europe and Latin America/Caribbean. They note that the lack of a global surveillance system or mechanism for tracking perinatally infected children as they transition to adulthood results in a lack of understanding of the needs of these children and whether they are retained in care or lost to follow-up. Agwu and Fairlie discuss the multiple challenges of antiretroviral therapy in perinatally infected youth, with a focus on adherence issues and a review of clinical, immune and viral outcomes [8]. Children with perinatal HIV infection initiate therapy during a period of rapid growth and face decades, if not a life-time, of antiretroviral drug exposure. Perinatally infected youth often have complex clinical histories, multi-class drug experience and often drug resistant virus, complicating their care and limiting choice of therapy. While treatment is life-saving, adherence to therapy is particularly problematic in infected adolescents, with multifaceted aetiologies and little specific research, particularly in resource-limited settings [9]. The authors note that successful treatment in perinatally infected youth is complicated by developmental, cognitive and psychosocial challenges, and that continued successful clinical outcomes of treatment in these youth may be particularly compromised by a resistant virus, non-adherence and the limited pipeline of new agents. Longitudinal data are needed to determine if the increased life-expectancy in treated HIV-infected adults will be duplicated in perinatally infected youth as they transition in to adulthood. Mellins and Malee discuss mental health issues in perinatally infected youth, reviewing the literature in this area, risk as well as protective factors, treatment modalities and need for further research [10]. Infected youth have a high rate of psychiatric symptoms, particularly attention-deficit disorder and depression, compared to children from similar socioeconomic circumstances [11,12]. The aetiology of these disorders is likely multifactorial, including biologic factors such as HIV itself, its treatment, as well as psychosocial factors including chronic illness, poverty, loss of parents, and stigma and rejection by peers. Psychiatric symptoms may be associated with poor behavioural outcomes, such as risky sexual behaviours which could promote HIV transmission (and pregnancy), drug use and poor adherence to therapy. The authors note the critical need for data from and tools for resource-limited settings, and the potential utility of resilience models to identify key areas that may be amenable to preventive interventions. Laughton and colleagues discuss neurodevelopmental issues in perinatally infected youth, noting that infected youth exhibit problems on general cognitive tests, processing and visual-spatial tasks and are at high risk for psychiatric and mental health problems as discussed by Mellins [10,13]. While antiretroviral therapy has significantly decreased HIV encephalopathy, as HIV-infected children survive into adolescence and young adulthood, more subtle manifestations of central nervous system disease are still seen. These cognitive deficits, problems with attention and psychiatric disorders are far less acutely devastating than encephalopathy but may well have a tremendous impact on these youth as they survive into adulthood. The etiologic factors are complex and may include the effects of HIV infection (both on-going central nervous system viral replication as well as past impact of infection on the developing brain), chronic inflammation, antiretroviral drugs toxic effects, social factors and other exposures (both in utero and behaviourally based, such as substance use). The authors note the paucity of data in infected adolescents and in youth from resource-limited settings. Lipshultz and colleagues discuss the cardiac effects of HIV and its treatment in perinatally infected children and adolescents, including the range of cardiovascular disease in children, the clinical manifestations, pathogenesis and monitoring, including cardiac biomarkers, and treatment [14]. They emphasize the need for routine systematic cardiac evaluation for perinatally infected youth and note that many of the metabolic complications of therapy may also be associated with future cardiovascular disease as the youth age into adulthood. Barlow-Mosha and colleagues discuss the myriad of metabolic complications of HIV and its treatment that are being observed in youth [15]. While potent antiretroviral therapy has reduced morbidity and mortality, as in adults, long-term metabolic complications are common in infected children. Perinatally infected youth will have prolonged exposure to therapy throughout various stages of growth and development, receive multiple drug regimens as they age, and are at high risk for metabolic complications. High rates of obesity, dyslipidemia and insulin resistance have been described in perinatally infected youth, all of which are factors associated with cardiovascular disease in non-HIVinfected populations [16]. While these youth are still too young to have experienced cardiovascular outcomes, perinatally infected children and adolescents will be subject to the effects of these risk factors as they enter the third and fourth decades of life. The authors note that many of these metabolic toxicities may be asymptomatic and progress unnoticed, particularly in resource-limited settings where monitoring may be limited, and that developing effective strategies to monitor, prevent and manage metabolic complications of therapy in perinatally infected youth will be important, particularly in resource-limited settings. Puthanakit and Siberry discuss issues related to the effect of HIV infection and antiretroviral therapy on bone. They discuss normal bone development and non-HIV factors affecting development as well as HIV and treatment-related factors impacting bone, and approaches to detection, prevention and management of these problems in youth [17]. Bone undergoes profound changes in size, mass and strength from foetal life to adulthood, and children may be particularly vulnerable to HIV and antiretroviral-related effects on bone due to higher bone turnover; approximately 80% of peak bone mass is attained by age 1820 [18,19]. Numerous studies have reported lower bone mass in perinatally infected children compared to healthy children of similar 2 Mofenson LM and Cotton MF. Journal of the International AIDS Society 2013, 16:18650 http://www.jiasociety.org/index.php/jias/article/view/18650 | http://dx.doi.org/10.7448/IAS.16.1.18650 age and sex, but the causes, interaction with treatment and risk for fracture are poorly understood [4]. Clinical manifestations of these effects on bone may only become evident as these youth become adults. Bhimma and colleagues discuss the problem of kidney disease in youth with perinatal infection [20]. They note that while treatment has dramatically reduced HIV-associated nephropathy, other forms of renal disease due to HIV or its treatment have remained. They discuss the spectrum of renal disease that has been reported in children, including renal toxicity from antiretroviral drugs, including pathogenesis, clinical presentation and management. A number of studies have found that many perinatally infected adolescents may not be aware of their HIV status in both high- and low-resource settings [2123]. We refer readers to a study by Meless and colleagues, who assessed disclosure among perinatally infected adults in Abidjan, Côte d’Ivoı̂re [24]. They found a low disclosure rate, particularly for younger adolescents, with only 33% of youth having been informed of their HIV status, and note the need for the development of practical interventions to support ageappropriate HIV status disclosure to children and adolescents. Weber and colleagues note the emerging data and high prevalence of chronic lung disease in adolescents with perinatal HIV infection, as well as the need for more detailed prospective studies. They note that bronchiectasis and bronchiolitis obliterans are important problems in these children, with lung function tests showing significant impairment. The importance of co-infection with tuberculosis and the emergence of chronic lung disease is discussed, emphasizing the need for early antiretroviral therapy in children to minimize the risk of chronic lung problems. Lastly, they provide guidance for the evaluation of lung health and the need for more prospective data. This series of articles serves to focus attention on the growing population of perinatally infected adolescents and young adults globally, the complexities of their care, and helps to identify the future research needs. A holistic approach to improve the long-term health of these youth is needed to ensure that our success in achieving survival of HIV-infected children from infancy is maintained into adulthood. Authors’ affiliations 1 Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD 20852, USA; 2Division of Infectious Diseases, Tygerberg Children’s Hospital, Stellenbosch University, Cape Town, South Africa Competing interests The authors declare that they have no competing interests. Authors’ contributions Both authors contributed to the writing of the manuscript. LMM finalized the draft and all authors approved this version for publication. References 1. Brady MT, Oleske JM, Williams PL, Elgie C, Mofenson LM, Dankner WM, et al. Declines in mortality rates and changes in causes of death in HIV-1infected children during the HAART era. JAIDS. 2010;53:8694. 2. Davies MA, Keiser O, Technau K, Eley B, Rabie H, van Cutsem G, et al. Outcomes of the South African National Antiretroviral Treatment Programme for children: the IeDEA Southern Africa collaboration. S Afr Med J. 2009;99:7307. 3. Hazra R, Siberry GK, Mofenson LM. Growing up with HIV: children, adolescents and young adults with perinatally acquired HIV infection. Annu Rev Med. 2010;61:16985. 4. Heidari S, Mofenson LM, Hobbs CV, Cotton MF, Marlink R, Katabira E. Unresolved antiretroviral management issues in HIV-infected children. JAIDS. 2012;59:1619. 5. Fair C, Wiener L, Zadeh S, Albright J, Mellins CA, Mancilla M, et al. Reproductive health decision-making in perinatally HIV-infected adolescents and young adults. Matern Child Health J. 2012 (published on-line 27 June 2012). 6. Downshen N, D’Angelo L. Health care transition for youth living with HIV/ AIDS. Pediatrics. 2011;128:76271. 7. Sohn AH, Hazra R. The changing epidemiology of the global pediatric HIV epidemic: keeping track of perinatally HIV-infected adolescents. J Int AIDS Soc, 16: 18555. doi: 10.7448/IAS.16.1.18555. 8. Agwu AL, Fairlie L. Antiretroviral treatment, management challenges, and outcomes in perinatally HIV-infected adolescents. J Int AIDS Soc, 16: 18579. doi: 10.7448/IAS.16.1.18579. 9. MacDonell K, Naar-King S, Huszti H, Belzer M. Barriers to medication adherence in behaviorally and perinatally-infected youth living with HIV. AIDS Behav. 2013;17:8693. 10. Mellins CA, Malee KM. Understanding the mental health of youth living with perinatal HIV infection: lessons learned and current challenges. J Int AIDS Soc, 16: 18593. doi: 10.7448/IAS.16.1.18593. 11. Chernoff M, Nachman S, Williams P, Brouwers P, Heston J, Hodge J, et al. Mental health treatment patterns in perinatally HIV-infected youth and controls. Pediatrics. 2009;124:62735. 12. Gadow KD, Angelidou K, Chernoff M, Williams PL, Heston J, Hodge J, et al. Longitudinal study of emerging mental health concerns in youth perinatally infected with HIV and peer comparisons. J Dev Behav Pediatr. 2012;33:45668. 13. Laughton B, Cornell M, Boivin M, van Rie A. Neurodevelopment in perinatally HIV-infected children: a concern for adolescence. J Int AIDS Soc, 16: 18603. doi: 10.7448/IAS.16.1.18603. 14. Lipshultz SE, Miller TL, Wilkinson JD, Scott GB, Somarriba G, Cochran TR, et al. Cardiac effects in perinatally HIV-infected and HIV-exposed but uninfected children and adolescents. J Int AIDS Soc, 16: 18597. doi: 10.7448/ IAS.16.1.18597. 15. Barlow-Mosha L, Eckard AR, McComsey GA, Musoke P. Metabolic complications and treatment of perinatally HIV-infected children and adolescents. J Int AIDS Soc, 16: 18600. doi: 10.7448/IAS.16.1.18600. 16. Vigano A, Cerini C, Pattarino G, Fason S, Zuccotti GV. Metabolic complications associated with antiretroviral therapy in HIV-infected and HIVexposed uninfected paediatric patients. Expert Opin Drug Saf. 2010;9:43145. 17. Puthanakit T, Siberry GK. Bone health in children and adolescents with perinatal HIV infection. J Int AIDS Soc, 16: 18575. doi: 10.7448/IAS.16.1.18575. 18. Zemel B. Bone mineral accretion and its relationship to growth, sexual maturation, and body composition during childhood and adolescence. World Rev Nutr Diet. 2013;106:3945. 19. Baxter-Jones AD, Baxter-Jones F, Faulkner RA, Forwood MR, Mirwald RL, Bailey DA. Bone mineral accrual from 8 to 30 years of age: an estimation of peak bone mass. J Bone Miner Res. 2011;26(8):172939. 20. Bhimma R, Purswani M, Kala U. Kidney disease in children and adolescents with perinatal HIV-1 infection. J Internat AIDS Soc, 16: 18596. doi: 10.7448/ IAS.16.1.18596. 21. Arrive E, Dicko F, Amghar H, Aka AE, Dior H, Bouah B, et al. HIV status disclosure and retention in care in HIV-infected adolescents on antiretroviral therapy in West Africa. PLosOne. 2012;7:e33690. 22. Abebe W, Teferra S. Disclosure of diagnosis by parents and caregivers to children infected with HIV: prevalence associated factors and perceived barriers in Addis Ababa, Ethiopia. AIDS Care. 2012;24:1097102. 23. Oberdorfer P, Puthanakit T, Louthrenoo O, Charnsil C, Sirisanthana V, Sirisanthana T. Disclosure of HIV/AIDS diagnosis to HIV-infected children in Thailand. J Paediatr Child Health. 2006;42:2838. 24. Meless GD, Aka-Dago-Akribi H, Cacou C, Eboua TF, Aka AE, Oga AM, et al. HIV status disclosure and its related factors in HIV-infected adolescents in 2009 in the Aconda program (CePReF, CHU Yopougon) in Abidjan, Cote d’Ivoire, the PRADO-CI Study. J Int AIDS Soc, 16: 18569. doi: 10.7448/IAS.16.1.18569. 3 Sohn AH and Hazra R. Journal of the International AIDS Society 2013, 16:18555 http://www.jiasociety.org/index.php/jias/article/view/18555 | http://dx.doi.org/10.7448/IAS.16.1.18555 Review article The changing epidemiology of the global paediatric HIV epidemic: keeping track of perinatally HIV-infected adolescents Annette H Sohn§,1 and Rohan Hazra2 § Corresponding author: Annette H Sohn, TREAT Asia/amfAR The Foundation for AIDS Research, 388 Sukhumvit Road, Suite 2104, Klongtoey, Bangkok, Thailand 10110. Tel: 66 2 663 7561. Fax: 66 2 663 7562. ([email protected]) This article is part of the special issue Perinatally HIV-infected adolescents - more articles from this issue can be found at http://www.jiasociety.org Abstract The global paediatric HIV epidemic is shifting into a new phase as children on antiretroviral therapy (ART) move into adolescence and adulthood, and face new challenges of living with HIV. UNAIDS reports that 3.4 million children aged below 15 years and 2 million adolescents aged between 10 and 19 years have HIV. Although the vast majority of children were perinatally infected, older children are combined with behaviourally infected adolescents and youth in global reporting, making it difficult to keep track of their outcomes. Perinatally HIV-infected adolescents (PHIVA) are a highly unique patient sub-population, having been infected before development of their immune systems, been subject to suboptimal ART options and formulations, and now face transition from complete dependence on adult caregivers to becoming their own caregivers. As we are unable to track long-term complications and survival of PHIVA through national and global reporting systems, local and regional cohorts are the main sources for surveillance and research among PHIVA. This global review will utilize those data to highlight the epidemiology of PHIVA infection, treatment challenges and chronic disease risks. Unless mechanisms are created to count and separate out PHIVA outcomes, we will have few opportunities to characterize the negative consequences of life-long HIV infection in order to find ways to prevent them. Keywords: adolescent; HIV; outcomes; perinatal; surveillance. Received 23 January 2013; Revised 10 April 2013; Accepted 16 April 2013; Published 18 June 2013 Copyright: – 2013 Sohn AH and Hazra R; licensee International AIDS Society. This is an open access article distributed under the terms of the Creative Commons Attribution 3.0 Unported (CC BY 3.0) Licence (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction The global paediatric HIV epidemic is shifting into a new phase as children on antiretroviral therapy (ART) age into adolescence and adulthood. The evolution of HIV into a chronic disease has no greater impact than on the life of a child. Children that families, clinicians and policymakers at one time expected to die are living into their 20s and having children of their own [16]. Unanticipated issues such as reproductive health, higher education and career training are now urgent needs [7]. Unfortunately, we do not know how many perinatally HIVinfected adolescents (PHIVA) are living in our communities today, a necessary, but only a first step towards addressing the needs of this population. UNAIDS reports that there are 3.4 million children under 15 years of age with HIV and 2 million adolescents between 10 and 19 years of age [8]. Although the vast majority of children were perinatally infected, older children are combined with behaviourally infected adolescents and youth in global reporting, without disaggregation by sex. Maintaining separate reporting for PHIVA and conducting appropriate surveillance and cohort studies are necessary to keep track of long-term complications and survival through national and UNAIDS reporting systems. Local and regional cohorts are currently the main source for surveillance and research among PHIVA. The objective of this review was to utilize available data to highlight the global epidemiology of PHIVA infection, and treatment challenges and outcomes, including metabolic and neurocognitive complications, and identify gaps for future research and policy change. The challenge of reaching adulthood with active ART regimens There are multiple reasons why PHIVA are at high risk of having treatment failure and multiclass antiretroviral (ARV) drug resistance, starting from ARV exposure to prevent their infection around birth [9,10], a history of sub-optimal mono- and dual-therapy regimens [11,12] and having a limited range of approved ARVs for children and paediatric formulations. In the Madrid paediatric HIV cohort, of 112 adolescents who have been transferred to adult care and followed for a median of 15.6 years, 60% had started with monotherapy, and had had an average of five different ART regimens [11]. An analysis of children within the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) cohort demonstrated a 20% cumulative proportion of paediatric patients with triple-class failure by eight years of ART [13]. An urban cohort of PHIVA in the United States reported that patients had been exposed to a median of eight different ARVs across three classes due to resistance and toxicity [14]. 1 Sohn AH and Hazra R. Journal of the International AIDS Society 2013, 16:18555 http://www.jiasociety.org/index.php/jias/article/view/18555 | http://dx.doi.org/10.7448/IAS.16.1.18555 In low- and middle-income countries (LMICs), there are added difficulties in identifying treatment failure early enough to prevent accumulation of drug resistance mutations [15]. Current World Health Organization (WHO) criteria to assess paediatric failure have been repeatedly shown to be inaccurate for predicting failure [16,17]. The sensitivity of the 2006 and 2010 WHO immunologic failure guidelines was as low as 6% in a multicentre South African study [16] and 5% in a Cambodian study [17]. Although targeted viral load testing can significantly improve failure classifications [18], the importance of routine access to viral load testing relative to other monitoring priorities continues to be debated in the paediatric literature [19]. Common to all settings is the challenge of maintaining life-long adherence and access to increasingly expensive ART regimens. Adolescent adherence is particularly complex because of the socio-economic pressures related to orphanhood, neurocognitive deficits associated with chronic and severe HIV infection, and stigma and discrimination [5,20 22]. In a US cohort of treatment-experienced adolescents, poor adherence and pre-existing resistance led to poor viral load responses despite regular access to the third- and fourth-line ARVs darunavir, raltegravir and etravirine [14]. The monthly cost of darunavir for an adult in Thailand is 400 USD, (source: Thai Red Cross AIDS Research Centre, Bangkok, Thailand), making compassionate use programmes a critical and frequently the only way that children in LMICs can access these types of drugs. Without an improved understanding of how to achieve adherence and continuous access to potent ARVs, LMICs are at risk of running out of options for PHIVA transitioning into adulthood. Regional epidemiology and outcome data The adolescents in LMICs today are in some ways part of survivor cohorts of those who were largely slower progressors and able to access ART before late childhood. They are beginning to experience long-term complications that mirror those of western cohorts, where more prolonged ARV access and research experience have led to a deeper literature on PHIVA outcomes. Within the wide spectrum of relevant clinical HIV research, two emerging focus areas are metabolic and neurocognitive complications of life-long HIV disease. These have implications for future cardiovascular disease and fracture risk, as well as the ability of PHIVA to develop personal, medical and financial independence. Sub-Saharan Africa Epidemiology Over 3 million children under 15 years of age were living with HIV in sub-Saharan Africa in 2010, representing more than 90% of all children with HIV in the world [8]. Eastern and Southern Africa bear a larger burden with 2.2 million children with HIV, relative to the 990,000 in West and Central Africa. Paediatric ART coverage greatly lags behind that of adults at 21% compared to 55%. The largest groups of children with HIV worldwide in 2009 and their ART coverage in 2010 were in Nigeria (360,000; 11%), South Africa (330,000; 50%), Kenya (180,000; 28%), Tanzania (160,000; 12%), Uganda (150,000; 21%) and Zimbabwe (150,000; 35%) [8,23,24]. It has been widely publicized that 50% of African children will die by their second birthday without treatment [25]. Less is known about the 17% of slower progressors who may survive to 17 years of age, and fewer efforts are focused on identifying older children, who have not yet been diagnosed and linked to care [2,26]. A model of survival of these older children and PHIVA has projected expansion of this population until 2013 in Zimbabwe and 2020 in South Africa, with ongoing increases in deaths up to 23,000/year by 2030 at mean ages up to 18 years [2]. Investigators have further hypothesized that a greater proportion of children infected through breastfeeding would be slower progressors, compared to those with in utero infection [27]. However, slow progression does not prevent the infectious-related morbidity, growth delays and other sequelae that PHIVA would be expected to experience in the absence of treatment creating both a clinical challenge in terms of achieving immune reconstitution as well as a public health burden with regards to healthcare utilization [28]. Unless the effectiveness of prevention of mother-to-child transmission (PMTCT) interventions and diagnosis of older HIV-exposed children improves, the PHIVA component of the HIV epidemic in sub-Saharan Africa may emerge into a larger and especially challenging sub-population than previously anticipated. Metabolic complications Since the WHO made recommendations in 2009 to begin phasing out of stavudine (d4T) in adults due to toxicities such as lipodystrophy and peripheral neuropathy, countries such as South Africa have begun dropping d4T from standard firstline ART regimens [29]. However, the WHO 2010 paediatric guidelines continued to recommend the use of d4T, noting the need for additional research in this area to document the extent of d4T-related toxicities [30]. The ongoing use of d4T in children and the broader implementation of first-line protease inhibitor-based (PI) regimens after perinatal nonnucleoside reverse transcriptase inhibitor (NNRTI) exposure are both reasons for greater pharmacovigilence of metabolic complications in developing children and PHIVA in subSaharan Africa. A cross-sectional study of 364 children in Uganda using physical assessments of fat redistribution reported that 27% of children had lipodystrophy, primarily with lipoatrophy of the face, which was associated with d4T use (OR 3.43; CI 2.03, 5.80; pB0.001), older age ( ]5 years OR 3.87, CI 1.51, 9.88; p 0.005) and Tanner stage 1 (OR 2.26, CI 1.33, 3.84; p 0.003) [31]. A retrospective study of 2222 children in South Africa examined the frequency of d4T substitution as a marker for cases of severe d4T intolerance. After three years of d4T, 12.6% of children were switched; 91% of switches were due to lipodystrophy. In addition, toxicityrelated switches were 1.5 times more common in girls (p0.07) [32]. Another cross-sectional study of 156 children completing the NEVEREST trial in South Africa added skin-fold and bioimpedence measurements to clinician assessments [33]. All children (mean age of five years) were on d4T and either lopinavir or nevirapine, and 8.3% had confirmed and 11.5% had possible lipodystrophy after four years of ART. The effects of d4T may be less easily recognizable, although 2 Sohn AH and Hazra R. Journal of the International AIDS Society 2013, 16:18555 http://www.jiasociety.org/index.php/jias/article/view/18555 | http://dx.doi.org/10.7448/IAS.16.1.18555 still potentially present, in younger children due to the natural pattern of fat distribution in this age group. Recent data have also raised concerns over d4T-associated peripheral neuropathy. A cross-sectional study of 174 children in a rural setting in South Africa discovered that 24% met criteria for peripheral neuropathy [34]. Children were a median of nine years of age, and had been on ART for a median of two years; 86% were on d4T. Passively reported adverse event data and other cross-sectional studies have not previously demonstrated such high rates of neuropathy [35,36]. With regards to hyperlipidemia, available data to date have emphasized improvements in lipid profiles after initiation of ART in younger children [37,38]. The known association with PIs in adults has been observed in the children in NEVEREST; those on lopinavir had higher rates of elevated cholesterol (19% vs. 8.5%, p 0.03) and triglycerides (13% vs. 3%, p 0.04) compared to nevirapine [33]. Available resources for laboratory monitoring limit data on older children and PHIVA from larger cohorts. In a survey of 53 paediatric HIV sites across Africa in the International Epidemiologic Databases to Evaluate AIDS (IeDEA) global consortium, only 26% of sites regularly monitored lipid levels [39]. Behavioural and neurocognitive outcomes It is clear that immediately starting HIV-infected infants on ART drastically improves both mortality as well as neurodevelopmental outcomes [40,41]. However, most African PHIVA today would not have been able to access ART until they were older and after meeting previously more restrictive treatment criteria. Studies of school-age South African children who started ART after clinical and immunologic disease progression have demonstrated that up to 90% of them have significant developmental delays, with a seven-fold higher likelihood of severe delay (OR. 7.88; CI 1.9631.68) than HIVuninfected controls [42]. Children diagnosed after two to three years of age with CD4 levels above ART thresholds frequently have ART deferred, but there may be serious negative consequences to their neurodevelopment. A study of Ugandan children with CD4 levels 350 cells/mcl and 15% used three different neuropsychological batteries to compare them to HIV-uninfected children (i.e., Test of Variables of Attention; modified Kaufman Assessment Battery for Children; Bruininks-Oseretsky Test of Motor Proficiency, second edition) [43]. Children with HIV (median age of 8.7 years) lived in similar home environments with regards to stimulation and learning opportunities, but had lower socio-economic status. Although some of the testing outcomes were similar, children with HIV did significantly worse with regards to visual reaction times, sequential and simultaneous processing, planning/reasoning, and motor proficiency. Higher viral loads were associated with worse testing outcomes, indicating that deferring ART based on CD4 criteria alone may put children at risk of poorer longterm cognitive outcomes due to ongoing direct viral damage to the developing brain. Using a brief assessment of psychiatric disorders, investigators in Kenya found high rates of features consistent with anxiety disorders (32%) and major depression (17%) in a cohort of 162 children between 6 and 18 years of age (mean age of 9.7 years) [44]. Of note was that 49% of the study participants were also at least two grades below their ageappropriate levels, reported by the families to be due to poor health (41%) and/or poor performance (31%). The link between these delays and deficits and behaviour and functional outcomes remains to be studied. Asia Epidemiology An estimated 180,000 children under 15 years of age were living with HIV in the Asia-Pacific in 2010, with 39% ART coverage [8]. The largest national treatment programme for children B15 years of age in Asia is in India, where 18,000 of the 70,000 of those infected were on ART in 2009 [23]. In the same period, there were an estimated 16,000 children with HIV in Thailand, with 8000 receiving ART [23]. A study of those in the national ART programme before 2007 reported an 88% survival rate at five years of ART [45]. China’s national programme had enrolled around 5100 children by 2009 [46], with 1600 on ART [23]. Although general surveillance data for children are inconsistent, Cambodia was treating 3600 and Vietnam 2000 children by 2009 [23]. The largest regional adolescent cohort in Asia is the TREAT Asia Pediatric HIV Observational Database (TApHOD), which is part of the IeDEA network [47]. Of the 4045 children in the database from six countries enrolled through March 2011, 31% were adolescents 12 years of age or above, of whom 53% were female [6]. Of those reaching adolescence, 4.2% were lost to follow-up and 8.6% had been transferred out, but 85% were still under care at cohort sites. Most of those still under care (73%) were single- or double-orphans, 62% knew about their own HIV status (45% of 1214 year-olds; 82% of ]15 year-olds), and 93% were attending school of some kind. Of those on ART, 96% had been on highly active ART for a median of six years, with 71% on NNRTI-based regimens. The median CD4 count was 657 cells/mm3, and 718 of 830 (86%) with viral load testing were below 400 copies/mL. Overall, those who had reached adolescence at these primarily urban referral centres were on stable ART, with good immunologic and virologic disease control. Much of the data on long-term HIV and ART complications in Asia have come from Thailand, which has the oldest cohort of PHIVA due to earlier implementation of their national paediatric ART programme [45]. Metabolic complications Lipodystrophy was the first major toxicity of ART described in Thai children. Investigators prospectively monitoring children with serial photography and standardized assessments reported that 65% had lipoatrophy, lipohypertrophy, or both after 144 weeks of d4T-based ART. Girls had a higher prevalence of lipodystrophy than boys (61% vs. 39%, p 0.04) [48]. Subsequent studies after switching d4T for zidovudine (AZT) showed that these children and adolescents had no clinically significant AZT-associated anaemia [49], and that 73% of lipoatrophy and 47% of lipohypertrophy resolved by 96 weeks [50]. Other studies confirmed the association with d4T use, and the Thai national paediatric HIV 3 Sohn AH and Hazra R. Journal of the International AIDS Society 2013, 16:18555 http://www.jiasociety.org/index.php/jias/article/view/18555 | http://dx.doi.org/10.7448/IAS.16.1.18555 treatment guidelines were revised in 2010 to recommend short-term (i.e., B6 months) d4T only in cases of pre-ART anaemia [51]. However, hyperlipidemia continues to be a challenge, as more children are switched to second-line PI-based regimens. Although lipid screening is seldom part of routine paediatric treatment monitoring in LMICs, there is growing evidence that this may be a larger problem than previously anticipated. Within a cohort of ART-naı̈ve younger children from Cambodia and Thailand, 28% already had hypertriglyceridemia and 45% had low HDL [52]. In the TApHOD cohort, among children switched to PI-based second-line ART at a median of 10 years of age, 32% had hypercholesterolemia, 73% had hypertriglyceridemia, 18% had HDL, and 49% had elevated triglyceride to HDL ratios at 48 weeks of follow-up [53]. It remains unclear what this abnormal lipid metabolism will mean for PHIVA and their risk of cardiovascular disease. Bone mineral density (BMD) assessments using dual-energy x-ray absorptiometry (DXA) in Thai children has similarly raised questions about future fracture risk. Lumbar spine DXA scans were done in 101 PHIVA in Bangkok after a mean of seven years on successful ART (median CD4 646 cells/mm3; 90% with HIV viral load B50 copies/ml) [54]. Compared to healthy Thai controls, 24% of PHIVA had BMD Z-scores B2, and 25% had 25-hydroxy vitamin D levels B20 ng/ml; only 15% overall and 8% of those with low BMD were on tenofovircontaining regimens. There were no differences by sex. The percentage of low lumbar DXA scores in Thai PHIVA was much higher than the 4% seen in a national US cohort [55]. Although no fractures have yet been reported, these data reflect the negative impact of long-term ART and HIV on the metabolism of developing children and maturing adolescents. Behaviour and neurocognitive outcomes In the most comprehensive neurodevelopmental and neurocognitive testing done in children with HIV in Asia, investigators used a combination of multiple forms of IQ testing (i.e., Beery Visual Motor Integration, Purdue Pegboard, Colour Trails, Child Behavioural Checklist, Wechsler Intelligence Scale, Stanford Binet Memory test) to study outcomes of children in Thailand and Cambodia [56]. There were significant reductions in scores and performance across almost all domains tested in intelligence, memory, and psychomotor and behavioural outcomes for children with HIV (median age, nine years) in comparison to uninfected controls (median age, seven years). The impact of these clear differences in developmental and cognitive outcomes has been seen in school performance. Thai investigators compared children with HIV to HIVexposed and HIV-unexposed children (overall and groupspecific median age of nine years) [57]. Only 21% of those with HIV scored at or above average intelligence levels, compared to 76% of unexposed children. On multivariate analysis, HIV was the sole factor significantly associated with higher risk of poor cognitive outcomes (OR 6.20, p B0.01). Of particular concern was that 20% of HIV-infected children were below their age-appropriate grades in school compared to only 2% of HIV-exposed and 0% of HIV-unexposed children (pB0.01). Beyond these neurodevelopmental issues, families with HIV had lower income and caregiver education levels, while primary caregivers were older due to orphanhood and parental illness. Only 28% of those with HIV were cared for by one or both of their biological parents compared to 98% of HIV-unexposed children (p B0.001). In a pilot study using an audio computer-assisted selfinterview (ACASI) within TApHOD, investigators began assessing behavioural risk among PHIVA in Malaysia and Thailand. Of 46 PHIVA (median age, 14.5 years), 24% reported trying alcohol, 11% cigarettes, and 11% had engaged in sexual intercourse between 14 and 16 years of age [58]. How cognitive and performance deficits impact mental health, and risktaking behaviour in Asian PHIVA remains largely unknown, and represents an essential area for future research. United States Epidemiology According to UNAIDS, approximately 4500 HIV-infected children under 15 years of age lived in North America in 2011, the vast majority in the United States [8]. However, given the ageing population of PHIVA, this number under the age of 15 years likely represents less than half of the total number who are perinatally infected. By 2007, according to the CDC, 49% of PHIVA in the United States were over 15 years of age [59]. UNAIDS reports less than 100 deaths among HIV-infected children less than 15 years of age, but again, given the age distribution of the perinatally infected population, this likely represents less than half the number of deaths among the perinatally infected in the United States, especially since older individuals are at increased risk of death [1]. Nevertheless, given the low mortality and very low number of newly infected babies ( B100 per year), the perinatally infected population in the United States is at a relatively stable number of over 10,000 individuals, most of whom are now young adults and with the oldest members now entering the fourth decade of life. Approximately two-thirds of PHIVA in the United States are African-American/non-Hispanic, and approximately 20% are Hispanic; 53% are female [59]. There are a number of epidemiological studies focused on this population, including the Pediatric HIV/AIDS Cohort Study (PHACS), IMPAACT 1074, and the HIV Research Network (HIVRN), and several studies that have now ended but for which data are still available for further analyses (PACTG 219C, LEGACY, and WITS). As mentioned above, the mortality rate in this population has declined substantially to less than 1% [1,60]. To date, the studies of PHIVA in the United States have been based in paediatric clinical settings, but as this population enters young adulthood, studies will need to be adapted to continue to follow these youth as they transition to adultbased care. Preliminary data and multiple anecdotes suggest that this transition can be very difficult for some, threatening their health and well-being [61]. Metabolic complications Complications from chronic therapy and lifelong infection have emerged [62]. These include lipid abnormalities in approximately 2025% and insulin resistance in 15% [63]. 4 Sohn AH and Hazra R. Journal of the International AIDS Society 2013, 16:18555 http://www.jiasociety.org/index.php/jias/article/view/18555 | http://dx.doi.org/10.7448/IAS.16.1.18555 Low bone density has been reported in a number of studies, with boys potentially more affected than girls, but this finding may not be as severe as initially thought, since lower than expected height may explain a large part of the low BMD findings [55,64,65]. While concerns about renal impairment due to toxicity from prolonged ART have been raised, to date, studies have been reassuring that major renal toxicity is rare and much less common than was seen in in the era of suboptimal therapy [66]. Another organ system of concern for potential toxicity from long-term ART is the heart. Recent echocardiographic data have been reassuring that substantial cardiac disease is rare and much less common than was seen in in the pre-HAART era [67]. Neurocognitive complications and mental health issues With effective ART, HIV encephalopathy has practically disappeared in the United States, but concerns for more subtle, but potentially profound central nervous system and mental health disorders have emerged [68]. In one study based in New York City, 61% of perinatally infected youth had a psychiatric disorder, a rate that was statistically significantly higher than the 49% rate seen in the HIV-exposed, uninfected comparison group [69]. However, follow-up data from this study and data from other studies have shown that rates of mental health disorders are not different between perinatally infected and exposed/uninfected or HIV-affected youth, though alarmingly high in both groups [7072]. These findings suggest that HIV infection and its treatment may not be the major cause of these problems, but that other factors such as caregiver status, poverty, racism, stigma, exposure to violence, multiple losses and grief, are likely aetiologies. The co-occurrence of mental health problems, substance use, poor adherence to ART, and engagement in high risk activities threaten the health of PHIVA and increases the risk of HIV transmission to sexual partners and to infants [73,74]. Europe Epidemiology The UNAIDS estimate for the number of HIV-infected children under 15 years of age in Western and Central Europe in 2011 was 1600. As in the United States, this likely represents less than half of the perinatally infected population. The estimates for the number of deaths and new infections are similar to those for the United States. The perinatally infected population in Europe is likely slightly younger overall than in the United States and much more likely to have emigrated from abroad, as demonstrated by data from the Collaborative HIV Paediatric Study (CHIPS). In this study, which follows almost all HIV-infected children from 2006 onwards in the United Kingdom and Ireland, 55% were born abroad with 51% females, and 31% were 15 years of age or older in 2011 (http://www.chipscohort.ac.uk/default.asp). As of March 2012, 1188 of the 1791 enrolled were alive and in active follow-up at a paediatric clinical site. In France, the native-born perinatally infected population is followed until age 18 years in the French Perinatal Cohort study CO10 (http://cesp.inserm.fr/en/research/ongoing-studies/ 4716-anrs-epf-co1-co10-co11-en-gb.html). Of the 702 enrolled, 211 had reached the age of 18 years (According to data on the website accessed on January 2, 2013). Researchers in Spain have established a Cohort of the Spanish Paediatric HIV Network (CoRISpe) that is following approximately 800 of the 11001200 HIV-infected children in Spain [75]. About one-quarter were born outside of Spain, and over one-third are at least 18 years of age. In addition, a number of other European countries have set up paediatric HIV cohorts (http://www.eurocoord.net/cohort_registry.aspx). The characteristics of the epidemic in Eastern Europe are quite different from that in Western and Central Europe. Here, the prevalence among adults is actually increasing, fuelled predominantly by intravenous drug use. According to UNAIDS, the number of infected children under 15 years of age in Eastern Europe and Central Asia is estimated to be 11,000, with more new paediatric infections and deaths among HIV-infected children than seen in the United States and other parts of Europe. The number less than 15 years of age has been relatively stable for most of the past decade suggesting that the number of newly infected infants equals the number of deaths plus the number who reach 15 years of age every year. Metabolic and neurocognitive complications Metabolic and neurodevelopmental/behavioural findings in European PHIVA have been similar to those seen in PHIVA in the United States [7678]. Data from the French CO10 cohort showed that school performance was comparable to national statistics [79]. However, Swiss and UK studies have illustrated that coping with HIV was an ongoing challenge for PHIVA as they became older, and that inconsistent disclosure and poor psychological adjustment had a negative impact on long-term adherence [80,81]. As mentioned above, a very important issue that needs to be addressed is how to continue to follow these youth as they transition to adult care, especially given that a number of the findings to date regarding hyperlipidemia, bone density, and the impact of mental health and other central nervous system disorders may not be fully expressed until later in adulthood. British researchers leading CHIPS are collaborating with the UK Register of HIV Seroconverters to be able to continue to follow PHIVA into adulthood. In addition, they have established a more intensive study, Adolescents and Adults Living with Perinatal HIV Cohort (AALPHI) (http:// www.ctu.mrc.ac.uk/research_areas/study_details.aspx?s258), on metabolic, neurocognitive, and other areas as these youth enter adulthood. Similarly, the French group has created the Cohort of Young Adults Infected With HIV Since Birth or During Childhood (CO19 COVERTE; ClinicalTrials.gov Identifier: NCT01269632) to follow PHIVA after they reach the age of 18 years and discontinue participation in CO10. As in the United States, preliminary data on the transition to adult care are sobering. Data presented from the United Kingdom in abstract form demonstrated an over five-fold higher rate of mortality in youth reaching the age of 21 years compared to their younger peers [82]. Importantly, poor adherence and end-stage AIDS conditions along with a high burden of mental health disorders were paramount. 5 Sohn AH and Hazra R. Journal of the International AIDS Society 2013, 16:18555 http://www.jiasociety.org/index.php/jias/article/view/18555 | http://dx.doi.org/10.7448/IAS.16.1.18555 Latin America and the Caribbean Epidemiology and long-term complications The 2011 UNAIDS estimates for Latin America and the Caribbean were 60,000 HIV-infected children under 15 years of age, 3300 new paediatric infections, and 3500 deaths [8]. The two countries with the most infected children in these regions are Brazil (20,000 infected children under 15 years of age), the largest economy in Latin America, and Haiti (13,000 infected children under 15 years of age), the poorest country in the Western hemisphere. Since 2009 the decline in new infections has been 32% in the Caribbean and 24% in Latin America, as PMTCT coverage approaches 80% in the Caribbean and over 50% throughout Latin America. As new infections are prevented and as perinatally infected children survive and mature into adolescence and young adulthood, the number of infected children under 15 years of age has declined from a peak of 22,000 in the Caribbean in 2004 to 18,000 in 2011. The peak in Latin America was 54,000 in 20056, down to 42,000 in 2011. Given these trends, the number under 15 years of age reported by UNAIDS is an underestimate of the total perinatally infected population, though not to the same extent as seen in the United States and Western and Central Europe. Paediatric cohorts in these regions include the NICHD International Site Development Initiative (NISDI), which is now closed but has a database of over 1000 perinatally infected infants, children, and adolescents primarily in Brazil, but also several other Latin American countries [83]. CCASAnet, part of the IeDEA network, is in the process of expanding its paediatric agenda. As in other regions, efforts should be made to follow PHIVA as they enter young adulthood and transition to adult-based care to continue to assess both complications and positive outcomes. Findings from the NISDI study include a very low mortality rate, dyslipidemia in over a quarter, lower rates of insulin resistance than seen in the United States and Europe, low rates of opportunistic infections but higher than seen in comparable populations in the United States and Europe, and relatively low rates of renal and hepatic disease [8387]. Two cross-sectional studies of BMD in Brazil demonstrated that between 17 and 32% of PHIVA studied had low BMD, though larger studies with appropriate comparison groups are clearly needed [88,89]. Data on neurocognitive and mental health problems for PHIVA in this region remain very limited. Conclusions Depending on the setting, the paediatric HIV epidemic has entered or is entering the next phase of its evolution as children grow up and face new challenges of living with HIV. PHIVA are a highly unique patient sub-population, having been infected before development of their immune systems, been subject to suboptimal ART options and formulations, and face transitioning from complete dependence on adult caregivers to becoming their own caregivers. Regional data demonstrate that successful transition and HIV disease control are possible, but there are consequences of life-long HIV and ART many of which we still do not understand. However, unless national HIV programmes and UNAIDS create mechanisms to count and keep track of the perinatally infected, we will not know how many of these children are and are not surviving into adulthood. Every year that goes by without dedicated global PHIVA surveillance means that tens of thousands of children could be lost in the crowd. In addition, without longitudinal cohort studies, we would have few opportunities to characterize the consequences of HIV disease and treatment in order to find ways to prevent them. There are now multiple paediatric and adolescent cohorts scattered around the world. Although they vary with regards to both size and depth of data collection, global cohort collaborations could potentially generate the ‘‘big data’’ needed to answer common research questions. Providers and researchers will also have to transition into the next phase of the global paediatric epidemic in order to keep up with our patients. Authors’ affiliations 1 TREAT Asia/amfAR The Foundation for AIDS Research, Bangkok, Thailand; 2Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, USA Competing interests The authors report no competing interests. Authors’ contributions Both authors have read and approved the final version and both authors drafted the manuscript. References 1. Brady MT, Oleske JM, Williams PL, Elgie C, Mofenson LM, Dankner WM, et al. Declines in mortality rates and changes in causes of death in HIV-1infected children during the HAART era. J Acquir Immune Defic Syndr. 2010;53(1):8694. 2. Ferrand RA, Corbett EL, Wood R, Hargrove J, Ndhlovu CE, Cowan FM, et al. AIDS among older children and adolescents in Southern Africa: projecting the time course and magnitude of the epidemic. AIDS. 2009;23(15):203946. 3. Foster C, Judd A, Tookey P, Tudor-Williams G, Dunn D, Shingadia D, et al. Young people in the United Kingdom and Ireland with perinatally acquired HIV: the pediatric legacy for adult services. AIDS Patient Care STDS. 2009; 23(3):15966. 4. Vijayan T, Benin AL, Wagner K, Romano S, Andiman WA. We never thought this would happen: transitioning care of adolescents with perinatally acquired HIV infection from pediatrics to internal medicine. AIDS Care. 2009;21(10): 12229. 5. Santos Cruz ML, Freimanis Hance L, Korelitz J, Aguilar A, Byrne J, Serchuck LK, et al. Characteristics of HIV infected adolescents in Latin America: results from the NISDI pediatric study. J Trop Pediatr. 2011;57(3):16572. 6. Chokephaibulkit K, Kariminia A, Oberdorfer P, Nallusamy R, Bunupuradah T, Hansudewechakul R, et al. For the TREAT Asia pediatric HIV observational database. Characteristics of perinatally HIV-Infected adolescents in Asia: the TREAT Asia pediatric HIV observational database. 4th International Workshop on HIV Pediatrics, July 2021, 2012, Washington, DC. Abstract P_12. 7. Souza E, Santos N, Valentini S, Silva G, Falbo A. Long-termfollow-up outcomes of perinatally HIV-infected adolescents: infection control but school failure. J Trop Pediatr. 2010;56(6):4216. 8. WHO, UNAIDS, UNICEF. Global HIV/AIDS response: epidemic update and health sector progress towards universal Access, 2011 progress report. Geneva: World Health Organization; 2011. 9. Fogel JM, Mwatha A, Richardson P, Brown ER, Chipato T, Alexandre M, et al. Impact of maternal and infant antiretroviral drug regimens on drug resistance in HIV-Infected breastfeeding infants, Pediatr Infect Dis J. 2013. 32(4):e1649. 10. Hunt GM, Coovadia A, Abrams EJ, Sherman G, Meyers T, Morris L, et al. HIV-1drug resistance at antiretroviral treatment initiation in children previously exposed to single-dose nevirapine. AIDS. 2011;25(12):14619. 11. de Mulder M, Yebra G, Navas A, de José MI, Gurbindo MD, González-Tomé MI, et al. High drug resistance prevalence among vertically HIV-infected 6 Sohn AH and Hazra R. Journal of the International AIDS Society 2013, 16:18555 http://www.jiasociety.org/index.php/jias/article/view/18555 | http://dx.doi.org/10.7448/IAS.16.1.18555 patients transferred from pediatric care to adult units in Spain. PLoS One. 2012;7(12):e52155. 12. Hansudewechakul R, Sirisanthana V, Kurniati N, Puthanakit T, Lumbiganon P, Saphonn V, et al. Antiretroviral therapy outcomes of HIV-infected children in the TREAT Asia pediatric HIV observational database. J Acquir Immune Defic Syndr. 2010;55(4):5039. 13. Castro H, Judd A, Gibb DM, Butler K, Lodwick RK, van Sighem A, et al. Risk of triple-class virological failure in children with HIV: a retrospective cohort study. Lancet. 2011;377(9777):15807. 14. Wong FL, Hsu AJ, Pham PA, Siberry GK, Hutton N, Agwu AL. Antiretroviral treatment strategies in highly treatment experienced perinatally HIV-infected youth. Pediatr Infect Dis J. 2012;31(12):127983. 15. Ruel TD, Kamya MR, Li P, Pasutti W, Charlebois ED, Liegler T, et al. Early virologic failure and the development of antiretroviral drug resistance mutations in HIV-infected Ugandan children. J Acquir Immune Defic Syndr. 2011;56(1):4450. 16. Davies MA, Boulle A, Eley B, Moultrie H, Technau K, Rabie H, et al. Accuracy of immunological criteria for identifying virological failure in children on antiretroviral therapy the IeDEA Southern Africa Collaboration. Trop Med Int Health. 2011;16(11):136771. 17. Westley BP, DeLong AK, Tray CS, Sophearin D, Dufort EM, Nerrienet E, et al. Prediction of treatment failure using 2010 World Health Organization guidelines is associated with high misclassification rates and drug resistance among HIV-infected Cambodian children. Clin Infect Dis. 2012;55(3):43240. 18. Davies MA, Boulle A, Technau K, Eley B, Moultrie H, Rabie H, et al. The role of targeted viral load testing in diagnosing virological failure in children on antiretroviral therapy with immunological failure. Trop Med Int Health. 2012 Sep 14. 19. Babiker A, Castro nee Green H, Compagnucci A, Fiscus S, Giaquinto C, Gibb DM, et al. First-line antiretroviral therapy with a protease inhibitor versus nonnucleoside reverse transcriptase inhibitor and switch at higher versus low viral load in HIV-infected children: an open-label, randomised phase 2/3 trial. Lancet Infect Dis. 2011;11(4):27383. 20. Malee K, Williams P, Montepiedra G, McCabe M, Nichols S, Sirois PA, et al. Medication adherence in children and adolescents with HIV infection: associations with behavioral impairment. AIDS Patient Care STDS. 2011;25(3):191200. 21. Vreeman RC, Nyandiko WM, Ayaya SO, Walumbe EG, Marrero DG, Inui TS. Factors sustaining pediatric adherence to antiretroviral therapy in western Kenya. Qual Health Res. 2009;19(12):171629. 22. Ding H, Wilson CM, Modjarrad K, McGwin G Jr., Tang J, Vermund SH. Predictors of suboptimal virologic response to highly active antiretroviral therapy among human immunodeficiency virus-infected adolescents: analyses of the reaching for excellence in adolescent care and health (REACH) project. Arch Pediatr Adolesc Med. 2009;163(12):11005. 23. UNICEF. Children and AIDS, fifth stocktaking report. Geneva: UNICEF; 2010. 24. UNAIDS. Together we will end AIDS. Geneva: UNAIDS; 2012. 25. Newell ML, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet. 2004;364(9441):123643. 26. Stover J, Walker N, Grassly NC, Marston M. Projecting the demographic impact of AIDS and the number of people in need of treatment: updates to the Spectrum projection package. Sex Transm Infect. 2006;82(Suppl 3):iii4550. 27. Zijenah LS, Moulton LH, Iliff P, Nathoo K, Munjoma MW, Mutasa K, et al. Timing of mother-to-child transmission of HIV-1 and infant mortality in the first 6 months of life in Harare, Zimbabwe. AIDS. 2004;18(2):27380. 28. Gray GE. Adolescent HIV–cause for concern in Southern Africa. PLoS Med. 2010;7(2):e1000227. 29. WHO. Rapid advice: antiretroviral therapy for HIV infection in adults and adolescents. Geneva: WHO; 2009. 30. WHO. Antiretroviral therapy for HIV infection in infants and children: towards universal access: recommendations for a public health approach 2010 revision. Geneva: WHO; 2010. 31. Piloya T, Bakeera-Kitaka S, Kekitiinwa A, Kamya MR. Lipodystrophy among HIV-infected children and adolescents on highly active antiretroviral therapy in Uganda: a cross sectional study. J Int AIDS Soc. 2012;15(2):17427. 32. Palmer M, Chersich M, Moultrie H, Kuhn L, Fairlie L, Meyers T. Frequency of stavudine substitution due to toxicity in children receiving antiretroviral treatment in Soweto, South Africa. AIDS. 2012 Nov 19. 33. Arpadi S, Shiau S, Strehlau R, Martens L, Patel F, Coovadia A, et al. Metabolic abnormalities and body composition of HIV-infected children on Lopinavir or Nevirapine-based antiretroviral therapy. Arch Dis Child. 2013;98(4):25864. 34. van Ramshorst M, Struthers H, McIntyre JA, Peters RPH. Clinical screening shows high prevalence of peripheral neuropathy in children taking antiretroviral therapy in rural South Africa. 19th International Conference on AIDS, Washington, DC:2012, Abstract MOAB0205. 35. Tukei VJ, Asiimwe A, Maganda A, Atugonza R, Sebuliba I, Bakeera-Kitaka S, et al. Safety and tolerability of antiretroviral therapy among HIV-infected children and adolescents in Uganda. J Acquir Immune Defic Syndr. 2012; 59(3):27480. 36. Govender R, Eley B, Walker K, Petersen R, Wilmshurst JM. Neurologic and neurobehavioral sequelae in children with human immunodeficiency virus (HIV-1) infection. J Child Neurol. 2011;26(11):135564. 37. Cournil A, Mercier-Deheuvels S, Dupuy AM, Cristol JP, Anaky MF, Rouet F, et al. Evolution of lipid levels in HIV-infected children treated or not with HAART in Abidjan, Cote d’Ivoire. J Trop Pediatr. 2012;58(1):439. 38. Strehlau R, Coovadia A, Abrams EJ, Martens L, Arpadi S, Meyers T, et al. Lipid profiles in young HIV-infected children initiating and changing antiretroviral therapy. J Acquir Immune Defic Syndr. 2012;60(4):36976. 39. IeDEA Pediatric Working Group. A survey of paediatric HIV programmatic and clinical management practices in Asia and sub-Saharan Africa-the International epidemiologic Databases to Evaluate AIDS (IeDEA). J Int AIDS Soc. 2013;16(1):17998. 40. Laughton B, Cornell M, Grove D, Kidd M, Springer PE, Dobbels E, et al. Early antiretroviral therapy improves neurodevelopmental outcomes in infants. AIDS. 2012;26(13):168590. 41. Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med. 2008;359(21):223344. 42. Lowick S, Sawry S, Meyers T. Neurodevelopmental delay among HIVinfected preschool children receiving antiretroviral therapy and healthy preschool children in Soweto, South Africa. Psychol Health Med. 2012;17(5): 59910. 43. Ruel TD, Boivin MJ, Boal HE, Bangirana P, Charlebois E, Havlir DV, et al. Neurocognitive and motor deficits in HIV-infected Ugandan children with high CD4 cell counts. Clin Infect Dis. 2012;54(7):10019. 44. Kamau JW, Kuria W, Mathai M, Atwoli L, Kangethe R. Psychiatric morbidity among HIV-infected children and adolescents in a resource-poor Kenyan urban community. AIDS Care. 2012;24(7):83642. 45. McConnell MS, Chasombat S, Siangphoe U, Yuktanont P, Lolekha R, Pattarapayoon N, et al. National program scale-up and patient outcomes in a pediatric antiretroviral treatment program, Thailand, 20002007. J Acquir Immune Defic Syndr. 2010;54(4):4239. 46. Zhao Y, Sun X, He Y, Tang Z, Peng G, Liu A, et al. Progress of the national pediatric free antiretroviral therapy program in China, AIDS Care. 2010;22(10):11828. 47. Kariminia A, Chokephaibulkit K, Pang J, Lumbiganon P, Hansudewechakul R, Amin J, et al. Cohort profile: the TREAT Asia pediatric HIV observational database. Int J Epidemiol. 2011;40(1):1524. 48. Aurpibul L, Puthanakit T, Lee B, Mangklabruks A, Sirisanthana T, Sirisanthana V. Lipodystrophy and metabolic changes in HIV-infected children on non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy. Antivir Ther. 2007;12(8):124754. 49. Aurpibul L, Puthanakit T, Sirisanthana T, Sirisanthana V. Haematological changes after switching from stavudine to zidovudine in HIV-infected children receiving highly active antiretroviral therapy. HIV Med. 2008;9(5):31721. 50. Aurpibul L, Puthanakit T, Taejaroenkul S, Sirisanthana T, Sirisanthana V. Recovery from lipodystrophy in HIV-infected children after substitution of stavudine with zidovudine in a non-nucleoside reverse transcriptase inhibitorbased antiretroviral therapy. Pediatr Infect Dis J. 2012;31(4):3848. 51. Sawawiboon N, Wittawatmongkol O, Phongsamart W, Prasitsuebsai W, Lapphra K, Chokephaibulkit K. Lipodystrophy and reversal of facial lipoatrophy in perinatally HIV-infected children and adolescents after discontinuation of stavudine. Int J STD AIDS. 2012;23(7):497501. 52. Kanjanavanit S, Puthanakit T, Vibol U, Kosalaraksa P, Hansudewechakul R, Ngampiyasakul C, et al. High prevalence of lipid abnormalities among antiretroviral-naive HIV-infected Asian children with mild-to-moderate immunosuppression. Antivir Ther. 2011;16(8):13515. 53. Bunupuradah T, Puthanakit T, Fahey P, Kariminia A, Yusoff NK, Khanh TH, et al. Second-line protease inhibitor-based highly active antiretroviral therapy after failing non-nucleoside reverse transcriptase inhibitor-based regimens in Asian HIV-infected children. Antivir Ther. 2013 Jan 7. 7 Sohn AH and Hazra R. Journal of the International AIDS Society 2013, 16:18555 http://www.jiasociety.org/index.php/jias/article/view/18555 | http://dx.doi.org/10.7448/IAS.16.1.18555 54. Puthanakit T, Saksawad R, Bunupuradah T, Wittawatmongkol O, Chuanjaroen T, Ubolyam S, et al. Prevalence and risk factors of low bone mineral density among perinatally HIV-infected Thai adolescents receiving antiretroviral therapy. J Acquir Immune Defic Syndr. 2012;61(4):47783. 55. Dimeglio LA, Wang J, Siberry GK, Miller TL, Geffner ME, Hazra R, et al. Bone mineral density in children and adolescents with perinatal HIV infection. AIDS. 2013;27(2):21120. 56. Puthanakit T, Ananworanich J, Vonthanak S, Kosalaraksa P, Hansudewechakul R, van der Lugt J, et al. Cognitive function and neurodevelopmental outcomes in HIV-infected children older than 1 year of age randomized to early versus deferred antiretroviral therapy: the PREDICT neurodevelopmental study. Pediatr Infect Dis J. 2013 Jan 2. 57. Puthanakit T, Aurpibul L, Louthrenoo O, Tapanya P, Nadsasarn R, Insee-ard S, et al. Poor cognitive functioning of school-aged children in Thailand with perinatally acquired HIV infection taking antiretroviral therapy. AIDS Patient Care STDS. 2010;24(3):1416. 58. Prasitsuebsai W, Pang J, Hansudewechakul R, Razali K, Yusoff N, Fong S, et al. Risk behaviors and treatment adherence among HIV-infected adolescents in the TREAT Asia pediatric HIV observational database. 4th International Workshop on HIV Pediatrics, July 2021, 2012, Washington, DC: Abstract P_18. 59. Whitmore S, Hughes D, Taylor A, Koenig L. Estimated numbers and demographic characteristics of persons living With perinatally acquired HIV infection, 37 States, United States, 2007. XVIII International AIDS Conference. Vienna, Austria 2010. 60. Kapogiannis BG, Soe MM, Nesheim SR, Abrams EJ, Carter RJ, Farley J, et al. Mortality trends in the US perinatal AIDS collaborative transmission study (19862004). Clin Infect Dis. 2011;53(10):102434. 61. Agwu A, Althoff K, Rutstein R, Korthuis PT, Berry S, Gaur A, et al. Factors associated with falling out of care for older adolescents in the HIV research network. Abstract MOPE061. XIX International AIDS Conference, Washington, DC, 2012. 62. Hazra R, Siberry GK, Mofenson LM. Growing up with HIV: children, adolescents, and young adults with perinatally acquired HIV infection. Annual Rev Med. 2010;61:16985. 63. Geffner ME, Patel K, Miller TL, Hazra R, Silio M, Van Dyke RB, et al. Factors associated with insulin resistance among children and adolescents perinatally infected with HIV-1 in the pediatric HIV/AIDS cohort study. Horm Res Paediat. 2011;76(6):38691. 64. Hazra R, Gafni RI, Maldarelli F, Balis FM, Tullio AN, DeCarlo E, et al. Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as salvage therapy for pediatric HIV infection. Pediatrics. 2005;116(6):e84654. 65. Jacobson DL, Lindsey JC, Gordon CM, Moye J, Hardin DS, Mulligan K, et al. Total body and spinal bone mineral density across tanner stage in perinatally HIV-infected and uninfected children and youth in PACTG1045. AIDS. 2010;24(5):68796. 66. Purswani M, Patel K, Kopp JB, Seage GR 3rd, Chernoff MC, Hazra R, et al. Tenofovir treatment duration predicts proteinuria in a multi-ethnic United States cohort of children and adolescents with perinatal HIV-1 infection, Pediatr Infect Dis J. 2012 Dec 17. 67. Lipshultz SE, Williams PL, Wilkinson JD, Leister EC, Van Dyke RB, Shearer WT, et al. for the Pediatric HIV/AIDS Cohort Study (PHACS). Cardiac status of HIV-Infected children treated with long-term combination antiretroviral therapy: results from the adolescent master protocol of the NIH multicenter pediatric HIV/AIDS cohort study, JAMA Pediatr. 2013;22:18. 68. Patel K, Ming X, Williams PL, Robertson KR, Oleske JM, Seage GR 3rd Impact of HAART and CNS-penetrating antiretroviral regimens on HIV encephalopathy among perinatally infected children and adolescents. AIDS. 2009;23(14):1893901. 69. Mellins CA, Brackis-Cott E, Leu CS, Elkington KS, Dolezal C, Wiznia A, et al. Rates and types of psychiatric disorders in perinatally human immunodeficiency virus-infected youth and seroreverters. J Child Psychol Psyc Allied Disciplines. 2009;50(9):11318. 70. Mellins CA, Elkington KS, Leu CS, Santamaria EK, Dolezal C, Wiznia A, et al. Prevalence and change in psychiatric disorders among perinatally HIV-infected and HIV-exposed youth. AIDS Care. 2012;24(8):95362. 71. Malee KM, Tassiopoulos K, Huo Y, Siberry G, Williams PL, Hazra R, et al. Mental health functioning among children and adolescents with perinatal HIV infection and perinatal HIV exposure. AIDS Care. 2011;23(12):153344. 72. Gadow KD, Chernoff M, Williams PL, Brouwers P, Morse E, Heston J, et al. Co-occuring psychiatric symptoms in children perinatally infected with HIV and peer comparison sample. J Dev Behav Pediatr. 2010;31(2):11628. 73. Mellins CA, Tassiopoulos K, Malee K, Moscicki AB, Patton D, Smith R, et al. Behavioral health risks in perinatally HIV-exposed youth: co-occurrence of sexual and drug use behavior, mental health problems, and nonadherence to antiretroviral treatment. AIDS Patient Care STDS. 2011;25(7):41322. 74. Tassiopoulos K, Moscicki AB, Mellins C, Kacanek D, Malee K, Allison S, et al. Sexual risk behavior among youth with perinatal HIV infection in the United States: predictors and implications for intervention development. Clin Infect Dis. 2013;56(2):28390. 75. de Jose MI, Jimenez de Ory S, Espiau M, Fortuny C, Navarro ML, SolerPalacı́n P, et al. A new tool for the paediatric HIV research: general data from the Cohort of the Spanish Paediatric HIV network (CoRISpe). BMC Infect Dis. 2013;13:2. 76. European Paediatric Lipodystrophy Group. Antiretroviral therapy, fat redistribution and hyperlipidaemia in HIV-infected children in Europe. AIDS. 2004;18(10):144351. 77. Beregszaszi M, Dollfus C, Levine M, Faye A, Deghmoun S, Bellal N, et al. Longitudinal evaluation and risk factors of lipodystrophy and associated metabolic changes in HIV-infected children. J Acquir Immune Defic Syndr. 2005;40(2):1618. 78. Koekkoek S, de Sonneville LM, Wolfs TF, Licht R, Geelen SP. Neurocognitive function profile in HIV-infected school-age children. Eur J Paediatr Neurol. 2008;12(4):2907. 79. Dollfus C, Le Chenadec J, Faye A, Blanche S, Briand N, Rouzioux C, et al. Long-term outcomes in adolescents perinatally infected with HIV-1 and followed up since birth in the French perinatal cohort (EPF/ANRS CO10). Clin Infect Dis. 2010;51(2):21424. 80. Michaud PA, Suris JC, Thomas R, Gnehm HE, Cheseaux JJ. Coping with an HIV infection. A multicenter qualitative survey on HIV positive adolescents’ perceptions of their disease, therapeutic adherence and treatment. Swiss Med Wkly. 2010;140(1718):24753. 81. Sopena S, Evangeli M, Dodge J, Melvin D. Coping and psychological adjustment in adolescents with vertically acquired HIV. AIDS Care. 2010;22(10): 12528. 82. Foster C. Mortality amongst HIV-infected young people following transition to adult care: an HIV Young Persons Network (HYPNet) audit. Abstract 06. 18th Annual Conference of the British HIV Association. Birmingham, UK; 2012. 83. Hazra R, Stoszek SK, Freimanis Hance L, Pinto J, Marques H, Peixoto M, et al. Cohort profile: NICHD International Site Development Initiative (NISDI): a prospective, observational study of HIV-exposed and HIV-infected children at clinical sites in Latin American and Caribbean countries. Int J Epidemiol. 2009;38(5):120714. 84. Brewinski M, Megazzini K, Hance LF, Cruz MC, Pavia-Ruz N, Della Negra M, et al. Dyslipidemia in a cohort of HIV-infected Latin American children receiving highly active antiretroviral therapy. J Trop Pediatr. 2011;57(5):32432. 85. Hazra R, Hance LF, Monteiro JP, Pavia Ruz N, Machado DM, Saavedra M, et al. Insulin resistance and glucose and lipid concentrations in a cohort of perinatally HIV-Infected Latin American children, Pediatr Infect Dis J. 2013 Jan 28. 86. Alarcon JO, Freimanis-Hance L, Krauss M, Reyes MF, Cardoso CA, MussiPinhata MM, et al. Opportunistic and other infections in HIV-infected children in Latin America compared to a similar cohort in the United States. AIDS Res Hum Retroviruses. 2012;28(3):2828. 87. Siberry G, Cohen R, Harris D, Santos Cruz ML, Oliveira R, Peixoto MF, et al. Non-invasive estimate of liver fibrosis prevalence and risk factors in Latin American perinatally HIV-infected children. 3rd International Workshop on HIV Paediatrics. Rome, Italy, 2011. Abstract PP_11. 88. Schtscherbyna A, Pinheiro MF, Mendonca LM, Gouveia C, Luiz RR, Machado ES, et al. Factors associated with low bone mineral density in a Brazilian cohort of vertically HIV-infected adolescents. Int J Infect Dis. 2012;16(12):e8728. 89. de Lima LR, da Silva RC, Giuliano Ide C, Sakuno T, Brincas SM, de Carvalho AP. Bone mass in children and adolescents infected with human immunodeficiency virus. J Pediatr (Rio J). 2013;89(1):919. 8 Agwu AL and Fairlie L. Journal of the International AIDS Society 2013, 16:18579 http://www.jiasociety.org/index.php/jias/article/view/18579 | http://dx.doi.org/10.7448/IAS.16.1.18579 Review article Antiretroviral treatment, management challenges and outcomes in perinatally HIV-infected adolescents Allison L Agwu*§,1,2 and Lee Fairlie*3 § Corresponding author: Allison L Agwu, Division of Pediatric Infectious Diseases, Department of Pediatrics, Johns Hopkins School of Medicine, 200 N. Wolfe St, Baltimore, MD 21287, Maryland, USA. Phone: 1-410-614-3917, Fax: 1-410-614-1491 ([email protected]) *These authors contributed equally to this work. This article is part of the special issue Perinatally HIV-infected adolescents - more articles from this issue can be found at http://www.jiasociety.org Abstract Three decades into the HIV/AIDS epidemic there is a growing cohort of perinatally HIV-infected adolescents globally. Their survival into adolescence and beyond represent one of the major successes in the battle against the disease that has claimed the lives of millions of children. This population is diverse and there are unique issues related to antiretroviral treatment and management. Drawing from the literature and experience, this paper discusses several broad areas related to antiretroviral management, including: 1) diverse presentation of HIV, (2) use of combination antiretroviral therapy including in the setting of co-morbidities and rapid growth and development, (3) challenges of cART, including nonadherence, resistance, and management of the highly treatment-experienced adolescent patient, (4) additional unique concerns and management issues related to PHIVinfected adolescents, including the consequences of longterm inflammation, risk of transmission, and transitions to adult care. In each section, the experience in both resource-rich and limited settings are discussed with the aim of highlighting the differences and importantly the similarities, to share lessons learnt and provide insight into the multi-faceted approaches that may be needed to address the challenges faced by this unique and resilient population. Keywords: perinatally HIV-infected; adolescents; combination antiretroviral therapy; management; resistance; outcomes. Received 4 February 2013; Accepted 17 April 2013; Published 18 June 2013 Copyright: – 2013 Agwu AL and Fairlie L; licensee International AIDS Society. This is an open access article distributed under the terms of the Creative Commons Attribution 3.0 Unported (CC BY 3.0) Licence (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction With successful strategies for Prevention of Mother to Child Transmission (PMTCT), fewer infants are acquiring HIV perinatally or through breastfeeding, resulting in fewer children requiring HIV care. There are, however, approximately 2,000,000 children living with HIV globally, 90% of whom live in sub-Saharan Africa [1]. The current treatment guidelines recommend combination antiretroviral therapy (cART) initiation in infancy to prevent HIV-related morbidity and mortality [2,3]. It is expected that the majority of children who are diagnosed and treated early will survive into adolescence and adulthood [4]. Significant numbers of perinatally HIV (PHIV)-infected children newly diagnosed later in childhood only initiate cART as they approach adolescence. Knowledge of the clinical and psychosocial complexities of managing adolescent patients will be essential for both child care practitioners having their patients graduate to adolescence and adulthood, and adult care practitioners who care for adolescents as they transition to adult clinical settings [4]. Lessons learned from the decades of managing PHIV-infected adolescents in resource-rich countries will be invaluable to resource-limited countries where the burden of infection is greatest, and where cART treatment has lagged behind. To this aim, we review key differences in PHIV-infected adolescents in resource-rich vs. resource-limited settings, from diagnosis and presentation to cART recommendations and challenges, with particular emphasis on non-adherence, resistance and management strategies. Diagnosis and presenting features of HIVinfected adolescents There is a wide spectrum in timing of diagnosis and entry into care for PHIV-infected adolescents. In the United States, Europe and other resource-rich settings, perinatal HIV infection has been contained by the implementation of maternal testing and PMTCT programmes since the 1990s, early testing of HIV-exposed infants, and close follow up of HIV-infected children through adolescence. In the United Kingdom and Ireland, for example, 62% of the current adolescent population presented to care at a year of age or less [5,6]. A few PHIV-infected adolescents are identified late in resource-rich settings, usually due to unknown maternal infection and missed opportunities for diagnosis [7]. Suspicion of PHIV infection should arise where there is no history of sexual activity or risk behaviours, no sexual abuse, 1 Agwu AL and Fairlie L. Journal of the International AIDS Society 2013, 16:18579 http://www.jiasociety.org/index.php/jias/article/view/18579 | http://dx.doi.org/10.7448/IAS.16.1.18579 and history of maternal risk factors, HIV diagnosis, unexplained illness or death [8,9]. High mortality rates described in PHIV-infected children under the age of two years in the pre-cART era suggest that those who survive untreated into adolescence may be slow or non-progressors [5,6,10]. In resource-limited settings, aggressive measures to improve PMTCT and infant follow-up and testing have resulted in lower transmission rates in recent years, but many PHIVinfected adolescents will not have benefited from these programmes [1,11]. A sizable number of PHIV-infected adolescents only enter care after being diagnosed during routine clinic visits, hospital admissions for illness or as part of research studies. These late presenting adolescents frequently are clinically and immunologically severely compromised, with high risk of morbidity and mortality particularly for those diagnosed in hospital settings [9,1214]. Growth stunting and pubertal delay is common and the majority of adolescents diagnosed late have World Health Organization (WHO) Stage 3 or 4 disease, are often diagnosed with tuberculosis (TB) and may present with opportunistic infections (OIs), such as Cryptococcal disease [1215]. Up to 75% of these PHIV-infected youth have CD4 counts below 200 cells/mm3 at presentation and are desperately in need of treatment [9]. cART initiation in PHIV-infected adolescents Essentially, most PHIV-infected adolescents that are in care have met criteria for treatment in the past or meet criteria for treatment now and should be on cART; however, there are those that are initiating cART for the first time [913]. In general, recommendations for cART initiation in adolescents ]13 years of age are included in the adult guidelines for treatment and management. Both adult and paediatric guidelines alike include remarks about adolescent patients regarding dosing and management challenges, and considering regimens with a higher barrier to resistance given adherence challenges in adolescents [3,1618]. The physiologic changes (e.g., puberty, rapid growth) that occur in adolescence result in altered pharmacokinetics. Therefore, while it is generally appropriate for post-pubertal adolescents to be dosed with cART according to adult guidelines, adolescents in early puberty should be dosed according to the paediatric guidelines which factor in dosages by weight and Tanner staging. Several of the major guidelines for cART initiation are summarized in Table 1. Combination ART utilization among PHIVinfected adolescents Many PHIV-infected adolescents currently in HIV treatment programmes in sub-Saharan Africa were diagnosed in the first few years of life, starting cART at a median age between 3.6 and 4.6 years old [1921]. Data quantifying the proportion of PHIV-infected adolescents worldwide who are eligible to receive cART and are being treated is not readily available as the WHO and other entities present data in ‘‘under 15 years’’ and ‘‘ 15 years’’ categories [11]. While the estimated number of HIV-infected children under the age of 15 years receiving cART has improved overall, there are large disparities (665%) in the proportion of children who need and are receiving ART, with the largest disparities documented in North Africa and the Middle East (6% [37%]) and West and Central Africa (9% [811%]) [11]. As the priority is to get the youngest children on therapy and many of the youth who are not already treated are being identified in late childhood and even in adolescence, there may even be a greater disparity in treatment for PHIV-infected adolescents. By contrast, approximately 80% of the PHIV-infected adolescents in resource-rich countries have been on longstanding cART, many having initiated therapy when they were under two years old [10,22,23]. Challenges of cART in PHIV-infected adolescents There are many practical considerations when initiating cART in all patients, regardless of age, including drug-drug interactions, co-morbid conditions (e.g., HBV, TB, renal and liver disease), and access and affordability [1618,2426]. The unique considerations and challenges to cART use in PHIV-infected adolescents, including physiologic, developmental, and psychosocial considerations, are outlined in Table 2. There are additional concerns about potential side effects, for example, bone and renal toxicity with tenofovir in the rapidly growing adolescent, which should be considered prior to cART prescription. These concerns are magnified in low weight adolescents where appropriate lower dose formulations are not available, a common problem in resource-limited countries [27]. These are discussed in other sections of this issue. Non-adherence to cART A period of significant physical and psychosocial evolution [28] (e.g., concrete thinking, invincibility, risk taking, autonomy, decreased parental supervision), adolescent patients with chronic diseases such as cystic fibrosis, congenital cardiac disease, diabetes, and HIV often have decreased adherence with associated increased morbidity and mortality [6,29,30]. Successful clinical, immunological, and virological outcomes on cART are dependent on at least 95% adherence to the regimen [31]. Self-reported adherence in PHIV-infected adolescents may be anywhere between 40 and 84% in resource-rich countries [3240], a rate lower than reported for adults. In a sub-Saharan African cohort, the numbers of adolescents achieving 100% adherence estimated by pharmacy refills, was lower than that for adults, with 20.7% at 6 months, 14.3% at 12 months, 6.6% at 24 months compared to 100% adherence in adults in 40.5%, 27.9%, and 20.6% at each time point, respectively; (p B0.01) [41]. Chandwani et al. reported that 31% of PHIV-infected adolescents were incompletely adherent in a US-based study, a rate not statistically different from non-PHIV-infected adolescents [37]. Non-adherence was associated with ever having had an AIDS diagnosis, possibly reflecting a chronic pattern of poor adherence resulting in disease progression. Additionally, older age has consistently been related to poor adherence in both resource-rich and limited countries, with adolescents above 15 years of age having a greater risk of non-adherence compared to younger adolescents [35,39,42,43]. 2 CD4 count absolute Guidelines (date) World Health Organization [24] WHO Stage 3 or 4 disease Definition of (cells/mm3) Clinical criteria Initial regimen virologic failure Second line regimen NNRTI plus 2 NRTI’s (one of which HIV RNA 5000 copies/ TB or HBV co-infection either AZT or TDF) mL after at least 6 months lopinavir/ritonavir preferred) and 2 NRTI’s regardless of CD4 count Reduce stavudine use of ART B350 ABC or DDI may be used as Ritonavir-boosted PI (Atazanavir or (one of which either AZT or TDF) (ABC and DDI no longer recommended) back-up options USA Department of AIDS or significant symptoms Adult: all should initiate cART Preferred regimens: Health and Services (Category C or most Category B Strongest recommendation for 2NRTIsNNRTI/PI [17,18] conditions) Regardless of CD4 count CD4 B350 Paediatric: after 6 months of therapy class; guided by genotyping and prior Adult: preferred: EFV/TDF/FTC ATV/rTDF/FTC Pregnancy, AIDS-defining ]5: CD4B500 DRV/rTDF/FTC illness, HIV-associated (asymptomatic); mildly RALTDF/FTC nephropathy (HIVAN), and HBV symptomatic (CD4 500) HIV RNA 200 copies/mL ]2 fully active agents from more than 1 regimens Paediatric: ]6 years: ATV/rTDF/FTC or 3TC Pediatric Network for Treatment of AIDS [16] South Africa [25] Thailand [26] CDC stage B and C B350 ABC3TCEFV Guidelines refer to LPV/rAZTTDF WHO Stage 3 and 4 Consider if VL100,000 copies/mL Consider PI^ in children/adolescents at high risk of poor adherence. PENPACT-1 study [22]: NNRTI: switch at or LPV/rABCDDI (depending on initial HLA genotype B*5701 use AZT VL 1000 copies/mL regimen) 3TC/FTCEFV/lop/r 40 kg TDF Pi: switch if VL 30,000 PI-based first line, switch to EFV with same copies/mL VL 1000 copies/mL NRTI backbone WHO Stage 4 disease, TB B350 can replace ABC NVP/EFVTDF3TC/FTC co-infection Accelerate if CD4 B200 In adolescents B40 kg or B16 years consecutively 13 months regimen)3TC/FTClop/r Accelerate if MDR/XDR or TDF is replaced by ABC apart WHO 4 GFR B50 mL/min per 1.73 m2 AZT replaces TDF AIDS-defining illness and NVP/EFVAZT/TDF3TC/FTC or VL 400 copies/mL after HIV-related symptomatic Lop/r2 NRTI’s 6 months or 50 copies/ Pregnant (WHO option B) (Alternative NRTIs ABC/DDI/D4T mL after 12 months of 3TC; alternative PI’s ATV/r; ART DRV/r: SQV/r) DRT if VL 2000 copies/ B350 TDF/AZT (depending on initial Based on genotyping mL ^Alternative PIs: darunavir/r, atazanavir/r, fosamprenavir/r and saquinavir/r; ABC abacavir, AZTzidovudine, ATVatazanavir, D4Tstavudine, DDI didanosine, DRVdarunavir, EFV efavirenz, FTC emtricitabine, Lop/rlopinavir/ritonavir, NRTI nucleoside reverse transcriptase inhibitor, NNRTInon-nucleoside reverse transcriptase inhibitor, NVPnevirapine, PI protease inhibitor, TDFtenofovir, /r ritonavir boosting, 3TC lamivudine. Agwu AL and Fairlie L. Journal of the International AIDS Society 2013, 16:18579 http://www.jiasociety.org/index.php/jias/article/view/18579 | http://dx.doi.org/10.7448/IAS.16.1.18579 Table 1. Guidelines for initiation of combination antiretroviral treatment in adolescents 3 Agwu AL and Fairlie L. Journal of the International AIDS Society 2013, 16:18579 http://www.jiasociety.org/index.php/jias/article/view/18579 | http://dx.doi.org/10.7448/IAS.16.1.18579 Table 2. Challenges of cART treatment in PHIV-infected adolescents Problem Implication Solution Physiologic Rapid growth and puberty with changes Altered pharmacokinetics with suboptimal Routine dose adjustment per weight and Tanner stage drug levels assessment Weight stunting and delayed puberty in fat and muscle mass Over-dosage of ART with potential Routine dose adjustment per weight and Tanner stage increased toxicity risks assessment Oro-facial motor abnormalities or Difficulty with swallowing ART 0 Select regimens with ART agents available in liquid or decreased adherence powder formulations (e.g. AZT, 3TC, ABC), or are crushable or dissolvable or allow the capsules to be lesions (e.g. candidiasis, poor dentition) opened (e.g. ATV, DRV, EFV, FTC, TDF) Note: co-formulat agents cannot be crushed Poor palatability Decreased adherence Same as above; consider masking taste using soda, juice, apple sauce Adverse effects GI intolerance (e.g. nausea, diarrhoea) Decreased adherence Take with meals Alter timing of administration (e.g. nighttime dosing) Anti-emetic, anti-diarrhoeal agents Consider alternative regimen Central nervous system side effects Decreased adherence Alter timing of administration (e.g. nighttime dosing) (e.g. altered sensorium, unusual Consider alternative regimen dreams, headache) Change in physical appearance (e.g. sclera icterus with ATV, facial Decreased adherence Consider alternative regimen Suboptimal PI levels Increased boosting with ritonavir or double dosing the PI lipoatrophy with D4T) Pharmacokinetic Drug-drug interactions Rifampicin-based TB co-treatment Suboptimal hormonal levels with increased For females using ritonavir-boosted PIs and combination with boosted protease inhibitor (PI) therapy risk of pregnancy hormonal contraceptives (pills, patches and rings) or progestin-only pills, the use of an alternative Hormonal contraceptives and PI contraceptive methods or dual contraceptive methods is recommended Co-morbid conditions Malaria, low nutritional status and advanced HIV disease Cognitive impairment due to HIV encephalopathy, longstanding HIV Increased risk of anaemia with certain Regular assessment of hAemoglobin levels at initiation, ARVs (e.g. zidovudine) 1 month, 3 months and then every 6 month or symptoms Difficulty in understanding HIV disease and Simplified regimens, cognitive age-appropriate benefits of cART 0 decreased adherence education, high barrier to resistance regimens Difficulty in understanding consequences Simplified regimens, cognitive age-appropriate of HIV and poor adherence 0 decreased education, high barrier to resistance regimens adherence Address adherence frequently infection Developmental stage Concrete thinking and emotional immaturity ABCabacavir, AZT zidovudine, ATVatazanavir, D4T stavudine, DDI didanosine, DRVdarunavir, EFV efavirenz, FTCemtricitabine, Lop/r lopinavir/ritonavir, NRTI nucleoside reverse transcriptase inhibitor, NNRTInon-nucleoside reverse transcriptase inhibitor, NVPnevirapine, PI protease inhibitor, TDF tenofovir, /r ritonavir boosting, 3TClamivudine. Adherence barriers Non-adherence is the single most significant challenge to successful management of HIV-infected individuals, especially adolescents. It may be due to any combination of structural, patient-related, provider-related, medication-related, disease-related, and psychological barriers. Adherence is not stagnant and needs to be assessed continuously as the factors leading to non-adherence may change over time, necessitating different approaches to address them. Given the differences between PHIV-infected adolescents in 4 Agwu AL and Fairlie L. Journal of the International AIDS Society 2013, 16:18579 http://www.jiasociety.org/index.php/jias/article/view/18579 | http://dx.doi.org/10.7448/IAS.16.1.18579 resource-rich and resource-limited settings, there are likely similarities and differences between adherence barriers in those settings. Adherence barriers common to adolescents in both resource-rich and resource-limited settings Lifestyle barriers such as forgetting, worrying about disclosure of HIV status, falling asleep before taking cART, being away from home, and busy and varied schedules including school attendance are common to both settings [32,33,37,38,4446]. These factors may impact adolescents with good adherence and ways of optimizing adherence despite life’s demands need to be sought [33]. Physical factors, such as behavioural and cognitive issues may further impact on adherence barriers related to lifestyle [37]. Feeling well may be associated with non-adherence by resultant complacency about cART, leading to passivity and neglecting to take ART [37]. Medication-related barriers are also common in PHIVinfected adolescents and include treatment fatigue [44,47], complexity of regimens including pill burden and dosing frequency, and palatability of cART, particularly drugs such as nelfinavir and ritonavir [32,37,38,45,48]. Where possible regimens should be simplified to fixed-dose combination tablets to improve convenience, tolerability and adherence [33,48]. However, as adolescents age and become more treatment experienced, requiring complex regimens because of poor adherence and subsequent resistance, simplified regimens become less possible, compounding the problem [37]. Adverse drug effects, from nuisance ones such as nausea and diarrhoea, to long-term toxicities such as lipodystrophy may also cause non-adherence [49,50]. Poor treatment knowledge and understanding of the benefits of taking cART as a non-curative intervention may impact adherence [45]. Also, adolescents may be emotionally unprepared for cART, particularly if they have been newly diagnosed or recently disclosed to [45]. In fact, nondisclosure of HIV status to PHIV-infected adolescents by caregivers may impact adherence, particularly when adolescents begin to question their cART regimen and express regimen fatigue [33,51]. Disclosure stressors ranked second to medication stressors in a study investigating the impact of adolescent disclosure to friends, revealing that disclosing to more than one friend was linked to less medication hiding, with an increased CD4 count and percentage, but no change in viral load [47,52]. A high percentage of PHIV-infected adolescents have experienced the loss of a primary caregiver, and parents who have survived are frequently ill, with resultant [6,19,36] depression and psychological distress which may impact adherence [30,33,53]. The coping mechanisms employed by PHIV-infected adolescents to deal with stressors are directly linked to non-adherence. Specifically, those experiencing adherence problems most commonly use withdrawal and passive emotional regulation and less commonly use problem solving or social support as coping mechanisms, possibly because of fear of stigma or unwanted disclosure. Passive coping style is also associated with depression and poorer psychological adjustment [47]. Resource-rich settings Psychological factors related to non-adherence are more commonly described in the literature from resource-rich locales, possibly due to under-reporting of these factors in resource-limited settings. Low self efficacy (sense of one’s, ability to adhere to prescribed medication) and low outcome expectancy (ones belief in the benefits of taking a prescribed medication) are strongly associated with poor adherence in adolescents [34,46]. Mental illness as a standalone factor has not consistently been shown to affect adherence [31,34,54]. Non-adherence is associated with depression and anxiety, with those receiving antipsychotic drugs and having more than one neurologic diagnosis having improved adherence possibly due to improved observation by caregivers and healthcare providers [39]. In the LEGACY cohort of PHIVinfected US adolescents, psychiatric diagnosis which included mood disorders, Attention Deficit Hyperactivity Disorder (ADHD) and disruptive behaviour disorders was significantly associated with one of three risky health behaviours including adherence problems in 72%, preadult sexual activity in 12% and substance abuse in 9% [40]. Resource-limited settings Adolescents who experience structural problems such as lack of medical insurance, problems with work or school, concerns about dealing with family and looking after children, housing instability, lack of transportation to clinic visits or to obtain medications, may have lower adherence. While these issues exist commonly in resource-rich settings, they may be even more prevalent in resource-limited settings particularly those where social and political instability prevail [34,42,44,46]. Additionally, the higher prevalence of comorbidities in resource-limited settings such as tuberculosis (drug sensitive and resistant), malaria, malnutrition, and the consequent polypharmacy and drug-drug interactions resulting from treatment may also impact adherence. Lastly, the relative lack of healthcare professionals (medical care providers, support staff, psychologists, social workers, and counsellors) experienced in adolescent healthcare management may further impact the adherence counselling and support needed for PHIV-infected adolescents in resourcelimited settings. Interventions that improve adherence There is no gold standard intervention to address adherence as it is a highly individualized process. Time during every encounter should be spent assessing adherence to medications [55]. Interventions need to be tailored to the individual adolescent’s needs, and multiple modalities may be necessary to address non-adherence. Particularly for adolescents who have cognitive limitations as a result of longstanding HIV, with limited support, addressing adherence may be even more complex. It is critical that approaches are multi-disciplinary and appropriate for the patient’s cognitive age and psychosocial stage, given the variability that can occur with PHIVinfected adolescents [32]. Additionally, it is important for the provider to not become frustrated with the patient as multiple failures may precede successful improvements in adherence; and addressing adherence improvement is 5 Agwu AL and Fairlie L. Journal of the International AIDS Society 2013, 16:18579 http://www.jiasociety.org/index.php/jias/article/view/18579 | http://dx.doi.org/10.7448/IAS.16.1.18579 ongoing as non-adherence can recur. When possible, involving the parent/caregiver in addressing non-adherence may be critical as there are often discrepancies in perception of adherence between the parent/caregiver and the adolescent as the responsibility for medication taking is transferred to the adolescent. Interventions involving both parties are crucial to improving adherence [32]. Some strategies to improve adherence are outlined in Table 3. Treatment outcomes in PHIV-infected adolescents In their second decade of HIV infection, the delicate balance of the virus and host is altered and PHIV-infected adolescents, in the absence of effective cART, will usually have immunologic deterioration, with development of clinical illness, including OIs [8,12]. Studies have shown that adolescents, particularly older adolescents, comprise the majority of PHIV-infected children being hospitalized and have highest rates of morbidity and mortality [56]. Many PHIV-infected adolescents in longitudinal cohorts, mostly from well-resourced countries, remain stable on cART with good adherence, retention in care and have good clinical, immunological, and virological outcomes [6,10,22,23]. Despite these successes, adolescence is a high risk period for adherence problems, with clinical, immunological, and virological outcomes determined by adherence to ART, associated disease progression and availability of new cART regimens in those experiencing first, second or third line ART failure. Table 3. Strategies to address non-adherence in perinatally HIV-infected adolescents Strategy Medication-related barriers Palatable formulations (liquid, powder, crushing) Management of side effects Anti-nausea, anti-diarrhoeal agents Change timing of dosing (e.g. nighttime dosing) Regimen change Patient-related factors Data describing longitudinal follow up in PHIV-infected adolescents from resource-rich settings show that up to 26% had ever had a clinical Centers of Disease Control and Prevention (CDC) C disease classification, indicating severe clinical immunocompromise during their lifetime [5,6,10,22]. Despite this, 85% of adolescents were well at recent follow up and weight, height, and body mass index (BMI) was well maintained, consistent with population norms [6,10]. Studies from the UK, Ireland, and the US have shown reduction in mortality of up to 76% between 19962006 in children and adolescents on cART and significant reduction in hospital admission rates over the same period in the Collaborative HIV Paediatric Study (CHIPS) cohort [9,10,22,57]. Mortality outcomes from sub-Saharan Africa suggest no difference in mortality between adults and adolescents. In a comparative study from South Africa, mortality rate was 2.9 per 100 personyears [95% confidence interval (CI) 2.33.7], with no differences between adolescents (919 years) and young adults (2028 years), with similar findings in a Ugandan study, where adolescents (1119 years) and adults had higher mortality rates (8.5 and 10% respectively) compared to childrenB10 years (5.4%), but no differences between them [58,59]. Immunological outcomes of cART in PHIVinfected adolescents Immunologic characteristics of PHIV-infected youth in care show robust CD4 counts in both resource-rich and limited settings. The median CD4% for PHIV-infected youth, Disclosure Counselling to deal with loss/trauma Treatment of concurrent psych diagnosis (e.g. anxiety, depression, substance abuse) Education about HIV and benefits of Cart Behavioural interventions Motivational interviewing Counselling, support groups Life skills education with time-management and prioritization Parental/caregiver involvement Buddy systems Adherence clubs Peer motivators/educators Activity triggers (e.g. meals) Clinical outcomes in PHIV-infected adolescents Reduced pill burden (e.g. once daily/fixed-dose combinations) Calendars Technological interventions (e.g. cell phone (calls or SMS texts, watches, beepers)) Pill boxes Pharmacy clinic Directly observed therapy Structural barriers Address barriers such as transportation, insurance, child care, clinic hours Education of clinic staff about cognitive and development stage of adolescence entering the adolescent master protocol cohort (median age of 12.2 years) in the United States was 33% [35]. In the CHIPS and French (median age 15 years) cohorts CD4 at last follow up was 554 cells/mm3 [IQR 324802] and 550 cells/mm3 [IQR 832861], respectively [6,10,22]. In a Zimbabwean cohort (mean age 14 years) CD4 count was 384 cells/mm3 [12]. Younger adults (1830 years) have better immune recovery than older adults ( 30 years), related to high thymic scores and immune restoration driven by therapyassociated reversal of immune reactivation giving them greater capacity to recruit and repopulate CD4 cells [60]. This can be extrapolated to adolescents, who are newly initiating ART, where high initial increases in CD4 percentage in the first year of cART initiation are sustained for five years of follow-up [57]. In a report from South Africa, adolescents had a greater change in median CD4 from baseline to 48 6 Agwu AL and Fairlie L. Journal of the International AIDS Society 2013, 16:18579 http://www.jiasociety.org/index.php/jias/article/view/18579 | http://dx.doi.org/10.7448/IAS.16.1.18579 weeks (373 vs. 187 cells/mL; p 0.0001) compared to young adults (2028 years) in both the non-PHIV- and PHIV-infected groups [58]. non-adherence, similar challenges of treatment experience seen in resource-rich settings are becoming more common [63]. Virological outcomes in PHIV-infected adolescents Resistance outcomes for PHIV-infected adolescents In the setting of suboptimal ART drug levels there is resultant viral evolution and development of resistance [64]. Certain regimens have been associated with higher rates of resistance, e.g., prolonged failure on an NNRTI-based regimen, triple nucleoside regimens, use of ritonavir as a single PI and boosted PI regimens without additional ritonavir boosting for rifampicin-based tuberculosis co-treatment [62,6567]. Foster et al. reported that in a UK and Ireland cohort, 52% of PHIV-adolescents had dual and 12% had triple-class ART resistance [6]. Genotypic resistance testing revealed NNRTIassociated mutations (i.e. 103N, 181C/I, and 190A) (65%), the NRTI mutation, M184I/V (49%), non-M184I/V NRTI mutations (thymidine analogue mutations) (57%), and major PI mutations (26%) [6]. Although not routinely assessed in most non-research resource-limited settings, when studies have assessed resistance levels, in children (not specifically adolescents) failing first and second-line regimens, 3499% had evidence of resistance, primarily consisting of NNRTI resistance and the NRTI mutation M184V, leaving limited treatment options available in those settings (see Figure 1) [6871]. Data on resistance in resource-limited settings are limited although being garnered by the WHO HIVResNet, the Global HIV Drug Resistance Surveillance Network, a collaboration between WHO and the International AIDS Society. The network develops standards for detecting resistance; identifies factors leading to resistance; builds and maintains monitoring capacity in developing countries through technology transfer, training and technical assistance; monitors resistance in untreated patients and samples of selected treated patients; then disseminates data in order to inform containment strategies [72]. These data are critically needed as cART uptake increases. Emergence of drug resistance has been highly correlated with all-cause mortality, with resistance to particular classes of agents, NNRTI specifically, having a threefold higher correlation with mortality, likely due to virulence of these viral variants [73]. This correlation of resistance to morbidity and mortality has been consistently shown in several studies in various settings, resource-rich and resource-limited [74]. In analyses of paediatric cohorts, adolescents had the highest hospitalization and mortality rates, without the significant declines seen in other age groups [56]. Assuming that there is no underlying resistance to a regimen that is selected, virologic suppression for adolescents should be similar to adults starting on similar regimens. However, virologic suppression rates in longitudinal adolescent cohorts are lower than those in adults, ranging from 28 to 78% compared to as high as 90% for adults on similar regimens [6,10,11,30,35,36,38,39,58,61,62]. In one study, the rates of virological failure (defined as initially achieving virological suppression with two subsequent viral loads 400 copies/ mL) were significantly higher in adolescents compared to young adults 8.2 (95% CI 4.614.4) and 5.0 (95% CI 4.16.1) per 100 person-years, respectively (p 0.001). This association was weakened in a sub-analysis comparing PHIV-infected adolescents to young adults [AHR 1.51 (95% CI 0.683.33; p 0.31)] [42]. Also, a study from nine sub-Saharan African countries showed that adolescents were 7075% less likely to have undetectable viral loads at 12, 18, and 24 months on highly active antiretroviral therapy (HAART). Adolescents who were virally suppressed at 12 months were more likely to experience viral rebound compared to adults [40]. In general, with appropriate cART, virologic suppression and a CD4 increase of 150 cells/mm3 should occur by six months after initiation, with the caveat that with significantly elevated viral loads and markedly suppressed CD4 counts, this may vary [18]. In settings where there is virologic or immunologic failure, underlying reasons need to be assessed in order to determine a course of action (Table 4). Upon failure of the first cART regimen, patients are then categorized as treatment-experienced, with added challenges to devising suppressive regimens and maximizing outcomes. Treatment-experienced patients In resource-rich settings, many PHIV-infected adolescents are significantly treatment-experienced, with over a decade of antiretroviral exposure on average, often with suboptimal single and dual ART regimens before transitioning to cART when it became available [10,22]. For example, in the PHACS cohort, only 1020% of the adolescents had cART as their first regimen, and the median number of ART agents they had been exposed to was seven [22]. Many PHIV-infected adolescents have long histories of suboptimal drug regimens, reduced drug levels due to poor absorption, drug-drug interactions, and non-adherence, which has implications for their likelihood of virologic failure and resistance, and dramatically compromises the ability to design suppressive regimens. In resource-limited settings PHIV-infected adolescents present later in childhood and usually have sensitive virus as prior exposure to suboptimal mono- or dual ART exposure is uncommon. However with increasing uptake of PMTCT and earlier cART initiation for infants and children, issues of drug-drug interactions, medication security and Strategies to help guide targeted resistance testing for adolescents in resource-limited settings In resource-rich settings, resistance testing (genotypic and when necessary phenotypic assessment) is readily available and prudent in the setting of virologic failure in order to guide decisions about treatment. Particularly critical for adolescents who are highly treatment-experienced, is the cumulative genotype of all mutations previously documented as with decreased drug-selective pressure with poor adherence or switch to a different drug regimen, viral variants harbouring resistance may fade from the circulating plasma viral pool, but still be present in the latent reservoir, emerging 7 Agwu AL and Fairlie L. Journal of the International AIDS Society 2013, 16:18579 http://www.jiasociety.org/index.php/jias/article/view/18579 | http://dx.doi.org/10.7448/IAS.16.1.18579 Table 4. Assessment and management of treatment failure in perinatally HIV-infected adolescents Virologic failure Definition Immunologic failure Variable per guidelines (see Table 1) Failure to achieve and maintain an adequate CD4 response despite virologic suppression Failure to improve CD4350 cells/mm3 Note: Increases in CD4 counts in ARV-naive patients with initial ARV regimens are approximately 150 cells/mm3 over the first year Potential causes CD4 count B200/mm3 when starting cART Older age Patient characteristics associated with virologic failure Hgher pretreatment or baseline HIV RNA level Lower pretreatment or nadir CD4 T-cell count Co-infection (e.g. TB, hepatitis C virus, HIV-2, human T-cell Prior AIDS diagnosis leukemia virus type 1 [HTLV-1], HTLV-2) Incomplete treatment of opportunistic infections Medications, both ARVs (e.g. ZDV TDFdidanosine [ddI]) Comorbidities (e.g. active substance abuse, depression) and other medications Presence of drug-resistant virus, either transmitted or acquired Persistent immune activation Prior treatment failure Loss of regenerative potential of the immune system Incomplete medication adherence and missed clinic appointments Other medical conditions ARV regimen characteristics Drug side effects and toxicities Suboptimal pharmacokinetics (variable absorption, metabolism, or, theoretically, penetration into reservoirs) Food/fasting requirements Adverse drug-drug interactions with concomitant medications Adverse drug-drug interactions with concomitant medications Suboptimal virologic potency Prescription errors Provider characteristics, such as experience in treating HIV disease Evaluation Other or unknown reasons Lab error Confirm virologic failure by repeating HIV RNA after 13 months Confirm virologic failure by repeating Assess for HIV-related clinical events Assess for HIV-related clinical events Assess virologic response Review ARV treatment history and response Compile and review resistance test results through tools such as the Review medication taking behaviour and adherence, including adherence to dosing and food requirements Stanford Database Obtain new genotype while still on current cART Review concomitant meds (prescribed and over the Review medication taking behaviour and adherence, including counter and homeopathic) for drug-drug interactions and adherence to dosing and food requirements effect on immune system Review concomitant meds (prescribed and over the counter and Assess co-morbidities (malignancy other infections) homeopathic) for drug-drug interactions Assess co-morbidities Interpretation If continued virologic failure and no evolution of resistance, adherence most likely Management If all investigation unremarkable, isolated immunologic failure Drug-drug interaction: resolve by discontinuing, changing the If 200 cells/mm3 close monitoring, unclear if should offending drug or if not possible, consider changing the ART prompt change in therapy, therefore not recommended regimen Resistance: select new regimen with at least 2 new active agents (see Table 1) Adherence: re-enforce adherence, utilize strategies (see Table 2) when the drug-selective pressure is resumed. Also, all prior ART regimens and responses to those regimens should be reviewed to assess likelihood of residual activity and predicted presence of resistance [17,18]. In resource-limited settings, genotyping is not readily available and is often restricted for use in adolescents failing second line regimens. 8 Agwu AL and Fairlie L. Journal of the International AIDS Society 2013, 16:18579 http://www.jiasociety.org/index.php/jias/article/view/18579 | http://dx.doi.org/10.7448/IAS.16.1.18579 Figure 1. Multi-drug genotypic resistance from a treatmentexperienced PHIV-infected adolescent. ART strategies in highly treatment-experienced PHIVinfected adolescents Although the availability of newer agents, including integrase inhibitors and CCR5 antagonists in certain settings, has generated renewed hope for virologic suppression and immune recovery for heavily treatment-experienced PHIVinfected adolescents with extensive resistance, selecting an optimal background regimen to achieve virologic suppression is a challenge. As many PHIV-infected adolescents continue to struggle with adherence, timing of introducing the salvage regimen is critical to prevent failure on what is often the last available suppressive regimen. In a retrospective study by Wong et al., PHIV-infected youth on cART were assessed and their regimens characterized as optimal vs. sub-optimal based on cumulative genotypes and anticipated drug activity at the start of the regimen. More than half of the patients from each cohort had poor adherence. By 48 weeks, those in the optimal group had a greater median CD4 increase, 62 (25 to 200) than those in the suboptimal group 8 ( 93 to 54) cells/mm3 (p0.04), and were four times more likely to have an increased CD4 50 cells/mm3, a difference that persisted throughout the study period. There were no differences in clinical events or accumulation of new resistance mutations between the two groups. The authors’ caution that the group of highly treatment-experienced adolescents with ongoing poor adherence could develop resistance to the optimal regimen and conclude that the choice of initiating a new regimen needs to consider adherence, adverse effects, pill burden and fear of accumulating resistance [49]. In general, the principles that guide managing treatment-experienced PHIV-infected adolescents include: switch only once adherence issues resolved, never only switch one drug in a failing regimen and do not continue therapy with a failing NNRTI regimen for prolonged periods as there is an increased risk of accumulating NNRTI resistance mutations compromising the class [75]. The approach to managing treatment failure depends on what tools are available to providers (Tables 1 and 4) and must take into consideration adherence and disease stage [76]. Providers that care for PHIV-infected adolescents have been forced to be creative in managing treatment failure in this population. Possible strategies include: bridging strategies (minimalist strategies; 3TC monotherapy; simplification strategies), and treatment de-intensification or even discontinuation [7781]. Once treatment is initiated (person meets criteria for treatment) discontinuation has potential immunologic, virologic and inflammatory consequences and is therefore not recommended by the guidelines [17,18,63,82]. However, treatment interruption (patient or providerinitiated), so-called drug holiday, is a strategy that has been utilized to manage some PHIV-infected adolescents who are unable to adhere despite all adherence interventions, underscoring the management challenges. In the CHIPS cohort, at last follow up, 18% of PHIV-infected adolescents who were receiving cART previously, were not receiving it [6]. Similarly in a longitudinal French cohort, 16% of had discontinued therapy [10]. Siberry et al. examined treatment interruptions in PHACS and reported that 23% of the cohort, significantly more in the earlier birth cohort (19911993) vs. younger cohorts, had discontinued ART for at least one period of ]3 months after continuous ART for ]6 months [76]. While immunologic decline occurred overall, significant variability was seen across the cohort. In general, these alternative management strategies have proven to be safe; however, their use should be accompanied by continued adherence strengthening, close monitoring and research to determine their effectiveness. PHIV-infected adolescents may be ideal candidates for future innovative strategies such as therapeutic vaccines and novel approaches, such as depot ART should they become available. Additional concerns and management issues related to PHIV-infected adolescents Unchecked inflammation Inflammation is increasingly being recognized as a significant consequence of HIV infection. Initially shown in adult studies, subsequent paediatric studies have also shown that PHIVinfected children have a high degree of inflammation related to uncontrolled HIV replication [83]. The sequelae of this heightened inflammation includes vascular anomalies with resultant heart disease, strokes, altered glucose metabolism, malignancy, neurologic disease, etc [84]. This inflammation is lowered, but not aborted/terminated by ART. In the PHACS cohort, markers of inflammation, coagulant, endothelial and metabolic dysfunction were assessed and correlated with ART and viremia [83]. HIV-infected children with a median age of 12.3 years had higher levels of cholesterol and triglycerides, despite lower body mass index, waist and hip circumference and percentage body fat. This cohort also had 9 Agwu AL and Fairlie L. Journal of the International AIDS Society 2013, 16:18579 http://www.jiasociety.org/index.php/jias/article/view/18579 | http://dx.doi.org/10.7448/IAS.16.1.18579 higher measurements of all of the inflammatory markers measured. Specifically, increased HIV viral load was associated with markers of inflammation and endothelial dysfunction [83]. Given that HIV infection is lifelong, and with ART there is increased survival of PHIV-infected adolescents, the sequelae of this unchecked inflammation, particularly in those non-adherent to ART, is of concern. Transmission Studies have reported mixed findings regarding sexual activity in PHIV-infected adolescents with some studies reporting delayed penetrative sex in young HIV-infected adolescents [35,85] with no association between HIV status and sexual risk behaviour, and others reporting increased risk-taking behaviour, including sexual behaviour, substance abuse, and an increased risk of pregnancy [40,8587]. A recent study of PHIV-infected adolescents revealed that 28% reported sexual intercourse with a median age of coitarche of 14 years; 62% reported unprotected sexual intercourse, and only 33% of youth disclosed their HIV status to their partners. Interestingly, of youth who did not report being sexually active at baseline, ART non-adherence was associated with sexual debut during the follow-up period. The investigators also examined genotypic resistance in the 42% of the sexually active youth that had viral loads ]5000 copies/mL, identifying 62, 57, 38, and 22% to NRTIs, NNRTIs, PIs, and all three ARV classes, respectively. The sequelae of these unprotected acts include sexually transmitted infections and pregnancies, which have been reported in PHIV-infected adolescents. The rates of reported sexual activity and failure to use barrier protection raise concern for secondary transmission, horizontal and vertical. In the setting of non-adherence, the concern is heightened as there is a risk of transmission of resistant virus, limiting treatment options for the individual acquiring primary infection. The authors rightfully conclude that the combination of unprotected sexual activity, non-disclosure and ART resistance places partners at risk for HIV infection and call for interventions to facilitate youth adherence, safer-sex practices and disclosure [88]. Transition to adult care PHIV-infected adolescents often have complex psychosocial situations and clinical histories, including complicated resistance patterns [6,10]. These patients may be seen in paediatric or adult clinics where there is significant variability including, but not limited to the clinic appearance, services provided, target populations, providerpatient ratios, availability of youth-friendly services, training and experience of the clinic personnel in adolescent health and development and HIV outcomes for this population [89]. The transfer of care from a paediatric/adolescent to an adult clinic may be accompanied by significant anxiety and may lead to a disruption in care [90]. As adolescents transition between paediatric and adult clinical venues, it will be critical for providers on both sides to have a thorough understanding of the multi-faceted issues including complicated treatment histories, complex psychosocial dynamics and developmental stage, in order to effectively manage PHIV-infected adolescents and optimize outcomes after transfer. Gender considerations in PHIV-infected youth In published studies of PHIV-infected adolescents, there is usually equal gender distribution between male and female PHIV-infected adolescents, a characteristic which distinguishes PHIV and non-PHIV-infected adolescents, where there tend to be varying gender distributions depending on the epidemic (e.g., majority males infected via MSM activity in the United States, and females infected through heterosexual sex in Sub-Saharan Africa). Gender may significantly affect outcomes and clinical practice in PHIV-infected adolescents for a number of reasons. Contrasting findings regarding the impact of gender on adherence and virological suppression warrant further investigation. A French cohort demonstrated greater virological suppression rates in female adolescents in a multivariate analysis of the cohort [10], while two studies in the United States reported that male gender was associated with improved adherence and virological suppression [22,39]. One study has reported lower efficacy of lopinavir in male adolescents over 12 years of age, and although the numbers in this group were insufficient to analyze statistically, the clinical and virological significance of this finding warrants further investigation [91]. Female PHIV-infected adolescents may enter puberty earlier than males which may affect safety and dosing of ARVs such as tenofovir. Use of hormonal contraceptives, particularly the combined oral contraceptive pill with concurrent PI use and the subsequent drug-drug interactions may result in reduced contraceptive efficacy with possible pregnancy in female PHIV-infected adolescents. For females using ritonavir-boosted PIs and combination hormonal contraceptives (pills, patches and rings) or progestin-only pills, the use of an alternative contraceptive method (e.g. intrauterine device [IUD]) and/or dual contraception methods is recommended (Table 2). Hormonal contraception particularly the injectable methods may result in increased HIV transmission to HIV negative partners, likely due to a combination of decreased condom use and increased vaginal inflammation and intravaginal viral load [92]. Discussion of contraceptive needs with sexually active adolescents is an important component of HIV care. Practitioners managing PHIV-infected adolescents need to be aware of these potential differences related to gender in order to provide comprehensive, safe care for this population. Conclusions In conclusion, the growing cohort of PHIV-infected children that are emerging into adolescence and young adulthood require cART treatment to control viral replication, prevent immune deterioration and avert secondary transmission. Successful treatment is complicated by developmental, cognitive and psychosocial challenges that can compromise adherence leading to the development of resistance and reduced treatment options, with resultant morbidity and mortality. While recent data in adults has estimated that the life expectancy for HIV-infected individuals has improved to near normal, with significant proportions of PHIV-infected 10 Agwu AL and Fairlie L. Journal of the International AIDS Society 2013, 16:18579 http://www.jiasociety.org/index.php/jias/article/view/18579 | http://dx.doi.org/10.7448/IAS.16.1.18579 adolescents emerging into adulthood with resistant virus, continued non-adherence, and the limited pipeline of new agents, there is concern that the survival seen in HIV-infected adults may not be duplicated for PHIV-infected adolescents. Resource-rich settings are over a decade ahead of resourcelimited settings in their treatment of PHIV-infected adolescents, providing foreshadowing for some of the challenges ahead for resource-limited settings and insight into the multifaceted approaches that may be needed to address these challenges. Lessons learnt from resource-rich settings and research about the unique barriers that may exist in resourcelimited settings will be critical to assuring that PHIV-infected youth continue to benefit from treatment as they navigate the challenging period of adolescence. Authors’ affiliations 1 Division of Paediatric Infectious Diseases, Department of Paediatrics, Johns Hopkins School of Medicine Baltimore, MD, USA; 2Division of Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine Baltimore, MD, USA; 3Wits Reproductive Health and HIV Institute (WRHI), University of the Witwatersrand, Johannesburg, South Africa Competing interests Dr Agwu was supported by the National Institutes of Allergy and Infectious Diseases (1K23 AI084549) and Johns Hopkins Ross Clinician Scientist Award. Dr Fairlie is supported by USAID, PEPFAR. Authors’ contributions Both authors have read and approved the final version and both authors drafted the manuscript. References 1. UNAIDS. UNAIDS Report on the global AIDS epidemic 2012; 2012. 1-22-0013. 2. Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med. 2008;359:223344. 3. World Health Organization. Antiretroviral therapy for HIV infection in infants and children: towards universal access. Recommendations for a public health approach 2010 version. Geneva, Switzerland: World Health Organization; 2010. 4. Hazra R, Siberry GK, Mofenson LM. Growing up with HIV: children, adolescents, and young adults with perinatally acquired HIV infection. Annu Rev Med. 2010;61:16985. 5. Judd A, Doerholt K, Tookey PA, Sharland M, Riordan A, Menson E, et al. Morbidity, mortality, and response to treatment by children in the United Kingdom and Ireland with perinatally acquired HIV infection during 1996 2006: planning for teenage and adult care. Clin Infect Dis. 2007;45:91824. 6. Foster C, Judd A, Tookey P, Tudor-Williams G, Dunn D, Shingadia D, et al. Young people in the United Kingdom and Ireland with perinatally acquired HIV: the pediatric legacy for adult services. AIDS Patient Care STDS. 2009;23: 15966. 7. Centers for Disease Control and Prevention. Pediatric HIV Surveillance (through 2010); 2012. 12-18-0012. 8. Ferrand RA, Munaiwa L, Matsekete J, Bandason T, Nathoo K, Ndhlovu CE, et al. Undiagnosed HIV infection among adolescents seeking primary health care in Zimbabwe. Clin Infect Dis. 2010;51:84451. 9. Ferrand RA, Luethy R, Bwakura F, Mujuru H, Miller RF, Corbett EL. HIV infection presenting in older children and adolescents: a case series from Harare, Zimbabwe. Clin Infect Dis. 2007;44:8748. 10. Dollfus C, Le CJ, Faye A, Blanche S, Briand N, Rouzioux C, et al. Long-term outcomes in adolescents perinatally infected with HIV-1 and followed up since birth in the French perinatal cohort (EPF/ANRS CO10). Clin Infect Dis. 2010; 51:21424. 11. World Health Organization. Paediatric HIV data and statistics 2010; 2010. 12. Ferrand RA, Desai SR, Hopkins C, Elston CM, Copley SJ, Nathoo K, et al. Chronic lung disease in adolescents with delayed diagnosis of vertically acquired HIV infection. Clin Infect Dis. 2012;55:14552. 13. Ferrand RA, Bandason T, Musvaire P, Larke N, Nathoo K, Mujuru H, et al. Causes of acute hospitalization in adolescence: burden and spectrum of HIV- related morbidity in a country with an early-onset and severe HIV epidemic: a prospective survey. PLoS Med. 2010;7:e1000178. 14. Lowe S, Ferrand RA, Morris-Jones R, Salisbury J, Mangeya N, Dimairo M, et al. Skin disease among human immunodeficiency virus-infected adolescents in Zimbabwe: a strong indicator of underlying HIV infection. Pediatr Infect Dis J. 2010;29:34651. 15. Harrison A, Pierre RB, Palmer P, Moore J, Davis D, Dunkley-Thompson J, et al. Clinical manifestations of adolescents with HIV/AIDS in Jamaica. West Indian Med J. 2008;57(3):25764. 16. Welch S, Sharland M, Lyall EG, Tudor-Williams G, Niehues T, Wintergerst U, et al. PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infection. HIV Med. 2009;10:591613. 17. Panel of Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. Department of Health and Human Services. 3-27-2012. 10-8-2012. 18. Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. 2012. 12-12-2012. 19. Meyers TM, Yotebieng M, Kuhn L, Moultrie H. Antiretroviral therapy responses among children attending a large public clinic in Soweto, South Africa. Pediatr Infect Dis J. 2011;30:9749. 20. Davies MA, Keiser O, Technau K, Eley B, Rabie H, van CG, et al. Outcomes of the South African National Antiretroviral Treatment Programme for children: the IeDEA Southern Africa collaboration. S Afr Med J. 2009;99:7307. 21. McNairy ML, Lamb MR, Carter RJ, Fayorsey R, Tene G, Mutabazi V, et al. Retention of HIV-infected children on antiretroviral treatment in HIV care and treatment programs in Kenya, Mozambique, Rwanda and Tanzania. J Acquir Immune Defic Syndr. 2012 Oct 29. [Epub ahead of print]. 22. Van Dyke RB, Patel K, Siberry GK, Burchett SK, Spector SA, Chernoff MC, et al. Antiretroviral treatment of US children with perinatally acquired HIV infection: temporal changes in therapy between 1991 and 2009 and predictors of immunologic and virologic outcomes. J Acquir Immune Defic Syndr. 2011; 57:16573. 23. Agwu AL, Korthuis PT, Gaur A, Spector SA, Rutstein R, Warford R, et al. HIV Viremia and advanced immunosuppression among perinatally HIV-infected youth in the multi-site US HIV research network, J Pediatr Infect Dis. 2013 March 12. [Epub ahead of print]. 24. World Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach 2010 revision. Geneva, Switzerland: World Health Organization; 2010. 25. National Department of Health South Africa. Clinical guidelines for the management of HIV & AIDS in adults and adolescents. South Africa; 2010. 26. Sungkanuparph S, Techasathit W, Utaipiboon C, Chasombat S, Bhakeecheep S, Leechawengwongs M, et al. Thai national guidelines for antiretroviral therapy in HIV-1 infected adults and adolescents 2010. Asian Biomed. 2010;4:51528. 27. World Health Organization. Technical update of treatment optimization. Use of tenofovir in HIV-infected children and adolescents: a public health perspective. World Health Organization; 2012. 28. Blum RW, McNeely C, Nonnemaker J. Vulnerability, risk, and protection. J Adolesc Health. 2002;31:2839. 29. Betz CL. Adolescents in transition of adult care: why the concern? Nurs Clin North Am. 2004;39:681713. 30. Battles HB, Wiener LS. From adolescence through young adulthood: psychosocial adjustment associated with long-term survival of HIV. J Adolesc Health. 2002;30:1618. 31. Paterson DL, Swindells S, Mohr J, Brester M, Vergis EN, Squier C, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med. 2000;133:2130. 32. Buchanan AL, Montepiedra G, Sirois PA, Kammerer B, Garvie PA, Storm DS, et al. Barriers to medication adherence in HIV-infected children and youth based on self- and caregiver report. Pediatrics. 2012;129:e124451. 33. Merzel C, VanDevanter N, Irvine M. Adherence to antiretroviral therapy among older children and adolescents with HIV: a qualitative study of psychosocial contexts. AIDS Patient Care STDS. 2008;22:97787. 34. Rudy BJ, Murphy DA, Harris DR, Muenz L, Ellen J. Prevalence and interactions of patient-related risks for nonadherence to antiretroviral therapy among perinatally infected youth in the United States. AIDS Patient Care STDS. 2010;24:97104. 35. Mellins CA, Tassiopoulos K, Malee K, Moscicki AB, Patton D, Smith R, et al. Behavioral health risks in perinatally HIV-exposed youth: co-occurrence of 11 Agwu AL and Fairlie L. Journal of the International AIDS Society 2013, 16:18579 http://www.jiasociety.org/index.php/jias/article/view/18579 | http://dx.doi.org/10.7448/IAS.16.1.18579 sexual and drug use behavior, mental health problems, and nonadherence to antiretroviral treatment. AIDS Patient Care STDS. 2011;25:41322. 36. Van Dyke RB, Lee S, Johnson GM, Wiznia A, Mohan K, Stanley K, et al. Reported adherence as a determinant of response to highly active antiretroviral therapy in children who have human immunodeficiency virus infection. Pediatrics. 2002;109:e61. 37. Chandwani S, Koenig LJ, Sill AM, Abramowitz S, Conner LC, D’Angelo L. Predictors of antiretroviral medication adherence among a diverse cohort of adolescents with HIV. J Adolesc Health. 2012;51:24251. 38. Goode M, McMaugh A, Crisp J, Wales S, Ziegler JB. Adherence issues in children and adolescents receiving highly active antiretroviral therapy. AIDS Care. 2003;15:4038. 39. Williams PL, Storm D, Montepiedra G, Nichols S, Kammerer B, Sirois PA, et al. Predictors of adherence to antiretroviral medications in children and adolescents with HIV infection. Pediatrics. 2006;118:e174557. 40. Kapetanovic S, Wiegand RE, Dominguez K, Blumberg D, Bohannon B, Wheeling J, et al. Associations of medically documented psychiatric diagnoses and risky health behaviors in highly active antiretroviral therapy-experienced perinatally HIV-infected youth. AIDS Patient Care STDS. 2011;25:493501. 41. Nachega JB, Hislop M, Nguyen H, Dowdy DW, Chaisson RE, Regensberg L, et al. Antiretroviral therapy adherence, virologic and immunologic outcomes in adolescents compared with adults in southern Africa. J Acquir Immune Defic Syndr. 2009;51:6571. 42. Bygrave H, Mtangirwa J, Ncube K, Ford N, Kranzer K, Munyaradzi D. Antiretroviral therapy outcomes among adolescents and youth in rural Zimbabwe. PLoS One. 2012;7:e52856. 43. Williams PL, Van DR, Eagle M, Smith D, Vincent C, Ciupak G, et al. Association of site-specific and participant-specific factors with retention of children in a long-term pediatric HIV cohort study. Am J Epidemiol. 2008; 167:137586. 44. Garvie PA, Flynn PM, Belzer M, Britto P, Hu C, Graham B, et al. Psychological factors, beliefs about medication, and adherence of youth with human immunodeficiency virus in a multisite directly observed therapy pilot study. J Adolesc Health. 2011;48:63740. 45. Veinot TC, Flicker SE, Skinner HA, McClelland A, Saulnier P, Read SE, et al. ‘‘Supposed to make you better but it doesn’t really’’: HIV-positive youths’ perceptions of HIV treatment. J Adolesc Health. 2006;38:2617. 46. Mills EJ, Nachega JB, Bangsberg DR, Singh S, Rachlis B, Wu P, et al. Adherence to HAART: a systematic review of developed and developing nation patient-reported barriers and facilitators. PLoS Med. 2006;3:e438. 47. Orban LA, Stein R, Koenig LJ, Conner LC, Rexhouse EL, Lewis JV, et al. Coping strategies of adolescents living with HIV: disease-specific stressors and responses. AIDS Care. 2010;22:42030. 48. Rosso R, Di BA, Maggiolo F, Nulvesu L, Callegaro AP, Taramasso L, et al. Patient-reported outcomes and low-level residual HIV-RNA in adolescents perinatally infected with HIV-1 after switching to one-pill fixed-dose regimen. AIDS Care. 2012;24:548. 49. Wong FL, Hsu AJ, Pham PA, Siberry GK, Hutton N, Agwu AL. Antiretroviral treatment strategies in highly treatment experienced perinatally HIV-infected youth. Pediatr Infect Dis J. 2012;31:127983. 50. Sawawiboon N, Wittawatmongkol O, Phongsamart W, Prasitsuebsai W, Lapphra K, Chokephaibulkit K. Lipodystrophy and reversal of facial lipoatrophy in perinatally HIV-infected children and adolescents after discontinuation of stavudine. Int J STD AIDS. 2012;23:497501. 51. Arrive E, Dicko F, Amghar H, Aka AE, Dior H, Bouah B, et al. HIV status disclosure and retention in care in HIV-infected adolescents on antiretroviral therapy (ART) in West Africa. PLoS One. 2012;7:e33690. 52. Calabrese SK, Martin S, Wolters PL, Toledo-Tamula MA, Brennan TL, Wood LV. Diagnosis disclosure, medication hiding, and medical functioning among perinatally infected, HIV-positive children and adolescents. AIDS Care. 2012;24:10926. 53. Mellins CA, Ehrhardt AA. Families affected by pediatric acquired immunodeficiency syndrome: sources of stress and coping. J Dev Behav Pediatr. 1994;15:S5460. 54. Agwu A, Lindsey JC, Ferguson K, Zhang H, Spector S, Rudy BJ, et al. Analyses of HIV-1 drug-resistance profiles among infected adolescents experiencing delayed antiretroviral treatment switch after initial nonsuppressive highly active antiretroviral therapy. AIDS Patient Care STDS. 2008;22: 54552. 55. Reisner S, Mimiaga M, Skeer M, Perkovich B, Johnson C, Safren S. A review of HIV antiretroviral adherence and intervention studies among HIV-infected youth. Top HIV Med. 2009;17(1):1425. 56. Berry, S, Gebo K, Rutstein R, Warford R, Agwu A. Alive and not well: hospitalization rates highest for oldest perinatally HIV-infected youth 20012008. Infect Dis Soc Am. 2011 Oct 2023. Boston, MA. 57. Patel K, Hernan MA, Williams PL, Seeger JD, McIntosh K, Van Dyke RB, et al. Long-term effectiveness of highly active antiretroviral therapy on the survival of children and adolescents with HIV infection: a 10-year follow-up study. Clin Infect Dis. 2008;46:50715. 58. Nglazi MD, Kranzer K, Holele P, Kaplan R, Mark D, Jaspan H, et al. Treatment outcomes in HIV-infected adolescents attending a community-based antiretroviral therapy clinic in South Africa. BMC Infect Dis. 2012;12:21. 59. Bakanda C, Birungi J, Mwesigwa R, Nachega JB, Chan K, Palmer A, et al. Survival of HIV-infected adolescents on antiretroviral therapy in Uganda: findings from a nationally representative cohort in Uganda. PLoS One. 2011; 6:e19261. 60. Kalayjian RC, Spritzler J, Pu M, Landay A, Pollard RB, Stocker V, et al. Distinct mechanisms of T cell reconstitution can be identified by estimating thymic volume in adult HIV-1 disease. JID. 2005;192. 61. Santoro MM, Armenia D, Alteri C, Flandre P, Calcagno A, Santoro M, et al. Impact of pre-therapy viral load on virological response to modern first-line HAART. Antivir Ther. 2013 Jan 23. doi: 10.3851/IMP2531. [Epub ahead of print]. 62. WHO. WHO HIV Drug Resistance Report 2012. Available from: http://www. who.int/hiv/pub/drugresistance/report2012/en/index.html. 63. Van Zyl GU, Rabie H, Nuttall JJ, Cotton MF. It is time to consider third-line options in antiretroviral-experienced paediatric patients? J Int AIDS Soc. 2011; 14(55). doi: 10.1186/1758-2652-14-55. 64. Bangsberg D. Preventing HIV antiretroviral resistance through better monitoring of treatment adherence. J Infect Dis. 2008;197(Suppl 3):S2728. 65. Gulick R, Ribaudo H, Shikuma C, Lustgarten S, Squires K III, Meyer W, et al. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med. 2004;350(18):185061. 66. McIlleron H, Ren Y, Nuttall J, Fairlie L, Rabie H, Cotton M, et al. Lopinavir exposure is insufficient in children given double doses of lopinavir/ ritonavir during rifampicin-based treatment for tuberculosis. Antivir Ther. 2011;16(3):41721. 67. Frohoff C, Moodley M, Fairlie L, Coovadia A, Moultrie H, Kuhn L, et al. Treatment outcomes among HIV-infected infants and young children following modifications to protease inhibitor-based therapy due to tuberculosis treatment. PLoS One. 2011;6(2):e17273 68. Zhao Y, Mu W, Harwell J, Zhou H, Sun X, Cheng Y, et al. Drug resistance profiles among HIV-1-infected children experiencing delayed switch and 12month efficacy after using second-line antiretroviral therapy: an observational cohort study in rural China. J Acquir Immune Defic Syndr. 2011;58(1):4753. 69. Wamalwa D, Lehman D, Benki-Nugent S, Gasper M, Gichohi R, Maleche-Obimbo E, et al. Long-term virologic response and genotypic resistance mutations in HIV-1 infected Kenyan children on combination antiretroviral therapy. J Acquir Immune Defic Syndr. 2012 Nov 28. [Epub ahead of print]. 70. Charpentier C, Gody J, Mbitikon O, Moussa S, Matta M, Péré H, et al. Virological response and resistance profiles after 18 to 30 months of first- or second-/third-line antiretroviral treatment: a cross-sectional evaluation in HIV type 1-infected children living in the Central African Republic. AIDS Res Hum Retroviruses. 2012;28(1):8794. 71. Sigaloff K, Calis J, Gleen S, Vugt M, Wit T. HIV-1-resistance-associated mutations after failure of first-line antiretroviral treatment among children in resource-poor regions: a systematic review. Lancet Infect Dis. 2011;11(109): 7697. 72. WHO. The global HIV drug resistance surveillance network. Available from: http://www.who.int/drugresistance/hivaids/en/HIVdrugnetwork.pdf. 73. Hogg R, Bangsberg D, Lima V, Alexander C, Bonner S, Yip B, et al. Emergence of drug resistance is associated with an increased risk of death among patients first starting HAART. PLoS Med. 2006;3(9): e356. 74. Wang X, Xing H, Ruan Y, Liao L, Zhou H, et al. Effect of viral load and drug resistance on mortality among Chinese HIV-infected patients receiving antiretroviral treatment. J Antivir Antiretrovir. 2012;4:0605. 75. Agwu A, Bethel J, Hightow-Weidman L, Sleasman J, Wilson C, Rudy B, et al. Substantial multiclass transmitted drug resistance and drug-relevant polymorphisms among treatment-naı̈ve behaviorally HIV-infected youth. AIDS Patient Care STDS. 2012;26(4):1936. 76. Siberry G, Patel K, Dyke RV, Hazra R, Burchett S, Spector S, et al. CD4 lymphocyte-based immunologic outcomes of perinatally HIV-infected children during antiretroviral therapy interruption. J Acquir Immune Defic Syndr. 2011; 57(3):2239. 12 Agwu AL and Fairlie L. Journal of the International AIDS Society 2013, 16:18579 http://www.jiasociety.org/index.php/jias/article/view/18579 | http://dx.doi.org/10.7448/IAS.16.1.18579 77. Abadi J, Sprecher E, Rosenberg MG, Dobroszycki J, Sansary J, Fennelly G, et al. Partial treatment interruption of protease inhibitor-based highly active antiretroviral therapy regimens in HIV-infected children. J Acquir Immune Defic Syndr. 2006;41(3):298303. 78. Legrand F, Abadi J, Jordan K, Davenport M, Deeks S, Fennelly G, et al. Partial treatment interruption of protease inhibitors augments HIV-specific immune responses in vertically infected pediatric patients. AIDS. 2005;19(15): 157585. 79. Rabie H, Essack G, Cotton M. Monotherapy with lamivudine in HIVinfected children: the experience at Tygerberg hospital. SA HIV Clin Soc Conference. November 2528, 2012. Capetown, South Africa. 80. Castagna A, Galli L, Bigoloni A, Carini E, Segala D, Antinori A, et al. Impact of lamivudine monotherapy in failing patients with multidrug-resistant HIV: final 48 weeks results (MONO-AIFA FARM7PAZS3). J Int AIDS Soc. 2012;15(6): 18289. 81. Castagna A, Danise A, Menzo S, Galli L, Gianotti N, Carini E, et al. Lamivudine monotherapy in HIV-1-infected patients harbouring a lamivudineresistant virus: a randomized pilot study (E-184V study). AIDS. 2006;20: 795803. 82. El-Sadr W, Lundgren J, Neaton J, Gordin F, Abrams D, Arduino R, et al. CD4 count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355(22):228396. 83. Miller T, Borkowsky W, DiMeglio L, Dooley L, Geffner M, Hazra R. Metabolic abnormalities and viral replication are associated with biomarkers of vascular dysfunction in HIV-infected children. HIV Med. 2012;13(5):26475. 84. Deeks S. HIV infection, inflammation, immunosenescence, and aging. Annu Rev Med. 2011;62:14155. 85. Bauermeister JA, Elkington KS, Robbins RN, Kang E, Mellins CA. A prospective study of the onset of sexual behavior and sexual risk in youth perinatally infected with HIV. J Sex Res. 2012;49(5):41322. 86. Elkington KS, Bauermeister JA, Brackis-Cott E, Dolezal C, Mellins CA. Substance use and sexual risk behaviors in perinatally human immunodeficiency virus-exposed youth: roles of caregivers, peers and HIV status. J Adolesc Health. 2009;45:13341. 87. Setse RW, Siberry GK, Gravitt PE, Moss WJ, Agwu AL, Wheeling JT, et al. Correlates of sexual activity and sexually transmitted infections among human immunodeficiency virus-infected youth in the LEGACY cohort, United States, 2006. Pediatr Infect Dis J. 2011;30(11):96773. 88. Tassiopoulos K, Moscicki A, Mellins C, Kacanek D, Malee K, Allison S, et al. Sexual risk behavior among youth with perinatal HIV infection in the United States: predictors and implications for intervention development. Clin Infect Dis. 2013;56(2):28390. 89. HIVguidelines.org. Transitioning HIV-infected adolescents into adult care. Available from: http://wwwhivguidelinesorg/clinical-guidelines/adolescents/ transitioning-hiv-infected-adolescents-into-adult-care/. 90. Fair C, Sullivan K, Dizney R, Stackpole A. ‘‘It’s like losing a part of my family’’: transition expectations of adolescents living with perinatally acquired HIV and their guardians. AIDS Patient Care STDS. 2012;26(7): 4239. 91. Jullien V, Urien S, Hirt D, Delaugerre C, Rey E, Teglas J, et al. Population analysis of weight-, age-, and sex-related differences in the pharmacokinetics of lopinavir in children from birth to 18 years. Antimicrob Agents Chemother. 2006;50(11):354855. 92. Heffron R, Donnell D, Rees H, Celum C, Mugo N, Were E, et al. Hormonal contraceptive use and risk of HIV-1 transmission: a prospective cohort analysis. Lancet Infect Dis. 2012;12(1):1926. 13 Mellins CA and Malee KM. Journal of the International AIDS Society 2013, 16:18593 http://www.jiasociety.org/index.php/jias/article/view/18593 | http://dx.doi.org/10.7448/IAS.16.1.18593 Review article Understanding the mental health of youth living with perinatal HIV infection: lessons learned and current challenges Claude A Mellins§,1 and Kathleen M Malee2 § Corresponding author: Claude A Mellins, New York State Psychiatric Institute, Box 15, 1051 Riverside Drive, New York, NY 10032, USA. Tel: 1-212-543-5383, Fax: 1-212-543-6003. ([email protected]) This article is part of the special issue Perinatally HIV-infected adolescents - more articles from this issue can be found at http://www.jiasociety.org Abstract Introduction: Across the globe, children born with perinatal HIV infection (PHIV) are reaching adolescence and young adulthood in large numbers. The majority of research has focused on biomedical outcomes yet there is increasing awareness that long-term survivors with PHIV are at high risk for mental health problems, given genetic, biomedical, familial and environmental risk. This article presents a review of the literature on the mental health functioning of perinatally HIV-infected (PHIV) adolescents, corresponding risk and protective factors, treatment modalities and critical needs for future interventions and research. Methods: An extensive review of online databases was conducted. Articles including: (1) PHIV youth; (2) age 10 and older; (3) mental health outcomes; and (4) mental health treatment were reviewed. Of 93 articles identified, 38 met inclusion criteria, the vast majority from the United States and Europe. Results: These studies suggest that PHIV youth experience emotional and behavioural problems, including psychiatric disorders, at higher than expected rates, often exceeding those of the general population and other high-risk groups. Yet, the specific role of HIV per se remains unclear, as uninfected youth with HIV exposure or those living in HIV-affected households displayed similar prevalence rates in some studies, higher rates in others and lower rates in still others. Although studies are limited with mixed findings, this review indicates that child-health status, cognitive function, parental health and mental health, stressful life events and neighbourhood disorder have been associated with worse mental health outcomes, while parentchild involvement and communication, and peer, parent and teacher social support have been associated with better function. Few evidence-based interventions exist; CHAMP, a mental health programme for PHIV youth, shows promise across cultures. Conclusions: This review highlights research limitations that preclude both conclusions and full understanding of aetiology. Conversely, these limitations present opportunities for future research. Many PHIV youth experience adequate mental health despite vulnerabilities. However, the focus of research to date highlights the identification of risks rather than positive attributes, which could inform preventive interventions. Development and evaluation of mental health interventions and preventions are urgently needed to optimize mental health, particularly for PHIV youth growing up in low-and-middle income countries. Keywords: mental health; psychiatric disorders; emotional and behavioural problems; perinatal HIV infection; adolescence; paediatric HIV. Received 15 February 2013; Revised 10 April 2013; Accepted 16 April 2013; Published 18 June 2013 Copyright: – 2013 Mellins CA and Malee KM; licensee International AIDS Society. This is an open access article distributed under the terms of the Creative Commons Attribution 3.0 Unported (CC BY 3.0) Licence (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction With widespread use of highly active antiretroviral therapy (HAART), children born with perinatal HIV infection (PHIV ) are reaching adolescence and young adulthood in large numbers, such that paediatric HIV is an adolescent epidemic in many parts of the world [1,2]. Adolescents coping with HIV since birth share stressors experienced by youth with other chronic illnesses, including on-going medical treatment, hospitalizations, exposure to pain and sheltered life experiences [35]. They also face a host of unique issues related to the psychosocial impact of HIV, a highly stigmatized and transmittable illness that may make transition through adolescence difficult. Until recently, research on this developmental period for PHIV youth has been limited, with focus primarily on biomedical outcomes, adherence to antiretroviral therapy (ART) and prevention of HIV transmission to others. Yet, there is increasing awareness that longterm survivors with PHIV are at high risk for mental health problems given exposure to genetic, biomedical, familial and environmental factors [6,7]. Since HAART was not routinely available to children in the United States (US) until 1998, and until much later for many low-to-middle-income countries (LMIC), many PHIV adolescents were exposed to years of sub-optimal treatment and the possibility of active neurotropic and neuroinflammatory HIV disease [8]. Significant and subtle neurocognitive deficits have been observed in PHIV children affecting their school achievement, relationships and autonomy [911]. HIV may affect subcortical white 1 Mellins CA and Malee KM. Journal of the International AIDS Society 2013, 16:18593 http://www.jiasociety.org/index.php/jias/article/view/18593 | http://dx.doi.org/10.7448/IAS.16.1.18593 matter and frontostriatal systems involved in the regulation of emotion and behaviour [12,13], further placing youth at risk for mental health problems during adolescence [7]. For youth exposed to early severe HIV disease, psychosocial ramifications of hospitalizations, potential mortality, missed school and social opportunities, and delayed puberty, are significant. With age, the impact of these experiences and residual deficits, even in the presence of reconstituted immune systems, may mildly or profoundly limit PHIV youth’s ability to successfully complete high school, find employment, have relationships and function independently, all of which may have a reciprocal influence on mental health [14]. Multiple family and contextual factors may influence mental health in PHIV youth. In many parts of the world, the majority of PHIV youth are from ethnic-minority families, living in impoverished, limited-resource communities affected by violence, substance abuse and neighbourhood disintegration [1,2,1517]. These circumstances present challenges for any youth population, but particularly those growing up with a stigmatized health condition [14]. Confronting HIV stigma and managing disclosure of HIV status to others may significantly impact mental health function [18,19]. Furthermore, many PHIV youth live with single parents and/or have experienced multiple caretaking transitions due to parental illness or death [20,21]. Loss of a parent is one of the most significant stressors linked to poor mental health outcomes [22,23]. Parental psychiatric and substance abuse disorders are additional risk factors for mental health problems in many PHIV youth [2426]. The potential heritability of these disorders, possible intrauterine exposure to illicit drugs and alcohol, and the stressful family and social environments associated with these disorders can contribute to poor child outcomes [27]. The erosion of parenting capacities that often accompanies illness such as HIV, mental illness, or substance use can be devastating to youth mental health [28]. In summary, there are multiple risk factors for mental health problems in PHIV youth. In other populations, mental health functioning is among the most significant predictors of health and behavioural outcomes, with increasing evidence of the economic and social costs of mental health problems to society [29]. In countries with limited financial resources, meeting basic living and health needs of youth are likely the highest priority, yet ignoring youth mental health may preclude youth achievement of health, social and economic stability [16,30,31]. This article reviews the literature on the mental health functioning of adolescents who were born with HIV, the corresponding risk and protective factors associated with mental health, mental health treatment modalities and critical needs for future interventions and research. Mental health problems are defined broadly to include psychiatric disorders and indicators of more general psychological distress and emotional and behavioural problems. For context, an understanding of adolescence as a developmental stage is important. Adolescence is marked by the onset of physical and emotional maturation, accompanied by the challenges of adapting to social, emotional and cognitive changes. Adolescence covers a large age range, beginning as young as nine or 10 and lasting up until 18 or older [32,33]. Brain development continues through the early 20s and includes neural myelination and synaptic pruning responsible for efficient information processing and executive function [34]. Atypical or compromised brain development may increase adolescent risk for poor impulse control, inhibition, and decision-making and associated problems, including violence, aggression, substance abuse, accidents and risky sexual behaviours [35]. Psychosocial issues are prominent as youth progress through adolescence towards adulthood, attempting to develop a sense of self while striving for autonomy. As relationships with parents and peers change, youth may experience stressful challenges, with immature coping skills and/or inadequate resources. Youth who enter adolescence under adverse circumstances may be ill-prepared to effectively cope with normative changes, making this period particularly challenging [32]. For PHIV youth, adolescent developmental tasks are accompanied by the challenges of coping with HIV as a stigmatizing, sexually transmittable chronic illness, the management of medical treatment, and adjustment to family loss. Given the significant association of mental health problems with substance use, sexual risk and poor healthcare behaviours in other populations [29,36], there is a critical need to understand mental health functioning in PHIV youth, identify risk and protective factors associated with mental health outcomes, develop treatment models and inform prevention programmes. Although the paediatric HIV epidemic in the United States and other high-resource countries is near eradication, staggering numbers of children in LMIC have been or will be infected with HIV [2]. With increasing access to ART, they will reach adolescence and young adulthood, requiring proven mental health treatment and prevention programmes. Methods Search strategy We conducted an extensive review of online databases including MEDLINE, Psychinfo, PubMed, JSTOR and Google Scholar. Key terminology entered into these databases included: mental health, psychiatric/psychological, emotional and behavioural problems, perinatal HIV infection, paediatric HIV and adolescence. Titles, abstracts and methodology of identified articles were reviewed. In addition to the online databases, reference lists of articles included in the search were examined for additional key studies. Inclusion criteria Articles included in this review reported data on: (1) PHIV youth; (2) youth who were 10 years of age and older (younger youth could be in total sample but sample had to include youth who were adolescents); (3) mental health outcomes; and (4) mental health treatment, including psychopharmacology, mental health services or evidence-based interventions. Only English language articles were included, with no exclusion based on country of origin. 2 Mellins CA and Malee KM. Journal of the International AIDS Society 2013, 16:18593 http://www.jiasociety.org/index.php/jias/article/view/18593 | http://dx.doi.org/10.7448/IAS.16.1.18593 Exclusion criteria Articles were excluded if: (1) no participants were PHIV ; (2) the majority of the study population was less than 10 years; and (3) original research was not reported. Publication year was not a reason for exclusion but given the focus on adolescence, most articles were published within the past decade. A number of papers identified clinical issues for PHIV adolescents, primarily as part of larger reviews on the impact of HIV on children and adolescents, including uninfected youth from HIV-affected families (HIV-A), behaviourally-infected youth, and uninfected, un-affected youth (HIV) at risk for HIV [7,37,38] or as part of opinion papers on the full range of psychosocial needs of PHIV youth [16,31,39]. These clinical reports and review articles are not included, but referenced for the purpose of understanding the data. Several studies described psychiatric functioning of HIV adolescents and young adults who were primarily behaviourally-infected [40,41] and these were also excluded. We are unaware of review articles that have focused only on PHIV adolescents and mental health as broadly defined here. Two research assistants and at least one author read all articles for inclusion and exclusion decisions. A total of 93 articles were reviewed, 55 were excluded and 38 were included (see Table 1). Results Rates of DSM-defined psychiatric disorders (see Tables 1 and 2) Relatively few studies focused on rates of psychiatric disorders in PHIV adolescents. Sharko reviewed eight studies of Diagnostic and Statistical Manual of Mental Disorders (DSM)-defined psychiatric disorders among HIV youth aged 420 [42], many, but not all [40,41], of whom were PHIV [4346]. The average prevalence across studies revealed high rates of attention deficit hyperactivity disorders (ADHD; 29%), anxiety disorders (24%) and depression (25%). However, conclusions relevant to the role of perinatal HIV were difficult to determine, given the large age range (421 years), frequent failure to distinguish mode of transmission and limited use of comparison groups. More recent studies have focused on the prevalence of psychiatric disorders among PHIV youth who are close to or within the adolescent age range, using well-validated psychiatric assessments based on DSM-IV diagnoses or medical chart reviews. In the Child and Adolescent SelfAwareness and Health (CASAH) study, a large longitudinal cohort study of PHIV youth recruited at age 916 from four New York City (NYC) hospitals, a high prevalence of any non-substance use psychiatric disorders (61%) was identified using the Diagnostic Interview Schedule for Children (DISC-IV) [47,48]. Rates exceeded those of a comparison group of 134 perinatally HIV-exposed but uninfected (PHEU) youth. The most prevalent disorders were anxiety (46%) and behavioural (25%) disorders; mood disorders (e.g., depression, mania, cyclothymia) were less prevalent (7%). The rates of most individual disorders were similar in both groups, although ADHD was more prevalent among PHIV (18%) than PHEU (8%) youth. By the 18-month follow-up, rates of any disorder in PHIV youth decreased substantively to 44%, while rates among PHEU remained constant [49]. Rates of disorder over time were high, with 69% of youth in both groups meeting criteria for a disorder at either baseline or follow-up; onethird of youth reported comorbid disorders. Similar results were observed in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) 1055 study [50,51] using the Child and Adolescent Symptom Inventory-4R (CASI-4R) [52]. PHIV youth and a comparison group of PHEU youth or HIV youth with an HIV family member (HIV-A), aged 617, were recruited from 29 US sites. Psychiatric disorders were identified among 60% of PHIV and 62% of PHEU/HIV-A youth at baseline, and 39% and 43%, respectively, at follow-up. Baseline disorders among PHIV youth included ADHD (25%), anxiety (24%), disruptive behaviours (22%) and depression (21%). Among those who did not meet diagnostic criteria at entry, comparable numbers of PHIV (36%) and PHEU/HIV-A youth (42%) met criteria during follow-up. Similar to CASAH, 69% of PHIV and 70% of PHEU/HIV-A youth met criteria for any psychiatric disorder during at least one time point, often resulting in problems with social and academic functioning or use of psychotropic medications (PHIV 43%; PHEU/HIV-A 37%) [53]. Several studies examined psychiatric disorders through medical chart review with similar findings [54,55]. For example, in the 22 US-site Longitudinal Epidemiologic Study to Gain Insight into HIV/AIDS Children and Youth (LEGACY) study, 55% of 197 PHIV youth (1324 years) had a documented mental health diagnosis, including mood disorders (25%), disruptive behaviour disorders (28%) and ADHD (17%). However, comparison groups were not included in these studies and it is unclear how documented diagnoses were derived. Thus, the few cohort studies which examined DSM-IVdefined psychiatric disorders, using different measures, revealed similarly high rates that were considerably higher than comparable studies of youth in the general population [5658]. However, the studies were all US-based and the specific role of PHIV could not be established given inconsistent associations of HIV with mental health [4851,53] or the lack of comparison groups [54,55]. Symptoms of psychological distress or emotional and behavioural problems Many more studies of PHIV youth mental health utilized symptoms checklists of youth- or parent-reported emotional and behavioural problems, depression symptoms, or overall psychological distress (see Tables 1 and 2). Methodology, measures and cohorts varied, as did results across studies. For example, three of the largest cohort studies in the United States, Pediatric AIDS Clinical Trials Group (PACTG) 219C, Pediatric HIV/AIDS Cohort Study (PHACS) and CASAH used well-validated but different instruments to describe mental health symptoms, including the Conners’ Parent Rating Scale (CPRS-48) [59], the Behavior Assessment System for Children, 2nd edition (BASC-2) [60] and the Child Behavior Checklist (CBCL) [61]. PHIV children and adolescents, aged 317, enrolled in PACTG 219C, an observational late outcome study, had 3 Mental health studies of PHIV youth 1st Author Ref. Bacha (1999) [100] Population Description N 5 PHIV youth Age range: 912 yrs 3 females, 2 males 2 African-American, 1 Latino, Location and Study Type Florida pediatric infectious Mental Health Measures No formal assessment Mental Health Findings Caregiver (Cg) and youth reported satisfaction with the disease clinic, US group program but no mental health findings Pilot study of psychoeducational mental health group reported 2 White Battles and N 80 Cg/youth dyads at time 1 (39% PHIV, 61% transfusion); Weiner (2002) 55 dyads at time 3 [93] Mean age 12 yrs at time 1, 13 yrs at time 2, 14 yrs at time 3 Time 1: 56% male National Cancer Institute (NCI), Maryland, US Descriptive longitudinal study Youth: no mental health Youth social support significantly associated with assessment; only social better CBCL scores on withdrawal, anxiety, support and self-esteem depression, delinquent, aggression and social Cg: Child Behavior Checklist (CBCL) Medical chart data-5 yrs Time 1: 72% White, 14% African- post time 1 on psychiatric American, 7% Hispanic diagnoses/ hospitalizations, 100% disclosed suicidal ideation/ attempts problems 5 yr chart data on mental health: a) 317 yr olds: 32% anxiety, 45% depression, 13% suicidal ideation, 8% psychiatric hospitalization b) 18 yr old group: 26% anxiety, 30% depression, 15% suicidal ideation, 4% psych. hospitalization c) loss of a parent associated with depression dx Bomba (2010) [68] N 54 (27 PHIV) 27 HIV youthage/gender matched convenience sample PHIV Age range: 518 yrs PHIV: 52% female Pediatrics department University of Brescia, Italy Cross-sectional descriptive study Youth and Cg: Pediatric PHIV youth vs HIV youth had worse scores on: Quality of Life Inventory (PedsQOL) with mental health a) overall quality of life, school functioning, and psychosocial health (PedsQOL); questions b) CBCL internalizing and total problems, but not Cg: CBCL Medical chart review of HIV RNA externalizing scale; and c) withdrawal, anxiety, social, thought, attention Viral Load (VL) and delinquent behavior problem subscales of CBCL Chernoff (2009) [51] N 575 (319 PHIV) 29 US sites Comparison youth: either PHEU International Maternal Pediatric or HIV youth living with HIV Adolescent AIDS Clinical Trials person (HIV-A) Group (IMPAACT) 1055 Age range: 617 yrs PHIV50% male 54% African-American, nonHispanic, 32% Hispanic Youth: Child Inventory-4 (CI-4)/Youth Inventory4R (YI-4R) 2 yr longitudinal study Symptom Inventory-4 Baseline analysis Revised (CASI-4R); life events and treatment Youth not living with bio parent had better CBCL total competence scale 23% of PHIV and 12% of HIV youth received psychiatric medications Cg: Child and Adolescent VL associated with CBCL delinquent behavior scale PHIV youth 2 times as likely to receive stimulants and more than 4 times as likely to receive antidepressants 27% PHIV and 17% HIV youth had behavioral treatments Mellins CA and Malee KM. Journal of the International AIDS Society 2013, 16:18593 http://www.jiasociety.org/index.php/jias/article/view/18593 | http://dx.doi.org/10.7448/IAS.16.1.18593 Table 1. 4 1st Author Ref. Elkington (2011) Population Description [66] Location and Study Type Mental Health Measures 545 Cg/youth dyads (196 NYC hospitals, US. PHIV, 229 PHEU/HIV-A, 120 2 studies: Depression Inventory a) CASAH: Child and Adolescent (CDI); State Trait Anxiety HIV youth) Age range: 916 yrs 50% male 50% African-American Self-awareness and Health Study; N55 PHIV youth Multiple sites in US (2009) Age range: 817 yrs Participants from ARV treatment [64] 55% male protocols at medical research 46% African-American; 44% Caucasian facilities Cross-sectional study Elliott-DeSorbo Ellis (2006) [104] N19 PHIV youth Age range: 216 yrs, mean 11 Fielden (2006) 62% male 84% African-American Foster (2012) N32 (10 PHIV youth, 11 (MST) British Columbia, PHIV youth twice as likely to have CDI scores within clinical range than PHEU/HIV-A or HIV youth Better youth mental health associated with having an HIV caregiver (BDI) and STAI for self Youth and Cg: Behavior Assessment System for Children (BASC) Cg: Stressful Events (SLE) Medical Chart data at study visits: CD4 and VL Retrospective chart review No mental health measures Only health (VL) and adherence Data collected through 4 Canada focus groups and 7 in-depth Qualitative cross-sectional case interviews, using semi-structured study interview scripts Means on BASC depression and anxiety scales within normal limits School-related SLE were most common (44%) and predictive of youth report of depression No association of Total # SLE with BASC Disclosure to others associated with youth anxiety assessments caregivers and 11 providers) [86] Children’s Hospital of Michigan, US Pilot of Multisystemic therapy Cg: CBCL on child; Mean scores on CBCL within normal range for all groups Beck Depression Inventory Mothers Baseline data analysis Index- Child (STAI-C) b) Youth with and without HIV Youth: Children’s Mental Health Findings Mental health outcomes not examined even though MST mental health intervention Statistically significant change in VL from study referral to treatment termination Participants raised issues concerning: a) mental health, including youth’s emotions, Youth: Age range: 916 yrs Youth: 50% male Youth: 20% Caucasian, 30% of b) social stigma of HIV; and color, 50% aboriginal c) sexual health [65] N73 (38 PHIV, 11 PHEU, 22 Baylor College of Medicine, Texas Cg and youth: BASC-2 HIV non-exposed, 2 unknown Children’s Hospital and University Neurocognitive tests exposure status) of Miami Pediatric HIV Research Sleep assessments Age range: 817 yrs Clinics 50% male PHIV: 79% AfricanAmerican, 11% Latino bereavement, feeling ‘normal’, security, stability, self-esteem; No significant group differences in BASC-2 scores Pro-inflammatory intracellular cytokine factors associated with increased problems on 12 mos longitudinal study BASC-2 Sleep efficiency associated with fewer parentreported problems on BASC-2 and cognitive measures (executive function) Mellins CA and Malee KM. Journal of the International AIDS Society 2013, 16:18593 http://www.jiasociety.org/index.php/jias/article/view/18593 | http://dx.doi.org/10.7448/IAS.16.1.18593 Table 1 (Continued ) 5 1st Author Ref. Funck-Brentano Population Description Mental Health Measures Mental Health Findings French Prospective study of No mental health measures transfusion) psychodynamic oriented support Youth measures: perceived illness Age range: 1217 yrs group 37% male 60% European, 27% African (2005) [102] N 30 (25 PHIV, 5 HIV Location and Study Type and treatment experiences, self 10 participants vs 20 who refused or didn’t come esteem No mental health analyses Youth in intervention had better perceptions of illness and treatments at 2 years post baseline Medical chart review on health Percentage of participants with undetectable VL increased from 30 to 80%, vs. no change in the other groups Gadow (2010) [50] N 575 (319 PHIV), HIV youth 174 PHEU and 29 US sites IMPAACT 1055 sample 82 HIV-A Longitudinal study Age range: 617 yrs Baseline data analysis 50% male 86% African-American or Youth: YI-4R and CI-4 Cg: CASI-4R Both groups showed higher rates of psychiatric disorders than general population PHIV youth less conduct disorder and depression and more somatization disorder than PHEU/HIV-A youth PHIV youth most prevalent disorders12% ADHD and 5% Oppositional Defiant Disorder Hispanic For 73% of PHIV and 74% PHEU/HIV A youth, disorders did not currently interfere with functioning Gadow (2012) N 573 (319 PHIV, 168 29 US sites Youth: YI-4R and CI-4 PHEU-, 86 HIV-A) IMPAACT 1055 sample Cg: CASI-4R Entry age range: 617 yrs Longitudinal study 51% male (PHIV group) Longitudinal data 48% male (PHEU/HIV ) 86% African-American or [53] 69% PHIV and 70% HIV met DSM-IV criteria for at least 1 psychiatric disorder at at least one time Depression more common for females and youth whose Cg had at least 1 psychiatric disorder analysis Emerging anxiety ]for females and younger youth Hispanic Gaughan (2004) [96] N 1808 PHIV and 1021 PHEU Multiple sites in US PHIV median age10 yrs Pediatric AIDS Clinical Trials Group psychiatric hospitalizations PHEU median age 1 yrs 219C (PACTG219C) between 20002002 51% female Data from PACTG219C database on All children with psychiatric hospitalization were PHIV (n 32); median age at hospitalization 11 yrs Primary reasons: depression (n 16), behavioral disorders (n 8), and suicidal ideation/attempt (n 6) Prospective cohort study PHIV: 57% Black, non-Hispanic, 27% Hispanic, 14% White Knowledge of HIV status and experiences of significant life event associated with increased risk of psychiatric hospitalization Kang (2011) [85] N 325 (196 PHIV; 129 PHEU) 4 NYC hospitals, US Youth: CDI; STAI-C Age range: 916 yrs CASAH Youth also completed measures on 50% male Longitudinal study neighborhood disorder, stressful life events (SLE), problem solving, religiosity More neighborhood stress associated with more depression and anxiety for both groups SLE mediated relationship between exposure to neighborhood disorder and mental health Mellins CA and Malee KM. Journal of the International AIDS Society 2013, 16:18593 http://www.jiasociety.org/index.php/jias/article/view/18593 | http://dx.doi.org/10.7448/IAS.16.1.18593 Table 1 (Continued ) 6 1st Author Ref. Population Description 46% African-American, 39% Location and Study Type Latino Mental Health Measures Mental Health Findings Cross-sectional data analysis (baseline) No significant differences by HIV status No significant interaction effect between religiosity or problem solving and neighborhood stress on either anxiety/depression Kapetanovic N 236 PHIV in short-term 80 US sites and 198 in long-term analyses PACTG219C Entry age range: 318 yrs Longitudinal study of participants 71% male prescribed second generation 11% White, 58% African- anti-psychotics (SGA) vs. matched American, 29% Hispanic controls (2009) [99] No mental health measures described Cg report and medical review of psychiatric diagnosis Clinical exam of youth: Body Mass Index (BMI) N 197 PHIV youth 22 US sites Entry age range: 1324 years Longitudinal [54] 56% female Epidemiologic Study to Gain Insight Medical chart data on medication 51% Black non-Hispanic, 44% into HIV/AIDS Children and Youth adherence and substance abuse Hispanic (LEGACY) (20012006) Kmita (2002) [101] Medical charts for mental N 30 (17 PHIV and 12 HIV-A Warsaw, Poland youth, 1 HIV youth infected Two settings: through transfusion) 1) an outpatient clinic Age range: 215 years 2) a therapeutic camp for families Parents of 80% of youth were Qualitative analysis of audiotapes Lowenthal (2012) [118] N 219 (54 PHIV; 165 HIV) Age ]13 years 47% male 100% PHIV disclosed N 692 HIV (90% PHIV) Odds of having at least 1 of 3 risky behaviors (ART Themes raised: disclosure, stigma in schools, death of parent, multiple losses, child development, and ART problems Psychosocial strategies Therapeutic interventions focused on negative emotions and positive coping (individual, family, group) described None of the children had been 9% substance abuse disorder non-adherence, substance use, sex) were greater of sessions Interventions involving both cgs and youth in collaboration with providers were most effective told diagnosis by family [72] 55% PHIV had at least 1 psychiatric diagnosis, primarily mood (25%) and disruptive (15%) disorders among youth with a psychiatric diagnosis former drug users Lee (2011) health diagnoses (ICD-9) 100% disclosed Participants receiving both protease inhibitors (PIs) and SGAs showed especially large BMI increases Association of SGAs (particularly Risperidone) with both short- and long-term changes in BMI (2011) Kapetanovic No mental health findings reported Thailand hospital and public schools 1:3 Case vs. control, cross-sectional Botswana, South Africa clinics in two cities Youth reported on use of substances and sex behavior Cg. Report: Pediatric Symptoms Checklist (PSC)- screening for PHIV youth had lower mean CDI scores and less clinical depression compared to HIV youth Inventory (CDI) data analysis Youth: Thai Children’s Depression Interventions at clinic and therapeutic camp were considered effective Youth who screened positive for depression were more likely to report sexual intercourse 17.3% met symptom cutoff score Virologic failure more common among those with more Ages 8 517 emotional/ symptoms of attention/executive dysfunction and 50.3% female behavior problems depression Mellins CA and Malee KM. Journal of the International AIDS Society 2013, 16:18593 http://www.jiasociety.org/index.php/jias/article/view/18593 | http://dx.doi.org/10.7448/IAS.16.1.18593 Table 1 (Continued ) 7 1st Author Ref. Malee (2011) [62] Population Description Location and Study Type N 1134 PHIV youth Over 80 US sites (PACTG 219C) Age range: 317 yrs Prospective cohort study 52% female Cross-sectional data analysis Mental Health Measures Conners’ Parent Rating Mental Health Findings Scale (CPRS-48) 61% African-American, 24% Hispanic Measures of adherence also included Youth impairment in CPRS in conduct (14%), learning (22%), somatic (22%), impulsivity-hyperactivity (20%), and hyperactivity (19%) problems Youth with impairment in one or more areas had increased odds of non-adherence In adjusted analysis, odds of non-adherence higher for those with conduct problems or hyperactivity Malee (2011) N 416 Cg/youth dyads (295 15 US sites Youth and Cg: BASC-2 PHIV; 121 PHEU) AMP protocol of Pediatric HIV/AIDS Cg: The Parent-Child Relationship Age range: 716 yrs 52% female Cohort Study (PHACS) Longitudinal study 81% African-American [63] Inventory (PCRI) and Cg. psychiatric disorder (CDQ) Overall mental health problems more likely for PHEU (38%) vs. PHIV (25%) youth Cross-sectional data Both groups: elevated caregiver reported behavior problems, but not youth reported emotional problems analysis (baseline) Odds of problems associated with: Cg psychiatric disorder, limit-setting problems, and health-related functional limits and youth younger age and lower cognition Marhefka (2009) [97] Mellins (2006) [76] 5 clinics in NY, Baltimore, and Washington DC youth) Adolescent Impact study Age range: 1321 yrs Cross-sectional baseline data 52% female 81% Black 62% Heterosexual N 47 PHIV youth and Cg dyads Age range: 916 yrs 53% male Mellins (2009) [91] N 164 (60% PHIV, 40 HIV behaviorally-infected Youth report: Achenbach system of empirically based assessment (ASEBA) analysis from intervention trial Medical record review for had not received psychiatric care Psychiatric diagnoses/treatment Questioning one’s sexual identity associated with more internalizing problems; bisexual identity associated with more externalizing problems Pediatric HIV program in NYC, US Youth: Diagnostic Interview Schedule for Children Version IV (DISC-IV); CDI Cg: DISC-IV, CBCL Cg mental health: BDI, STAI, and CDQ 83% African-American, 15% (substance use disorder and PTSD Hispanic only) Cross-sectional study No differences by HIV transmission group 55% of PHIV youth met criteria for psychiatric disorder on DISC-IV: 40% anxiety, 23% behavioral (21% ADHD), 13% conduct, and 11% ODD CBCL and CDI scores in normative range Cg depression and anxiety associated with worse youth behavioral functioning on CBCL 77% Disclosed N 320 Cg/youth dyads (193PHIV and 127 PHEU) 31% reported clinically significant levels of internalizing, externalizing and total problem scores, 27% of whom 56% youth had ever been to a therapist 4 NYC hospitals, US CASAH Youth: CDI; STAI Youth reports on sexual risk and substance use No HIV group differences in youth mental health Cg mental health predicted youth mental health Mellins CA and Malee KM. Journal of the International AIDS Society 2013, 16:18593 http://www.jiasociety.org/index.php/jias/article/view/18593 | http://dx.doi.org/10.7448/IAS.16.1.18593 Table 1 (Continued ) 8 1st Author Ref. Population Description Location and Study Type Age range 916 yrs; Longitudinal study 50% male Cross-sectional data 55% African-American, 31% Mental Health Measures Cg: BDI, STAI, and parent- child Mental Health Findings relationship measure Youth mental health associated with substance use and sexual risk behavior analysis (baseline) Latino Mellins (2009) N 340 Cg/youth dyads 4 NYC hospitals, US (206 PHIV, 134 PHEU youth) CASAH Age range: 916 yrs Longitudinal study 51% female Cross-sectional data [48] 54% African-American, 31% Caregiver and Youth Versions of the DISC-IV Medical charts for PHIV youth (CD4 and VL) analysis (baseline) Mellins (2011) [77] N 349 Cg/youth dyads (238 PHIV; 111 PHEU youth) 15 sites in US and Puerto Youth and Cg reports on BASC-2 Rico Youth reports on sexual Age range: 1016 yrs PHACS risk behavior and substance 50% male Longitudinal study use assessments Cross-sectional data analysis Youth and Cg reports on adherence to ART Medical charts on VL PHIV youths had higher rates of ADHD and greater use of mental health services than PHEU Latino 61% of PHIV vs. 49% of PHEU met criteria for psychiatric disorder; 33% for multiple disorders Older age associated with behavioral disorder ADHD less likely if youth living with bio parent, HIV Cg, or Cg with less education HIV health variables and mental health not associated 43% PHIV and 50% of PHEU youth report risks in at least one area (mental health, sex, substance use); 16% PHIV and 11% PHEU report 2 risks. Age, but not HIV-status associated with 2 vs 0 risks Among PHIVyouth, detectable VL and living with bio mom associated with having 2 vs 0 risks In PHIV most frequent combination of risks was mental health problems and non-adherence (23%) Mellins (2012) [49] N 280 youth/Cg dyads (166 4 NYC hospitals, US PHIV; 114 PHEU youth) CASAH baseline and at 18 month Entry age range: 916 yrs Longitudinal study follow-up (FU) on psych. disorders Longitudinal data analysis and substance use disorders (SUD) Medical record review for 49% male 48% African-American 70% disclosed at baseline, 81% Youth and Cg: DISC-IV at [70] N 127 (123 PHIV) Age range: 1115 yrs 55% male Lusaka, Zambia Zambian sample compared to British community sample Youth and Cg: Strengths and Difficulties Questionnaire (SDQ-Y and SDQ-P) 69% of PHIV and PHEU met criteria for a psychiatric disorder at baseline or FU Among PHIV youth, significant decrease in prevalence of any psychiatric disorder (6044%) Among PHEU, no significant change (5753%), with PHIV: CD4 count, VL disclosed at follow-up Menon (2007) significant increase in mood disorders SUD low in both groups, increasing slightly at FU Gender and age differences at baseline, not FU PHIV youth had more mental health services at FU Zambian PHIV youth had greater risk of mental health problems than HIV British youth Those who reported health problems had higher SDQ-Y scores Mellins CA and Malee KM. Journal of the International AIDS Society 2013, 16:18593 http://www.jiasociety.org/index.php/jias/article/view/18593 | http://dx.doi.org/10.7448/IAS.16.1.18593 Table 1 (Continued ) 9 1st Author Ref. Population Description HIV (age and gender matched Location and Study Type peers from British community sample) Nachman (2012) [75] Cross-sectional Mental Health Measures descriptive survey Youth also reported on feelings N 319 PHIV 29 US sites Youth: YI-4R and CI-4 Age range: 617 yrs IMPAACT 1055 Cg: CASI-4R 51% male Longitudinal study Cross-sectional data analysis 54% African-American, 32% Hispanic about health and peer support group (only the latter was analyzed) Mental Health Findings Disclosed PHIV youth 2.5 times less likely to score in abnormal range for emotional difficulties, after controlling for age, gender, and ARV treatment 33% any disorder, 18% ADHD, 14% depression, 10% anxiety, 14% disruptive behaviors Little evidence of a relationship between specific ART regimens and severity of psychiatric disorders Inconsistent associations of HIV disease markers and psychiatric symptom severity (e.g. CDC Class C associated with less severe ADHD inattention; higher VL and higher CD4% at baseline associated with depression) Nichols (2012) [90] N 151 PHIV 38 US sites Age range: 8 to 18 yrs Data from PACTG P1042s 54% male Longitudinal study Cross-sectional data analysis 17% white, 54% AfricanAmerican, 29% Hispanic Youth and Cg report on Non-adherence to ART associated with impairment on BASC-2 (SRP and PRS the BASC-2 SRP: respectively) a) Locus of Control scale (youth perceived lack of Adherence data collected control over life events or low self-efficacy) and b) Relation to Parents scale (youth reported poor relationships with parents) Nozyce (2006) [73] N 274 HIV youth 48 US clinical sites (PACTG) Age range: 24 months-17 yrs Longitudinal study (median 7.2 yrs) Baseline data analysis Cg: Conners’ Parent Rating Scale (CPRS) Youth neuropsych anxiety, and 20% hyperactive problems 47% male measures from medical 49% African-American, 34% charts (WISC III for older Hispanic youth) [87] N 25 HIV youth and 15 Cg Age range: 1416 yrs 52% male 100% South African Durban, South Africa Large HIV clinic Qualitative cross-sectional individual interviews Qualitative analysis of transcripts of 52% at least 1 behavioral problem Children 9 years old were more likely to have anxiety problems Petersen (2010) On CPRS: 16% conduct, 25% learning, 28% psychosomatic, 19% impulsive-hyperactive, 8% in-depth, individual interviews Lower WISC-III score associated with hyperactivity and behaviors associated with ADHD Youth-reported psychosocial challenges: loss of biological parents, coping with their HIV status, external stigma and discrimination, and disclosure difficulties Cg-reported challenges: disclosure and lack of financial, family and social support Medication, HIV information, a future orientation, and social support identified as important for coping and general well-being of adolescents Mellins CA and Malee KM. Journal of the International AIDS Society 2013, 16:18593 http://www.jiasociety.org/index.php/jias/article/view/18593 | http://dx.doi.org/10.7448/IAS.16.1.18593 Table 1 (Continued ) 10 1st Author Ref. Puthanakit Population Description and 164 HIV ) (2012) [71] N 603 (284 PHIV, 155 PHEU, Location and Study Type Age: 112 years Mental Health Measures 9 sites in Thailand and sites in Cg report: CBCL Cambodia Medical chart data on CD4 Children with HIV Early Antiretroviral and whether youth in early Therapy (CHER) study or deferred ART treatment arm 58% female 60% Thai Santamaria N 196 PHIV Cg/youth dyads 4 NYC Hospitals, US Youth: CDI, STAI-C (2011) Age range: 916 years CASAH Cg: CBCL-P [18] 50% male Longitudinal study 58% African-American, 42% Baseline data analysis Hispanic 70% Disclosed N 576 (320 PHIV, 256 HIV ) 29 US sites Youth and Cg:SI-4 Age range: 617 yrs IMPAACT 1055 Youth and Cg Reports of pain 49% male Cross-sectional study 49% Black, 36% Hispanic Serchuck (2010) [74] Sirois (2009) [98] N 2251 PHIV youth 215 have prescriptions for ADHD medications, 2036 without Entry age range: 319 yrs 53% female 80 US sites PACTG, P219C PHIV youth more likely to meet borderline-clinical cutoff on CBCL compared to control groups Disclosed youth significantly less anxious than nondisclosed youth stigma and disclosure Disclosure not related to any other mental health outcomes (CDI or CBCL) For PHIV only: youth- reported pain associated with higher severity of generalized anxiety, major depression, and dysthymia Longitudinal observational study Compared to the HIV controls, PHIV youth had higher total and externalizing problem scores prescriptions Youth reports on HIV Mental Health Findings Only examined use of commonly prescribed ADHD medications PHIV had more reports of pain than HIV youth Youth who were prescribed stimulant medications were similar in height and weight growth velocities to general population and to those without stimulant Height and weight measurements medications Youth who were prescribed non-stimulant medications had height and weight growth similar to general 59% African-American, 26% population but slower than HIV youth without Hispanic prescriptions for ADHD; also had diverse neurological and psychiatric diagnoses that could impact growth Williams (2010) N 299 (196 PHIV, 103 PHEU/ 29 US sites HIV-A) IMPAACT 1055 Entry age range: 617 yrs Longitudinal study Age range for paper: 1218 yrs Cross sectional data 50% female [89] Race: 46% Black, non-Hispanic 38% Hispanic analysis (baseline) Youth and Cg Symptom Inventory instruments (YI-4 and CASI-4R) Substance use self-reports 20% met criteria for ADHD, 12% conduct disorder (CD), 15% ODD, and 11% either major depression or dysthymia At entry, 14% reported substance use ADHD, major depression/dysthymia, ODD, and CD diagnosis each associated with greater substance use Link between psychiatric symptoms and substance use did not differ by HIV status Mellins CA and Malee KM. Journal of the International AIDS Society 2013, 16:18593 http://www.jiasociety.org/index.php/jias/article/view/18593 | http://dx.doi.org/10.7448/IAS.16.1.18593 Table 1 (Continued ) 11 48% with psychiatric illness; 19% with multiple psychiatric comorbidities Lifetime prevalence of disorders: 31% mood disorder, 9% psychotic disorder, 18% ADHD, 14% other behavioral disorders 32% ever received psychotropic medications 16% lifetime history of psychiatric hospitalization Significant association between class C diagnosis and: a) history of psychiatric illness; b) multiple diagnoses; c) mood disorder; d) psychotic disorder; e) psychotropic medication use; and f) psychiatric hospitalization No association between class C status and diagnosis with ADHD or behavioral disorder Cg: CPRS Psychiatric diagnosis via medical record review Children’s Hospital of Philadelphia, PA, US Retrospective cohort study of youth with chart data N 81 PHIV Age range: 1317 yrs 47% female 72% African-American [55] Wood (2009) 1st Author Ref. Table 1 (Continued ) Population Description Location and Study Type Mental Health Measures Mental Health Findings Mellins CA and Malee KM. Journal of the International AIDS Society 2013, 16:18593 http://www.jiasociety.org/index.php/jias/article/view/18593 | http://dx.doi.org/10.7448/IAS.16.1.18593 higher rates of behavioural impairment on most scales of the CPRS-48, including conduct, learning and psychosomatic problems, impulsivityhyperactivity and hyperactivity. Behavioural impairment increased with age for impulsive hyperactive behaviours and learning problems [62]. Among PHIV and PHEU youth, aged 716, enrolled in PHACS, a US longitudinal study, mental health problems as assessed on the BASC-2 were more prevalent than in the general population, but were more likely among PHEU than PHIV youth. Parent-reported behavioural symptoms were elevated for both groups whereas youth-reported emotional symptoms were not [63]. In contrast, several smaller US cross-sectional studies of PHIV youth, aged 817, reported BASC depression and anxiety scores within the normative range [64,65]. Analysis of combined data from CASAH (PHIV and PHEU youth, aged 916) and a NYC cohort study of uninfected youth (aged 1014), with and without HIV mothers, revealed internalizing and externalizing behavioural problems within the normal range on the CBCL, although uninfected youth with uninfected caregivers had higher rates of problems than other groups [66]. However, on a measure of depression (Child Depression Inventory; CDI) [67], scores were more likely to be in the clinical range among PHIV youth than among other groups [66]. Other investigations examined emotional and behavioural problems among PHIV youth in other countries, including LMIC. In an Italian study comparing 27 PHIV youth, aged 518, to a group of healthy age- and gender-matched peers (presumably HIV ), PHIV youth had significantly higher CBCL total problem and internalizing problem scores [68]. Similarly, 127 PHIV youth in Zambia, aged 1115, had higher rates of total difficulties, emotional symptoms and peer problems on the Strengths and Difficulties Questionnaire (SDQ) [69] compared to a British sample of age- and gender-matched presumably HIV youth [70]. Among a Thai and Cambodian sample, PHIV youth also demonstrated more problems in the clinical range of the externalizing scale of the CBCL than a comparison group of HIV youth [71]. In contrast, less depression on the CDI was observed among Thai PHIV youth than among age- and gender-matched HIV-peers [72]. To summarize, studies that measured mental health symptoms using different checklists across different countries and regions, at different ages, revealed mixed results. Some suggest that PHIV youth have higher prevalence rates than normative data or comparison groups, and others indicate normal functioning, lack of differences with comparison groups, or higher rates of emotional and behavioural problems in PHEU or HIV-A or HIV youth than PHIV youth from similar communities. Differences observed across studies may reflect cohort or cross-cultural differences, including variability in timing of HIV diagnosis and variability in access to and duration of ART or mental health services. Differences are also likely related to methodological variations, including different measures with different cut-offs or severity scores, varying sample sizes and age ranges, and different comparison groups and/or insufficient examination of factors that differentiate groups across investigations. 12 Mellins CA and Malee KM. Journal of the International AIDS Society 2013, 16:18593 http://www.jiasociety.org/index.php/jias/article/view/18593 | http://dx.doi.org/10.7448/IAS.16.1.18593 Table 2. Publications from the major US cohort studies of PHIV youth Population Measures Disorder Prevalence PACTG Nozyce, 2006 [73] Malee, 2011 [62] 274 PHIV CPRS Parent 217 years (yrs) Report 1134 PHIV CPRS Parent Report 317 yrs Behavioral Problems 52% with one or more; 16% Conduct Prob., 25% Learning Prob., 19% Impulsiv-Hyper., 8% Anxiety; 20% Hyperactivity Behavioral 14% Conduct Prob., 22% Learning Prob., 20% Problems Impulsive-Hyper; 19% Hyperactivity CASAH DISC-IV-youth and caregiver Psychiatric Disorders PHIV61%; PHEU 49% with at least one (DSM-IV) disorder 166 PHIV, 114 DISC-IV at entry and 18 Psychiatric Disorders PHIV60% at entry; 44% at FU PHEU mos. follow-up youth (DSM-IV) Mellins, 2009 [48] 206 PHIV, 134 PHEU Mellins, 2012 916 yrs [49] and caregiver PHEU 57% at entry; 53% at FU Anxiety disorders were most prevalent at both time points CASAH Risk and Resilience (study of uninfected youth) Elkington, 2011 [66] 196 PHIV, 129 CDI, STAI-C -youth Depression, Anxiety; PHIVhigher PHEU, 220 HIV CBCL-caregiver Behavioral Problems likelihood of depression Diagnostic Interview Mental Health Diagnoses 55% with at least one psychiatric diagnosis; 25% mood disorder, 17% ADHD, 15% disruptive disorder, (ICD-9) 9% substance abuse disorder Psychiatric Disorder 61% PHIV and 62% PHEU/HIV-A with at least one 916 yrs LEGACY Kapetanovic, 2011 197 PHIV [54] 1324 yrs IMPAACT Gadow, 2010 [50] 319 PHIV, YI-4R and CI-4- Youth; 174 PHEU, CASI-4R- Caregiver disorder 82 HIV-A 617 yrs Williams, 2010 [89] 196 PHIV, YI-R-Youth; Psychiatric Disorder; ADHD 20%; CD12%, ODD 15%; Depression/ 103 HIV CASI-4R-Caregiver Substance Use Dysthymia11% 319PHIV, YI-4R and CI-4- Youth; Psychiatric Disorder PHIV69%; HIV 70% with at least one 168 PHEU, CASI-4R- Caregiver 1218 yrs Gadow, 2012 [53] Substance use14% disorder at entry or FU 86 HIV Nachman, 2012 617 yrs 319 PHIV [75] YI-4R and CI-4- Youth; Psychiatric Disorder PHIV33% with at least one disorder PHIV25%; PHEU 38% CASI-4R- Caregiver PHACS Malee, 2011 [63] Mellins, 2011 [77] 295 PHIV, BASC-2-Parent and Youth Emotional/ 121 PHEU Report Behavioral Problems at risk or impaired in emotional or behavioral 716 yrs 238 PHIV, BASC-2-Parent and Youth Emotional/ 111 PHEU Report Behavioral Problems PHEU 50% with risk in mental health, sexual 1016 yrs Correlates of mental health problems A number of studies identified risk factors for mental health problems among PHIV youth. However, with the exception of basic socio-demographic factors (age, gender, maternal HIV-status, type of caregiver), few studies examined the same characteristics and there is considerable variability in find- function PHIV43% activity, OR substance use ings. In some studies, child age and gender were associated with the presence of emotional and behavioural symptoms [53,63,66,71], with increased depression and anxiety symptoms found among girls [49,53], more behavioural problems in boys [48], or more mood and behavioural problems in older youth [48,73], all consistent with studies in the general 13 Mellins CA and Malee KM. Journal of the International AIDS Society 2013, 16:18593 http://www.jiasociety.org/index.php/jias/article/view/18593 | http://dx.doi.org/10.7448/IAS.16.1.18593 population. Other studies found mixed or inconsistent gender differences among PHIV youth [63], particularly as youth age [48]. Several studies examined the association of cognitive function and HIV disease characteristics with mental health. PHIV adolescents with lower cognitive functioning scores were more likely to have mental health problems on the CBCL [71], BASC-2 [63] and CPRS [73] across countries. In addition to cognitive function, experience of pain [74] and HIV disease characteristics, including the history of AIDS defining illness [55,75], low CD4 percentage [53,75] and higher HIV RNA viral load [68,75] were associated with the presence and/or severity of specific problems, including ADHD inattention symptoms, conduct and depression. However, associations were inconsistent across studies, with some finding no mental health association with disease markers [48,66,76]. Examination of the role of maternal/caregiver health yielded mixed results. Some studies found that maternal/ caregiver HIV status was associated with better youth mental health [48,66] and others with worse youth mental health outcomes [77]. Although several studies of uninfected children of HIV mothers (HIV-A) suggest a significant impact of maternal illness and loss on children [7881], it has proven challenging to disentangle the impact of perinatal and maternal HIV infection from each other among PHIV cohorts. However, consistent with the literature on youth from other populations [82,83], parental/caregiver mental health was associated with PHIV youth mental health, particularly depression and anxiety [48,53,63,66] and illnessprovoked caregiver functional limitations increased the risk for child mental health problems [63]. Increasing evidence suggests that social and contextual influences, including exposure to poverty, stressful life events and disadvantaged neighbourhoods, are critical predictors of mental health [29,84]. However, few studies of PHIV youth examined contextual factors, although the vast majority of PHIV youth across the globe live in impoverished conditions with exposure to stressful and traumatic life events [2]. In one US-based study, exposure to neighbourhood disorder and stressful life events was associated with higher levels of depression and anxiety in PHIV and PHEU youth [85]. In another study, although no association between total stressful life events and youth depression and anxiety was found, school-related stressors were significantly associated with youth self-reported depression [64]. Two qualitative studies from Canada and South Africa utilized focus groups and individual interviews to identify psychosocial issues that could impact youth mental health. These included loss of parents and peers, problems developing a healthy sense of identity and sexuality in the context of a stigmatized and transmittable illness, need for autonomy and sense of self-competence, difficulties with peer affiliation, disclosure and social stigma [86,87]. Few studies of PHIV youth examined the association of many of these psychosocial factors with mental health function, with the exception of disclosure. Unfortunately, findings regarding the impact of disclosure are mixed in PHIV adolescent studies and often confounded with age [18]. Among youth who know their diagnosis, some studies suggest less [18] and others more [19] anxiety. Finally, several US-cohort studies revealed significant cooccurrence of mental health problems with other behavioural risks, similar to studies of adolescents in the general population [88]. Mental health problems in PHIV youth were associated with substance use [89], non-adherence [54,62,90] and sexual risk behaviour [54,91]. Importantly, few studies in this review focused on protective factors that promote mental health. Among several that examined positive assets, family process variables including stronger caregiverchild relationships and increased caregiver support [64,92], caregiver limit-setting [63], and parentchild communication and involvement [66] were associated with better mental health. Similarly, increased peer, parent or teacher social support was associated with less anxiety and depression, fewer withdrawal symptoms and fewer behavioural problems [93]. Mental health interventions for PHIV youth Services research To address the observed mental health problems, many hospitals and community-based organizations across the globe provide psychosocial services for PHIV youth. Although a number of case reports and descriptions have been published [17,94,95], few service programmes were evaluated for efficacy. Similarly, many of the large US-cohort studies documented the use of mental health treatment among PHIV youth, but few examined the impact of this treatment on mental health outcomes. Among PHIV and PHEU/ HIV-A youth in IMPAACT 1055, 18% of youth received psychotropic medications, and 22% received behavioural treatment, including individual, family and group counselling, behavioural modification, after-school tutoring and psychiatric hospitalization [51]. PHIV youth were more likely to receive such treatment, but the mental health impact was not reported. Medical chart data from PACTG 219C indicated that psychiatric hospitalization was more likely for PHIV than PHEU youth; however, a significant age confound in this study limited conclusions [96]. Finally, in another study, 27% of youth with clinically elevated behavioural problem scores had not received treatment for identified problems, despite available mental health services [97]. Psychopharmacology Psychopharmacological treatments for mental health problems have been successful with adolescents from other populations. However, few studies examined psychopharmacological approaches in PHIV youth, with the exception of PACTG 219C. An examination of stimulant and non-stimulant medication prescribed for PHIV youth found slower rates of growth in height and weight for those on non-stimulant medications [98]. In another study, prescribed secondgeneration antipsychotic (SGA) medications, in general, and risperidone, specifically, were associated with both shortand long-term changes in body mass index (BMI) Z-scores [99]. Neither of these reports evaluated adherence to the prescribed medications or treatment effects on mental health, yet both point to the need for caution and continued pharmacological studies including assessment of impact. 14 Mellins CA and Malee KM. Journal of the International AIDS Society 2013, 16:18593 http://www.jiasociety.org/index.php/jias/article/view/18593 | http://dx.doi.org/10.7448/IAS.16.1.18593 Evidence-based interventions We found no evidence-based interventions targeting only mental health outcomes in PHIV youth, although several papers described preliminary evaluations of treatment programmes [100102] and pilot trials of interventions [103 105]. For example, Funck-Brentano and colleagues evaluated a psychodynamic group therapy programme for French PHIV adolescents, aged 1218, who met every 6 weeks for 26 months [102]. Participants acquired HIV either perinatally or through blood transfusions. Outcomes in 10 participants were compared to 10 youth who refused treatment and 10 youth who could not access the clinic. While the intervention was promising in terms of improved viral load and perceptions of health and treatment, mental health was not assessed and groups were not randomly assigned. Two other programme evaluations (Poland and United States) only described qualitative feedback of participants or providers [100,101]. Multisystemic therapy (MST) [103], originally designed for adolescents with antisocial behaviour, is an intensive family-centred community-based psychotherapy approach. Evidence-based techniques drawn from cognitive behavioural and behavioural family therapy and parent training are utilized. MST was adapted for use as an adherence intervention for non-adherent PHIV youth [104]. Psychotherapists delivered MST to 19 participants (mean age 11 years), 23 times a week for approximately 7 months. Although the results were promising in terms of improved health outcomes, the absence of mental health assessment precludes conclusions regarding mental health impact. Moreover, a larger scale randomized controlled trial (RCT) has not been done and MST remains costly and labour-intensive, which may prove prohibitive in LMIC. Finally, the Collaborative HIV/AIDS Mental Health Program (CHAMP), a family-based intervention originally developed to promote mental health and reduce sexual risk behaviour among inner-city uninfected pre- and early adolescents in the United States [105], was adapted for PHIV early adolescents (CHAMP ) [105,106]. CHAMP is a 10-session multiple family group programme administered by lay staff to address family variables (parentchild supervision, monitoring, communication, involvement and support), and youth variables (coping, self-esteem, mental health and peer negotiation skills). In multiple clinical trials, families involved in CHAMP consistently demonstrated significant improvements relative to comparison groups in family and youth variables, including mental health [107109]. CHAMP was created for PHIV youth to address the above topics, as well as ART adherence [105,106]. Preliminary evidence from three pilot trials based in the United States, South Africa and Argentina showed promise in promoting family supervision, monitoring and communication, as well as child adherence, self-esteem and mental health. A larger trial is currently being initiated in South Africa [92]. Discussion Studies to date suggest that youth born with HIV are at high risk for mental health problems, although HIV infection per se may not be the primary mechanism. There is emerging consensus that the aetiology of psychiatric disorders and other mental health problems is a diagnostic challenge and multifactorial, given the abundance of risks and potential pathways to poor mental health in this population. PHIV youth are from vulnerable backgrounds with a constellation of biomedical, genetic, familial and environmental characteristics that have been associated with mental health problems in other populations. Although studies are limited with mixed findings, this review indicates that child HIV and health status are not consistent predictors of mental health problems in the United States or LMIC. Other factors, such as age, worse cognitive function, parental health and mental health, stressful life events and neighbourhood disorder have been associated with worse mental health outcomes in multiple studies, while other factors such as parentchild involvement and communication, and peer, parent and teacher social support have been associated with better function. Unfortunately, this review highlights many gaps and limitations, precluding both firm conclusions and full understanding of aetiology. However, these limitations present opportunities for future mental health research. The vast majority of studies took place in the United States where the perinatal HIV epidemic is near eradication. There is a clear need for research with PHIV youth in subSaharan Africa and Asia, where hundreds of thousands of PHIV children will reach adolescence in upcoming years [2]. Although many studies have focused on orphans and vulnerable children affected by parental HIV/AIDS, very few studies in Sub-Saharan Africa have focused on the mental health of PHIV adolescents and we found none that examined psychiatric disorders. The lack of diagnostic instruments validated for use in this context is likely a significant limitation to extending this work to where the need is most critical. That said, only a few studies in any context examined psychiatric disorders using validated DSM-IV referenced psychiatric interviews, and several used chart reviews with limited information on the professional training of the informant, indicating a global need for studies of psychiatric functioning. Considerably more studies examined mental health symptoms. However, different checklists were used with different outcomes and scoring systems, making it difficult to compare clinical significance across studies and countries. Not all measures had validated clinical cut-offs. Some studies had relatively small cohorts with large age ranges, including older children and pre-adolescents, with limited power to examine age differences or confounding factors. There is overlap among children and adolescents enrolled in some cohort studies, with multiple papers from the same project, such that results across studies were not necessarily independent (Table 2). The use of different comparison groups (PHEU, HIV-A, HIV youth) or lack thereof was an additional noteworthy constraint. In spite of the number of studies identifying mental health problems, and a number of opinion pieces highlighting needs, we identified few evaluations of mental health services or evidence-based mental health treatment programmes targeting PHIV adolescents. The identified studies focused either on non-mental health outcomes (e.g. health outcomes or 15 Mellins CA and Malee KM. Journal of the International AIDS Society 2013, 16:18593 http://www.jiasociety.org/index.php/jias/article/view/18593 | http://dx.doi.org/10.7448/IAS.16.1.18593 adherence), or a combination of health and mental health outcomes. Further, we found no published RCTs of treatments for specific disorders among PHIV youth. Recommendations (1) It is clear that the vast majority of research on PHIV adolescents focused on risk, yet in other vulnerable populations of youth, there is increasing attention being paid to ‘‘resilience’’ or ‘‘positive youth development’’ [110112]. Resilience, typically defined as positive development despite exposure to significant adversity, and positive youth development models that focus on youth strengths regardless of adversity exposure, have been helpful in identifying youth, family and community characteristics which can be utilized in preventive interventions to promote positive psychosocial function. For example, studies in other populations suggest that key strengths amenable to interventions include: (a) at the individual level, youth social, academic and emotional competence, self-regulation, problem-solving skills and adaptive coping; (b) at the family level, parentchild relationships/involvement, family communication and support; and (c) at the contextual level, school and community support systems [110112]. Resilience models have not been widely used in research with PHIV youth [38], yet multiple studies suggest that many PHIV youth display signs of resilience despite vulnerability [49,63,66]. There is a substantive need for studies of both risk and resilience in PHIV youth at different developmental stages and in different cultures so that appropriate preventive interventions can be developed. As yet, it is unclear from the literature whether there is one typical pattern of resilience or whether population-specific risk and protective factors and/or individual level variables are important, and whether there are critical ages that are most amenable to interventions [112]. Equally important are studies grounded in theoretical models of behavioural health that could identify factors amenable to prevention for the development of evidence-based interventions. (2) Evidence-based mental health treatments for psychiatric disorders have been successful in other populations, including cognitive-behavioural therapies [113], interpersonal psychotherapy [114], dialectical behavioural therapy [115] and family systems approaches [116]. We found no studies of these interventions with PHIV adolescents. Research is needed to assess the utility of these interventions for PHIV youth, and whether modifications might be necessary to address unique issues such as HIV-related health and neurological complications, and grief-related complications due to loss. As previously demonstrated, mental health interventions are most effective when they are tailored to specific populations and cultures [112,117]. (3) Given that the majority of PHIV adolescents lives or will live in LMIC with limited resources for mental health evaluation and treatment [2], there is an urgent need for larger cohort studies in these contexts using reliable and valid assessment tools that can be used across cultures. Developing such tools should be a priority for future work. Efforts are underway, for example, to refine a mental health screening tool that could be utilized to allocate scarce psychosocial evaluation and support for those most in need [118]. (4) In addition, evidence-based mental health treatment programmes that can be used by community-based workers or lay staff are urgently needed in LMIC, where the dearth of psychiatrists, psychologists and other mental health professionals is significant. In some African countries, healthcare systems are beginning to use a task-shifting or task-sharing approach in which community-based lay counsellors under the supervision of healthcare professionals are providing an increasing number of services, including mental health treatment [119]. A critical strength of CHAMP is that it was developed with this professional shortage in mind and can be administered by lay counsellors [92,109]. (5) PHIV has been described as the prototypical bioneuropsychosocial disease, with risks from the cellular to the behavioural to the social and structural level [37,92]. As such, the scope of mental health research with PHIV youth going forward should exploit findings from behavioural and social sciences but also from genomics and neuroscience, both of which are already shifting our understanding of psychiatric illness in general [120]. New insights may improve our ability to identify early signals of mental illness and have important implications for type, timing and intensity of interventions. For example, results from research with PHIV infants and children during the earlier years of the US epidemic could be examined in concert with current investigations of these same aging youth to determine whether such signals exist in this population and to describe their trajectory. (6) There remains a substantive need for studies that examine multiple factors associated with mental health problems at different stages of childhood, adolescence and young adulthood in PHIV youth across contexts to inform preventive interventions. These multi-level investigations necessitate theoretical models and statistical approaches that examine multiple pathways of causality as well as mediating and moderating effects. Moreover, meta-analysis of results of previous and current investigations is likely a critical next step in further clarifying the nature and extent of mental health problems among PHIV youth as well. Statistically, this process would help ascertain the commonalities in various prevalence estimates and also clarify conclusions that were difficult to discern. Conclusions The results of this review suggest a high need for mental health treatment programmes for PHIV youth as well as mental health-related research, particularly in LMIC. Although research-to-date indicates that adolescence is a risky period for poor behavioural outcomes in vulnerable populations, adolescence has also been conceptualized as a strategic opportunity for healthy development, including mental health. Service and research systems with both a risk and resilience perspective may be most effective in ensuring healthy development for all youth, including those who have grown up with HIV. Authors’ affiliations 1 HIV Center for Clinical and Behavioral Studies, New York State Psychiatric Institute and Columbia University, New York, NY, USA; 2Psychiatry and 16 Mellins CA and Malee KM. Journal of the International AIDS Society 2013, 16:18593 http://www.jiasociety.org/index.php/jias/article/view/18593 | http://dx.doi.org/10.7448/IAS.16.1.18593 Behavioral Sciences, Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA Competing interests The authors have no competing interests to declare. Authors’ contributions Both CAM and KMM have made substantial contributions to the review process and analyses of studies. Both were involved in drafting and revising the article and both have given final approval to the submitted article. Acknowledgements Dr. Mellins’ effort was supported by two grants from the National Institute of Mental Health: (1) R01-MH069133 (PI: CA Mellins, PhD), (2) P30 MH43520 (Center PI: RH Remien, PhD), as well as by the Division of Gender, Sexuality and Health (Director Anke A Ehrhardt, PhD), in the Department of Psychiatry, Columbia University and the New York State Psychiatric Institute. Dr. Malee’s effort was supported by the Special Infectious Diseases section of the Division of Infectious Diseases, Ann & Robert H. Lurie Children’s Hospital of Chicago. The authors acknowledge the following people for their input and assistance in preparing this article (in alphabetical order): Jessica M Benavides, Catherine M Castillo, Katherine Elkington, PhD, Danielle Friedman Nestadt, Marie A Hayes, E Karina Santamaria, Renee Smith, PhD. References 1. Centers for Disease Control and Prevention [Internet]. HIV/AIDS surveillance report [cited 2013 Feb 11]. Available from: http://www.cdc.gov/hiv/surveillance/ resources/reports/2002report/. 2. UNAIDS, AIDS Epidemic Update December, 2012. www.UNAIDS.org. 3. Gortmaker SL, Walker DK, Weitzman M, Sobol AM. Chronic conditions, socioeconomic risks and behavioral problems in children and adolescents. Pediatrics. 1990;85(3):26776. 4. Hysing M, Elgen I, Gillberg C, Lie SA, Lundervold AJ. Chronic physical illness and mental health in children. Results from a large-scale population study. J Child Psychol Psychiatry. 2007;48(8):78592. 5. Wallander JL, Varni JW. Effects of pediatric chronic physical disorders on child and family adjustment. J Child Psychol Psychiatry. 1998;39:2946. 6. Havens JF, Mellins CA, Hunter JS. Psychiatric aspects of HIV/AIDS in childhood and adolescence. In: Rutter M, Taylor E, editors. Child and adolescent psychiatry. Oxford: Blackwell; 2008. p. 82841. 7. Donenberg GR, Pao M. Youths and HIV/AIDS: psychiatry’s role in a changing epidemic. J Am Acad Child Adolesc Psychiatry. 2005;44(8):72847. 8. Gonzalez-Scarano F, Martin-Garcia J. The neuropathogenesis of AIDS. Nat Rev Immunol. 2005;5(1):6981. 9. Smith R, Chernoff M, Williams P, Malee K, Sirois P, Kammerer B, et al. Impact of HIV severity on cognitive and adaptive functioning during childhood and adolescence. PIDJ. 2012;31(6):5928. 10. Van Rie A, Dow A. Infants, children and adolescents nervous system disease in the era of combination antiretroviral therapy. In: Gendelman HE, Everall IP, Fox HS, Grant I, Lipton S, Swindells S, editors. The neurology of AIDS. Oxford, UK: Oxford University Press; 2012. p. 92542. 11. Mintz M, Sharer L, Civitello J. Clinical and pathological features of HIV-1 encephalopathy in children and adolescents. In: Gendelman HE, Everall IP, Fox HS, Grant I, Lipton S, Swindells S, editors. The neurology of AIDS. 3rd ed. New York: Oxford University Press; 2012. p. 875906. 12. Sharer LR. Neuropathological aspects of HIV-1 infection in children. In: Gendelman HE, Grant I, Everall IP, Lipton SA, Swindells S, editors. The neurology of AIDS. Oxford: Oxford University Press; 2005. p. 875906. 13. Sowell ER, Peterson BS, Thompson PM, Welcome SE, Henkenius AL, Toga AW. Mapping cortical change across the human life span. Nat Neurosci. 2003;6(3):30915. 14. Wiener L, Mellins CA. Psychosocial aspects of neurological impairment in children with AIDS. In: Gendelman HE, Everall IP, Fox HS, Grant I, Lipton S, Swindells S, editors. The neurology of AIDS. Oxford, UK: Oxford University Press; 2012. p. 92542. 15. Boyd-Franklin N, Aleman J, del C, Jean-Gilles MM, Lewis SY. Cultural sensitivity and competence: African-American, Latino, and Haitian families with HIV/AIDS. In: Boyd-Franklin N, Steiner GL, Boland MG, editors. Children, families and HIV/AIDS: psychosocial and therapeutic issues. New York: Guilford Press; 1995. p. 5377. 16. Domek GJ. Facing adolescence and adulthood: the importance of mental health care in the global pediatric AIDS epidemic. J Dev Behav Pediatr. 2009; 30(2):14750. 17. Kang E, Mellins CA, Ng WYK, Robinson LG, Abrams EJ. Standing between two worlds in Harlem: a developmental psychopathology perspective of perinatally acquired human immunodeficiency virus and adolescence. J Appl Dev Psychol. 2008;29:22737. 18. Santamaria EK, Dolezal C, Marhefka SL, Hoffman S, Ahmed Y, Elkington K, et al. Psychosocial implications of HIV serostatus disclosure to youth with perinatally acquired HIV. AIDS Patient CareSTDs. 2011;25(4):25764. 19. Lester P, Chesney M, Cooke M, Weiss R, Whalley P, Perez B, et al. When the time comes to talk about HIV: factors associated with diagnostic disclosure and emotional distress in HIV-infected children. J AIDS. 2002;31(3):30917. 20. Rotheram-Borus M, Leonard NR, Lightfoot M, Franzke LH, Tottenham N, Lee S. Picking up the pieces: caregivers of adolescents bereaved by parental AIDS. Clin Child Psychol Psychiatry. 2002;7(1):11524. 21. Bell CC, Jenkins EJ. Community violence and children on Chicago’s southside. Psychiatry. 1993;56(1):4654. 22. Rutter M. Children of sick parents. London: Oxford University Press; 1966. 23. Kranzler EM, Shaffer D, Wasserman G, Davies M. Early childhood bereavement. J Am Acad Child Adolesc Psychiatry. 1990;29(4):51320. 24. Lipsitz JD, Williams JBW, Rabkin J, Remien RH, Bradbury M, El-Sadr W, et al. Psychopathology in male and female intravenous drug users with and without HIV infection. Am J Psychiatry. 1994;151:16628. 25. Morrison MF, Petitto JM, Ten Have T, Gettes DR, Chiappini MS, Weber AL, et al. Depressive and anxiety disorders in women with HIV infection. Am J Psychiatry. 2002;159:78996. 26. Van den Bergh B, Mulder E, Mennes M, Glover V. Antenatal maternal anxiety and stress and the neurobehavioral development of the fetus and child: links and possible mechanisms. A review. Neurosci Biobehav Rev. 2005;29:23758. 27. Kelley S. Parenting stress and child maltreatment in drug-exposed children. Child Abuse Negl. 1992;16:31228. 28. Pilowsky D, Wissow L, Hutton N. Children affected by HIV. Child Adolesc Psychiatr Clin N Am. 2000;9(2):45164. 29. Collins PY, Patel V, Joestl SS, March D, Insel TR, Daar AS, et al. Grand challenges in global mental health. Nature. 2011;475(7354):2730. 30. Williamson J. Finding a way forward: principles and strategies to reduce the impacts of AIDS on children and families. In: Levine C, Foster G, editors. The orphan generation: the global legacy of the AIDS epidemic. Cambridge, UK: Cambridge University Press; 2006. p. 25477. 31. Domek GJ. Social consequences of antiretroviral therapy: preparing for the unexpected futures of HIV-positive children. Lancet. 2006;367:13679. 32. Hamburg BA. Life skills training: preventive interventions for young adolescents. Carnegie Council on Adolescent Development: working papers. New York: Carnegie Corporation; 1990. 33. Hauser ST. Understanding resilient outcomes: adolescent lives across time and generations. J Res Adolesc. 1999;9(1):124. 34. Hunter S, Hinkle CD, Edidin JP. The neurobiology of executive functions. In: Hunter SJ, Sparrow EP, editors. Executive function and dysfunction. New York: Cambridge University Press; 2012. p. 3764. 35. Cuffe SP. Assessing adolescents. In: Dulcan MK, editor. Dulcan’s textbook of child and adolescent psychiatry. Arlington, VA: American Psychiatric Publishing; 2010. p. 4757. 36. Remien RH, Mellins CA. Long-term psychosocial challenges for people living with HIV: let’s not forget the individual in our global response to the pandemic. AIDS. 2007;21(Suppl 5):S5563. 37. Brown L, Whiteley L, Peters A. HIV and AIDS. In: Dulcan MK, editor. Dulcan’s textbook of child and adolescent psychiatry. Arlington, VA: American Psychiatric Publishing; 2010. p. 495507. 38. Betancourt TS, Meyers-Ohki SE, Charrow A, Hansen N. Research review: mental health and resilience in HIV/AIDS-affected children: a review of the literature and recommendations for future research. J Child Psychol Psychiatry. 2013;54(4):42344. 39. Palmer A. HIV-infected adolescents have multiple risk factors for mental illness. HIV Clin. 2011;23(3):14. 40. Pao M, Lyon M, D’Angelo L, Schuman W, Tipnis T, Mrazek D. Psychiatric diagnoses in adolescents seropositive for the human immunodeficiency virus. Arch Pediatr Adolesc Med. 2000;154:2404. 41. Remafedi G, Lauer T. The health and psychosocial status of HIVseropositive youth in Minnesota. J Adolesc Health. 1996;18(4):2639. 17 Mellins CA and Malee KM. Journal of the International AIDS Society 2013, 16:18593 http://www.jiasociety.org/index.php/jias/article/view/18593 | http://dx.doi.org/10.7448/IAS.16.1.18593 42. Sharko AM. DSM psychiatric disorders in the context of pediatric AIDS. AIDS Care. 2006;18(5):4415. 43. Misdrahi D, Vila G, Funck-Brentano I, Tardieu M, Blanche S, MourenSimeoni M. DSM-IV mental disorders and neurological complications in children and adolescents with human immunodeficiency virus type 1 infection. Eur Psychiatry. 2004;19(5):1824. 44. Cohen H, Papola P, Alvarez M. Neurodevelopmental abnormalities in school-age children with HIV infection. J School Health. 1994;64(1):113. 45. Havens JF, Whitaker AH, Feldman JF, Ehrhardt AA. Psychiatric morbidity in school-age children with congenital human immunodeficiency virus infection: a pilot study. J Dev Behav Pediatr. 1994;15(Suppl 3):S1825. 46. Papola P, Alvarez M, Cohen HJ. Developmental and service needs of school-age children with human immunodeficiency virus infection: a descriptive study. Pediatrics. 1994;94(6):9148. 47. Shaffer D, Fisher P, Lucas CP, Dulcan MK, Schwab-Stone ME. NIMH Diagnostic Interview Schedule for Children Version IV (NIMH DISC-IV): description, differences from previous versions, and reliability of some common diagnoses. J Am Acad Child Adolesc Psychiatry. 2000;39(1):2838. 48. Mellins CA, Brackis-Cott E, Leu C-S, Elkington KS, Dolezal C, Wiznia A, et al. Rates and types of psychiatric disorders in perinatally human immunodeficiency virus-infected youth and seroreverters. J Child Psychol Psychiatry. 2009;50(9):11318. 49. Mellins CA, Elkington KS, Leu CS, Santamaria EK, Dolezal C, Wiznia A, et al. Prevalence and change in psychiatric disorders among perinatally HIV-infected and HIV-exposed youth. AIDS Care. 2012;24(8):95362. 50. Gadow KD, Chernoff M, Williams PL, Brouwers P, Morse E, Heston J, et al. Co-occuring psychiatric symptoms in children perinatally infected with HIV and peer comparison sample. J Dev Behav Pediatr. 2010;31:11628. 51. Chernoff M, Nachman S, Williams P, Brouwers P, Heston J, Hodge J, et al. Mental health treatment patterns in perinatally HIV-infected youth and controls. Pediatrics. 2009;124(2):62736. 52. Gadow KD, Sprafkin J. Adolescent symptom inventory-4 screening and norms manual. Stony Brook, NY: Checkmate Plus; 2008. 53. Gadow KD, Angelidou K, Chernoff M, Williams PL, Heston J, Hodge J, et al. Longitudinal study of emerging mental health concerns in youth perinatally infected with HIV and peer comparisons. J Dev Behav Pediatr. 2012;33(6): 45668. 54. Kapetanovic S, Wiegand R, Dominguez K, Blumberg D, Bohannon B, Wheeling J, et al. Associations of medically documented psychiatric diagnoses and risky health behaviors in highly active antiretroviral therapy-experienced perinatally HIV-infected youth. AIDS Patient Care STDs. 2011;25(8):493501. 55. Wood SM, Shah SS, Steenhoff AP, Rutstein RM. The impact of AIDS diagnoses on long-term neurocognitive and psychiatric outcomes of surviving adolescents with perinatally acquired HIV. AIDS. 2009;23(14):185965. 56. Merikangas KR, He JP, Burstein M, Swanson SA, Avenevoli S, Cui L, et al. Lifetime prevalence of mental disorders in US adolescents: results from the national comorbidity study-adolescent supplement (NCS-A). J Am Acad Child Adolesc Psychiatry. 2010;49(10):9809. 57. Kessler RC, Avenevoli S, Costello EJ, Georgiades K, Green JG, Gruber MJ, et al. Prevalence, persistence, and sociodemographic correlates of DSM-IV disorders in the national comorbidity survey replication adolescent supplement. Arch Gen Psychiatry. 2012;69(4):37280. 58. Costello EJ. Grand challenges in child and neurodevelopmental psychiatry. Front Psychiatry. 2010;10:1. 59. Conners CK. Conners rating scales: technical manual, revised. North Tonawanda, NY: MultiHealth Systems; 1989. 60. Reynolds CR, Kamphaus RW. Behavior assessment for children, (BASC-2). Circle Pines, MN: American Guidance Service; 2004. 61. Achenbach TM. Manual for the child behavior checklist/4-18 and 1991 profile. Burlington, VT: University of Vermont, Department of Psychiatry; 1991. 62. Malee KM, Williams P, Montepiedra G, McCabe M, Nichols S, Sirois PA, et al. Medication adherence in children and adolescents with HIV infection: associations with behavioral impairment. AIDS Patient Care STDs. 2011;25(3): 191200. 63. Malee KM, Tassiopoulos K, Huo Y, Siberry G, Williams PL, Hazra R, et al. Mental health functioning among children and adolescents with perinatal HIV infection and perinatal HIV exposure. AIDS Care. 2011;23(12):153344. 64. Elliott-DeSorbo DK, Martin S, Wolters P. Stressful life events and their relationship to psychological and medical functioning in children and adolescents with HIV infection. J Acquir Immune Defic Syndr. 2009;52(3): 36470. 65. Foster SB, Lu M, Glaze DG, Reuben JM, Harris LL, Cohen EN, et al. Associations of cytokines, sleep patterns, and neurocognitive function in youth with HIV infection. Clin Immunol. 2012;144(1):1323. 66. Elkington KS, Robbins RN, Bauermeister JA, Abrams EJ, McKay M, Mellins CA. Mental health in youth infected with and affected by HIV: the role of caregiver HIV. J Pediatr Psychol. 2011;36(3):36073. 67. Kovacs M. Children’s depression inventory manual. North Tonawanda, NY: Multi-Health Systems; 1992. 68. Bomba M, Nacinovich R, Oggiano S, Cassani M, Baushi L, Bertulli C, et al. Poor health-related quality of life and abnormal psychosocial adjustment in Italian children with perinatal HIV infection receiving highly active antiretroviral treatment. AIDS Care. 2010;22(7):85865. 69. Goodman R. The strengths and difficulties questionnaire: a research note. J Child Psychol Psychiatry. 1997;38(5):5816. 70. Menon A, Glazebrook C, Campain N, Ngoma M. Mental health and disclosure of HIV status in Zambian adolescents with HIV infection. J Acquir Immune Defic Syndr. 2007;46(3):34954. 71. Puthanakit T, Ananworanich J, Vonthanak S, Kosalaraksa P, Hansudewechakul R, van der Lugt J, et al. Cognitive function and neurodevelopmental outcomes in HIV-infected children older than 1 year of age randomized to early versus deferred antiretroviral therapy: the PREDICT neurodevelopmental study. Pediatr Infect Dis J. 2013. [Epub ahead of print]. 72. Lee B, Chhabra M, Oberdorfer P. Depression among vertically HIV-infected adolescents in Northern Thailand. J Int Assoc Physicians AIDS Care (Chic). 2011;10(2):8996. 73. Nozyce M, Lee S, Wiznia A, Nachman S, Mofenson L, Smith M, et al. A behavioral and cognitive profile of clinically stable HIV infected children. Pediatrics. 2006;117(3):76370. 74. Serchuck LK, Williams PL, Nachman S, Gadow KD, Chernoff M Schwartz L for the IMPAACT 1055 Team. Prevalence of pain and association with psychiatric symptom severity in perinatally HIV-infected children as compared to controls living in HIV-affected households. AIDS Care. 2010;22(5): 6408. 75. Nachman S, Chernoff M, Williams P, Hodge J, Heston J, Gadow KD. Human immunodeficiency virus disease severity, psychiatric symptoms, and functional outcomes in perinatally infected youth. Arch Pediatr Adolesc Med. 2012; 166(6):12835. 76. Mellins CA, Brackis-Cott E, Dolezal C, Abrams EJ. Psychiatric disorders in youth with perinatally acquired human immunodeficiency virus infection. Pediatr Infect Dis J. 2006;25:4327. 77. Mellins CA, Tassiopoulos K, Malee KM, Moscicki B, Patton D, Smith R, et al. for the Pediatric HIV/AIDS Cohort Study. Behavioral health risks in perinatally HIV-exposed youth: co-occurrence of sexual and drug use behavior, mental health problems, and non-adherence to antiretroviral treatment. AIDS Patient Care STDs. 2011;25(7):41322. 78. Bauman LJ, Camacho S, Silver EJ, Hudis J, Draimin B. Behavioral problems in school-aged children of mothers with HIV/AIDS. Clin Child Psychol Psychiatry. 2002;7:3954. 79. Rotheram-Borus MJ, Lee ML, Lin Y, Franzke L, Turner E, Lightfoot M, et al. Four year behavioral outcomes of an intervention for parents living with HIV and their adolescent children. AIDS. 2003;17(8):121725. 80. Cluver L, Operario D, Gardner F. A family disease: children orphaned by AIDS and living with HIV caregivers. In: Fitzgerald HE, Puura K, Tomlinson M, Campbell P, editors. International perspectives on children and mental health. California: ABC-CLIO, LLC; 2011. p. 6588. 81. Forehand R, Jones DJ, Kotchick BA, Armistead L, Morse E, Morse PS, et al. Non-infected children of HIV-infected mothers: a four year longitudinal study of child psychosocial adjustment and parenting. Behav Ther. 2002;33:579600. 82. Billings AG, Moss RH. Children of parents with unipolar depression: a controlled 1-year follow-up. J Abnorm Child Psychol. 1985;14:14966. 83. Cummings EM, Keller PS, Davies PT. Towards a family process model of maternal and paternal depressive symptoms: exploring multiple relations with child and family functioning. J Child Psychol and Psychiatry. 2005;46:47989. 84. Costello EJ, Compton SN, Keeler G, Angold A. Relationships between poverty and psychopathology: a natural experiment. JAMA. 2003;390(15): 20239. 85. Kang E, Mellins CA, Dolezal C, Elkington KS, Abrams EJ. Disadvantaged neighborhood influences on depression and anxiety in youth with perinatally acquired human immunodeficiency virus: how life stressors matter. J Community Psychol. 2011;39:95671. 86. Fielden SJ, Sheckter L, Chapman GE, Alimenti A, Forbes JC, Sheps S, et al. Growing up: perspectives of children, families and service providers regarding 18 Mellins CA and Malee KM. Journal of the International AIDS Society 2013, 16:18593 http://www.jiasociety.org/index.php/jias/article/view/18593 | http://dx.doi.org/10.7448/IAS.16.1.18593 the needs of older children with perinatally-acquired HIV. AIDS Care. 2006; 18(8):10503. 87. Petersen I, Bhana A, Myeza N, Alicea S, John S, Holst H, et al. Psychosocial challenges and protective influences for socio-emotional coping of HIV adolescents in South Africa: a qualitative investigation. AIDS Care. 2010; 22(8):9708. 88. Jessor R, Jessor SL. Problem behavior and psychosocial development: a longitudinal study of youth. New York: Academic Press; 1977. 89. Williams P, Leister E, Chernoff M, Nachman S, Morse E, DiPoalo V, et al. Substance use and its association with psychiatric symptoms in perinatally HIVinfected and HIV-affected adolescents. AIDS Behav. 2010;14:107282. 90. Nichols SL, Montepiedra G, Farley JJ, Sirois PA, Malee K, Kammerer B, et al. Cognitive, academic, and behavioral correlates of medication adherence in children and adolescents with perinatally acquired HIV infection. J Dev Behav Pediatr. 2012;33(4):298308. 91. Mellins CA, Elkington KS, Bauermeister JA, Brackis-Cott E, Dolezal C, McKay M, et al. Sexual and drug use behavior in perinatally HIV-infected youth: mental health and family influences. J Am Acad Child Adolesc Psychiatry. 2009;48:8109. 92. Mellins CA. The VUKA family project. Invited presentation at the XVIVth International AIDS Conference. Washington, DC; 2012. 93. Battles HB, Wiener LS. From adolescence through young adulthood: psychosocial adjustment associated with long-term survival of HIV. J Adolesc Health. 2002;30(3):1618. 94. Ledlie SW. The psychosocial issues of children with perinatally acquired HIV disease becoming adolescents: a growing challenge for providers. AIDS Patient Care STDs. 2001;15(5):2316. 95. Havens JF, Mellins C, Ryan S, Locker A. Mental health needs of children and families affected by HIV/AIDS. In: Goodman H, Landsburg G, Spitz-Toth A, editors. Mental health services for HIV impacted populations in New York City: a program perspective. New York: The Coalition of Voluntary Mental Health Agencies; 1996. p. 2543. 96. Gaughan DM, Hughes MD, Oleske JM, Malee K, Gore CA, Nachman S for the pediatric AIDS clinical trials group 219C team. Psychiatric hospitalizations among children and youths with human immunodeficiency virus infection. Pediatrics. 2004;113(6):e5441. 97. Marhefka SL, Lyon M, Koenig LJ, Orban L, Stein R, Lewis J, et al. Emotional and behavioral problems and mental health service utilization of youth living with HIV acquired perinatally or later in life. AIDS Care. 2009;21(11):144754. 98. Sirois P, Montepiedra G, Kapetanovic S, Williams P, Pearson D, Malee K, et al. Impact of medications prescribed for treatment of attentiondeficit-hyperactivity disorder on physical growth in children and adolescents with HIV. J Dev Behav Pediatr. 2009;30:40312. 99. Kapetanovic S, Aaron L, Montepiedra G, Sirois P, Oleske J, Malee K, et al. The use of second-generation antipsychotics and the changes in physical growth in children and adolescents with perinatally acquired HIV. AIDS Patient Care STDs. 2009;23(11):93947. 100. Bacha T, Pomeroy EC, Gilbert D. A psychoeducational group intervention for HIV-positive children: a pilot study. Health Soc Work. 1999;24(4):3036. 101. Kmita G, Baranska M, Niemiec T. Psychosocial intervention in the process of empowering families with children living with HIV/AIDS–a descriptive study. AIDS Care. 2002;14(2):27984. 102. Funck-Brentano I, Dalban C, Veber F, Quartier P, Hefez S, Costagliola S, et al. Evaluation of a peer support group therapy for HIV-infected adolescents. AIDS. 2005;19(14):15018. 103. Multisystemic Therapy Services. Complete overview: research on effectiveness. Mt. Pleasant, SC: Multisystemic Therapy Services; 2007. 104. Ellis DA, Naar-King S, Cunningham PB, Secord E. Use of multisystemic therapy to improve antiretroviral adherence and health outcomes in HIVinfected pediatric patients: evaluation of a pilot program. AIDS Patient Care STDs. 2006;20(2):11221. 105. McKay MM, Alicea S, Elwyn L, McClaim ZRB, Parker G, Small L, et al. Addressing the need for theory-driven programs capable of impacting povertyimpacted children’s health, mental health and prevention needs: CHAMP and CHAMP, evidence-informed, family-based interventions to address HIV risk and care. J Clin Child Adolesc Psychol. Forthcoming. 106. McKay M, Block M, Mellins C, Traube DE, Brackis-Cottt E, Minott D, et al. Adapting a family-based HIV prevention program for HIV infected preadolescents and their families: youth, families and health care providers coming together to address complex needs. Soc Work Ment Health. 2007;5(3):35578. 107. McKay MM, Chasse KT, Paikoff R, McKinney LD, Baptiste D, Coleman D, et al. Family level impact of the CHAMP Family Program: a community collaborative effort to support urban families and reduce youth HIV risk exposure. Fam Process. 2004;43(1):7993. 108. McKay MM, Baptiste D, Coleman D, Madison S, Paikoff R, Scott R. Preventing HIV risk exposure in urban communities: the CHAMP family program. In: Pequegnat W, Szapocznik J, editors. Working with families in the era of HIV/AIDS. Thousand Oaks: CA; 2000. p. 6787. 109. Bhana A, McKay MM, Mellins C, Petersen I, Bell C. Family-based HIV prevention and intervention services for youth living in poverty-affected contexts: the CHAMP model of collaborative, evidence-informed programme development. J Int AIDS Soc. 2010;13(S2):S8. 110. Luthar SS, Sawyer JA, Brown PJ. Conceptual issues in studies of resilience: past, present and future research. Ann NY Acad Sci. 2006;1094:10515. 111. Catalano RF, Hawkins JD, Berglund L, Pollard JA, Arthur MW. Prevention science and positive youth development: competitive or cooperative frameworks? J Adolesc Health. 2002;31:2309. 112. Kia-Keating M, Dowdy E, Morgan ML, Noam GG. Protecting and promoting: an integrative conceptual model for healthy development of adolescents. J Adolesc Health. 2011;48(3):2208. 113. Klein JB, Jacobs RH, Reinecke MA. Cognitive-behavioral therapy for adolescent depression: a meta-analytic investigation of changes in effect-size estimates. J Am Acad Child Adolesc Psychiatry. 2007;46(11):140313. 114. Mufson L, Dorta KP, Moreau D, Weissman MM. Interpersonal psychotherapy for depressed adolescents. New York: Guilford Press; 2004. 115. Miller A, Rathus JH, Linehan MM. Dialectical behavior therapy with suicidal adolescents. New York, NY: Guilford Press; 2007. 116. Carr A. Evidence based practice in family therapy and systemic consultation. J Fam Ther. 2000;22(1):2960. 117. Tolan PH, Dodge KA. Children’s mental health as a primary care and concern: a system for comprehensive support and service. Am Psychol. 2005; 60(6):60114. 118. Lowenthal E, Lawler K, Harari N, Moamogwe L, Masunge J, Masedi M, et al. Rapid psychosocial function screening test identified treatment failure in HIV African youth. AIDS Care. 2012;24(6):7227. 119. Petersen I, Lund C, Bhana A, Flisher AJ. A task shifting approach to primary mental health care for adults in South Africa: human resource requirements and costs for rural settings. Health Policy Plan. 2012;27(1): 4251. 120. Insel TR, Wang PS. Rethinking mental illness. JAMA: J Am Med Assoc. 2010;303(19):19701. 19 Laughton B et al. Journal of the International AIDS Society 2013, 16:18603 http://www.jiasociety.org/index.php/jias/article/view/18603 | http://dx.doi.org/10.7448/IAS.16.1.18603 Review article Neurodevelopment in perinatally HIV-infected children: a concern for adolescence Barbara Laughton§,1, Morna Cornell2, Michael Boivin3 and Annelies Van Rie4 § Corresponding author: Barbara Laughton, Children’s Infectious Diseases Clinical Research Unit, Ward J8, Tygerberg Hospital, Private Bag X3, Tygerberg 7505, South Africa. Tel: 27 21 938 4987. Fax: 27 21 938 4151. ([email protected]) This article is part of the special issue Perinatally HIV-infected adolescents - more articles from this issue can be found at http://www.jiasociety.org Abstract Globally, an estimated 3.4 million children are living with HIV, yet little is known about the effects of HIV and antiretroviral treatment (ART) on the developing brain, and the neurodevelopmental and behavioural outcomes of perinatally HIV-infected (PHIV) adolescents. We reviewed the literature on neurodevelopmental outcomes in PHIV children and adolescents, and summarized the current evidence on behaviour, general cognition, specific domains, hearing and language, school performance and physical disabilities due to neurological problems. Evidence suggests that PHIV children do not perform as well as controls on general cognitive tests, processing speed and visualspatial tasks, and are at much higher risk for psychiatric and mental health problems. Children with AIDS-defining diagnoses are particularly at risk for poorer outcomes. A striking finding is the lack of published data specific to the adolescent age group (1025 years), particularly from resourceconstrained countries, which have the highest HIV prevalence. In addition, extreme heterogeneity in terms of timing and source of infection, and antiretroviral experience limits our ability to summarize findings of studies and generalize results to other settings. Due to the complex nature of the developing adolescent brain, environmental influences and variation in access to ART, there is an urgent need for research on the longitudinal trajectory of neurodevelopment among children and adolescents perinatally infected with HIV, especially in high burden resource-constrained settings. Keywords: adolescents; children; perinatally HIV infected; neurodevelopment; neurocognitive; neurological; hearing; executive function. Received 24 February 2013; Revised 4 April 2013; Accepted 16 April 2013; Published 18 June 2013 Copyright: – 2013 Laughton B et al; licensee International AIDS Society. This is an open access article distributed under the terms of the Creative Commons Attribution 3.0 Unported (CC BY 3.0) Licence (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction An estimated 3.4 million children are living with HIV worldwide [1], 28% of whom have started antiretroviral therapy (ART) [2]. Yet, little is known about the effects of HIV and ART on the developing brain and the neurodevelopmental outcomes of perinatally HIV-infected (PHIV) adolescents. In neuropsychological terms, adolescence spans the age range of 1025 years [3], which in 2013 includes those born between 1988 and 2003. Over this time period, the management of PHIV infants, children and adolescents changed dramatically. Before the introduction of ART in 1995, 50% of PHIV children died before the age of two [4], with a few slow progressors surviving to adolescence [5]. Prior to 1997, children in Europe and the United States may have received multiple antiretroviral regimens, including those that would now be considered suboptimal therapy. In 1997, combination ART was introduced in the United States. Since 2004, access to ART has expanded rapidly in resource-poor settings and depending on the country, 2880% of treatment-eligible children have initiated ART [2]. Context-specific differences in access to ART over the past two decades have resulted in great variability in disease severity and in exposure to ART among PHIV adolescents: some started ART soon after HIV infection, prior to clinical diagnosis of neurodevelopmental delay [6]; some initiated ART after the diagnosis of HIV encephalopathy [7,8], resulting in neurological deficits that remained permanent despite ART [9,10]; other PHIV adolescents are slow progressors and remain ART-naı̈ve as they have not yet reached the ART eligibility threshold [2]. The source and time of infection cannot always be determined in HIV adolescents, especially in settings with generalized HIV epidemics. There is also substantial heterogeneity in the literature in terms of the age of study participants. Most published studies have focused on younger children aged 612 years [1113] or 716 years [14], crossing from childhood to adolescence. The issue is further compounded by the measures used to assess functionally relevant outcomes for PHIV adolescents in diverse cultural settings. In some settings, the emphasis may be on achieving good school grades to 1 Laughton B et al. Journal of the International AIDS Society 2013, 16:18603 http://www.jiasociety.org/index.php/jias/article/view/18603 | http://dx.doi.org/10.7448/IAS.16.1.18603 maximize employment options, while in other settings adolescents may be more concerned about starting a family and providing resources to support a household or extended family. Given this extreme heterogeneity in the age of study participants, severity of disease, antiretroviral experience, and the definition and measurement of outcomes, we reviewed the literature on neurodevelopmental outcomes in PHIV adolescents. We conducted a literature search using the following key words: neurodevelopment/al, development, neurocognitive, cognitive, adolescents, youth, perinatal/vertical HIV-infected, HIV exposed, school performance, adaptive functioning, hearing and neuroimaging. We reviewed bibliographies and relevant articles from different contexts globally, limited to the most recent papers. We included all ages spanning adolescence. The original aim was to review evidence on neurodevelopmental outcomes among perinatally HIVinfected adolescents. However, the paucity of strictly adolescent data was striking. In the absence of these data, we drew on published studies of neurodevelopmental in younger children with HIV as a guide to what could be expected to impair neurodevelopment in adolescence. Neurodevelopmental changes during adolescence The key developmental tasks during adolescence are to develop an identity, to become more independent, and to consider the future in terms of career, relationships, families, housing, etc. [15]. Traditionally, adolescence is viewed as the age when abstract thought develops, together with improvements in memory, language, processing speed, attention and concentration [16]. A more contemporary view is that the major dimensions of cognitive development during adolescence are the refinement of executive control and the attainment of a more conscious, self-directed and selfregulating mind [1719]. Central to these are executive function (EF) processes such as voluntary response inhibition, working memory, response planning, improved processing speed, cognitive flexibility, and rule-guided behaviour [18,19]. While the adolescent’s brain does not increase substantially in volume, changes in maturation reflect reorganization of regulatory systems and correlate with neurocognitive and behavioural outcomes [17]. During adolescence, white matter increases in a linear fashion with increased myelination and re-organization with synaptogenesis and pruning, especially in the frontal lobes and prefrontal cortex, which serve as the governor of cognition and action [17,18]. Maturational changes are influenced by numerous factors including genetic and environmental factors as well as overall health status, resulting in variation between children and within the same child for the various domains of neurodevelopment. The impulsive and risk-taking behaviour of adolescents is also thought to be a consequence of the interaction of social context and the development of judgment, decision-making and internal control [17,20]. Neuropathology caused by HIV is most evident in basal ganglia and cerebral white matter. Neuronal loss is prominent in the prefrontal cortical regions, which may cause difficulty in complex mental processing [21]. These are the regions where myelination and remodelling of synaptic connections are still occurring during adolescence [22,23]. When coupled with the high risk for psychiatric difficulties in PHIV adolescents, the relationship between impaired EF and risktaking behaviour can be compounded. General cognition The most common measure of neurodevelopmental outcome is general cognition. General cognitive assessments provide a global score of performances in various domains. In this case, appropriate perinatally HIV-unexposed (PHU) children can be used as controls [12]. Neighbourhood-matched perinatally HIV-exposed uninfected (PHEU) children can be used to control for confounding effects of prenatal HIV exposure, ART exposure and maternal illness, etc. [11,24], but they should not be seen as an ideal control group. Table 1 summarizes recent studies of general cognition in PHIV children. Most neurocognitive assessment studies of PHIV children have been performed in the United States and Europe [14,2527], though some studies from other continents have been published [1113,24]. There are many differences between the study populations, with each group having particular areas of vulnerability of the brain and life experiences (e.g., higher drug abuse and lower adherence in some parts of the United States; higher poverty and lower access to comprehensive treatment in some limited-resource countries; different treatment when infants). Overall, PHIV children and adolescents perform more poorly in neurodevelopmental assessments than PHU controls or national norms [11,13,24], although in some studies there were no significant differences between groups [12,26,27]. For children in the United States, better cognitive outcomes have been associated with having a biological parent as caregiver, higher family income level, and higher caregiver cognitive function [14]. In PHIV children with less severe disease progression (WHO clinical stage I or II) and those on ART without a history of an AIDS defining illness, overall cognitive development has been found to be similar to that of PHEU children [14] although still significantly poorer than PHU children [13]. Martin and colleagues evaluated predictors of cognitive decline in older children in the United States who had been on ART for at least a year. Overall, PHIV children on ART remain at risk for developing CNS disease, with children with minimal to moderate CT brain scan abnormalities scoring significantly lower than children with normal scans on composite measures of cognitive ability [21]. The risk in asymptomatic adolescents was confirmed in a small pilot study which found a higher rate of neurocognitive impairment in asymptomatic adolescents compared to adults 60 years old (67 vs. 19%) [28]. Few studies have addressed the effect of ART initiation on cognitive development in PHIV school-age children and adolescents in low- and middle-income countries. In a cohort of Thai children, cognitive function did not improve in response to ART, even in children who achieved virological suppression and immunological recovery [11]. There were 2 Study Koekkoek et al. Participants 22 PHIV 2008 [26] Age (range) Median 9.46 years Measure SON-R (613.5) Findings No gross cognitive deficits Antiretroviral therapy Median age HAART initiation 5.6 years compared to normative values The Netherlands Smith et al. 2012 270 PHIV/noC USAPuerto Rico 88 PHIV/C [14] 200 PHEU Blanchette et al. 2002 [27] Canada 14 PHIV 11 control 716 years WISC-IV Scores significantly lower for PHIV/C group after Median age: first ART 0.6 years; first dual adjusting for covariates 77.8 vs. 83.4 and 83.3 therapy 1.25 years 12 were on ART 6.314 years WISC-R or WISC-III Mean FISQ 91.7 vs. 100.5 KABC-2 PHIV performed worse than HIV- children siblings Ruel et al. 2011 93 PHIV Median 8.7 years Uganda [13] 106 HIV (612) 28 HIV 612 years KABC No significant difference ART-naı̈ve Median 15.2 years (1124) WISC-IV or WASI Median FISQ of PHIV/noC fell within normal range; Median FISQ of HIV/C in below average range Median age: ART initiation: 3.1 years; Median age: HAART initiation: 6.5 years WISC-III Mean FISQ of HIV and affected groups significantly 87% on ART for median of 35 weeks (IQR lower than healthy controls 2953) Bagenda 2006 Uganda [12] All children above WHO threshold for ART initiation 42 HEU 37 HIV Wood 2009 USA [25] 81 PHIV 38 PHIV/C Puthanakit et al. 39 HIV Median 9.3 years 2010 [11] 40 affected (612) Thailand 42 healthy controls 43 PHIV/noC Puthanakit et al. 2013 [29] 284 PHIV, 155 PHEU, Median age 9 years No difference between early and deferred ART Early versus deferred HAART at enrolment from 164 PHU (112) initiation RCT arms. PHIV children performance 1 to 12 years of age 812 years ART-naı̈ve Thailand, Cambodia Hoare et al. 2012 12 PHIV South Africa [24] 79 vs. 88 vs. 96 pB0.01 WISC-Thai WASI: worse than PHEU and PHU on IQ Mean scores: 12 HIV community verbal 87.8 vs. 101.2 controls performance 73.7 vs. 85.7 PHIV/C Perinatally HIV-infected with a previous class C event. PHIV/noC Perinatally HIV-infected with no past history of class C event. KABC Kaufman Assessment Battery for children. KABC-2 Kaufman Assessment Battery for children, 2nd edition. SON-R Snijders-Oomen nonverbal intelligence test for children and adolescents (abridged). WASI Wechsler Abbreviated Scale of Intelligence. WISC-R Wechsler Intelligence Scale for Children Revised. WISC-III & IV Wechsler Intelligence Scale for Children versions 3, 4. WISC-Thai Wechsler Intelligence Scale for Children Thai version. Laughton B et al. Journal of the International AIDS Society 2013, 16:18603 http://www.jiasociety.org/index.php/jias/article/view/18603 | http://dx.doi.org/10.7448/IAS.16.1.18603 Table 1. Summary of recent studies on general cognition in HIV-infected children 3 Laughton B et al. Journal of the International AIDS Society 2013, 16:18603 http://www.jiasociety.org/index.php/jias/article/view/18603 | http://dx.doi.org/10.7448/IAS.16.1.18603 also similar neurodevelopmental and neuropsychological outcomes in Thai and Cambodian children between early and deferred ART groups, although both groups performed worse than PHEU children [29]. A small study of younger South African children (median age five years) also failed to observe neurodevelopmental improvement following ART initiation [9]. Specific domains of cognitive development Global cognitive scores may overlook subtle deficits in one or more areas specific to PHIV children and may affect their performance on a different level [26,30,31]. For example, even in PHIV children with global cognitive scores in the normal range, EF may be impaired, especially in children with cortical atrophy, lower fractional anisotropy of the corpus callosum and those with CD4 counts below 500 cells/mm3 [21,24]. Specific domains may be measured as subtests on cognitive assessments or by a test specifically designed for that purpose. The development of EF starts in childhood, but is highly important in the development of adolescents. EF is a composite of different domains including processing speed, response inhibition, working memory, response planning, cognitive flexibility with task switching, attention and concentration [32]. Processing speed is associated with increased capacity for working memory, enhanced inductive reasoning and greater accuracy in solving arithmetic word problems, and consistently predicts performance on cognitive tasks [16]. Table 2 summarizes studies that explore the impact of HIV on important neurocognitive domains. PHIV children have been found to perform significantly poorer in EF tasks, particularly in terms of processing speed [13,14,26,33], memory [12,14,21,24,34] and attention [13]. Lower scores on visualspatial processing have also been described in younger PHIV children [27,35]. Visualspatial processing is important for adolescents as it impacts on reading, writing and learning. PHIV children have been shown to be slower and less accurate on pattern recognition [26], and to have lower scores than controls on sequential processing, simultaneous processing [36], planning/reasoning [13] and visual memory [24]. Adaptive functioning Adaptive functioning has been defined as the ability to function effectively in a number of settings requiring social and problem solving skills, including school, home and social settings [37]. Cognitive assessments may not be the appropriate measurement tools to capture the ability of children and adolescents to function in real life situations. For example, in child-headed households in resource-constrained settings, children are required to take far more responsibility than in resource-rich countries. Measuring adaptive functioning, as previously used in younger children, may provide a more meaningful way of assessing how adolescents are functioning in their own environments. There is conflicting evidence on the correlation of scores. Gosling et al. found significant weakness in adaptive functioning compared with cognitive functioning in PHIV children [38]. In contrast, Smith et al. found some disparity, with higher scores in adaptive function at lower cognitive scores [14]. As the number of PHIV children grow, further research on this is needed to determine whether measuring adaptive functioning is a useful measurement tool for neurodevelopmental outcomes in PHIV adolescents in less developed settings. The interplay between HIV, neurodevelopment, behaviour and mental health Several studies have focused on the burden of psychiatric problems and mental health functioning impairment in PHIV children and the interplay with EF, risk-taking behaviour and treatment adherence. A study in the United States observed a 25% prevalence of mental health problems among PHIV children and adolescents, well above that of the general population though lower than the 38% rate observed in the PHEU comparison group [39]. Caregiver characteristics (psychiatric disorder, limit-setting problems and health-related functional limitations) and child characteristics (younger age and lower IQ) were most predictive of the occurrence of mental health problems. Another US study documented that 18% of 617 year old PHIV children had a lifetime history of psychiatric medications, 13% were on medication (largely stimulants and antidepressants) for psychiatric problems and 22% had a past or current history of non-medication psychological intervention [40]. There is a strong association between psychological and neurocognitive functioning. In a study in Atlanta and New York City, depressive symptoms in PHIV adolescents were best predicted by a combination of negative coping skills and poor neuropsychological functioning. Conduct disorder problems were directly associated with neuropsychological functioning (cognitive inflexibility) and negative coping skills [41]. A study in New Zealand reported that risky personality and performance on the neuropsychological and EF tests were significant predictors of risk-taking [42]. Furthermore, psychiatric disorders and behavioural health challenges in PHIV children can lead to poor ART adherence, risk-taking behaviour, including risky sexual behaviour, precocious sexual debut, teenage pregnancy and substance abuse [40,4348]. These findings add weight to the increasing concern about long-term neurodevelopmental problems among PHIV adolescents [8,49] and the burden that these pose for individuals, families and the education and health care systems. Language and hearing As children transition to early and middle adolescence, language and reading skills are the critical building blocks for literacy and future academic success, with an important transition from ‘‘learning to read and reading to learn’’ [50]. There is evidence that verbal skills are negatively affected in PHIV children [14,24,36,50,51]. In a large study in New York City, vocabulary and reading were worse in PHIV youths compared to PHEU, even after adjusting for demographic variables [50]. In contrast, Rice et al. in a multisite US (including Puerto Rico) study found that both PHIV and PHEU performed poorly on verbal tests, but there was no difference between the two groups [51]. 4 Specific neurocognitive domains affected in perinatally HIV-infected children Study Participants Age (range) Measure Findings Processing speed: Koekkoek et al. 2008 [26] The Netherlands Smith et al. 2012 [14] USA Puerto Rico Nachman et al. 2012 [34] USA Ruel et al. 2012 Uganda [13] 22 PHIV Median 9.5 yrs Amsterdam neuro-psychological task: Significantly slower compared to age-appropriate norms 88 PHIV/C (613.5) 716 years baseline speed WISC-IV Lower scores on processing speed for PHIV/C compared to PHIV Processing speed /NoC and PHEU. PHIV/NoC and PHEU scores were similar 617 years WISC-IV coding recall Median 8.7 yrs Test of variables of attention Higher peak viral load (100 000 copies/ml)and lower nadir CD4% (B15%) associated with slower speed Worse visual, auditory and overall reaction time than HIV-community age matched 270 PHIV/NoC 200 PHEU 319 PHIV IQ 70 93 PHIV 106 PHU CD4 ]15% (612) CD4 count ]350 cells/ml Set Shifting: Koekkoek et al. 2008 [26] The Netherlands 22 PHIV Median 9.5 yrs Amsterdam Neuro-psychological task: Attentional flexibility Significantly slower compared to age-appropriate norms Better outcomes with longer HAART duration Verbal fluency Significantly lower scores compared to age appropriate norms Semantic fluency Significantly lower than HIV-negative controls from same neighbourhood WISC-digit span and information No difference between groups (613.5) Verbal Fluency: (EF in the verbal domain) Koekkoek et al. 2008 [26] 22 PHIV Hoare et al. 2012 [24] South Africa Median 9.5 yrs The Netherlands 12 PHIV 12 HIV (613.5) Mean 10.4 yrs (812) 14 PHIV 6.314.9 yrs Memory Blanchette et al. 2002 [27] Canada Bagenda 2006 Uganda [12] Martin et al. 2006 [21] USA 11 control siblings 28 HIV Story recall 612 years 42 HEU 37 HIV 41 PHIV Mean 11.2 yrs (616) Rey Complex figure KABC Sequential processing HIV significantly lower scores than HEU (Immediate memory recall) No difference between PHIV and HIV- groups WISC III working memory: Digit span backwards Significantly lower scores in those with abnormal CT brain scans compared to those with normal scans Arithmetic Laughton B et al. Journal of the International AIDS Society 2013, 16:18603 http://www.jiasociety.org/index.php/jias/article/view/18603 | http://dx.doi.org/10.7448/IAS.16.1.18603 Table 2. 5 Study Hoare et al. 2012 [24] South Africa Smith et al. 2012 USAPuerto Rico [14] Participants Age (range) Measure Findings 12 PHIV Mean 10.4 yrs Working memory: Groups performed similar for working memory 12 HIV (812) WISC IV digit span Backward Visual memory significantly worse in PHIV compared to HIV- Visual memory: Rey complex figure controls 270 PHIV/noC 716 years 88 PHIV/C WISC IV: 2 to 5 fold increased risk of impairment for HIV/C group compared Working memory to PHEU group Amsterdam neuro-psychological task: visuospatial memory Significantly lower scores in visuospatial working memory compared to age-appropriate norms. Beery Visual Motor Integration No difference between early and deferred ART initiation RCT arms 200 PHEU Visual spatial memory/integration Koekkoek et al. 2008 [26] The Netherlands 22 PHIV Median 9.5 yrs Puthanakit et al. 2013 [29] 284 PHIV, Median 9 yrs 155 PHEU, (112), (613.5) Thailand, Cambodia PHIV children performance worse than PHEU and PHU 164 PHU Hoare et al. 2012 [24] South Africa 12 PHIV Mean 10.4 yrs Spatial processing: 12 HIV (812) WASI block design Rey complex figure test PHIV/C: Perinatally HIV-infected with a previous class C event. PHIV/noC: Perinatally HIV-infected with no past history of class C event. Significantly worse than HIV-negative controls Laughton B et al. Journal of the International AIDS Society 2013, 16:18603 http://www.jiasociety.org/index.php/jias/article/view/18603 | http://dx.doi.org/10.7448/IAS.16.1.18603 Table 2 (Continued ) 6 Laughton B et al. Journal of the International AIDS Society 2013, 16:18603 http://www.jiasociety.org/index.php/jias/article/view/18603 | http://dx.doi.org/10.7448/IAS.16.1.18603 While CD4 cell count, HIV viral load and CDC Classification were not associated with verbal scores in the New York City study [50], two other US studies found that a history of an AIDS-defining illness was associated with verbal comprehension impairment [14,51]. In addition, Rice et al. found that after controlling for cognitive and hearing impairment, children who were PHIV with detectable viral load and ART initiation less than six months of age had an increased risk of language impairment. Other risk factors for language impairment combined with cognitive or hearing impairment were race/ethnicity, caregiver’s education and intelligence quotient (IQ) status and having a non-biological parent as caregiver [51]. Adjustment for hearing deficits in language assessment of PHIV children is important as the prevalence of hearing loss in PHIV children is high and ranges from 20% in higher income countries to 38% in low-resource settings [52,53]. In resource-poor settings, hearing loss was largely conductive, including chronic suppurative otitis media and dry tympanic membrane perforations, which may reflect the lack of consistent otological care, whereas in well-resourced settings more children had sensorineural hearing loss [54], which may possibly be related to measurement in the United States. A low CD4 count and a history of AIDS-defining illness were associated with both hearing and language impairment [53,54]. School performance School performance is a functional outcome that is highly relevant in terms of future quality of life and employment prospects [55]. Academic failure predicts problems in schooling and leads to an increase in school dropouts [56]. Insight into the school performance of PHIV children is important in order to plan appropriate resources to support this vulnerable population. However, accurate measurement is problematic due to the abundance of potential confounders. A child’s school performance is dependent on numerous variables including social and family factors [55,56]. In addition, the indirect effects of HIV infection including hearing loss, school absenteeism due to ill health or ART management, depression and/or social problems need to be considered when interpreting school performance [33]. Several studies have explored school performance among PHIV children and adolescents, and identified poorer outcomes compared with children without HIV, with the exception of a French study, which reported an academic failure rate of 16%, similar to the general population [57]. Outcome measurements were highly variable and included 42% with a learning disability [25], 2733% receiving special education [50,57,58], 15% having repeated two or more grades [57] and 51% having failed at least one grade [59]. Limited caregiver education or intelligence level increased the risk of poor educational outcomes [14]. There is a striking lack of studies on academic achievement in resource-limited countries. Although such research would be difficult to undertake, it would provide valuable information to guide interventions. Physical disabilities due to neurological problems Physical problems due to HIV encephalopathy have been well described in the pre-ART era [10]. There is however a paucity of data on neurological outcomes of ART-naı̈ve PHIV child non-progressors as well as those on ART, particularly in older children. In Uganda, Bagenda et al. describe children with hypotonia, hyperreflexia and delayed milestones, which disappeared as they grew older [12]. Boivin et al. also found motor impairment in PHIV asymptomatic children in the first two years of life and later in childhood (ages 812 years) [36]. Two South African studies described motor deficits and neurological manifestations in PHIV children [9,60]. Govender et al. reported 59% abnormal neurological examinations in children aged one month to 12 years, 41% with global pyramidal long tract signs and 16% with cortical visual impairment. However, there were many participants with neurological sequelae due to secondary infections and the direct effects of HIV infection are not clear [60]. Smith et al. found evidence of motor dysfunction in 33% of ART-naı̈ve children with no improvement after six months of treatment [9]. In a cohort of 210 PHIV French children followed since birth, at a median age of 15 years, three children had persistent motor dysfunction and five had mild to moderate physical impairment, indicating a low incidence of physical disabilities due to neurological problems in children who gain timely access to ART [57]. Some of the neurological manifestations in the young child may not be reversible and may still be evident in the adolescent. We have included these studies to emphasize that a neurological examination should be included when measuring functional outcomes in PHIV adolescents. CNS disease and stroke have been documented as causes of death in PHIV children, adolescents and young adults in the USA [8]. In the pre-ART era, the annual risk of cerebrovascular events was 1.3% [61], but there are no data on the incidence of stroke in PHIV children on ART. Similarly, the incidence and effect of central nervous system insults caused by infections such as tuberculosis and meningitis have not been well documented. Markers of HIV disease progression and severity Traditional markers of HIV disease progression and severity including high plasma viral load, lower CD4 cell counts and/or CD4%, and history of an AIDS defining illness have been associated with poorer neurocognitive performance [13,14,21]. In addition, some markers of vascular dysfunction and T-cell activation have been found to correlate with global cognitive outcomes in PHIV youth. Specifically, higher soluble P-selectin, a marker and mediator for inflammatory vascular disease, and lower fibrinogen (a pro-coagulant state marker) have been associated with poorer cognitive function [62]. CD4 activation and, under certain circumstances, CD8 activation have been shown to have favourable neurodevelopmental implications in PHIV-infected children [63]. In a study of ART-naive Ugandan children, HIV subtypeA was associated with higher viral loads and poorer 7 Laughton B et al. Journal of the International AIDS Society 2013, 16:18603 http://www.jiasociety.org/index.php/jias/article/view/18603 | http://dx.doi.org/10.7448/IAS.16.1.18603 performance compared to subtype-D, suggesting that subtypeA may be more neuropathogenic in children [64]. Intervention strategies Studies have found that ART alone is not sufficient to reverse the neurodevelopmental consequences of HIV infection [31,65]. Highly active ART (HAART) may even contribute to neuromotor decline over time [31,66]. The inability of ART alone to restore HIV children to ‘‘normal’’ neuropsychological performance is a compelling rationale to evaluate alternative interventions for neurocognitive disability in paediatric HIV. Despite knowledge of deficits in PHIV children, there have been very few intervention studies. One intervention is computerized cognitive rehabilitation training [67,68]. Preliminary results in Uganda indicate that using computer games for cognitive rehabilitation can be of great benefit to PHIV children and adolescents [69]. For younger children with HIV, caregiver training on practical strategies to enrich the developmental milieu of these children can also have significant neurocognitive benefit [70]. There is evidence to suggest a strong link between psychological well-being and the immunological impact of disease progression [71]. HIV-infected children who exhibited signs of resilience tended to have better neurodevelopmental functioning, socialemotional and gross motor functioning [72]. Some approaches to fostering resilience in PHIV children have centred around family dynamics within a cultural framework [7376]. In a qualitative study of resilience among Rwandan HIV-affected children and families [74], Betancourt and colleagues identified five factors that increased resilience in children and families affected by HIV: perseverance, self-esteem/self-confidence, family unity/trust, good parenting, and collective/communal support. Interventions and strategies to leverage these resources may help to prevent mental health problems in these children as they grow into adolescence and adulthood [73]. Psychosocial intervention may also significantly enhance subsequent neurocognitive development of the child in response to the direct physiological, psychological, social and immunological impacts of this disease. For example, Coscia et al. showed that home environment had a stronger association with child IQ during the advanced than the early stages of disease [77]. Parental support has been shown to provide a stress-buffering effect for the effects of depression in these school children, that seemed to improve psychosocial and cognitive development [78,79]. Discussion Each child has their own set of unique factors that shapes their development, making it difficult to identify the relative contribution of different factors impacting on the neurodevelopmental outcomes of PHIV adolescents. While HIV has a direct effect on neurocognitive development, the effects of deprivation and poverty, quality of home environment, genetics, opportunistic infections, and access to care may overshadow the effects of HIV, particularly in resourceconstrained settings. Important variables that have been shown to affect neurodevelopmental outcomes include caregiver mental health or substance problems [14], orphan status and chronic illness [60], nutritional status [60,80] formal education and home environment [80] as well as having a biological parent as caregiver, higher family income level and higher caregiver cognitive functioning [14]. Given the psychosocial impact of diagnosis and treatment, as well as the contribution of coping with cognitive weaknesses, additional attention to behavioural and mood symptoms associated with childhood HIV is essential. It is possible that ART initiation in school-aged children and adolescents may be too late to reverse impairment. Cohorts initiating ART earlier report better outcomes, suggesting that earlier ART initiation is beneficial [6,29]. However, there is inadequate evidence of the effects of long-term ART on the developing brain. Lower nadir CD4 counts, higher viral loads and the history of an AIDS-defining illness are associated with poorer neurodevelopmental outcomes, further supporting the need for early ART initiation in children. Children presenting with these risk factors should be offered neurodevelopmental screening as part of routine HIV care and referral to supportive services or formal assessments where appropriate. PHIV adolescents should be provided with multidisciplinary support services including adherence support, reproductive health counselling and mental health and educational/vocational planning [81]. Preliminary evaluations of these multi-faceted interventions for PHIV adolescents have shown good results in improving adherence and reducing risk-taking behaviours [8184]. While most studies describe the proportions of male and female study participants, generally the data were not analysed and compared for sex differences in outcomes. This is possibly because it is generally accepted that the neurodevelopment of boys and girls are similar. However, possible sex differences in adolescent neurodevelopmental outcomes require further exploration. Conclusions PHIV adolescents constitute a large heterogeneous population. Overall, HIV children and adolescents have poorer neurodevelopmental outcomes than uninfected peers, particularly those with more advanced HIV disease. There is also emerging evidence that PHIV adolescents are especially at risk for poorer psychiatric outcomes and EFs. However, the impact of HIV on the developing adolescent brain is highly complex, influenced by many factors and not well understood. Compounding and contributory factors may include an increased risk of substance use, risky sexual and other risktaking behaviours, and poorer ART adherence. A striking finding is the paucity of data specific to the adolescent age group (1025 years) and the lack of longitudinal cohort studies designed to assess the effect of HIV on neurocognitive functioning in PHIV adolescents. While much of the current evidence is from younger ages, evidence from these studies provides valuable information as neurodevelopmental problems occurring at younger ages are likely to persist in adolescence and adulthood. Furthermore, the majority of studies on neurodevelopmental outcomes in adolescents are from the United States and Europe, with few studies from low- and middle-income countries which have 8 Laughton B et al. Journal of the International AIDS Society 2013, 16:18603 http://www.jiasociety.org/index.php/jias/article/view/18603 | http://dx.doi.org/10.7448/IAS.16.1.18603 the highest prevalence of PHIV adolescents. Few studies explore possible gender differences in adolescent neurodevelopment. Finally, little is known about the complex nature of recovery of the brain after initiation of ART. Thus, there is an urgent need for longitudinal research assessing the long-term effect of ART and timing of ART initiation on neurodevelopmental outcomes of perinatally HIV-infected adolescents by gender, particularly in resource-constrained settings. Authors’ affiliations 1 Children’s Infectious Diseases Clinical Research Unit, Department of Paediatrics and Child Health, Stellenbosch University, Cape Town, South Africa; 2 Centre for Infectious Disease Epidemiology & Research, School of Public Health & Family Medicine, University of Cape Town, Cape Town, South Africa; 3 Departments of Psychiatry and Neurology/Ophthalmology, Michigan State University, East Lansing, MI, USA; 4Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Competing interests The authors declare that they have no competing interests. Authors’ contributions All authors contributed to the content of the manuscript and all authors have read and approved the final version. References 1. WHO Department of HIV/AIDS: The strategic use of antiretrovirals to help end the HIV epidemic. WHO Press, Geneva 2012. 2. UNAIDS. Global Report: UNAIDS Report on the global AIDS epidemic 2012. Geneva: UNAIDS; 2012. 3. American Psychological Association. Developing adolescents: a reference for professionals. Washington, DC: American Psychological Association; 2002. 4. Newell ML, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet. 2004;364(9441):123643. 5. Brady MT, Oleske JM, Williams PL, Elgie C, Mofenson LM, Dankner WM, et al. Declines in mortality rates and changes in causes of death in HIV-1infected children during the HAART era. J Acquir Immune Defic Syndr. 2010; 53(1):8694. 6. Faye A, Le Chenadec J, Dollfus C, Thuret I, Douard D, Firtion G, et al. Early versus deferred antiretroviral multidrug therapy in infants infected with HIV type 1. Clin Infect Dis. 2004;39(11):16928. 7. Patel K, Ming X, Williams PL, Robertson KR, Oleske JM, Seage GR 3rd. Impact of HAART and CNS-penetrating antiretroviral regimens on HIV encephalopathy among perinatally infected children and adolescents. AIDS. 2009;23(14): 1893901. 8. Hazra R, Siberry GK, Mofenson LM. Growing up with HIV: children, adolescents, and young adults with perinatally acquired HIV infection. Annu Rev Med. 2010;61:16985. 9. Smith L, Adnams C, Eley B. Neurological and neurocognitive function of HIVinfected children commenced on antiretroviral therapy. South Afr J Child Health. 2008;2(3):10813. 10. Chiriboga CA, Fleishman S, Champion S, Gaye-Robinson L, Abrams EJ. Incidence and prevalence of HIV encephalopathy in children with HIV infection receiving highly active anti-retroviral therapy (HAART). J Pediatr. 2005; 146(3):4027. 11. Puthanakit T, Aurpibul L, Louthrenoo O, Tapanya P, Nadsasarn R, Insee-ard S, et al. Poor cognitive functioning of school-aged children in Thailand with perinatally acquired HIV infection taking antiretroviral therapy. AIDS Patient Care STDS. 2010;24(3):1416. 12. Bagenda D, Nassali A, Kalyesubula I, Sherman B, Drotar D, Boivin MJ, et al. Health, neurologic, and cognitive status of HIV-infected, long-surviving, and antiretroviral-naive Ugandan children. Pediatrics. 2006;117(3):72940. 13. Ruel TD, Boivin MJ, Boal HE, Bangirana P, Charlebois E, Havlir DV, et al. Neurocognitive and motor deficits in HIV-infected Ugandan children with high CD4 cell counts. Clin Infect Dis. 2012;54(7):10019. 14. Smith R, Chernoff M, Williams PL, Malee KM, Sirois PA, Kammerer B, et al. Impact of HIV severity on cognitive and adaptive functioning during childhood and adolescence. Pediatr Infect Dis J. 2012;31(6):5928. 15. Levine M, Carey W, Crocker A. Developmental-behavioral pedicatrics. 3rd ed. Philadelphia, PA: W B Saunders; 1999. 16. Kail RV, Ferrer E. Processing speed in childhood and adolescence: longitudinal models for examining developmental change. Child Dev. 2007; 78(6):176070. 17. Steinberg L. Cognitive and affective development in adolescence. Trends Cogn Sci. 2005;9(2):6974. 18. Luna B. Developmental changes in cognitive control through adolescence. Adv Child Dev Behav. 2009;37:23378. 19. Kuhn D. Do cognitive changes accompany developments in the adolescent brain? Perspect Psychol Sci. 2006;1:5967. 20. Casey BJ, Getz S, Galvan A. The adolescent brain. Dev Rev. 2008;28(1): 6277. 21. Martin SC, Wolters PL, Toledo-Tamula MA, Zeichner SL, Hazra R, Civitello L. Cognitive functioning in school-aged children with vertically acquired HIV infection being treated with highly active antiretroviral therapy (HAART). Dev Neuropsychol. 2006;30(2):63357. 22. Tau GZ, Peterson BS. Normal development of brain circuits. Neuropsychopharmacology. 2010;35(1):14768. 23. Sowell ER, Trauner DA, Gamst A, Jernigan TL. Development of cortical and subcortical brain structures in childhood and adolescence: a structural MRI study. Dev Med Child Neurol. 2002;44(1):416. 24. Hoare J, Fouche J, Spottiswoode B, Donald K, Philipps N, Bezuidenhout H, et al. A diffusion tensor imaging and neurocognitive study of HIV-positive children who are HAART-naive ‘‘slow progressors’’. J Neurovirol. 2012;18: 20512. 25. Wood SM, Shah SS, Steenhoff AP, Rutstein RM. The impact of AIDS diagnoses on long-term neurocognitive and psychiatric outcomes of surviving adolescents with perinatally acquired HIV. AIDS. 2009;23(14):185965. 26. Koekkoek S, de Sonneville LM, Wolfs TF, Licht R, Geelen SP. Neurocognitive function profile in HIV-infected school-age children. Eur J Paediatr Neurol. 2008;12(4):2907. 27. Blanchette N, Smith ML, King S, Fernandes-Penney A, Read S. Cognitive development in school-age children with vertically transmitted HIV infection. Dev Neuropsychol. 2002;21(3):22341. 28. Paramesparan Y, Garvey LJ, Ashby J, Foster CJ, Fidler S, Winston A. High rates of asymptomatic neurocognitive impairment in vertically acquired HIV-1infected adolescents surviving to adulthood. J Acquir Immune Defic Syndr. 2010;55(1):1346. 29. Puthanakit T, Ananworanich J, Vonthanak S, Kosalaraksa P, Hansudewechakul R, van der Lugt J et al. Cognitive function and neurodevelopmental outcomes in HIV-infected children older than 1 year of age randomized to early versus deferred antiretroviral therapy: the PREDICT neurodevelopmental study. Pediatr Infect Dis J 2013;32:(5):501508. 30. Boivin MJ, Giordani B. Neuropsychological assessment of African children: evidence for a universal brain/behavior omnibus within a coconstructivist paradigm. Prog Brain Res. 2009;178:11335. 31. Koekkoek S, Eggermont L, De Sonneville L, Jupimai T, Wicharuk S, Apateerapong W, et al. Effects of highly active antiretroviral therapy (HAART) on psychomotor performance in children with HIV disease. J Neurol. 2006;253(12):161524. 32. Blakemore SJ, Choudhury S. Development of the adolescent brain: implications for executive function and social cognition. J Child Psychol Psychiatry. 2006;47(34):296312. 33. Nachman S, Chernoff M, Williams P, Hodge J, Heston J, Gadow KD. Human immunodeficiency virus disease severity, psychiatric symptoms, and functional outcomes in perinatally infected youth. Arch Pediatr Adolesc Med. 2012; 166(6):52835. 34. Allison S, Wolters PL, Brouwers P. Youth with HIV/AIDS: neurobehavioral consequences. HIV and the brain: new challenges in the modern era. New York: Humana Press (c/o Springer ScienceBusiness Media); 2009. p. 187212. 35. Diamond GW, Kaufman J, Belman AL, Cohen L, Cohen HJ, Rubinstein A. Characterization of cognitive functioning in a subgroup of children with congenital HIV infection. Arch Clin Neuropsychol. 1987;2(3):24556. 36. Boivin MJ, Green SD, Davies AG, Giordani B, Mokili JK, Cutting WA. A preliminary evaluation of the cognitive and motor effects of pediatric HIV infection in Zairian children. Health Psychol. 1995;14(1):1321. 37. Allen-Meares P. Assessing the adaptive behavior of youths: multicultural responsivity. Soc Work. 2008;53(4):30716. 38. Gosling A, Burns J, Hirst F. Children with HIV in the UK: a longitudinal study of adaptive and cognitive functioning. Clin Child Psychol Psychiatry. 2004;9: 2537. 9 Laughton B et al. Journal of the International AIDS Society 2013, 16:18603 http://www.jiasociety.org/index.php/jias/article/view/18603 | http://dx.doi.org/10.7448/IAS.16.1.18603 39. Malee KM, Tassiopoulos K, Huo Y, Siberry G, Williams PL, Hazra R, et al. Mental health functioning among children and adolescents with perinatal HIV infection and perinatal HIV exposure. AIDS Care. 2011;23(12):153344. 40. Chernoff M, Nachman S, Williams P, Brouwers P, Heston J, Hodge J, et al. Mental health treatment patterns in perinatally HIV-infected youth and controls. Pediatrics. 2009;124(2):62736. 41. Salama C, Morris M, Armistead L, Koenig LJ, Demas P, Ferdon C, et al. Depressive and conduct disorder symptoms in youth living with HIV: the independent and interactive roles of coping and neuropsychological functioning. AIDS Care. 2013;25(2):1608. 42. Pharo H, Sim C, Graham M, Gross J, Hayne H. Risky business: executive function, personality, and reckless behavior during adolescence and emerging adulthood. Behav Neurosci. 2011;125(6):9708. 43. Conner LC, Wiener J, Lewis JV, Phill R, Peralta L, Chandwani S, et al. Prevalence and predictors of drug use among adolescents with HIV infection acquired perinatally or later in life. AIDS Behav. 2013;17:97686. 44. Elkington KS, Bauermeister JA, Brackis-Cott E, Dolezal C, Mellins CA. Substance use and sexual risk behaviors in perinatally human immunodeficiency virus-exposed youth: roles of caregivers, peers and HIV status. J Adolesc Health. 2009;45(2):13341. 45. Koenig LJ, Nesheim S, Abramowitz S. Adolescents with perinatally acquired HIV: emerging behavioral and health needs for long-term survivors. Curr Opin Obstet Gynecol. 2011;23(5):3217. 46. Mellins CA, Elkington KS, Leu CS, Santamaria EK, Dolezal C, Wiznia A, et al. Prevalence and change in psychiatric disorders among perinatally HIV-infected and HIV-exposed youth. AIDS Care. 2012;24(8):95362. 47. Mellins CA, Elkington KS, Bauermeister JA, Brackis-Cott E, Dolezal C, McKay M, et al. Sexual and drug use behavior in perinatally HIV-infected youth: mental health and family influences. J Am Acad Child Adolesc Psychiatry. 2009; 48(8):8109. 48. Kapetanovic S, Wiegand RE, Dominguez K, Blumberg D, Bohannon B, Wheeling J, et al. Associations of medically documented psychiatric diagnoses and risky health behaviors in highly active antiretroviral therapy-experienced perinatally HIV-infected youth. AIDS Patient Care STDS. 2011;25(8):493501. 49. Gray G. Adolescent HIV cause for concern in Southern Africa. PLoS Med. 2009;7(2):e1000227. 50. Brackis-Cott E, Kang E, Dolezal C, Abrams EJ, Mellins CA. The impact of perinatal HIV infection on older school-aged children’s and adolescents’ receptive language and word recognition skills. AIDS Patient Care STDS. 2009; 23(6):41521. 51. Rice ML, Buchanan AL, Siberry GK, Malee KM, Zeldow B, Frederick T, et al. Language impairment in children perinatally infected with HIV compared to children who were HIV-exposed and uninfected. J Dev Behav Pediatr. 2012; 33(2):11223. 52. Taipale A, Pelkonen T, Taipale M, Roine I, Bernardino L, Peltola H, et al. Otorhinolaryngological findings and hearing in HIV-positive and HIV-negative children in a developing country. Eur Arch Otorhinolaryngol. 2011;268(10): 152732. 53. Chao CK, Czechowicz JA, Messner AH, Alarcon J, Kolevic Roca L, Larragan Rodriguez MM et al. High prevalence of hearing impairment in HIV-infected peruvian children. Otolaryngol Head Neck Surg. 2011;146(2):259265. 54. Torre P 3rd, Zeldow B, Hoffman HJ, Buchanan A, Siberry GK, Rice M, et al. Hearing loss in perinatally HIV-infected and HIV-exposed but uninfected children and adolescents. Pediatr Infect Dis J. 2012;31(8):83541. 55. Freudenberg N, Ruglis J. Reframing school dropout as a public health issue. Prev Chronic Dis. 2007;4(4):A107. 56. Duncan GJ, Dowsett CJ, Claessens A, Magnuson K, Huston AC, Klebanov P, et al. School readiness and later achievement. Dev Psychol. 2007;43(6): 142846. 57. Dollfus C, Le Chenadec J, Faye A, Blanche S, Briand N, Rouzioux C, et al. Long-term outcomes in adolescents perinatally infected with HIV-1 and followed up since birth in the French perinatal cohort (EPF/ANRS CO10). Clin Infect Dis. 2010;51(2):21424. 58. Gadow KD, Chernoff M, Williams PL, Brouwers P, Morse E, Heston J, et al. Co-occuring psychiatric symptoms in children perinatally infected with HIV and peer comparison sample. J Dev Behav Pediatr. 2010;31(2):11628. 59. Souza E, Santos N, Valentini S, Silva G, Falbo A. Long-term follow-up outcomes of perinatally HIV-infected adolescents: infection control but school failure. J Trop Pediatr. 2010;56(6):4216. 60. Govender R, Eley B, Walker K, Petersen R, Wilmshurst JM. Neurologic and neurobehavioral sequelae in children with human immunodeficiency virus (HIV-1) infection. J Child Neurol. 2011;26(11):135564. 61. Park YD, Belman AL, Kim TS, Kure K, Llena JF, Lantos G, et al. Stroke in pediatric acquired immunodeficiency syndrome. Ann Neurol. 1990;28(3): 30311. 62. Kapetanovic S, Leister E, Nichols S, Miller T, Tassiopoulos K, Hazra R, et al. Relationships between markers of vascular dysfunction and neurodevelopmental outcomes in perinatally HIV-infected youth. AIDS. 2010;24(10): 148191. 63. Kapetanovic S, Aaron L, Montepiedra G, Burchett SK, Kovacs A. T-cell activation and neurodevelopmental outcomes in perinatally HIV-infected children. AIDS. 2012;26(8):95969. 64. Boivin MJ, Ruel TD, Boal HE, Bangirana P, Cao H, Eller LA, et al. HIV-subtype A is associated with poorer neuropsychological performance compared with subtype D in antiretroviral therapy-naive Ugandan children. AIDS. 2010;24(8): 116370. 65. Shanbhag MC, Rutstein RM, Zaoutis T, Zhao H, Chao D, Radcliffe J. Neurocognitive functioning in pediatric human immunodeficiency virus infection: effects of combined therapy. Arch Pediatr Adolesc Med. 2005;159(7): 6516. 66. von Giesen HJ, Niehues T, Reumel J, Haslinger BA, Ndagijimana J, Arendt G. Delayed motor learning and psychomotor slowing in HIV-infected children. Neuropediatrics. 2003;34(4):17781. 67. Boivin MJ, Bangirana P, Tomac R, Parikh S, Opoka RO, Nakasujja N, et al. Neuropsychological benefits of computerized cognitive rehabilitation training in Ugandan children surviving cerebral malaria and children with HIV. BMC Proc. 2008;2(suppl 1):P7. 68. Boivin MJ, Busman RA, Parikh SM, Bangirana P, Page CF, Opoka RO, et al. A pilot study of the neuropsychological benefits of computerized cognitive rehabilitation in Ugandan children with HIV. Neuropsychology. 2010;24(5): 66773. 69. Boivin MJ, Giordani B. Neuropsychological assessment of African children: evidence for a universal basis to cognitive ability. In: Chiao JY, editor. Cultural neuroscience: cultural influences on brain function. New York: Elsevier; 2009. p. 11335. 70. Boivin MJ, Bangirana P, Nakasuja N, Page CF, Shohet C, Givon D et al. A year-long caregiver training program to improve neurocognition in preschool Ugandan HIV-exposed children. J Dev Behav Pediatr. 2013. [Epub ahead of print]. 71. Moss H, Bose S, Wolters P, Brouwers P. A preliminary study of factors associated with psychological adjustment and disease course in school-age children infected with the human immunodeficiency virus. J Dev Behav Pediatr. 1998;19(1):1825. 72. Bose S. An examination of adaptive functioning in HIV infected children: exploring the relationships with HIV diesase, neurocognitive functioning, and psychosocial characteristics. ProQuest Information & Learning, Jul 1997. AAM9719709. 1997; Dissertation Abstracts International:Section B: The sciences and Engineering (58):409. 73. Betancourt TS, Meyers-Ohki SE, Charrow A, Hansen N. Research review: mental health and resilience in HIV/AIDS-affected children: a review of the literature and recommendations for future research. J Child Psychol Psychiatry. 2013;54:42344. 74. Betancourt TS, Meyers-Ohki S, Stulac SN, Barrera AE, Mushashi C, Beardslee WR. Nothing can defeat combined hands (Abashize hamwe ntakibananira): protective processes and resilience in Rwandan children and families affected by HIV/AIDS. Soc Sci Med. 2011;73(5):693701. 75. Betancourt TS, Rubin-Smith JE, Beardslee WR, Stulac SN, Fayida I, Safren S. Understanding locally, culturally, and contextually relevant mental health problems among Rwandan children and adolescents affected by HIV/AIDS. AIDS Care. 2011;23(4):40112. 76. Betancourt TS, Abrams EJ, McBain R, Fawzi MC. Family-centred approaches to the prevention of mother to child transmission of HIV. J Int AIDS Soc. 2010;13(suppl 2):S2. 77. Coscia JM, Christensen BK, Henry RR, Wallston K, Radcliffe J, Rutstein R. Effects of home environment, socioeconomic status, and health status on cognitive functioning in children with HIV-1 infection. J Pediatr Psychol. 2001;26(6):3219. 78. Hochhauser CJ, Gaur S, Marone R, Lewis M. The impact of environmental risk factors on HIV-associated cognitive decline in children. AIDS Care. 2008;20(6):6929. 79. Kotchick BA, Summers P, Forehand R, Steele RG. The role of parental and extrafamilial social support in the psychosocial adjustment of children with a chronically ill father. Behav Modif. 1997;21(4):40932. 10 Laughton B et al. Journal of the International AIDS Society 2013, 16:18603 http://www.jiasociety.org/index.php/jias/article/view/18603 | http://dx.doi.org/10.7448/IAS.16.1.18603 80. Bangirana P, John C, Idro R, Opoka R, Byarugaba J, Jurek A, et al. Socioeconomic predictors of cognition in Ugandan children: implications for community interventions. PLoS One. 2009;4(11):e7898. 81. LaGrange RD, Abramowitz S, Koenig LJ, Barnes W, Conner L, Moschel D. Participant satisfaction with group and individual components of adolescent impact: a secondary prevention intervention for HIV-positive youth. AIDS Care. 2012;24(1):11928. 82. Koenig LJ, Pals SL, Chandwani S, Hodge K, Abramowitz S, Barnes W, et al. Sexual transmission risk behavior of adolescents with HIV acquired perinatally or through risky behaviors. J Acquir Immune Defic Syndr. 2010;55(3): 38090. 83. Chandwani S, Abramowitz S, Koenig LJ, Barnes W, D’Angelo L. A multimodal behavioral intervention to impact adherence and risk behavior among perinatally and behaviorally HIV-infected youth: description, delivery, and receptivity of adolescent impact. AIDS Educ Prev. 2011;23(3): 22235. 84. Chandwani S, Koenig LJ, Sill AM, Abramowitz S, Conner LC, D’Angelo L. Predictors of antiretroviral medication adherence among a diverse cohort of adolescents with HIV. J Adolesc Health. 2012;51(3):24251. 11 Lipshultz SE et al. Journal of the International AIDS Society 2013, 16:18597 http://www.jiasociety.org/index.php/jias/article/view/18597 | http://dx.doi.org/10.7448/IAS.16.1.18597 Review article Cardiac effects in perinatally HIV-infected and HIV-exposed but uninfected children and adolescents: a view from the United States of America Steven E Lipshultz§,1, Tracie L Miller1, James D Wilkinson1, Gwendolyn B Scott1, Gabriel Somarriba1, Thomas R Cochran1 and Stacy D Fisher2 § Corresponding author: Steven E Lipshultz, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, USA. Tel: 1-305 243-3993, Fax: 1-305 243-3990. ([email protected]) This article is part of the special issue Perinatally HIV-infected adolescents - more articles from this issue can be found at http://www.jiasociety.org Abstract Introduction: Human immunodeficiency virus (HIV) infection is a primary cause of acquired heart disease, particularly of accelerated atherosclerosis, symptomatic heart failure, and pulmonary arterial hypertension. Cardiac complications often occur in late-stage HIV infections as prolonged viral infection is becoming more relevant as longevity improves. Thus, multi-agent HIV therapies that help sustain life may also increase the risk of cardiovascular events and accelerated atherosclerosis. Discussion: Before highly active antiretroviral therapy (HAART), the two-to-five-year incidence of symptomatic heart failure ranged from 4 to 28% in HIV patients. Patients both before and after HAART also frequently have asymptomatic abnormalities in cardiovascular structure. Echocardiographic measurements indicate left ventricular (LV) systolic dysfunction in 18%, LV hypertrophy in 6.5%, and left atrial dilation in 40% of patients followed on HAART therapy. Diastolic dysfunction is also common in long-term survivors of HIV infection. Accelerated atherosclerosis has been found in HIV-infected young adults and children without traditional coronary risk factors. Infective endocarditis, although rare in children, has high mortality in late-stage AIDS patients with poor nutritional status and severely compromised immune systems. Although lymphomas have been found in HIVinfected children, the incidence is low and cardiac malignancy is rare. Rates of congenital cardiovascular malformations range from 5.6 to 8.9% in cohorts of HIV-uninfected and HIV-infected children with HIV-infected mothers. In non-HIV-infected infants born to HIV-infected mothers, foetal exposure to ART is associated with reduced LV dimension, LV mass, and septal wall thickness and with higher LV fractional shortening and contractility during the first two years of life. Conclusions: Routine, systematic, and comprehensive cardiac evaluation, including a thorough history and directed laboratory assays, is essential for the care of HIV-infected adults and children as cardiovascular illness has become a part of care for longterm survivors of HIV infection. The history should include traditional risk factors for atherosclerosis, prior opportunistic infections, environmental exposures, and therapeutic and illicit drug use. Laboratory tests should include a lipid profile, fasting glucose, and HIV viral load. Asymptomatic cardiac disease related to HIV can be fatal, and secondary effects of HIV infection often disguise cardiac symptoms, so systematic echocardiographic monitoring is warranted. Keywords: HIV; AIDS; child; cardiac outcomes; antiretroviral therapies; therapeutic complications; cardiovascular risk. Received 20 February 2013; Accepted 16 April 2013; Published 18 June 2013 Copyright: – 2013 Lipshultz SE et al; licensee International AIDS Society. This is an open access article distributed under the terms of the Creative Commons Attribution 3.0 Unported (CC BY 3.0) Licence (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction (HIV) infection is a primary cause of acquired heart disease, particularly of accelerated atherosclerosis, symptomatic heart failure and pulmonary arterial hypertension [117]. Cardiac complications often occur in the later stages of HIV infection with prolonged viral infection and are therefore becoming more relevant as longevity improves [117]. Multiagent HIV therapies that help sustain life may also directly increase the risk of cardiovascular events and accelerated atherosclerosis [1,1822]. By 2011, between 31 and 36 million people were living with HIV [23], an estimated 0.8% of all people aged 1549 years. Globally, treatment and burden of this epidemic varies greatly from one region to the next. One of the most severely afflicted regions is sub-Saharan Africa, where 69% of all people living with HIV reside and nearly 1 in every 20 adults is infected [23]. In 2011, 330,000 children acquired HIV infection (90% of whom are in sub-Saharan Africa), 43% less than in 2003 [23]. HIV-infected children did not usually receive antiretroviral therapy (ART) or only received monotherapy with zidovudine in the early 1990s. These children often experienced abnormal left ventricular (LV) structure and function, a predictor of mortality [24]. Although the cardiovascular effects of HIV and ART are not fully understood, HIV-infected children are routinely exposed to ARTor highly active antiretroviral therapy (HAART) while the cardiovascular system is still developing. Sub-clinical cardiac abnormalities may develop into symptomatic cardiomyopathy in adulthood. 1 Lipshultz SE et al. Journal of the International AIDS Society 2013, 16:18597 http://www.jiasociety.org/index.php/jias/article/view/18597 | http://dx.doi.org/10.7448/IAS.16.1.18597 Cardiac abnormalities (Table 1) associated with HIV infection include premature myocardial infarction (MI) or stroke, pericardial effusion, lymphocytic interstitial myocarditis, LV diastolic dysfunction, dilated cardiomyopathy (frequently with myocarditis) infective endocarditis, and malignancy (myocardial Kaposi’s sarcoma and B-cell immunoblastic lymphoma; Table 1) [3,4,25,26]. Treatment-related drug effects and interactions are considerably more prevalent and directly challenge the cardiovascular system through lipid abnormalities with protease inhibitors (PIs) and an increased statin serum concentration with PIs [18]. Therapies may also change repolarization or prolong the QT interval, increasing the risk of sudden cardiac death [18]. Discussion Accelerated atherosclerosis Since the advent of ART, patients with HIV infection have longer life expectancies, but chronic conditions including atherosclerotic and metabolic disease are becoming more prevalent in this population [27]. Highly active ART (HAART) causes a metabolic syndrome well-characterized in adults as unfavourable body composition (reduction in subcutaneous and increase in visceral fat), insulin resistance and abnormal glucose metabolism, and dyslipidemia [28,29]. The physiologic effect of the metabolic syndrome places patients at risk for atherosclerotic cardiovascular disorders. In fact, in adults with HAART-related fat redistribution, several studies have suggested an increase in the risk of MI relating to the level of viral control (increased inflammation) or to ART exposures (including PIs and certain nucleoside reverse transcriptase inhibitors) [3032]. Acute MI can be the primary presentation of atherosclerotic disease [33]. However, there is controversy over whether the metabolic syndrome in HIVinfected patients is exclusively related to ART exposure or HIV infection itself. Synergistic causes may include traditional risk factors such as family history, high LDL cholesterol, low HDL cholesterol, diabetes, hypertension, age 55, HIV viral load, and medication specific ART exposure. Studies in children show similar although not identical findings, including abnormal body composition, insulin resistance, and dyslipidemia with the use of ART, with increased risk at older age and longer duration of HAART [3440]. The onset of puberty has been proposed as another factor that is associated with accelerating these changes [41]. Early studies in children showed that PI therapy improved weight, weight-for-height and mid-arm muscle circumference of HIV-infected children, independent of the concurrent decrease in HIV viral load and improved CD4 T-lymphocyte counts [42]. The immediate treatment effects were most apparent with an improvement in weight and mid-arm muscle circumference and there was a trend towards increased height and lean body mass. In addition to the positive improvements in growth and lean body mass, however, HAART is also associated with abnormalities in fat distribution in children though some studies report similar lean mass in HIV-infected and uninfected children [43]. Arpadi et al. observed similar total fat, trunk fat, and percentage of total fat between HIV-infected and uninfected children, but lower leg and higher arm fat in infected children [44]. Jacobson et al. showed there were decreased limb/trunk fat ratios in HIV-infected children when compared with HIV-exposed uninfected (HIVEU) [35]. These findings suggest that both peripheral lipoatrophy, as well as central obesity occur in these children. Further studies have shown that a majority of children develop fat redistribution within three years of initiating a protease inhibitor (PI) - containing regimen, and that these changes progress over time [45]. Other studies have identified metabolic abnormalities induced by other specific classes of drugs. Stavudine use has been associated with lipoatrophy [46], potentially by altering mitochondrial number and function [47]. Following exposure to ART, there are increases in total, LDL, and HDL cholesterol in both adults and children. Children newly exposed to ART experienced a rapid rise in LDL cholesterol over the first six months that continued through 12 months [48]. A total of 10% of a cohort of 449 children in the United Kingdom had LDL cholesterols over the 95% for age and PIs caused greater rises in total cholesterol than nonnucleoside reverse transcriptase inhibitors. The authors concluded that dietary and exercise interventions and a change in ART might help address these metabolic abnormalities [49]. In children with incident hypercholesterolemia, Jacobson et al. found that a switch in the ART regimen was associated with cholesterol levels that returned to normal [50]. There was limited power to detect the effects of switching to specific ARTs; however, a higher viral load at baseline was associated with the normalization of cholesterol. According to the Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents, switching from one PI to another PI or to the same PI at a lower dosing frequency may reduce dyslipidemia [51]. Evaluating metabolic changes in children as they start or change ART can be helpful to determine specific effects of ART because children have fewer confounding psychosocial factors (such as smoking, alcohol, obesity) that can independently impact metabolic outcomes. Atherosclerotic cardiovascular disease (CVD) often results from an environment that is hostile to the endothelium, which may occur from a complex interaction of HIV, the adverse effects of ART, traditional risk factors for CVD, inflammation and co-infections [52]. Autopsies in HIV-infected patients aged 2332 years who died unexpectedly revealed atherosclerotic plaque with features common to both coronary atherosclerosis and transplant vasculopathy, histologic characteristics more frequently seen with single-vessel disease in which the cause of MI is plaque rupture [53,54]. Imaging data suggest inflammation as the cause of such premature cardiovascular events (Table 2). Endothelial dysfunction is one possible causative link between HIV infection and atherosclerosis. HIV-infected patients have increased expression of vascular adhesion molecules (E-selectin, ICAM, VCAM) and inflammatory cytokines such as interleukin (IL-6) and tumour necrosis factor (TNF)-a [55,56]. The presence of an endothelial response to injury is supported by the correlation of viral load with higher plasma TNF-a, IL-6, and von Willebrand factor concentrations [37,55,57]. The risk of myocardial infarction has been found to increase with the exposure to combination ART (Figure 1) [57]. 2 Summary of HIV-associated cardiovascular diseases Incidence/ Disease Accelerated atherosclerosis Possible causes Protease inhibitors, atherogenesis with virus-infected macrophages, prevalence Diagnosis Treatment Up to 8% prevalence ECG, Stress testing, echocardiography, lipid Smoking cessation, low fat diet, aerobic chronic inflammation, glucose intolerance, dyslipidemia, endothelial profile, CT angiography, and calcium exercise, blood pressure control, dysfunction scoring guideline based statin use, percutaneous coronary intervention, coronary artery Dilated bypass surgery Diuretics, digoxin, ACE inhibitors, Coronary Artery Disease Drug related: Up to 8% of Chest radiograph findings cardiomyopathy cocaine, AZT, IL-2, doxorubicin, interferon asymptomatic ECG: Nonspecific conduction abnormalities, b-blockers systolic Infectious: patients PVCs, PACs Adjunctive treatment in HIV patients dysfunction HIV, toxo-plasma, coxsackievirus group B, EBV, CMV, adenovirus Up to 25% of Echocardiogram findings: low-normal LV Treatment of infection nutritional Metabolic or endocrine: autopsy cases wall thickness, increased LV mass, dilated replacement Selenium or carnitine deficiency, anaemia, hypocalcemia, LV, systolic LV dysfunction. IVIg hypophosphatemia, hyponatremia, hypokalemia, hypoalbuminemia, hypothyroidism, growth hormone deficiency, adrenal insufficiency, Possible laboratory studies: Intensify antiretroviral therapy Troponin T, brain natriuretic peptide level, Follow-up serial echocardiograms hyperinsulinemia CD4 count, viral load, viral PCR, toxoplasma Cytokines: serology, thyroid-stimulating hormone, TNF-a, nitric oxide, TGF-b, endothelin-I, interleukins cortisol, carnitine, selenium, serum ACE, Immunodeficiency: stress testing, myocardial biopsy, cardiac CD4 B 100 catheterization LV diastolic dysfunction Pulmonary Autoimmune TNF, Interleukin (6) Up to 37% Echocardiography Treat hypertension Hypertension asymptomatic Tissue doppler imaging Intensify antiretroviral therapy Chronic viral infection Plexogenic pulmonary arteriopathy 0.5% hypertension Pericardial disease ECG, echocardiography, right heart Anticoagulation, vasodilators, catheterization prostacyclin analogs Bacteria: Staphylococcus, Streptococcus, Proteus, Klebsiella, 11%/year- markedly Pericardial rub on examination Endothelin antagonists, PDE-5 Inhibitors Treat the cause Pericardiocentesis Enterococcus, Listeria, Nocardia, reduced in post Echocardiogram Followup: Mycobacterium Viral pathogens: HIV, HSV, CMV, adenovirus, echovirus HAART studies. Fluid analysis for gram stain, and culture, Serial echocardiograms Other pathogens: Spontaneous cytology ECG-low voltage/PR depression Intensify antiretroviral therapy Cryptococcus, Toxoplasma, Histoplasma resolution in 42% of Associated pleural and peritoneal fluid Pericardiocentesis or window Malignancy: affected patients analysis Histoplasma Kaposi’s sarcoma, lymphoma, capillary leak/wasting/malnutrition Hypothyroidism Approximately 30% increase in Pericardial biopsy Immunodeficiency six-month mortality Uremia Lipshultz SE et al. Journal of the International AIDS Society 2013, 16:18597 http://www.jiasociety.org/index.php/jias/article/view/18597 | http://dx.doi.org/10.7448/IAS.16.1.18597 Table 1. 3 Disease Infective endocarditis Possible causes Incidence/ prevalence Autoimmune Bacteria: Staphylococcus aureus or Staphylococcus Increased incidence epidermidis, Salmonella, Streptococcus, Hemophilus parainfluenzae, in IVDA, regardless Pseudallescheria boydii, of HIV status Diagnosis Blood cultures; Echocardiogram Treatment IV antibiotics, valve replacements HASEK organisms Fungal: Aspergillus fumigatus, Candida, Cryptococcus neoformans Valvular damage, vitamin C deficiency, malnutrition, wasting, DIC, Rare condition, but thrombotic hypercoagulable state, prolonged acquired immunodeficiency clinically relevant endocarditis emboli in 42% of cases Kaposi’s sarcoma, non-Hodgkin lymphoma, leiomyosarcoma Low CD4 Approximately 1% Nonbacterial Malignancy Echocardiogram Anticoagulation, treat vasculitis or underlying illness Echocardiogram, biopsy Chemotherapy possible Recurrent pulmonary infections, pulmonary arteritis, microvascular ECG, echocardiography, right heart Diuretics, treat underlying lung infection pulmonary emboli, COPD catheterization or disease, anticoagulation as clinically indicated Systemic corticosteroids, withdrawal of count, prolonged immunodeficiency HHV-8, EBV incidence Usually metastatic in HIV patients Right ventricle disease Vasculitis Drug therapy with antibiotics and antivirals Autonomic CNS disease, drug therapy, prolonged immunodeficiency, malnutrition, Increased in dysfunction sedentary lifestyle Increasing incidence Clinical diagnosis Tilt-table test, Holter or Event monitoring drug Procedural precautions patients, with CNS disease Arrhythmias Drug therapy, pentamidine, autonomic dysfunction, acidosis electrolyte abnormalities ECG*long QT, Holter monitoring, exercise Discontinue drug, procedural stress testing precautions Lipodystrophy Drug therapy: protease inhibitors Echocardiography, lipid profile, cardiac Lipid therapy (beware of drug catheterization, coronary calcium score interactions), aerobic exercise, altered Electrolyte replacement antiretroviral, therapy, cosmetic surgery/fat implantation 4 ACEangiotensin-converting enzyme; AZTazidothymidine; CMV cytomegalovirus; CNS central nervous system; DICdisseminated intravascular coagulation; EBVEpstein-Barr virus; ECGelectrocardiogram; HHV human herpes virus; HIV human immunodeficiency virus; HSV herpes simplex virus; HTN hypertension; IL-2 interleukin-2; IVDAintravenous drug abuse; IVIgintravenous immunoglobulin; LVleft ventricular; PACpremature atrial complex; PCR polymerase chain reaction; PVC premature ventricular complex; TGFtransforming growth factor; TNFtumour necrosis factor. Modified with permission from Fisher SD, Lipshultz SE. Chapter 72: Cardiovascular abnormalities in HIV-infected individuals. In: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, Ninth Edition. Editors: Bonow RO, Mann DL, Zipes DP, Libby P. Philadelphia: Elsevier Saunders. 161827. 2011 ISBN: 978-1-4377-0398-6. Lipshultz SE et al. Journal of the International AIDS Society 2013, 16:18597 http://www.jiasociety.org/index.php/jias/article/view/18597 | http://dx.doi.org/10.7448/IAS.16.1.18597 Table 1 (Continued ) Lipshultz SE et al. Journal of the International AIDS Society 2013, 16:18597 http://www.jiasociety.org/index.php/jias/article/view/18597 | http://dx.doi.org/10.7448/IAS.16.1.18597 Table 2. Imaging and support that atherosclerosis is inflammatory in HIV-infected people Modality Carotid ultrasound HIV vs Matched Controls Associations First to show higher rates of Smoking, dyslipidemia, low nadir CD4 T-cell count, and increased Carotid intimal-medial atherosclerosis lymphocyte activation correlated with higher IMT and progression thickness 0.04 mm thicker in HIV (metanalysis) Computed tomography calcium scores CT angiography HIV-infected have higher mean Agatston Framingham risk, metabolic syndrome, higher levels of asymmetric scores and proportion of scores 0 dimethylarginine, and fatty liver Higher prevalence of noncalcified plaque CD4/CD8 ratio and HIV duration independently predict plaque burden Association of HIV viremia and atherosclerotic plaque burden in Magnetic resonance angiography the aorta Extensively used in cerebral and peripheral vascular beds Flow-mediated brachial artery Impaired in HIV-infected dilation Degree of HIV viremia, injection drug use, periodontal disease, and vitamin D deficiency Statins, niacin, and pentoxifylline have been beneficial in improving flow-mediated dilation Future potential imaging Intravascular ultrasound Intracoronary optical coherence tomography Future PET imaging of 18 FDG uptake Molecular targeted magnetic resonance imaging Modified with permission from Fisher SD, Lipshultz SE. Chapter 72: Cardiovascular abnormalities in HIV-infected individuals. In: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, Ninth Edition. Editors: Bonow RO, Mann DL, Zipes DP, Libby P. Philadelphia: Elsevier Saunders. 161827. 2011 ISBN: 978-1-4377-0398-6. Premature cerebrovascular disease is also prevalent in HIVinfected adults and providers should be aware of its risks in young adults. A review of autopsies from 1983 to 1987 found that AIDS patients had an estimated 8% prevalence of stroke. Evidence of cerebral emboli was found in four of the 13 patients with stroke and the embolus had a clear cardiac source in three of these four patients. Considering these patients were in the pre-HAART era, the aetiology is possibly Figure 1. Risk of myocardial infarction according to exposure to combination antiretroviral therapy. The adjusted relative rate of myocardial infarction according to cumulative exposure to combination antiretroviral therapy was 1.16 per year of exposure (95% CI, 1.091.23). The I bars denote the 95% CIs. Reproduced with permission from ref. 57. 5 Lipshultz SE et al. Journal of the International AIDS Society 2013, 16:18597 http://www.jiasociety.org/index.php/jias/article/view/18597 | http://dx.doi.org/10.7448/IAS.16.1.18597 different. As HIV-infected children age, the common origins of stroke should be sought and atherosclerotic disease should be suspected. Premature atherosclerosis is generally found in children treated with ART, although it is not clearly ART related. Acute stroke investigation in HIV-infected individuals should be somewhat different than in the general population as a result of infectious and immune-mediated vasculopathy, tumours, opportunistic infections, and cardioembolism [58]. Prevention of premature CVD should be directed at identifying and decreasing known risk factors. Low cholesterol diets reduce the incidence of dyslipidemia [59]. In addition, patients should be encouraged to follow heart-healthy diets with increased aerobic activities and avoid smoking as it has been found that exercise and smoking cessation also markedly lower lipid levels and help prevent lipodystrophy [60]. It is also recommended that the patient’s glucose and lipid concentrations be monitored regularly [59,60]. Current guidelines should be followed for patients with dyslipidemia for primary and secondary risk prevention. Known drug interactions should be avoided, such as that with simvastatin and ritonavir, which can lead to a 400-fold increase in simvastatin concentrations [61,62]. Left ventricular systolic dysfunction Incidence Before HAART therapy, the two-to-five-year incidence of symptomatic heart failure ranged from 4 to 28% in HIV patients, suggesting a prevalence of symptomatic HIV-related heart failure of between 4 and 5 million cases worldwide [5,6]. The incidence of clinically important cardiac disease in HIV-infected patients has been markedly reduced by HAART. However, HAART is only available to a minority of those in need [6,6365]. Patients receiving HAART also frequently have asymptomatic abnormalities in cardiac structure [66]. Echocardiographic measurements indicate 18% have LV systolic dysfunction, 6.5% have LV hypertrophy, and 40% have left atrial dilation [64]. A history of MI, current tobacco smoking, and elevated highly sensitive C-reactive protein were associated with LV systolic dysfunction [64]. During pre-HAART era HIV-infected children aged ten or younger, 25% died from chronic cardiac disease [5,6], and 28% experienced serious cardiac events after an AIDSdefining illness [1,5,6,65]. Increased mortality is only associated with a mild decrease in LV systolic function or an increase in LV mass in children [24]. The NHLBI-funded Highly Active Antiretroviral Therapy-Associated Cardiotoxicity (CHAART-II) study collected longitudinal echocardiographic measurements in HIV-infected children and adolescents exposed to HAART or multi-drug ART. When compared to HIV-infected but relatively less ART-exposed children from the HIV-infected cohort from the Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2 HIV) study, the CHAART-II patients had persistently decreased LV mass. Although in infancy, the CHAART-II patients had significantly better LV contractility compared to the P2C2 HIV group, at ten years of follow-up, LV contractility significantly decreased in the CHAART-II group to a level equivalent to decreased LV systolic function in infancy in the P2C2 HIV group. These findings suggest that long-term HAART exposure may be cardioprotective for a finite period early in life, but decreases as this HIV-infected population ages into adolescence and early adulthood. Further longitudinal follow-up studies are needed in adolescents and young adults who were perinatally infected with HIV to better characterize their future cardiac risk. After 11 years of HAART exposure, in CHAART-II patients, LV function was equivalent to that of the HAART-unexposed P2C2 HIVinfected cohort. The conclusion was that the protective effects of HAART exposure on cardiac function appeared to diminish 11 years after exposure. A larger, but otherwise similar HIV-infected paediatric cohort from the NIH-funded Pediatric HIV/AIDS Cohort Study’s Adolescent Master protocol required only a single echocardiogram. Generally, measures of LV structure and function were better in this long-term HAART-exposed group than in the relatively HAART-unexposed P2C2 HIV cohort, but were not as normal as those in an HIVEU control group [67]. Although the general conclusion was that HAART exposure in HIV-infected children appeared to be cardioprotective, the cross-sectional study could not support conclusions regarding the long-term trajectories of cardiac health or dysfunction. Serial echocardiographic and other cardiovascular risk screening in this cohort as they age could inform the long-term cardiovascular risk in perinatally HIV-infected children in the HAART era. The CHAART-I study collected serial echocardiograms in a cohort of HIVEU children exposed perinatally to either multidrug ART or HAART [68]. At age two, these children had below-normal LV mass, LV dimension, and septal wall thickness, indicating smaller hearts. In contrast, LV function was increased. These differences were more pronounced in girls [68]. In a larger cohort of HIVEU, perinatally HAART-exposed and slightly older (aged 35 years) children from the PHACS SMARTT protocol, preliminary results from a single echocardiogram showed that 16% of children had at least one abnormal echocardiographic measure. First trimester exposure to various ART agents was associated with specific echocardiographic abnormalities. For instance, first trimester exposure to abacavir was associated with decreased LV wall thickness. In a separate study of the PHACS SMARTT HIVEU cohort, serum cardiac biomarker measurements suggested that HIVEU children perinatally exposed to multiple ART agents might have subclinical myocardial inflammation. Specifically, abacavir exposure was potentially associated with deleterious cardiac effects [69]. The results of cardiac biomarkers in the PHACS AMP HIVinfected cohort are still being analyzed and could provide further insights into both the long-term pathophysiologic effects of HAART exposure as well as how best to evaluate long-term cardiovascular risk. Currently, additional analyses are on-going comparing the cross-sectional echocardiographic measures in this PHACS SMARTT cohort to the relatively ART-unexposed P2C2 HIV cohort and the smaller but longitudinally followed CHAART-I perinatally HAARTexposed cohort. The results of these on-going analyses may better elucidate the effects of prenatal HIV and ART exposures on cardiac measures of structure and function in HIVEU children. 6 Lipshultz SE et al. Journal of the International AIDS Society 2013, 16:18597 http://www.jiasociety.org/index.php/jias/article/view/18597 | http://dx.doi.org/10.7448/IAS.16.1.18597 Recent data show a marked decline in the incidence of both clinical cardiomyopathy and structural abnormalities and an apparent cardioprotective effect of HAART in children and adolescents [58,6365,68]. Clinical presentation Concurrent pulmonary infections, anaemia, pulmonary hypertension, malnutrition, portal hypertension, and malignancy can modify or confuse the distinctive signs in HIV-infected patients that define heart failure in other populations. Patients can present with LV systolic dysfunction that is anywhere from asymptomatic to New York Heart Association Class III (marked functional limitations) or IV heart failure (severe functional limitations) [62]. Echocardiography, including strain measurements, and cardiac magnetic resonance imaging is useful for assessing LV function, in addition to diagnosing LV dysfunction. Images often reveal LV hypertrophy, dilation, or low-to-normal wall thickness, as well as left atrial dilation [5,24,33,62,64]. Echocardiographic assessment is recommended at baseline and every 12 years thereafter, or as indicated, in any patient at elevated cardiovascular risk who has unexplained or persistent pulmonary symptoms or viral co-infections or with any clinical manifestations of CVD [5,54,62,64]. Electrocardiography (ECG) often reveals nonspecific conduction defects or repolarization changes in ART naı̈ve patients. Chest radiography has low sensitivity and specificity for diagnosing heart failure in HIV-infected patients treated or untreated with ART. Several small studies of HIV-infected individuals revealed that blood brain natriuretic peptide concentrations were inversely correlated with LV ejection fraction. This inverse correlation can be useful in the differential diagnosis of congestive cardiomyopathy in HIVinfected patients [33,69,70]. Progressive LV dilation is common in children infected with HIV. LV dilation may precede heart failure (five-year cumulative incidence, 12.3%) and is associated with elevated LV afterload, LV hypertrophy, and reduced LV function [65]. Early and continuous treatment with HAART for at least five years in HIV-infected children prevented clinically important heart failure better than in earlier groups and preserved cardiac structure and function, indicating that HAART may be cardioprotective [65]. Both the PHACS and CHAART studies suggest that any cardiac changes in the HAART era are generally subclinical in children. Further, in addition to characterizing lifetime ART exposure, traditional non-HIV cardiovascular risk factors, will be needed to best determine differences in global cardiovascular risk between perinatally HIV-infected and HIVEU children, and that in the general population. Pathogenesis in children Two mechanisms of pathogenesis have been described in children treated with ART in the pre-HAART with perinatallytransmitted HIV infection: dilation of the LV with a reduced ratio of the LV wall thickness to end-systolic dimension and concentric hypertrophy of the muscle and dilation, in which the ratio of LV thickness to end-systolic dimension remains normal or is increased [5]. Pathogenesis in young adults As these children enter young adulthood, adult pathogenesis of the disease becomes more relevant. Several causative agents have been postulated for HIV-related cardiomyopathy in children and adults receiving treatment who are from the pre-HAART era (Table 1) [62,65,68]. Myocarditis Dilated cardiomyopathy can be related to the direct action of HIV on myocardial tissue or to proteolytic enzymes or cytokine mediators induced by HIV alone or with co-infecting viruses [71]. Endomyocardial biopsy specimens have revealed Toxoplasma gondii, coxsackievirus group B, Epstein-Barr virus, cytomegalovirus, adenovirus, and HIV in myocytes. Further research is required to determine if these coinfecting agents also apply in the post-HAART era. Only scant and patchy inflammatory cell infiltrates in the myocardium have been identified in autopsy and biopsy findings [5,62,71,72], indicating that HIV can infect myocardial interstitial cells and are rarely found in cardiomyocytes. Patients with confirmed myocarditis have an increased number of infected interstitial cells where proteolytic enzymes or increased concentrations of TNF-a or interleukin may injure the myocytes. Studies have revealed that these affected patients have increased concentrations of TNF-a, inducible nitric oxide synthase, and IL-6 [5,62,71,73]. About 40% of patients with HIV-related cardiomyopathy have no opportunistic infection before the onset of cardiac symptoms [5,6], although this cardiomyopathy is commonly not associated with specific opportunistic infections. Cytokine alterations Increased TNF-a production induced by HIV infection can elevate nitric oxide production and alter intracellular calcium homeostasis, transforming growth factor-b and endothelin-1 activity [74]. When nitric oxide concentrations were elevated experimentally, myocytes were killed or injured, causing negative inotropic effects [74]. Clinical trials are needed in order to determine the effect of cytokine alterations in the current post-HAART era. Nutritional deficiencies Nutritional deficiencies are common in HIV-infected individuals, particularly in the late stages and in young infants. Electrolyte imbalances and deficiencies in elemental nutrients are often a result of diarrhoea and poor absorption. Deficiencies of trace elements have been associated with cardiomyopathy. For example, coxsackievirus is more virulent in selenium-deficient cardiac tissue [54]. Left ventricular function is restored and cardiomyopathy is reversed with selenium replacement. Concentrations of vitamin B12, carnitine, growth hormone, and thyroid hormone can be altered in HIV disease; all have been associated with LV dysfunction [69,75]. Course of disease Patients with asymptomatic LV dysfunction, defined as a LV fractional shortening B28% with global LV hypokinesis, may have echocardiographically defined transient disease. One serial echocardiographic study reported that three out 7 Lipshultz SE et al. Journal of the International AIDS Society 2013, 16:18597 http://www.jiasociety.org/index.php/jias/article/view/18597 | http://dx.doi.org/10.7448/IAS.16.1.18597 of six patients with abnormal LV fractional shortening had normal readings after a mean of nine months. The three patients with persistently depressed LV function all died within one year of diagnosis of LV systolic dysfunction [5]. Prognosis Mortality has increased in HIV-infected patients with cardiomyopathy, independently of CD4 count, sex, age, or HIV risk group. In the pre-HAART era, median survival from diagnosis to AIDS-related death was 101 days in patients with LV dysfunction. Patients with normal hearts had a median survival of 472 days at a similar stage of infection [1,5]. Neither isolated right ventricular dysfunction nor borderline LV dysfunction increased the risk of AIDS-related death. In the P2C2 HIV study, the median age was 2.1 years and fiveyear cumulative survival was 64% [5]. Children with baseline measurements showing depressed LV fractional shortening or increased LV dimension, mass, thickness, heart rate, blood pressure, or wall stress had a higher mortality. Increased LV wall thickness and decreased LV fractional shortening also predicted adjusted survival (Figure 2) [5]. Although increased LV wall thickness identified a population at risk only 1824 months before death, LV fractional shortening was abnormal for three years before death. Although most patients received zidovudine at some point during the P2C2 study, a separate report found that zidovudine was not associated with cardiac complications [76]. Thus, LV fractional shortening may be a useful long-term predictor of mortality, and LV wall thickness, a useful short-term predictor in children receiving ART from the pre-HAART era [5,24,65,77]. In the P2C2 HIV-infected cohort, echocardiographic evidence of increased LV mass was associated with post-mortem cardiomegaly and documented chronically increased heart rate before death but not with anaemia, HIV viral load, or encephalopathy [5]. Mild persistent depression of LV function and elevated LV mass were associated with higher all-cause mortality in children infected with HIV [24,65,68]. A reduction in LV fractional shortening from 34 to 30% in a ten-year Figure 2. Mildly increased LV mass is a risk marker for early HIV mortality even though it is still inadequate for LV dimension. Reproduced with permission from ref. 24. old, equivalent to a reduction of 2 Z-scores, is associated with an increase from 15 to 55% in five-year mortality [65,68]. Fractional shortening was higher in HIV-uninfected children of HIV-infected mothers with in utero exposure to ART than in HIV-uninfected children of HIV-infected mothers unexposed to ART. However, exposure to ART was associated with decreased LV mass, LV dimension, and septal thickness [68]. Any exposure to HAART in perinatally-infected children with HIV markedly affects LV mass, LV contractility, and LV afterload [78]. Rapid-onset heart failure has a grim prognosis in both HIV-infected children and adults. More than half of patients die from primary cardiac failure within a year of presentation [1,5,62]. Therapy Similar to non-ischemic cardiomyopathy, therapy for dilated cardiomyopathy associated with HIV infection includes diuretics, digoxin, aldosterone antagonists, b-blockers, and angiotensin-converting enzyme inhibitors, as tolerated. The efficacy of specific cardiac therapeutic regimens other than intravenous immunoglobulin is unknown [2]. Due to low systemic vascular resistance, patients may be very sensitive to angiotensin-converting enzyme inhibitors. Preventing heart failure using HAART remains the best treatment [59,60,62]. Infections should be treated to improve or resolve related cardiomyopathy. Right ventricular biopsy may assist in target therapy in addition to identifying infectious causes of failure [62]. Right ventricular biopsy may be underused [6,62,64,71]. Serial echocardiographic measurements should be performed at clinically relevant intervals, such as four months, after medical therapy is begun. Monitoring recommendations for testing and timing of follow-up are based on studies relating impaired LV fractional shortening to a worse prognosis. A biopsy should be considered if cardiac function continues to deteriorate or if the clinical course worsens. Patients with heart failure who have not responded to two weeks of medical therapy may benefit from cardiac catheterization and endomyocardial biopsy, which may reveal lymphocytic infiltrates suggesting myocarditis or treatable opportunistic infections (by special stains), permitting aggressive therapy of an underlying pathogen [5,52,62,68,71,74]. Angiography should be performed selectively if there are risk factors for atherosclerotic disease or suggestive clinical symptoms (Figure 3) [33,44]. In HIV-uninfected children, intravenous immunoglobulins help treat acute congestive cardiomyopathy and nonspecific myocarditis. Monthly immunoglobulin infusions have minimized LV dysfunction, increased LV wall thickness, and reduced peak LV wall stress in HIV-infected children, suggesting that both impaired myocardial growth and LV dysfunction can be immunologically mediated [2]. Although transplantation therapy is not widely available, it remains an area of active research and has been successfully performed [70]. Animal models Exposure to a ubiquitous environmental agent, heat-killed Mycobacterium avium complex, results in exaggerated myocardial pathology in Rhesus macaques infected with simian immunodeficiency virus. In this model, enternacept 8 Lipshultz SE et al. Journal of the International AIDS Society 2013, 16:18597 http://www.jiasociety.org/index.php/jias/article/view/18597 | http://dx.doi.org/10.7448/IAS.16.1.18597 Figure 3. Cardiac dysfunction in HIV-infected patients. HAART highly active antiretroviral therapy; LVleft ventricular; PPDpurified protein derivative; TSH thyroid-stimulating hormone. Reproduced with permission from ‘‘Fisher SD, Lipshultz SE. Chapter 72: Cardiovascular abnormalities in HIV-infected individuals. In: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, Ninth Edition. Editors: Bonow RO, Mann DL, Zipes DP, Libby P. Philadelphia: Elsevier Saunders. 161827. 2011 ISBN: 978-1-4377-0398-6.’’ (a TNF antagonist) prevented LV dysfunction, suggesting a TNF-a-dependent pathway in the development of cardiomyopathy in HIV infection [74]. Left ventricular diastolic dysfunction Diastolic dysfunction is relatively common in long-term survivors of HIV infection, as suggested by clinical and echocardiographic data. Such LV dysfunction may precede LV systolic dysfunction and mark an early manifestation of HIVassociated cardiac disease [18,75,7981]. However, LV diastolic function has not been characterized in HIV-uninfected children exposed in utero to ART. Slower LV relaxation during diastole leads to a decrease in early diastolic filling. Left ventricular compliance decreases as LV diastolic dysfunction worsens and left atrial pressure increases. Moderate-tosevere LV diastolic dysfunction, an independently predicts mortality, regardless of normal LV systolic function [82]. The clinical impact of LV diastolic function has been studied in children with cardiomyopathy along with other comorbidities, such as obesity, generalized autoimmune disease, and diabetes [8388]. In one cross-sectional study, early diastolic mitral valve annular velocity was lower in HIVEU children born to HIVinfected mothers who were exposed in utero to ART compared to a group of HIV-uninfected children born to HIV-uninfected mothers with no perinatal ART exposure. In addition, lower early diastolic mitral valve annular velocity was associated with lower maternal CD4 counts in the final trimester [89]. The longitudinal CHAART-I study found subclinical LV diastolic abnormalities in both LV compliance and relaxation among HIVEU children exposed perinatally to multi-drug ART [83]. In a study of 656 asymptomatic HIV-infected adults, 26% had screening echocardiographic evidence of LV diastolic dysfunction [64]. Adults with LV 9 Lipshultz SE et al. Journal of the International AIDS Society 2013, 16:18597 http://www.jiasociety.org/index.php/jias/article/view/18597 | http://dx.doi.org/10.7448/IAS.16.1.18597 diastolic dysfunction, compared to those without, were older, tended to have higher body mass indexes, more likely to have hypertension, and had been infected longer [81]. Whether LV diastolic dysfunction is associated with an increased risk of early coronary disease is unknown [75,81]. In children, also unknown is the clinical importance of LV systolic versus diastolic dysfunction in HIV-infected and HIVEU children perinatally exposed to multi-drug ART. The temporal occurrence of these LV systolic versus diastolic echocardiographic changes is important in determining the effects of HIV exposure and ART exposure. Uncontrolled HIV replication and ART increase IL-6 concentrations [90]. Viral proteins or replication in the myocardial macrophages in animal models may cause LV diastolic dysfunction. Longitudinal mitral inflow and tissue Doppler echocardiographic studies of Rhesus macaques infected with simian immunodeficiency virus found that LV diastolic dysfunction was common and strongly correlated with the extent of viral replication in the myocardium [90]. Pulmonary hypertension Pulmonary arterial hypertension (PAH) occurs in about 0.5% of HIV-infected patients. This does not include cases of elevated pulmonary pressure secondary to interstitial lung disease or chronic obstructive pulmonary disease where the pathophysiology and response to therapies differ. The introduction of HAART has not changed the prevalence of pulmonary arterial hypertension [3,9194]. In HIV-infected patients, normal endothelial structure is replaced by plexogenic pulmonary arteriopathy, which is characterized by remodelling of the pulmonary vasculature with intimal fibrosis [92,93]. Perfusion scans are normal and lung fields may be clear on examination and chest radiographs [92]. Pulmonary arterial hypertension has been reported in HIV-infected patients without a history of thromboembolic disease, intravenous drug use, or pulmonary infections associated with HIV [3,93,94]. Primary pulmonary hypertension has been found in patients with haemophilia receiving lyophilized factor VIII, intravenous drug users, and patients with LV dysfunction, obscuring any relationship with HIV [3,93]. Whether PAH is associated with human herpesvirus 8 is unclear. HIV or a coinfection might cause endothelial damage and mediatorrelated vasoconstriction of the pulmonary arteries. Two recent studies found that CD4 count was independently associated with survival in 154 patients with HIV and PAH, with pulmonary hypertension as the direct cause of death in 72% of those affected. Survival rates at one, two, and three years were 73, 60, and 47%, respectively. Survival rates in New York Heart Association functional Class IIIIV patients at the time of diagnosis were 60, 45, and 28% at one, two, and three years [93,94], respectively. In one year, 52% of 549 patients with HIV and PAH died with 51% from right heart failure [94]. Standard treatments for PAH, such as PDE-5 inhibitors, endothelin antagonists, and prostacyclin analogues, have been effective in HIV-infected patients. Therapy also includes anticoagulation (on the basis of individual risk-benefit analysis) [92]. Affected patients have continued HAART. In patients with HIV and PAH, PAH should be aggressively treated because it is life-threatening as set forward in the American College of Cardiology Foundation’s treatment guidelines for PAH [92]. Morbidity and mortality seem to be caused by PAH more than by HIV infection and, therefore, should be clinically managed based on current recommendations from the American College of Cardiology expert consensus document on pulmonary hypertension [92]. Pericardial effusion Incidence Pericardial effusions were found in up to 11% of patients with AIDS before the HAART era. The prevalence of effusion in asymptomatic AIDS patients reaches a mean of about 22% after 25 months, rising over time [95]. In a recent study, only 2 out of 802 HAART-treated patients had clinically important effusions, indicating the greatly reduced incidence with treatment of HIV [95]. Clinical presentation HIV-infected patients with pericardial effusions generally have lower CD4 counts than those without effusions [92]. Effusions are generally small and asymptomatic. HIV infection should be suspected whenever a patient presents with unexplained pericardial effusion or tamponade. In a retrospective series from a city hospital, 13 out of 37 (35%) patients with cardiac tamponade had HIV infection [95]. Although rare, tuberculosis has been found as a presenting infection for pericardial effusions in underdeveloped areas where tuberculosis is prevalent [95,96]. These cases have therapeutic implications and deserve special attention [97]. Pathogenesis Pericardial effusion is often part of a generalized serous effusive process also involving pleural and peritoneal surfaces. Enhanced cytokine production in AIDS may be associated with this ‘‘capillary leak’’. Other well-described associations (Table 1) include uremia from HIV-associated nephropathy or drug nephrotoxicity. Effusion nearly triples the risk of death among AIDS patients [95]. Immune reconstruction inflammatory syndrome can cause pericardial effusions and pericarditis in patients co-infected with HIV and tuberculosis [98]. Pericardiocentesis has been found to be a safe and effective treatment of tuberculosis pericardial effusions in HIV-infected patients [99]. Monitoring and therapy Baseline echocardiography and ECG measurements should be taken on all HIV-infected patients with evidence of heart failure, Kaposi’s sarcoma, tuberculosis, or other pulmonary infections. Pericardiocentesis is indicated for pericardial effusion when there are clinical signs of tamponade (such as elevated jugular venous pressure, dyspnea, hypotension, persistent tachycardia, or pulsus paradoxus), or echocardiographic signs of tamponade (such as continuous-wave Doppler echocardiographic evidence of respiratory variation in valvular inflow, septal bounce, right ventricular diastolic collapse, and a large effusion). 10 Lipshultz SE et al. Journal of the International AIDS Society 2013, 16:18597 http://www.jiasociety.org/index.php/jias/article/view/18597 | http://dx.doi.org/10.7448/IAS.16.1.18597 Patients with pericardial effusion without tamponade should be evaluated for malignancy and opportunistic infections, such as tuberculosis. HAART should be considered if it has not already been instituted. Repeat echocardiography is recommended after one month or sooner if indicated (Figure 3) [20,62]. Infective endocarditis Infective endocarditis has been reported in adults with HIV infection, most commonly in intravenous drug users, and usually causes right-sided endocarditis. The most common organism associated with endocarditis in HIV-infected adult patients is Staphylococcus aureus. Endocarditis caused by Aspergillus fumigatus, Candida species, and Cryptococcus neoformans are more common in intravenous drug users with HIV than in those without HIV. Generally, HIV does not appear to significantly influence the response to treatment or outcome (Table 1) [20]. Late-stage AIDS patients with poor nutritional status and severely compromised immune systems may experience a more fulminant course and a higher mortality. However, several patients have been successfully treated with antibiotics. Surgical indications in HIV-infected patients with endocarditis include persistent bacteremia despite intravenous antibiotics to which the organism is sensitive, hemodynamic instability, persistent embolization and severe valvular destruction in patients with a reasonable life expectancy after surgery. Endocarditis in HIV-infected children is rare. There is a report of a two month old HIV-infected Ugandan boy who presented with disseminated Staphylococcus aureus infection with a large obstructing vegetation on the free wall of the left ventricle in association with a purulent pericardial effusion and an empyema. Echocardiogram showed no structural abnormalities other than a patent foramen ovale [100]. Nonbacterial thrombotic endocarditis Marantic or non-bacterial thrombotic endocarditis involves deposition of large, friable, sterile vegetations predominantly on the cardiac valves. These vegetations have been associated with disseminated intravascular coagulation and systemic embolization. Vegetations are rarely diagnosed before death, but when they are, clinically important emboli are likely [20]. Marantic endocarditis is rare in children, but was described in a child newly diagnosed with HIV at age 14 months. The child developed pneumonia, Staphylococcus sepsis, and later developed acute cardiac failure with valvular dysfunction, hepatosplenomegaly, ascites and failure to thrive. An echocardiogram showed bright echoes within the chordea of the tricuspid valve and the tips of the leaflets. After a complicated course, the child died of pulmonary insufficiency at age 34 months [101]. It is likely that this type of endocarditis is more likely to be identified in patients with delayed HIV diagnosis, limited or no access to ART and those with progressive disease. In the early HIV epidemic, several case series in adults suggested a high incidence of this uncommon disorder; however, few cases have since been reported. Cardiovascular malignancy Malignancy affects many adult AIDS patients, generally in the later stages of disease. Cardiac malignancy may be a primary tumour or a metastatic secondary site. Although lymphomas have been associated with malignancy in HIV-infected children, the incidence is low and cardiac malignancy is rare in children with HIV infection. The Children’s Cancer Group and the Paediatric HIV Clinic at the National Cancer Institute reported 65 tumours diagnosed between 1982 and 1997 in 64 HIV-infected children [102], although these patients were not on treatment. Non-Hodgkin’s lymphoma accounted for 65% of these tumours. In this study, almost one-third of the children with this disease had normal or moderate immune suppression. Leiomyosarcoma occurred in 17% and Kaposi’s sarcoma in 5%. Kaposi’s sarcoma (angiosarcoma) affected up to 35% of AIDS patients early in the HIV epidemic and is associated with human herpesvirus 8. Its incidence is inversely related to CD4 count. Although sarcoma is infrequently described as a primary cardiac tumour, autopsy studies have found that 28% of HIV-infected patients with widespread Kaposi’s sarcoma had cardiac involvement [4]. Kaposi’s sarcoma is often an endothelial cell neoplasm with a predilection in the heart for sub-pericardial fat around the coronary arteries [4,20]. Combination antiretroviral therapy has markedly decreased the incidence of Kaposi’s sarcoma from that in the pre-HAART era [20]. Children with HIV infection may harbour human herpesvirus 8, the virus associated with Kaposi’s sarcoma. Kaposi’s sarcoma is endemic in eastern equatorial Africa. It can cause a lymphadenopathic type of Kaposi’s sarcoma that is found mainly in children, which may have a fulminant course and ultimately also invade organ systems. Two children were reported in the United States early in the epidemic, both died before one year of age and had progressive HIV infection with severe immune deficiency. There were lesions of Kaposi’s sarcoma in the lymph glands and spleen and in one case in the thymus [103]. Primary cardiac malignancy associated with HIV infection is generally caused by cardiac lymphoma. Lymphoma, an AIDSdefining illness, has a higher incidence in HIV-infected populations. Non-Hodgkin’s lymphomas are 2560 times more common in HIV-infected individuals. They are the first manifestation of AIDS in up to 4% of new cases [4]. This disease is not specifically associated with severe immune suppression. Patients with primary cardiac lymphoma can present with signs of heart failure, chest pain, or arrhythmias. Cardiac lymphoma can cause rapid progression to cardiac tamponade, heart failure, myocardial infarction, tachyarrhythmias, conduction abnormalities, or superior vena cava syndrome. Malignant cells can be found in the pericardial fluid. Systemic multi-agent chemotherapy with and without concomitant radiation or surgery has benefitted some patients, but overall, the prognosis is poor [4]. Treatment with HAART has not substantially affected the incidence of HIV-related non-Hodgkin’s lymphomas [20,104]. 11 Lipshultz SE et al. Journal of the International AIDS Society 2013, 16:18597 http://www.jiasociety.org/index.php/jias/article/view/18597 | http://dx.doi.org/10.7448/IAS.16.1.18597 Isolated right ventricular disease Isolated right ventricular hypertrophy is rare in HIV-infected individuals, with or without right ventricular dilation. It is generally related to pulmonary disease that increases pulmonary vascular resistance. Possible causes include pulmonary arteritis from the immunological effects of HIV disease, multiple bronchopulmonary infections, or microvascular pulmonary emboli caused by thrombus or contaminants in injected drugs such as Talc [3]. Right ventricular diastolic dysfunction has been reported in asymptomatic patients studied with Doppler tissue imaging [105]. Vasculitis Vasculitis may occur in patients with fever of unknown origin, unexplained arthritis or myositis, unexplained multisystem disease, glomerulonephritis, or peripheral neuropathy (especially mononeuritis multiplex), and in unexplained gastrointestinal, cardiac or central nervous system ischemia. Several types have been described in HIV-infected patients, but all types show diffuse inflammation of the vessel walls [106]. Successful immunomodulatory therapy has been reported, chiefly with systemic corticosteroid therapy [106]. The HIV protein, transactivator of transcription (Tat), has been implicated in the pathogenesis of vasculitis [106]. Sudden cardiac death Sudden cardiac death is becoming increasingly common as the HIV-infected population ages. In one study, sudden cardiac death accounted for 86% of all cardiac-related deaths (30 of 35). The mean rate of sudden cardiac death was 2.6 per 1000 person-years (95% confidence interval: 1.83.8), which was 4.5-fold as high as that expected in an age-matched uninfected population [107]. One report found that patients dying from sudden cardiac death were older than those dying from AIDS (mean age at death, 49 vs. 45 years, p 0.02), had a higher prevalence of prior MI (17% vs. 1%, pB0.001), cardiomyopathy (23% vs. 3%, p B0.001), heart failure (30% vs. 9%, p 0.004), and arrhythmias (20% vs. 3%, p0.003) [107]. QT interval and PR prolongation HIV infection is associated with QT prolongation and Torsades de Pointes ventricular tachycardia. There is an increased risk of sudden death late in HIV infection and specifically with AIDS. The incidence of QT prolongation increases as the disease progresses to AIDS [108]. Hepatitis C is independently associated with increased QT duration. One study found that the risk of QT prolongation (that is, QTc values of 470 ms or higher) was 16% with HIV alone and 30% with both HIV and hepatitis C infections [109]. The risk of increased QT duration is also higher in patients treated with ART as well as anti-tuberculosis medications, such as levofloxacin, moxifloxacin, and bedaquoline [51]. Different protease inhibitor-based regimens have a similar, minimal effect on the QT interval, but significantly prolong the PR interval by a difference of 3 ms in non-boosted protease inhibitor regimen to 5.11 ms in boosted protease inhibitor regimen. The intervals do normalize on withdrawal of the protease inhibitor therapy and prolongation is not associated with NNRTIs. The clinical significance is not well established [110]. It is thought that PR prolongation may lead to a higher likelihood of complete heart block during immune reconstitution inflammatory syndrome during initiation of ART. Autonomic dysfunction Preliminary clinical signs of autonomic dysfunction in HIVinfected patients include syncope and presyncope, diarrhoea, diminished sweating, bladder dysfunction, and impotence. One study found heart rate variability Valsalva ratio, cold pressor testing, hemodynamic responses to isometric exercise, tilt-table testing, and standing showed that autonomic dysfunction occurred in HIV-infected individuals and was pronounced in AIDS patients. AIDS patients receiving HAART were relatively protected. Patients with HIV-associated nervous system disease had the greatest abnormalities in autonomic function (Figure 4) [111]. Complications of therapy Antiretroviral medications have greatly reduced mortality by delaying the progression to AIDS and increased quality of life of HIV-infected patients [52]. However, these same therapies are associated with a number of complications [20,57,80,112,113]. As previously detailed, altered body composition and hyperlipidemia are associated with PIs. Nucleoside reverse transcriptase inhibitors may lead to increasing the child’s cardiometabolic risk [112,113]. Lipid abnormalities vary with different PIs. Ritonavir had the most adverse effects on lipids, with a mean increase in total cholesterol concentration of 2.0 mmol/L and a mean increase in triglyceride concentration of 1.83 mmol/L [57,80,114]. More modest increases of total cholesterol concentration without marked triglyceride increases were found in patients taking indinavir and nelfinavir. Combination with saquinavir (including atanazavir and saquinavir in salvage therapy) did not further elevate total cholesterol concentrations. Protease inhibitors significantly increased lipoprotein (a) in patients with elevated pretreatment values ( 20 mg/dL), which is another risk marker for atherosclerotic cardiovascular disease [57,80,114]. In some cases, switching PIs may reverse both elevations in triglyceride concentrations and abnormal fat deposition. Lowlevel aerobic exercise may also help reverse lipid abnormalities [20,53]. Zidovudine or azidothymidine (AZT) has been implicated in skeletal muscle myopathies. In culture, AZT causes a dose-dependent destruction of human myotubes. Human cultured cardiac muscle cells treated with AZT developed mitochondrial abnormalities, and nucleoside reverse transcriptase inhibitors in general have been associated with altered mitochondrial DNA replication and cardiac structure [20,115]; it is uncertain whether altered mitochondrial DNA replication is the cause of cardiomyopathy. However, cardiac myopathies have not been evident in clinical data. Some patients with LV dysfunction may improve when AZT therapy is stopped [20]. Some evidence has been presented associating ARTs and mitochondrial toxicity [116]. This and additional factors may predispose children infected with HIV to reduced aerobic capacity. HIV-infected children 12 Lipshultz SE et al. Journal of the International AIDS Society 2013, 16:18597 http://www.jiasociety.org/index.php/jias/article/view/18597 | http://dx.doi.org/10.7448/IAS.16.1.18597 Figure 4. Evaluation and management of dysautonomia. ECGelectrocardiography. Reproduced with permission from ‘‘Fisher SD, Lipshultz SE. Chapter 72: Cardiovascular abnormalities in HIV-infected individuals. In: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, Ninth Edition. Editors: Bonow RO, Mann DL, Zipes DP, Libby P. Philadelphia: Elsevier Saunders. 161827. 2011 ISBN: 978-1-43770398-6.’’ and adolescents had lower cardiorespiratory fitness, lower extremity strength, and flexibility than did their uninfected counterparts. Additionally, HAART exposure for greater than five-years and higher total body fat percentage independently had a negative effect on aerobic capacity [60]. Intravenous pentamidine, used to treat Pneumocystis jirovecii pneumonia in patients intolerant of trimethoprimsulfamethoxazole, has been associated with Torsades de Pointes and refractory ventricular tachycardia [20]. Pentamidine should be reserved for patients with a QTc interval below 480 ms. Multiple medication reactions and interactions have occurred during HIV treatment and are a major cause of cardiac emergencies in HIV-infected patients (Table 3) [62,65,117]. Mother-to-child transmission has been reduced in the United States to approximately 12% (CDC). Intrauterine exposures to these potent ARTs have been shown to have some effects on the child [118]. At birth, children exposed to HIV and ARTs were lighter than a comparison group with no exposures to ARTs and showed accelerated growth during the first two years of life. Additionally, these children had less subcutaneous fat and decreasing mid-upper arm circumference over time when compared to national standards [119]. Perinatal transmission of HIV-infection Although HIV transmission can be minimized if mothers are given ART in the second and third trimesters or short courses before parturition, most children with HIV are infected in the perinatal period [120]. Current therapies, some including up to six months of neonatal AZT, can limit the incidence of perinatal transmission to B2%. A worldwide UNAIDS goal is to eliminate perinatal transmission by the end of 2014. Rates of congenital cardiovascular malformations ranged from 5.6 to 8.9% in cohorts of HIV-uninfected and HIVinfected children born to HIV-infected mothers. Although these rates were not higher than in similarly screened normal populations, they were 5 to 10 times as high as those reported in population-based epidemiological studies [120]. In the same cohorts, serial echocardiograms performed at four- to six-month intervals showed subclinical cardiac abnormalities to be common, persistent, and often progressive [5,62,68]. Some patients had dilated cardiomyopathy (LV contractility 2 standard deviations or more below the mean of a normative population and LV end-diastolic dimension 2 standard deviations or more above the mean) whereas others had mildly increased cardiac mass for height and weight. Depressed LV function correlated with immune dysfunction at baseline but not over time. This correlation suggests that the CD4 cell count may not be a useful surrogate marker of HIV-associated LV dysfunction. Disease can progress rapidly or slowly in children with perinatallytransmitted HIV-1 infection [62]. Rapid progressors have higher heart rates, higher respiratory rates, and lower fractional shortening on serial examinations than do nonrapid progressors and HIV-uninfected children who are similarly screened. Rapid progressors also have higher HIV1 viral loads, higher five-year cumulative mortality, and lower CD8 (cytotoxic) T-cell counts. Studies of non-HIV-infected infants born to HIV-infected mothers have reported that foetal exposure to ART is associated with reduced LV dimension, LV mass, and septal wall thickness along with higher LV fractional shortening and contractility during the first two years of life [121]. In utero exposure to ART may initially improve LV function while impairing myocardial growth. Although LV function is improved, it is still below normal [68]. These effects are more pronounced in girls [68]. Conclusions Cardiac monitoring recommendations Routine, systematic cardiac evaluation, including a comprehensive history and thorough cardiac examination, is essential 13 Lipshultz SE et al. Journal of the International AIDS Society 2013, 16:18597 http://www.jiasociety.org/index.php/jias/article/view/18597 | http://dx.doi.org/10.7448/IAS.16.1.18597 Table 3. Cardiac interactions and side effects of drugs commonly used in HIV therapy Class Cardiac drug interactions Cardiac side effects Antiretroviral Zidovudine and dipyridamole Rare: lactic acidosis, hypotension Nucleoside (and nucleotide) reverse Stavdine and DDI Accelerated risk with cardiopulmonary bypass transcriptase inhibitors Zidovudine: skeletal muscle myopathy, Abacavir (ABC), Didanosine (ddI), myocarditis Emtricitabine (FTC) Lamivudine (3TC), Mitochondrial toxicity with lipodystrophy Stavudine (d4T), Tenofovir (TDF), Zalcitabine (ddC), Zidovudine (ZDV, AZT) Nonnucleoside reverse transcriptase Calcium channel blockers, warfarin, inhibitors b-blockers, nifedipine, quinidine, steroids, Delavirdine (DLV), Efavirenz (EFV), theophylline. Nevirapine (NVP), Rilpivirine (RPV) Delavirdine can cause serious toxic effects if given with antiarrhythmic drugs and calcium channel Protease inhibitors Amprenavir (APV), Atazanavir (ATV), Arrhythmia blockers Metabolized by cytochrome P450 and interact Implicated in premature atherosclerosis, with other drugs metabolized through this dyslipidemia, insulin resistance, diabetes mellitus, Darunavir (DRV), Fosamprenavir (FPV) pathway, such as selected antimicrobials, fat wasting, and redistribution Indinavir (IDV), Lopinavir/ritonavir (LPV/r), Nelfinavir (NFV), Ritonavir antidepressant and antihistamine agents, cisapride, HMG CoA reductase inhibitors Abacavir may be associated with increased risk of MI13 (RTV), Saquinavir (SQV), Tipranavir (lovastatin, simvastatin), and sildenafil. (TPV) Potentially dangerous interactions that require close monitoring or dose adjustment can occur with amiodarone, disopyramide, flecainide, lidocaine, mexiletine, propafenone, and quinidine. Ranolazine (1.82.3 increase in Ranolazine level) Ritonavir is the most potent cytochrome activator (CYP3A) and P-glycoprotein inhibitor and is most likely to interact. Indinavir, amprenavir, and nelfinavir are moderate. Saquinavir has the lowest probability to interact Calcium channel blockers, prednisone, quinine, b-blockers (1.5- to 3-fold increase). Decreases theophylline concentrations Integrase strand transfer inhibitors (INSTIs) Elvitegravir (EVG), Raltegravir (RAL) CCR5 antagonists Maraviroc Fusion inhibitor Enfuvirtide Anti-infective antibiotics Rifampin: Erythromycin: Reduces therapeutic effect of digoxin by inducing Orthostatic hypotension, ventricular tachycardia, intestinal P-glycoprotein, reduces protease bradycardia, Torsades (with drug interactions) inhibitor concentration and effect Clarithromycin: Erythromycin: QT prolongation and Torsades de Pointes Cytochrome P450 metabolism and drug Trimethoprim-sulfamethoxazole: Orthostatic interactions hypotension, anaphylaxis, QT prolongation, Trimethoprim-sulfamethoxazole: Torsades de Pointes, hypokalemia (Bactrim) increases warfarin effects Sparfloxacin (fluoroquinolones): QT prolongation 14 Lipshultz SE et al. Journal of the International AIDS Society 2013, 16:18597 http://www.jiasociety.org/index.php/jias/article/view/18597 | http://dx.doi.org/10.7448/IAS.16.1.18597 Table 3 (Continued ) Class Antifungal agents Cardiac drug interactions Cardiac side effects Amphotericin B: Digoxin toxicity Amphotericin B: Hypertension, arrhythmia, renal failure, Ketoconazole or itraconazole: Cytochrome P450 hypokalemia, thrombophlebitis, bradycardia, metabolism and drug interactions*increases angioedema, dilated cardiomyopathy. Liposomal levels of sildenafil, warfarin, HMG CoA reductase formulations still have the potential for electrolyte inhibitors, nifedipine, digoxin imbalance and QT prolongation Ketoconazole, fluconazole, itraconazole: QT prolongation and torsades de pointes Antiviral agents Ganciclovir: Foscarnet: Zidovudine Reversible cardiac failure, electrolyte abnormalities Ganciclovir: Ventricular tachycardia, hypotension Antiparasitic Pentamidine: Hypotension, QT prolongation, arrhythmias (Torsades de Pointes), ventricular tachycardia, hyperglycemia, hypoglycemia, sudden death. These effects are enhanced by hypomagnesemia and hypokalemia Chemotherapy agents Vincristine, doxorubicin: Vincristine: Decrease digoxin level Arrhythmia, myocardial infarction, cardiomyopathy, autonomic neuropathy Recombinant human interferon-alpha: Hypertension, hypotension, tachycardia, acute coronary events, dilated cardiomyopathy, arrhythmias, sudden death, atrioventricular block, peripheral vasodilation. Contraindicated in patients with unstable angina or recent myocardial infarction Interleukin-2: Hypotension, arrhythmia, sudden death, myocardial infarction, dilated cardiomyopathy, capillary leak, thyroid alterations Anthracyclines (doxorubicin, daunorubicin, mitoxantrone): Myocarditis, cardiomyopathy Liposomal anthracyclines: As above for doxorubicin and also vasculitis Pentoxifylline Pentoxifylline: Decreased triglyceride levels, arrhythmias, chest pain Megace: Edema, thrombophlebitis, hyperglycemia Megestrol acetate (Megace) Epoetin alpha (erythropoietin): Hypertension, ventricular dysfunction Methadone Prolonged QT interval Amphetamines Increased heart rate and blood pressure Modified with permission from Fisher SD, Lipshultz SE. Chapter 72: Cardiovascular abnormalities in HIV-infected individuals. In: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, Ninth Edition. Editors: Bonow RO, Mann DL, Zipes DP, Libby P. Philadelphia: Elsevier Saunders. 161827. 2011 ISBN: 978-1-4377-0398-6. 15 Lipshultz SE et al. Journal of the International AIDS Society 2013, 16:18597 http://www.jiasociety.org/index.php/jias/article/view/18597 | http://dx.doi.org/10.7448/IAS.16.1.18597 care for HIV-infected children and adults. The history should include traditional risk factors, environmental exposures, prior opportunistic infections, and therapeutic and illicit drug use. Laboratories should include a lipid profile, fasting glucose, and HIV viral load (Figure 5). Routine blood pressure monitoring is important because HIV-infected individuals can experience hypertension at a younger age and more frequently than in the general population [20,33,52]. Unless patients have symptoms such as palpitations, syncope, stroke, or dysautonomia, routine ECG and Holter monitoring are not warranted. These tests can be useful for baseline and monitoring before, during, and after therapies, such as pentamidine, methadone, or antibiotics that may prolong the QT interval [108]. Asymptomatic cardiac disease related to HIV can be fatal. When present, cardiac symptoms are often disguised by secondary effects of HIV infection. Thus, systematic echocardiographic monitoring is warranted [64,65,122,123]. An international consensus panel recommended echocardiographic monitoring, with a baseline, for any patient at high risk or with any clinical manifestation of CVD, in addition to studies every 12 years or as clinically indicated. Patients with cardiac symptoms should begin directed therapy and receive a formal cardiac assessment, including baseline ECG, echocardiography, and Holter monitoring [124]. Brain natriuretic peptide concentrations may help diagnose ventricular dysfunction [125,126]. Serum troponin assays are indicated in patients with LV dysfunction. Elevated concentrations of serum troponin warrant consideration of endomyocardial biopsy and cardiac catheterization. Therapy with intravenous immunoglobulin should be considered for biopsy-proven myocarditis [2]. Echocardiography should be repeated after two weeks of therapy to encourage continued therapy if improvement has occurred and adapt a more aggressive approach if LV dysfunction persists or worsens. Stress testing and coronary assessment such as CT angiography or cardiac catheterization should be considered in the appropriate clinical settings [33,44,54,62]. Guidelines for using implantable cardioverter-defibrillators should be followed in this population, especially in patients after MI being treated for HIV infection [33]. As a chronic disease, HIV-related CVD is a vital area of research. If HIV can be used as a model of chronic immunosuppression in a large population, findings may translate to other populations. Understanding genetic predispositions to QT prolongation may guide therapy. Understanding the causes of cardiomyopathy may benefit diverse research efforts, such as the effects of cytokines, mitochondria, and neurohormonal pathways. Observations, such as increased mortality related to LV mass and very mild LV dysfunction might enhance diagnostic testing in at-risk populations affected by other poorly understood cardiomyopathies. Authors’ affiliations 1 Department of Pediatrics, Jackson Memorial Medical Center and the Sylvester Comprehensive Cancer Center, Holtz Children’s Hospital, University of Miami Miller School of Medicine, Miami, FL, USA; 2Departments of Medicine and Pediatrics, Comprehensive Heart Center, University of Maryland School of Medicine, Baltimore, MD, USA Competing interests The authors declare that they have no competing interests. Authors’ contributions All authors contributed to the content and design of this review and have read and approved the final version. References Figure 5. Cardiovascular considerations when initiating highly active antiretroviral therapy (HAART). Reproduced with permission from ‘‘Fisher SD, Lipshultz SE. Chapter 72: Cardiovascular abnormalities in HIV-infected individuals. In: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, Ninth Edition. Editors: Bonow RO, Mann DL, Zipes DP, Libby P. Philadelphia: Elsevier Saunders. 1618 27. 2011 ISBN: 978-1-4377-0398-6.’’ 1. Currie PF, Jacob AJ, Foreman AR, Elton RA, Brettle RP, Boon NA. Heart muscle disease related to HIV infection: prognostic implications. BMJ. 1994;309:1605. 2. Lipshultz SE, Orav EJ, Sanders SP, Colan SD. Immunoglobulins and left ventricular structure and function in pediatric HIV infection. Circulation. 1995;92:22205. 3. Saidi A, Bricker JT. Pulmonary hypertension in patients infected with HIV. In: Lipshultz SE, editor. Cardiology in AIDS. New York: Chapman & Hall; 1998. p. 18794. 4. Jenson HB, Pollock BH. Cardiac cancers in HIV-infected patients. In: Lipshultz SE, editor. Cardiology in AIDS. New York: Chapman & Hall; 1998. p. 25563. 5. Lipshultz SE, Easley KA, Orav EJ, Kaplan S, Starc TJ, Bricker JT, et al. Cardiac dysfunction and mortality in HIV-infected children: the prospective P2C2 HIV multicenter study. Pediatric pulmonary and cardiac complications of vertically transmitted HIV infection (P2C2 HIV) study group. Circulation. 2000;102: 15428. 6. Morse CG, Kovacs JA. Metabolic and skeletal complications of HIV infection: the price of success. JAMA. 2006;296:84454. 16 Lipshultz SE et al. Journal of the International AIDS Society 2013, 16:18597 http://www.jiasociety.org/index.php/jias/article/view/18597 | http://dx.doi.org/10.7448/IAS.16.1.18597 7. Lipshultz SE, Fisher SD, Miller TL, Sharma TS, Milton AN. The cardiovascular manifestations of HIV infection. Dialog Cardiovasc Med. 2007;12(1):523. 8. Zareba KM, Miller TL, Lipshultz SE. Cardiovascular disease and toxicities related to HIV infection and its therapies. Expert Opin Drug Saf. 2005;4(6): 101725. 9. Zareba KM, Lipshultz SE. Cardiovascular complications in patients with HIV infection. Curr Infect Dis Rep. 2003;5(6):51320. 10. Barbaro G, Fisher SD, Lipshultz SE. Pathogenesis of HIV-associated cardiovascular complications. Lancet Infect Dis. 2001;1(2):11524. 11. Keesler MJ, Fisher SD, Lipshultz SE. Cardiac manifestations of HIV infection in infants and children. Ann N Y Acad Sci. 2001;946:16978. 12. Langston C, Cooper ER, Goldfarb J, Easley KA, Husak S, Sunkle S, et al. Human immunodeficiency virus-related mortality in infants and children: data from the pediatric pulmonary and cardiovascular complications of vertically transmitted HIV P2C2 study. Pediatrics. 2001;107(2):32838. 13. Starc TJ, Lipshultz SE, Kaplan S, Easley KA, Bricker JT, Colan SD, et al. Cardiac complications in children with human immunodeficiency virus infection. Pediatric pulmonary and cardiac complications of vertically transmitted HIV infection (P2C2 HIV) study group, national heart, lung, and blood institute. Pediatrics. 1999;104(2):14. 14. Lipshultz SE, Easley KA, Orav EJ, Kaplan S, Starc TJ, Bricker JT, et al. Left ventricular structure and function in children infected with human immunodeficiency virus: the prospective P2C2 HIV multicenter study. Pediatric pulmonary and cardiac complications of vertically transmitted HIV infection (P2C2 HIV) study group. Circulation. 1998;97(13):124656. 15. Epstein JE, Eichbaum QG, Lipshultz SE. Cardiovascular manifestations of HIV infection. Compr Ther. 1996;22(8):48591. 16. Lane-McAuliffe EM, Lipshultz SE. Cardiovascular manifestations of pediatric HIV infection. Nurs Clin North Am. 1995;30(2):291316. 17. Luginbuhl LM, Orav EJ, McIntosh K, Lipshultz SE. Cardiac morbidity and related mortality in children with HIV infection. JAMA. 1993;269(22):286975. 18. Patel N, Abdelsayed S, Veve M, Miller CD. Predictors of clinically significant drug-drug interactions among patients treated with nonnucleoside reverse transcriptase inhibitor-, protease inhibitor-, and raltegravir-based antiretroviral regimens. Ann Pharmacother. 2011;45(3):31724. 19. Mas CM, Miller TL, Cordero C, Dauphin D, White MD, Vila CK, et al. The effects of fetal and childhood exposure to antiretroviral agents, J AIDS Clin Res. 2011;S2:001. 20. Fisher SD, Kanda BS, Miller TL, Lipshultz SE. Cardiovascular disease and therapeutic drug-related cardiovascular consequences in HIV-infected patients. Am J Cardiovasc Drugs. 2011;11(6):38394. 21. Dubé MP, Lipshultz SE, Fichtenbaum CJ, Greenberg R, Schecter AD, Fisher SD. Effects of HIV infection and antiretroviral therapy on the heart and vasculature. Circulation. 2008;118(2):e3640. 22. Fisher SD, Miller TL, Lipshultz SE. Impact of HIV and highly active antiretroviral therapy on leukocyte adhesion molecules, arterial inflammation, dyslipidemia, and atherosclerosis. Atherosclerosis. 2006;185(1):111. 23. UNAIDS. 2012 Report on the Global AIDS epidemic. http://www.unaids. org. 24. Fisher SD, Easley KA, Orav EJ, Colan SD, Kaplan S, Starc TJ, et al. Mild dilated cardiomyopathy and increased left ventricular mass predict mortality: the prospective P2C2 HIV multicenter study. Am Heart J. 2005;150(3): 43947. 25. Lipshultz SE. Dilated cardiomyopathy in HIV-infected patients. N Engl J Med. 1998;339(16):11535. 26. Harmon WG, Dadlani GH, Fisher SD, Lipshultz SE. Myocardial and pericardial disease in HIV. Curr Treat Options Cardiovasc Med. 2002;4(6): 497509. 27. Fitch K, Grinspoon S. Nutritional and metabolic correlates of cardiovascular and bone disease in HIV-infected patients. Am J Clin Nutr. 2011;94(6): 1721S8S. 28. Carr A, Samaras K, Chisholm DJ, Cooper DA. Abnormal fat distribution and use of protease inhibitors. Lancet. 1998;351(9117):1736. 29. Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIVinfected adults. N Engl J Med. 2005;352(1):4862. 30. Palella FJ, Jr., Phair JP. Cardiovascular disease in HIV infection. Curr Opin HIV AIDS. 2011;6(4):26671. 31. Friis-Moller N, Weber R, Reiss P, Thiébaut R, Kirk O, d’Arminio Monforte A, et al. Cardiovascular disease risk factors in HIV patientsassociation with antiretroviral therapy. Results from the DAD study. AIDS. 2003;17(8): 117993. 32. Mary-Krause M, Cotte L, Simon A, Partisani M, Costagliola D. Increased risk of myocardial infarction with duration of protease inhibitor therapy in HIVinfected men. AIDS. 2003;17(17):247986. 33. Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, et al. Practice guideline: 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60: e44e164. 34. Arpadi SM, Bethel J, Horlick M, Sarr M, Bamji M, Abrams EJ, et al. Longitudinal changes in regional fat content in HIV-infected children and adolescents. AIDS. 2009;23(12):15019. 35. Jacobson DL, Patel K, Siberry GK, Van Dyke RB, DiMeglio LA, Geffner ME, et al. Body fat distribution in perinatally HIV-infected and HIV-exposed but uninfected children in the era of highly active antiretroviral therapy: outcomes from the Pediatric HIV/AIDS Cohort Study. Am J Clin Nutr. 2011;94(6):148595. 36. Geffner ME, Patel K, Miller TL, Hazra R, Silio M, Van Dyke RB, et al. Factors associated with insulin resistance among children and adolescents perinatally infected with HIV-1 in the pediatric HIV/AIDS cohort study. Horm Res Paediatr. 2011;76(6):38691. 37. Miller TL, Borkowsky W, DiMeglio LA, Dooley L, Geffner ME, Hazra R, et al. Metabolic abnormalities and viral replication are associated with biomarkers of vascular dysfunction in HIV-infected children. HIV Med. 2012;13(5):26475. 38. Miller TL, Orav EJ, Lipshultz SE, Arheart KL, Duggan C, Weinberg GA, et al. Risk factors for cardiovascular disease in children infected with human immunodeficiency virus-1. J Pediatr. 2008;153(4):4917. 39. Sanchez Torres AM, Munoz Muniz R, Madero R, Borque C, Garcia-Miguel MJ, De Jose Gomez MI. Prevalence of fat redistribution and metabolic disorders in human immunodeficiency virus-infected children. Eur J Pediatr. 2005;164(5):2716. 40. Brambilla P, Bricalli D, Sala N, Renzetti F, Manzoni P, Vanzulli A, et al. Highly active antiretroviral-treated HIV-infected children show fat distribution changes even in absence of lipodystrophy. AIDS. 2001;15(18):241522. 41. Moscicki AB, Ellenberg JH, Murphy DA, Jiahong X. Associations among body composition, androgen levels, and human immunodeficiency virus status in adolescents. J Adolesc Health. 2006;39(2):16473. 42. Miller TL, Mawn BE, Orav EJ, Wilk D, Weinberg GA, Nicchitta J, et al. The effect of protease inhibitor therapy on growth and body composition in human immunodeficiency virus type 1-infected children. Pediatrics. 2001;107(5):E77. 43. Aldrovandi GM, Lindsey JC, Jacobson DL, Zadzilka A, Sheeran E, Moye J, et al. Morphologic and metabolic abnormalities in vertically HIV-infected children and youth. AIDS. 2009;23(6):66172. 44. Boccara F, Teiger E, Cohen A, Ederhy S, Janower S, Odi G, et al. Percutaneous coronary intervention in HIV infected patients: immediate results and long term prognosis. Heart. 2006;92:5434. 45. Vigano A, Mora S, Testolin C, Beccio S, Schneider L, Bricalli D, et al. Increased lipodystrophy is associated with increased exposure to highly active antiretroviral therapy in HIV-infected children. J Acquir Immune Defic Syndr. 2003;32(5):4829. 46. Arpadi SM, Cuff PA, Horlick M, Wang J, Kotler DP. Lipodystrophy in HIVinfected children is associated with high viral load and low CD4 -lymphocyte count and CD4 -lymphocyte percentage at baseline and use of protease inhibitors and stavudine. J Acquir Immune Defic Syndr. 2001;27(1):304. 47. Gerschenson M, Shiramizu B, LiButti DE, Shikuma CM. Mitochondrial DNA levels of peripheral blood mononuclear cells and subcutaneous adipose tissue from thigh, fat and abdomen of HIV-1 seropositive and negative individuals. Antivir Ther. 2005;10(Suppl 2):M839. 48. Sztam KA, Jiang H, Jurgrau A, Deckelbaum RJ, Foca MD. Early increases in concentrations of total, LDL, and HDL cholesterol in HIV-infected children following new exposure to antiretroviral therapy. J Pediatr Gastroenterol Nutr. 2011;52(4):4958. 49. Rhoads MP, Lanigan J, Smith CJ, Lyall EG. Effect of specific ART drugs on lipid changes and the need for lipid management in children with HIV. J Acquir Immune Defic Syndr. 2011;57(5):40412. 50. Jacobson DL, Williams P, Tassiopoulos K, Melvin A, Hazra R, Farley J. Clinical management and follow-up of hypercholesterolemia among perinatally HIVinfected children enrolled in the PACTG 219C study. J Acquir Immune Defic Syndr. 2011;57(5):41320. 17 Lipshultz SE et al. Journal of the International AIDS Society 2013, 16:18597 http://www.jiasociety.org/index.php/jias/article/view/18597 | http://dx.doi.org/10.7448/IAS.16.1.18597 51. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl, 2012. 52. NHLBI AIDS working group. http://www.nhlbi.nih.gov/meetings/workshops/ AIDSworking.htm, September 67, 2012, Bethesda, MD. 53. Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009;54:212938. 54. Longenecker C, Hoit B. Imaging atherosclerosis in HIV: carotid intimamedia thickness and beyond. Translational research: J Lab Clin Med. 2012; 159(3):12739. 55. Miller TL, Somarriba G, Orav EJ, Mendez AJ, Neri D, Schaefer N, et al. Biomarkers of vascular dysfunction in children infected with human immunodeficiency virus-1. J Acquir Immune Defic Syndr. 2010;55(2):1828. 56. Foster SB, Lu M, Glaze DG, Reuben JM, Harris LL, Cohen EN, et al. Associations of cytokines, sleep patterns, and neurocognitive function in youth with HIV infection. Clin Immunol. 2012;144(1):1323. 57. DAD Study Group, Friis-Moller N, Reiss P, Sabin CA, Weber R, Monforte AD, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med. 2007;356:172335. 58. Cruse B, Cysique LA, Markus R, Brew BJ. Cerebrovascular disease in HIV-infected individuals in the era of highly active antiretroviral therapy. J Neurovirol. 2012;18(4):26476. 59. Lazzaretti RK, Kuhmmer R, Sprinz E, Polanczyk CA, Ribeiro JP. Clinical research: dietary intervention prevents dyslipidemia associated with highly active antiretroviral therapy in human immunodeficiency virus type 1-infected individuals. A randomized trial. J Am Coll Cardiol. 2012;59:97988. 60. Somarriba G, Lopez-Mitnik G, Ludwig DA, Neri D, Schaefer N, Lipshultz SE, et al. Physical fitness in children infected with the human immunodeficiency virus: associations with highly active antiretroviral therapy. AIDS Res Hum Retroviruses. 2013;29(1):11220. 61. Dubé MP, Cadden JJ. Lipid metabolism in treated HIV Infection. Best Practice Res Clin Endocrinol Metab. 2011;25(3):42942. 62. Lipshultz SE, Mas CM, Henkel JM, Franco VI, Fisher SD, Miller TL. HAART to heart: highly active antiretroviral therapy and the risk of cardiovascular disease in HIV-infected or exposed children and adults. Exp Rev Anti Infect Ther. 2012;10(6):66174. 63. Butt AA, Chang CC, Kuller L, Goetz MB, Leaf D, Rimland D, et al. Risk of heart failure with human immunodeficiency virus in the absence of prior diagnosis of coronary heart disease. Arch Intern Med. 2011;171(8):73743. 64. Mondy KE, Gottdiener J, Overton ET, Henry K, Bush TC, et al. High prevalence of echocardiographic abnormalities among HIV-infected persons in the era of highly active antiretroviral therapy. Clin Infect Dis. 2011;52(3): 37886. 65. Lipshultz SE, Williams PL, Wilkinson JD, Leister EC, Van Dyke RB, Shearer WT, et al. Cardiac status of HIV-infected children treated with long-term combination antiretroviral therapy: results from the Adolescent Master Protocol of the NIH multicenter pediatric HIV/AIDS cohort study. JAMA Pediatr. 2013; Apr 22:18 [Epub ahead of print]. 66. Zareba KM, Lavigne JE, Lipshultz SE. Cardiovascular effects of HAART in infants and children of HIV-infected mothers. Cardiovasc Toxicol. 2004;4(3): 2719. 67. Lipshultz SE, Easley KA, Orav EJ, Kaplan S, Starc TJ, Bricker JT, et al. Cardiovascular status of infants and children of women infected with HIV-1 (P2C2 HIV): a cohort study. Lancet. 2002;360(9330):36873. 68. Lipshultz SE, Shearer WT, Thompson B, Rich KC, Cheng I, Orav EJ, et al. Cardiac effects of antiretroviral therapy in HIV-negative infants born to HIVpositive mothers: NHLBI CHAART-1 (National Heart, Lung, and Blood Institute Cardiovascular Status of HAART Therapy in HIV-Exposed Infants and Children cohort study). J Am Coll Cardiol. 2011;57(1):7685. 69. Wilkinson JD, Williams PL, Leister E, Zeldow B, Shearer WT, Colan SD, et al. Cardiac biomarkers in HIV-exposed uninfected children: the pediatric HIV/AIDS cohort study (PHACS). AIDS. 2013; 27(7):1099108. 70. Grossi PA. Update in HIV infection in organ transplantation. Curr Opin Organ Transplant. 2012;17(6):58693. 71. Pozzan G, Pagliari C, Tuon FF, Takakura CF, Kauffman MR, Duarte MI. Diffuse-regressive alterations and apoptosis of myocytes: possible causes of myocardial dysfunction in HIV-related cardiomyopathy. Int J Cardiol. 2009; 132(1):905. 72. Bowles NE, Kearney DL, Ni J, Perez-Atayde AR, Kline MW, Bricker JT, et al. The detection of viral genomes by polymerase chain reaction in the myocardium of pediatric patients with advanced HIV disease. J Am Coll Cardiol. 1999;34(3):85765. 73. Rogers JS, Zakaria S, Thom KA, Flammer KM, Kanno M, Mehra MR. Immune reconstitution inflammatory syndrome and human immunodeficiency virus-associated myocarditis. Mayo Clin Proc. 2008;83(11):12759. 74. Yearley JH, Mansfield KG, Carville AAL, Sokos GG, Xia D, Pearson CB, et al. Antigenic stimulation in the simian model of HIV infection yields dilated cardiomyopathy through effects of TNF a. AIDS. 2008;22(5):58594. 75. Reinsch N, Neuhaus K, Esser S, Potthoff A, Hower M, Brockmeyer NH, et al. Prevalence of cardiac diastolic dysfunction in HIV-infected patients: results of the HIV-HEART study. HIV Clin Trials. 2010;11(3):15662. 76. Lipshultz SE, Orav EJ, Sanders SP, Hale AR, McIntosh K, Colan SD. Cardiac structure and function in children with human immunodeficiency virus infection treated with zidovudine. N Engl J Med. 1992;327(18):12605. 77. Lipshultz SE, Orav EJ, Sanders SP, McIntosh K, Colan SD. Limitations of fractional shortening as an index of contractility in pediatric patients infected with human immunodeficiency virus. J Pediatr. 1994;125(4):56370. 78. Lipshultz SE, Shearer WT, Thompson B, Rich K, Cheng I, Orav EJ, et al. Antiretroviral therapy (ART) cardiac effects in HIV-infected children: the multicenter NHLBI Cardiac Highly Active Antiretroviral Therapy (CHAART-II) study. Circulation. 2009;120:S90910. 79. Hulten E, Mitchell J, Scally J, Gibbs B, Villines TC. HIV positivity, protease inhibitor exposure and subclinical atherosclerosis: a systematic review and meta-analysis of observational studies. Heart. 2009;95:182635. 80. Worm SW, Sabin C, Weber R, Reiss P, El-Sadr W, Dabis F, et al. Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study. J Infect Dis. 2010;201:31830. 81. Nayak G, Ferguson M, Tribble DR, Porter CK, Rapena R, Marchicelli M, et al. Cardiac diastolic dysfunction is prevalent in HIV-infected patients. AIDS Patient Care STDs. 2009;23(4):2318. 82. O’Brien S, Sasaki N, Eidem BW, Colan SD, Cheng I, Wilkinson JD, et al. Left ventricular diastolic dysfunction in HIV-negative infants exposed in utero to antiretroviral therapy from HIV-positive mothers: the prospective NHLBI CHAART-I study. Circulation. 2011;124:A10808. 83. Halley CM, Houghtaling PL, Khalil MK, Thomas JD, Jaber WA. Mortality rate in patients with diastolic dysfunction and normal systolic function. Arch Intern Med. 2011;171(12):10827. 84. McMahon CJ, Nagueh SF, Pignatelli RH, Denfield SW, Dreyer WJ, Price JF, et al. Characterization of left ventricular diastolic function by tissue Doppler imaging and clinical status in children with hypertrophic cardiomyopathy. Circulation. 2004;109(14):175662. 85. McMahon CJ, Nagueh SF, Eapen RS, Dreyer WJ, Finkelshtyn I, Cao X, et al. Echocardiographic predictors of adverse clinical events in children with dilated cardiomyopathy: a prospective clinical study. Heart. 2004;90(8):90815. 86. Ingul CB, Tjonna AE, Stolen TO, Stoylen A, Wisloff U. Impaired cardiac function among obese adolescents: effect of aerobic interval training. Arch Pediatr Adolesc Med. 2010;164(9):8529. 87. Wojcik M, Rudzinski A, Starzyk J. Left ventricular diastolic dysfunction in adolescents with type 1 diabetes reflects the long- but not short-term metabolic control. J Pediatr Endocrinol Metab. 2010;23(10):105564. 88. Plazak W, Kopec G, Tomkiewicz-Pajak L, Rubis P, Dziedzic H, Suchon E, et al. Heart structure and function in patients with generalized autoimmune diseases: echocardiography with tissue Doppler study. Acta Cardiol. 2011; 66(2):15965. 89. Cade WT, Waggoner AD, Hubert S, Krauss MJ, Singh GK, Overton ET. Reduced diastolic function and left ventricular mass in HIV-negative preadolescent children exposed to antiretroviral therapy in utero. AIDS. 2012;26(16):20538. 90. Kelly KM, Tarwater PM, Karper JM, Bedia D, Queen SE, Tunin RS. Diastolic dysfunction is associated with myocardial viral load in simian immunodeficiency virus-infected macaques. AIDS. 2012;26(7):81523. 91. Opravil M, Sereni D. Natural history of HIV-associated pulmonary arterial hypertension: trends in the HAART era. AIDS. 2008;22(Suppl 3):S35. 92. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American 18 Lipshultz SE et al. Journal of the International AIDS Society 2013, 16:18597 http://www.jiasociety.org/index.php/jias/article/view/18597 | http://dx.doi.org/10.7448/IAS.16.1.18597 Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation. 2009;119(16):225094. 93. Cicalini S, Almodovar S, Grilli E, Flores S. Pulmonary hypertension and human immunodeficiency virus infection: epidemiology, pathogenesis, and clinical approach. Clin Microbiol Infect. 2011;17(1):2533. 94. Janda S, Quon B, Swiston J. HIV and pulmonary arterial hypertension: a systematic review. HIV and pulmonary arterial hypertension. HIV Med. 2011;11(10):62034. 95. Lindl A, Reinschl N, Nehausl K, Esser S, Brockmeyer NH, Potthoff A, et al. Pericardial effusion of HIV-infected patients results of a prospective multicenter cohort study in the era of antiretroviral therapy. Eur J Med Res. 2011;16:4803. 96. Bolt RJ, Rammeloo LA, van Furth AM, van Well GT. A 15-year-old girl with a large pericardial effusion. Eur J Pediatr. 2008;167(7):8112. 97. Yoon SA, Hahn YS, Hong JM, Lee OJ, Han HS. Tuberculous pericarditis presenting as multiple free floating masses in pericardial effusion. J Korean Med Sci. 2012;27(3):3258. 98. Rapose A, Sarvat B, Sarria JC. Immune reconstitution inflammatory syndrome presenting as pericarditis and pericardial effusion. Cardiology. 2008;110(2):1424. 99. Reuter H, Burgess LJ, Louw VJ, Doubell AF. The management of tuberculous pericardial effusion: experience in 233 consecutive patients. Cardiovasc J S Afr. 2007;18(1):205. 100. Van Doorn CA, Yates R, Tsang VT. Endocarditis as the first presentation of AIDS in infancy. Arch Dis Child. 1998;79(2):17980. 101. Steinherz LJ, Brochstein JA, Robins J. Cardiac involvement in congenital acquired immunodeficiency syndrome. Am J Dis Child. 1986;140(12):12414. 102. Granovsky MO, Mueller BU, Nicholson HS, Rosenberg PS, Rabkin CS. Cancer in human immunodeficiency virus-infected children: a case series from the Children’s Cancer Group and the National Cancer Institute. J Clin Oncol. 1998;16(5):172935. 103. Buck BE, Scott GB, Valdes-Dapena M, Parks WP. Kaposi sarcoma in two infants with acquired immune deficiency syndrome. J Pediatr. 1983;103(6): 9113. 104. Zoufaly A, Stellbrink HJ, Heiden MA, Kollan C, Hoffmann C, van Lunzen J, et al. Cumulative HIV viremia during highly active antiretroviral therapy is a strong predictor of AIDS-related lymphoma. J Infect Dis. 2009;200(1): 7987. 105. Karavidas A, Tsiachris D, Lazaros G, Xylomenos G, Arapi S, Potamitis N, et al. Doppler tissue imaging unmasks right ventricular function abnormalities in HIV-infected patients. Cardiol J. 2010;17(6):58793. 106. Guillevin L. Vasculitides in the context of HIV infection. AIDS. 2008; 22(3):S2733. 107. Tseng ZH, Secemsky EA, Dowdy D, Vittinghoff E, Moyers B, Wong JK, et al. Sudden cardiac death in patients with human immunodeficiency virus infection. J Am Coll Cardiol. 2012;59:18916. 108. Sani MU, Okeahialam BN. QTc interval prolongation in patients with HIV and AIDS. J Natl Med Assoc. 2005;97:165761. 109. Nordin C, Kohli A, Beca S, Zaharia V, Grant T, Leider J, et al. Importance of hepatitis C coinfection in the development of QT prolongation in HIV-infected patients. J Electrocardiol. 2006;39:199205. 110. Soliman EZ, Lundgren JD, Roediger MP, Duprez DA, Temesgen Z, Bickel M, et al. Boosted protease inhibitors and the electrocardiographic measures of QT and PR durations. AIDS. 2011;25(3):36777. 111. Correia D, Rodrigues De Resende LA, Molina RJ, Ferreira BD, Colombari F, Barbosa CJ, et al. Power spectral analysis of heart rate variability in HIVinfected and AIDS patients. Pacing Clin Electrophysiol. 2006;29:538. 112. Dapena M, Jiménez B, Noguera-Julian A, Soler-Palacı́n P, Fortuny C, Lahoz R, et al. Metabolic disorders in vertically HIV-infected children: future adults at risk for cardiovascular disease. J Pediatr Endocrinol Metab. 2012; 25(56):52935. 113. Piloya T, Bakeera-Kitaka S, Kekitiinwa A, Kamya MR. Lipodystrophy among HIV-infected children and adolescents on highly active antiretroviral therapy in Uganda: a cross sectional study. J Int AIDS Soc. 2012;15(2):17427. 114. Lang S, Mary-Krause M, Cotte L, Gilguin J, Partisani M, Simon A, et al. Impact of individual antiretroviral drugs on the risk of myocardial infarction in human immunodeficiency virus-infected patients: a case-control study nested within the French Hospital Database on HIV ANRS cohort CO4. Arch Intern Med. 2010;170:122838. 115. Lipshultz SE, Orav EJ, Sanders SP, Hale AR, McIntosh K, Colan SD. Cardiac structure and function in children with human immunodeficiency virus infection treated with zidovudine. N Engl J Med. 1992;327(18):12605. 116. Crain MJ, Chernoff MC, Oleske JM, Brogly SB, Malee KM, Borum PR, et al. Possible mitochondrial dysfunction and its association with antiretroviral therapy use in children perinatally infected with HIV. J Infect Dis. 2010;202(2): 291301. 117. Chanock SJ, Luginbuhl LM, McIntosh K, Lipshultz SE. Life-threatening reaction to trimethoprim/sulfamethoxazole in pediatric human immunodeficiency virus infection. Pediatrics. 1994;93(3):51921. 118. Centers of Disease Control and Prevention (CDC). Achievements in public health. Reduction in perinatal transmission of HIV infectionUnited States, 19852005. MMWR Morb Mortal Wkly Rep. 2006;55(21):5927. 119. Neri D, Somarriba GA, Schaefer NN, Chaparro AI, Scott GB, Lopez-Mitnik G, Ludwig DA, Miller TL. Growth and body composition of uninfected children exposed to human immunodeficiency virus: comparison with a contemporary cohort and United States national standards. J Pediatr. 2013; Jan 26 [Epub ahead of print]. 120. Mofenson LM, Brady MT, Danner SP, Domingquez KL, Hazara R, Handelsman E, et al. Guidelines for the prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected children: recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. MMWR Recomm Rep. 2009;58(RR-11):1166. 121. Hornberger LK, Lipshultz SE, Easley KA, Colan SD, Schwartz M, Kaplan S, et al. Cardiac structure and function in fetuses of mothers infected with HIV: the prospective P2C2 HIV multicenter study. Am Heart J. 2000;140(4): 57584. 122. Lipshultz SE, Fisher SD, Lai WW, Miller TL. Cardiovascular risk factors, monitoring, and therapy for HIV-infected patients. AIDS. 2003;17(Suppl 1): S96122. 123. Lipshultz SE, Fisher SD, Lai WW, Miller TL. Cardiovascular monitoring and therapy for HIV-infected patients. Ann N Y Acad Sci. 2001;946:23673. 124. Saidi AS, Moodie DS, Garson A, Jr., Lipshultz SE, Kaplan S, Lai WW, et al. Electrocardiography and 24-hour electrocardiographic ambulatory recording (Holter monitor) studies in children infected with human immunodeficiency virus type 1. The pediatric pulmonary and cardiac complications of vertically transmitted HIV-1 infection study group. Pediatr Cardiol. 2000;21(3): 18996. 125. Ratnasamy C, Kinnamon DD, Lipshultz SE, Rusconi P. Associations between neurohormonal and inflammatory activation and heart failure in children. Am Heart J. 2008;155:52733. 126. Rusconi PG, Ludwig DA, Ratnasamy C, Mas R, Harmon WG, Colan SD, et al. Serial measurements of serum NT-proBNP as markers of left ventricular systolic function and remodeling in children with heart failure. Am Heart J. 2010;160:77683. 19 Barlow-Mosha L et al. Journal of the International AIDS Society 2013, 16:18600 http://www.jiasociety.org/index.php/jias/article/view/18600 | http://dx.doi.org/10.7448/IAS.16.1.18600 Review article Metabolic complications and treatment of perinatally HIV-infected children and adolescents Linda Barlow-Mosha*1, Allison Ross Eckard*2, Grace A McComsey3 and Philippa M Musoke§,1,4 § Corresponding author: Philippa M Musoke, MU-JHU Research Collaboration, P.O. Box 23491, Kampala, Uganda; Tel/Fax: 256 414 541044. ([email protected]) *These authors contributed equally to this work. This article is part of the special issue Perinatally HIV-infected adolescents - more articles from this issue can be found at http://www.jiasociety.org Abstract The benefits of long-term antiretroviral therapy (ART) are recognized all over the world with infected children maturing into adults and HIV infection becoming a chronic illness. However, the improved survival is associated with serious metabolic complications, including lipodystrophy (LD), dyslipidemia, insulin resistance, lactic acidosis and bone loss. In addition, the dyslipidemia mainly seen with protease inhibitors may increase the risk of cardiovascular disease in adulthood and potentially in children as they mature into adults. Nucleoside reverse transcriptase inhibitors, particularly stavudine, zidovudine and didanosine are linked to development of LD and lactic acidosis. Perinatally infected children initiate ART early in life; they require lifelong therapy with multiple drug regimens leading to varying toxicities, all potentially impacting their quality of life. LD has a significant impact on the mental health of older children and adolescents leading to poor self-image, depression and subsequent poor adherence to therapy. Reduced bone mineral density (BMD) is reported in both adults and children on ART with the potential for children to develop more serious bone complications than adults due to their rapid growth spurts and puberty. The role of vitamin D in HIV-associated osteopenia and osteoporosis is not clear and needs further study. Most resource-limited settings are unable to monitor lipid profiles or BMD, exposing infected children and adolescents to on-going toxicities with unclear long-term consequences. Improved interventions are urgently needed to prevent and manage these metabolic complications. Longitudinal cohort studies in this area should remain a priority, particularly in resource-limited settings where the majority of infected children reside. Keywords: children; adolescents; HIV; antiretroviral therapy; metabolic complications; cardiovascular disease. Received 21 February 2013; Revised 8 April 2013; Accepted 16 April 2013; Published 18 June 2013 Copyright: – 2013 Barlow-Mosha L et al; licensee International AIDS Society. This is an open access article distributed under the terms of the Creative Commons Attribution 3.0 Unported (CC BY 3.0) Licence (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction Potent antiretroviral therapy (ART) has significantly reduced the morbidity and mortality of HIV-infected adults [1] and children [13]. The long-term benefits of ART are associated with metabolic complications, including lipodystrophy (LD), dyslipidemias, lactic acidosis, glucose intolerance, osteopenia and osteoporosis [49]. The current World Health Organization (WHO) ART guidelines recommend the initiation of paediatric treatment early in life leading to prolonged ART exposure through various stages of growth and development, treatment with multiple drug regimens and a higher risk for metabolic complications [810]. Metabolic complications of ART are well-documented in HIV-infected adults and children, although paediatric cohort studies are limited [4,8]. The nucleoside reverse transcriptase inhibitors (NRTIs), stavudine (d4T), zidovudine (AZT) and didanosine (ddI) are closely linked to LD and lactic acidosis [11]. Protease inhibitors (PI) have consistently been associated with dyslipidemias (increased cholesterol and triglycerides) in children which may increase the risk of cardiovascular disease (CVD) in adulthood [4,5,8,12]. A recent study has reported vitamin D deficiency in youth, which may occur as a complication of ART and result in bone demineralization [13]. Reduced bone mineral density (BMD) has been well described in HIV-infected adults and more recently similar bone loss has been reported in children on ART [14,15]. The combination of severe malnutrition and concurrent micronutrient deficiencies in children initiating ART in resource-limited settings may lead to further reductions in BMD in these populations [16]. The aim of this review is to discuss the epidemiology, clinical presentation and management of metabolic complications of perinatally HIV-infected children and adolescents on ART. Lipodystrophy syndrome LD syndrome is increasingly being recognized as a common complication among HIV-infected children and may be associated with hyperlipidemia and insulin resistance (IR) [17]. Body fat maldistribution is especially problematic for adolescent patients who are generally sensitive to their body image, vulnerable to depression, and prone to antiretroviral non-adherence [17]. These body changes often lead to stigmatization, which in turn may lead to poor adherence and ultimately to treatment failure. LD syndrome encompasses changes in regional fat distribution manifesting as 1 Barlow-Mosha L et al. Journal of the International AIDS Society 2013, 16:18600 http://www.jiasociety.org/index.php/jias/article/view/18600 | http://dx.doi.org/10.7448/IAS.16.1.18600 lipoatrophy (LA), with or without central adiposity (lipohypertrophy-LH) [7] and is frequently associated with abnormalities in lipid regulation and glucose homeostasis. Children affected with LD exhibit different patterns and severity of fat maldistribution; however, similar to adult subjects, LA is more specific for HIV infection and constitutes a key component of LD [7]. Aurpibul et al. noted that LH and LA often occur independent of one another [18]. Dyslipidemias can occur in the absence of LA and LH [7,19,20]. As more HIV-infected children receive life-long ART, the long-term consequences of LD and the associated dyslipidemias and IR, may increase their lifetime risk of CVD. However, long-term data for children as they progress into adolescence and young adulthood are lacking. Epidemiology The prevalence of LD ranges from 1 to 57% among HIVinfected children [5,20,21] and from 2 to 84% among HIV-infected adults [7]. In Europe, a recently completed cross-sectional analysis among HIV-infected children (n 426) aged 218 years with a median duration of 5.2 years on ART, reported a prevalence of 57% for LD [20]. A prospective longitudinal study among HIV-infected children in Thailand reported a prevalence of LD of 9, 47, and 65% at 48, 96, and 144 weeks, respectively, after non-nucleoside reverse transcriptase inhibitor (NNRTI) based ART [18]. In two subSaharan African studies, the prevalence of LD ranged from 27 to 30% among children aged 118 years [21,22]. Both these studies found that older children and the use of d4T are significant risk factors for LA. The prevalence of LD in children varies by geographic regions depending on the use of PIbased regimens, stavudine-containing therapy, and the availability and duration of ART. In addition, differences in methods used to determine and define LD in these studies complicate the estimation of true prevalence of LA and LH. Table 1. Aetiology Although the precise mechanisms of LD are not well understood, several hypotheses have been proposed (Table 1). The pathogenesis of ART-associated LA and LH differs; it is complex and multifactorial, including direct effects on lipid metabolism, genetic polymorphisms, mitochondrial and adipocyte cell function [33,34]. Mitochondrial DNA is affected by both HIV infection and NRTI therapy [27,28]. Exposure to NRTIs, including d4T and zidovudine (AZT), and to a lesser degree to PIs, has been implicated in the development of LA/LH [11,3538]. Mitochondrial dysfunction could lead to decreased ATP, decreased lipogenesis and increased pro-apoptotic mediators, which result in fat apoptosis [23,29]. Puberty has been identified as a time when LD is most likely to develop [7,22]. There is no consensus about whether females are more likely to have LD compared to males with some studies reporting higher prevalence in females and others higher in males [5,18,22]. A study by Resino et al. has also shown a higher prevalence of LD among HIV-infected children with rapid immunologic recovery [39]. Clinical presentation There are three patterns of body fat maldistribution: (1) LA: with decrease subcutaneous fat in the face, limbs and/or buttocks; (2) Lipohypertorphy: with accumulation of fat in the upper chest, abdomen, breast and/or dorsocervial region; (3) mixed/combined pattern with both LA and LH. Although LA is the most characteristic fat redistribution in adults, there is no consensus for children [7]. A study among Thai children found a 46% prevalence of central LH, 20% peripheral LA, and 34% combined pattern after 144 weeks of NNRTI-based ART [18]. However, a cross-sectional study in Uganda reported that LA with facial wasting was the most common body shape change among children with fat distribution after a median duration of 3.8 years on ART [22]. A recent study among European children found that LA occurred in 28% Potential aetiology of lipodystrophy syndrome complication Mechanism Lipoatrophy Available data Mitochondrial toxicity NRTIs inhibit mitochondrial DNA (mtDNA) polymerase gamma, leading to mtDNA depletion, respiratory chain dysfunction, and reduced energy production [2326]. However, the function of mitochondrial DNA is affected by both HIV infection and NRTI [27,28]. Mitochondrial dysfunction could lead to decreased ATP, decrease lipogeneis, and increased pro-apoptotic mediators, which result in fat apoptosis [23,29]. Lipoatrophy/ lipohypertrophy Effect of protease inhibitors PIs have a high affinity for a site of HIV-1 protease, which shares a sequence homology with 2 proteins involved in lipid metabolism, cytoplasmic retinoic acidbinding protein type 1 (CRABP-1), and low-density lipoprotein receptorrelated protein (LDLR-RP) [30]. Inhibition of CRABP-1 impairs the production of retinoic acid, which leads to decreased fat storage and adipocyte apoptosis. Subsequently lipids are released into the circulation [30]. Dyslipidemia Effect of protease Inhibition of LDLR-RP results in hyperlipidemia due to the failure of hepatocytes and Glucose homeostasis inhibitors Inhibition of GLUT-4 endothelial cells to removal of triglycerides from the circulation [30]. Both PIs and NRTIs have also been associated with insulin resistance, through inhibition of muscular and adipocyte GLUT4 (insulin-regulated transmembrane glucose transporter), resulting in decrease glucose intake mediated by insulin in these tissues [31,32]. 2 Barlow-Mosha L et al. Journal of the International AIDS Society 2013, 16:18600 http://www.jiasociety.org/index.php/jias/article/view/18600 | http://dx.doi.org/10.7448/IAS.16.1.18600 (n117), and LH in 27% (n 115), most commonly in the face and trunk, respectively [20]. In multivariable analysis, white ethnicity, body mass index (BMI) and exposure to lopinavir/ritonavir (LPV/r) and NNRTIs were each associated with increased risk of LD (p B0.05). White ethnicity, history of CDC-defined disease and d4T were associated with risk of LA (p B0.05) [20]. Dyslipdemia Dyslipidemias are a common component of ART-associated LD. However, low levels of high-density lipoprotein cholesterol (HDL), low levels of low-density lipoprotein cholesterol (LDL-C) and elevated triglycerides have been associated with HIV in adults [40,41]. The definition of hypercholesterolemia and hypertriglyceridemia varies among studies. Several guidelines to determine cut-off points for abnormal lipid levels for children and adolescents have been published, including the National Heart, Lung and Blood Institute (NHLBI)-released Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents, November 2011, which was endorsed by the American Academy of Pediatrics [4244]. Taylor et al. reported that receiving PI therapy in the age range of 1015 years and sustained control of viremia were associated with the development of fat redistribution and dyslipidemia [35]. All PIs are associated with elevated TG, LDL-C and total cholesterol levels [45]. Among the NRTIs, d4T is associated with increased levels of TC, LDL-C and TG [46]. Apradi et al. compared metabolic abnormalities in HIVinfected children on LPV/r to nevirapine (NVP)-based ART and found significantly higher LDL-C and TG levels among children who remained on LPV/r [12]. While the long-term CVD risk for HIV-infected children on ART is unknown, the observed elevations in cholesterol levels are similar to those seen in patients heterozygous for familial hypercholesterolemia and, therefore, may confer a similar risk for premature atherosclerotic disease [47]. Insulin resistance Insulin resistance is characterized by the decreased ability of insulin to stimulate the use of glucose by muscles and adipose tissue leading to increased production of pancreatic insulin. A variety of disorders of glucose metabolism have been associated with HIV infection and ART, including impaired glucose tolerance, impaired fasting glucose and type 2 diabetes mellitus (DM). Unlike adults, disturbances in glucose homeostasis are relatively uncommon in HIV-infected children. Studies have shown differing results on the association of glucose homeostasis with PIs and LD syndrome [48,49]. Impaired glucose homeostasis has been reported among 835% of HIV-infected children [31]. However, no differences were detected in fasting serum insulin, proinsulin, C-peptide, insulin:glucose ratio or Homeostasis Model of Assessment (HOMA-IR) between PI-treated and PI-naı̈ve children [48,50 52]. Normal fasting glucose level and glucose tolerance tests have been reported among children with LD [18,22,53,54]; however in this setting, high fasting insulin concentrations were found primarily among children with LH and inconsistently with LA [53,54]. However, prolonged exposure to high insulin levels may increase their risk of type 2 DM. There are limited longitudinal data on IR among HIV-infected children on ART but some reports document an increased prevalence over time [55,56]. Diagnosis Fat distribution A variety of techniques can be used to diagnose LD (Table 2); however, clinical presentation remains the most commonly used method, especially in resource-limited settings. Systematic objective measurements are required to detect abnormalities of fat distribution unless LD is severe enough to be recognized by the physician or caretaker. Anthropometric measurements are an inexpensive way to measure fat distribution, but they require significant standardization and experience and only measure subcutaneous fat [7]. While some studies have used Dual-energy X-ray absorptiometry (DXA) to assess fat distribution in HIV-infected children [54,61,62], the cost and availability in a resource-limited setting are prohibitive. Dyslipidemia Lipid profiles should be obtained from all children prior to the initiation of ART. Thereafter, they should be repeated every 612 months. In resource-limited settings where facilities to measure blood lipid levels are not available, the collection of dried blood spots and transfer to reference laboratories should be utilized [16,63]. Guidelines for screening have been published by the National Cholesterol Education Program Expert Panel [49]. However, an updated classification was published by Jolliffe and Janssen with age- and gender-specific lipid thresholds for adolescents aged 1220 years [42]. Insulin resistance A variety of methods have been used to diagnose IR, including the measurement of fasting glucose, fasting insulin, Cpeptide, oral glucose tolerance tests (OGTT) and derivations of various indices generated from these values [7]. The gold standard to assess IR is the hyperinsulinaemic euglycemic clamp [59]. Fasting insulin and glucose levels and indices derived from the OGTT correlate well with hyperinsulinaemic euglycemic clamp both in adults and paediatrics [59,60]. Management Fat distribution Switching the suspected offending antiretroviral agent has been the most common strategy to manage fat maldistribution in LD. In cases of LA, avoidance of d4T, ddI, and to a lesser extent AZT, are recommended and substitution with either abacavir (ABC) or tenofovir (TDF). Few studies using switch strategies for LA have been conducted in children. Vigano et al. reported on changes in body composition in a study where a simultaneous switch was made from d4T to TDF and from a PI to efavirenz (EFV) among 24 virologically suppressed HIV-infected children with LA, aged 517 years [64]. This prospective study compared body composition after the switch to that of healthy controls using DXA. Restoration of physiologic fat accrual and no further progression of LA was reported 96 weeks after replacement of d4T with TDF and a PI with EFV [64]. However, GonzalezTome et al. reported no significant changes in body fat 3 Barlow-Mosha L et al. Journal of the International AIDS Society 2013, 16:18600 http://www.jiasociety.org/index.php/jias/article/view/18600 | http://dx.doi.org/10.7448/IAS.16.1.18600 Table 2. Diagnosis of lipodystrophy syndrome Complication Fat distribution (lipoatrophy and Technique Comment Anthropometric measurements (waist-to-hip ratio, An inexpensive way to measure fat distribution but, they skinfolds, limb circumferences) require significant standardization and experience, and lipohypertrophy) only measure subcutaneous fat [7]. Bioelectrical impedance (BIA) Measures lean body mass and total body fat but not regional fat distribution [57]. Dual-energy X-ray absorptiometry (DXA) Measures regional fat distribution (except facial fat) and Computed tomography (CT) and magnetic resonance is ideal for longitudinal studies [58]. Both discriminate well between subcutaneous fat and imaging (MRI) visceral fat, however both are expensive and may require sedation for young children [7]. Dyslipidemia Fasting and non-fasting lipid levels The cut off points for abnormal lipid levels were defined as follows: total cholesterol ]200 mg/dl, low density lipoprotein cholesterol (LDL) ]130 mg/dl, triglycerides (TG) ]100 mg/dl in children 09 years, and TG ]130 mg/dl in adolescents 1019 years of age [43]. If lipid abnormalities are found then secondary causes should also be assessed such as obesity, hypothyroidism, and diabetes mellitus. Glucose homeostasis Hyperinuslinaemic euglycemic clamp This is the gold standard to assess insulin, however it is an expensive and labour intensive technique, primarily suitable for research alone [59]. Fasting glucose, fasting insulin, C-peptide, and oral Fasting insulin and glucose levels and indices derived glucose tolerance tests (OGTT) from the OGTT correlate well with hyperinsulinaemic euglycemic clamp both in adults and paediatrics [59,60]. Homeostatic model assessment (HOMA-IR), the fasting The most frequently used in clinical investigations are glucose:insulin ratio and the quantitative insulin fasting insulin resistance (IR) indices [50,59]. sensitivity check index (QUICKI) composition after substitution of a PI with NVP [65]. Other investigational strategies have been identified to manage LD including the use of growth hormone (GH) and other drugs. Impaired GH has been correlated to visceral adiposity [66]. A study among adolescents reported visceral fat reduction with the use of recombinant GH [67]. However, patients may develop glucose intolerance as a result of GH therapy. Other potential treatments include metformin, thiazolidinediones, and testosterone [55], but results have been conflicting. Reconstructive surgery may be considered for adolescents with disfiguring fat maldistribution and psychological problems [68]. However, surgical management of LD is only efficacious with lipohypertrophy [69]. Various procedures in adults have recently been proposed for facial LA including polylactic acid injections, fat autotransplantation and silicone implants [70]. Dyslipidemia The first step in management of dyslipidemias is lifestyle modification with a low-lipid diet and aerobic exercise. If the child is on a PI-based regimen then studies have shown that switching to a PI-sparing regimen or atazanavir (ATV) can reduce TC and TG levels [71]. McComsey et al. studied 17 children with viral suppression who were switched from a PI-containing regimen to EFV, with significant improvements in TC, LDL, TG and sustained viral suppression after 48 weeks [72]. Another prospective study which randomized 28 children to switch from PI to EFV and d4T to TDF at baseline (group 1) or 24 weeks (group 2) showed a significant improvement in lipid profiles at 48 weeks after substitution [73]. However, since both PIs and d4T were switched at the same time, it was difficult to attribute the improvement to a specific antiretroviral drug. If there is inadequate response after 612 months of the initial intervention, then lipid-lowering drugs such as statins (pravastatin and atorvastatin) may be considered for children ]810 years with LDL levels 190 mg/dl or 160 mg/dl with a family history of CVD [43]. There are limited data on the use of resins (bile acid sequestrants) and cholesterol-absorption blockers (Ezetimibe) in HIV-infected children; however, these drugs are Food and Drug Administration (FDA)-approved for use in children with familial hypercholesterolemia. Insulin resistance Lifestyle changes in diet and exercise are the first intervention to manage IR. If a PI is the suspected cause of insulin resistance, studies in adults and children have shown switching to a PI-sparing regimen or unboosted atazanavir could improve insulin sensitivity [50,56,74]. Vigano et al. 4 Barlow-Mosha L et al. Journal of the International AIDS Society 2013, 16:18600 http://www.jiasociety.org/index.php/jias/article/view/18600 | http://dx.doi.org/10.7448/IAS.16.1.18600 conducted a four-year prospective study of PI-treated HIVinfected children which showed that a treatment switch to an NNRTI-based treatment was associated with an improvement in insulin sensitivity compared with the previous PI-based regimens [56]. However, if substitution fails then metformin can be used in children 10 years of age. Metformin has been shown to improve insulin sensitivity and BMI in nondiabetic obese adolescents with fasting hyperinsulinemia and a family history of type 2 DM [50]. However, metformin should be used with caution in children receiving NRTIs because of the rare complication of lactic acidosis. Other potential agents are thiazolindinediones (rosiglitazone, pioglitazone), which improve insulin sensitivity in HIV-infected adults with LD, but are not yet FDA-approved for children. Preventive measures of LD should be incorporated in routine care, with active surveillance for fat maldistribution. In resource-limited settings, as the use of PIs (LPV/r) as firstline for children increases, monitoring of lipid levels and provision/availability of alternative antiretrovirals will become necessary and potentially lipid-lowering agents for severe hypercholesterolemia. More data are needed on the long-term outcome of HIV-infected children with early signs of IR and management in young children. Cardiovascular disease HIV-infected adults have an increased risk of CVD compared to the general population [75,76]. Both abnormal lipoprotein profiles and increased inflammation have been demonstrated in multiple studies of HIV-infected children and adolescents [7781]. Abnormal lipid profiles are also associated with inflammatory markers [8183]. In addition, endothelial dysfunction, underlying vascular disease and arterial stiffness have been associated with heightened inflammation and/ or immune activation in HIV-infected adults and children [8488]. Because clinical cardiovascular events are expected to be of low prevalence, non-invasive techniques have been widely used as surrogates of CVD risk in both adults and children with HIV. Pulse wave velocity (PWV), which measures arterial stiffness, and carotid intima-media thickness (IMT) measured by ultrasound are two of the most well-accepted and robust methods to estimate subclinical arterial stiffness and vascular disease. Each of these tests is a powerful and independent predictor of CVD events in various populations, even after adjustment for traditional CVD risk factors [8995]. A number of cross-sectional studies have also found increased carotid IMT in HIV-infected children and adolescents compared to healthy uninfected controls [77,9698]. To date, one study has evaluated longitudinal carotid IMT data [83] and found that in both the HIV-infected and control groups, IMT decreased (i.e. improved) over the 48-week time period, with more pronounced changes among the HIVinfected group for both internal carotid artery (ICA) and common carotid artery (CCA) IMT. While higher CD4 T-cell count and longer duration of ART may have contributed to the improvements seen, it is generally unknown what the natural course of carotid IMT is in this population. As Fernhall et al. [99] pointed out in a thorough review of the literature among healthy children, discrepancies among various studies may be due to the fact that IMT changes very little during childhood, and as it changes, so does arterial size and luminal diameter [100,101]. These complications likely make measuring carotid IMT longitudinally in children much more challenging and difficult to interpret than in adults, and thus may limit its use in this population. PWV has also been evaluated in HIV-infected children, but only in one crosssectional study, which showed that HIV-infected subjects had worse PWV compared to healthy controls [102]. While there are limited data evaluating subclinical atherosclerosis among HIV-infected adolescents, the fact that they have abnormal lipoprotein profiles and increased inflammation suggest that they too are at an increased CVD risk like their adult counterparts. Given the additive risk associated with HIV infection, evaluating CVD risk in HIV-infected adolescents is of paramount importance as the number of long-term survivors of perinatally infected children and behaviourally infected adolescents is growing at a significant rate due to combination ART. In addition, assessing the effect of safe interventions on CVD risk aimed at decreasing inflammation should be one of the primary research goals in the coming years. The challenge in resource-limited settings is that most of the diagnostic tests for CVD are not accessible to most infected children. Therefore, simpler tests and interventions need to be evaluated and prevention strategies implemented. Lactic acidosis Hyperlactatemia is a well-recognized complication of ART with the spectrum of disease ranging from mild to moderate asymptomatic hyperlactatemia to fulminant life-threatening lactic acidosis with lactate levels 5 mmol/L and hepatic steatosis [103]. The mechanism for severe lactic acidosis has been linked to NRTI inhibition of mitochondrial DNA (mtDNA) polymerases leading to mtDNA depletion. Stavudine and ddI have the greatest effect on mtDNA, with AZT, 3TC, TDF and ABC having less effect (in decreasing order). Chronic mitochondrial toxicity leads to mtDNA depletion and finally dysfunction with disturbance of oxidative phosphorylation and shifting of the pyruvatelactate equilibrium to lactate [104]. The clinical presentation is non-specific, including asthenia, malaise, vomiting, abdominal pain, weight loss, tachypnoea, dyspnoea, and muscle weakness. The most common laboratory abnormalities include an increased anion gap, elevated transaminases, increased creatinine phosphokinase (CPK), lactate dehydrogenase deficiency (LDH), amylase and lipase [103]. Mild to moderate asymptomatic hyperlactatemia is frequently reported with an estimated prevalence of 1530% in adults and 3550% in children [105]. The incidence of severe lactic acidosis ranges from three to 10 episodes/1000 personyears on ART [106,107]. In children, mild to moderate asymptomatic hyperlactatemia has been described but severe lactic acidosis is rare [108,109]. A large cohort of 1422 children in South Africa reported a low rate of d4T toxicity requiring medication changes at 28.8/1000 years on treatment with only three cases of lactic acidosis [110]. The majority of medication substitutions were due to LD. The authors conclude that where there are limited drug options, d4T remains relatively safe. In contrast to adults, d4T has less 5 Barlow-Mosha L et al. Journal of the International AIDS Society 2013, 16:18600 http://www.jiasociety.org/index.php/jias/article/view/18600 | http://dx.doi.org/10.7448/IAS.16.1.18600 toxicity in children, but the risk of LD remains, especially as children remain on disproportionately higher doses of d4T compared to adults [38]. Shah reported non-fatal lactic acidosis in two HIV-infected Indian children on a d4T based regimen for five and three years, respectively, when they presented with vomiting and diarrhoea [109]. Rey et al. reported a fatal case of lactic acidosis in a five-year old child on d4T and ddI [108] and Carter et al. reported a 10-year old male with severe lactic acidosis while on d4T, ddI and NVP [111]. These cases emphasize the increased risk of lactic acidosis with d4T alone or in combination with ddI. Noguera et al. documented at least one measurement of hyperlactatemia over a 28-month period in 23 of the 80 children on ART (with the majority on a NRTI backbone). Fourteen of the 23 (61%) had asymptomatic hyperlactatemia [112]. None of the children had lactic acidosis. Hyperlactatemia in these children was associated with higher CD4 cell count and younger age at ART initiation [112]. Another study, a retrospective chart review of 127 children, with 104 on ART, identified 41 (32%) with asymptomatic hyperlactatemia (lactate 2 mmol/l), but none of the children developed severe lactic acidosis. The hyperlactatemia was associated with NRTIs and PIs regardless of treatment regimen and viral suppression [113]. In conclusion, most of the children with hyperlactatemia are asymptomatic and do not require a specific intervention. Management of lactic acidosis requires a high index of suspicion and confirmation with measurement of a venous blood lactate level. If confirmed, then the offending NRTI, usually d4T and ddI alone or in combination, should be stopped and TDF or ABC substituted [114]. Anecdotal reports document the benefit of antioxidants including thiamine, riboflavin and L-carnitine, but there are no randomizedcontrolled trials. The prevention of hyperlactatemia requires the use of second generation NRTIs that have a lower capacity to inhibit DNA polymerase gamma [115]. However in cases of lactic acidosis, NRTI-sparing regimens are advisable. Bone disease Multiple studies have demonstrated decreased BMD in HIVinfected adults with a 15 and 52% prevalence of osteoporosis and osteopenia, respectively [116118]. This decreased BMD results in an increased risk of fractures in this population [119]. The effects of HIV and ART on bone health among HIVinfected children and adolescents may be even more detrimental than in adults. Most adolescents with perinatal HIV infection, for example, have been on ART for much of their lives, including through puberty which is a time of rapid growth and bone mineral accrual [120]. They will likely continue on ART for decades to come, potentially putting them at significant risk for osteoporosis and subsequent fractures later in life. Despite this, data on bone disease in this population remain sparse. Epidemiology A number of studies have investigated the prevalence of low BMD in this population. Different criteria to define low BMD and diverse subject populations make it challenging to compare results among studies. However, most studies show that a quarter to half of subjects have low BMD, as defined by a Z-score of 5 2 as per the 2007 International Society for Clinical Densitometry Pediatric Official Positions [15,121126]. In most studies, these numbers are significantly lower than matched healthy adolescents [124,126129]. In contrast to the aforementioned studies, a recent multicentred, cross-sectional analysis of a relatively large cohort of perinatally infected adolescents showed not only a lower prevalence of low BMD (23 and 21% of HIV-infected subjects had a total body and lumbar spine sex- and age-adjusted BMD z-score B 1.0, respectively), but after adjusting the mean total body Z-scores for sex, race, pubertal maturity, height, weight, and BMI Z-score, there were no differences between the HIV-infected group and the HIV-exposed but uninfected group [130]. This study adjusted for many variables that are known to be altered by HIV infection and/or its therapy; thus, the results of this study should be interpreted with caution. In addition, the proportion of HIVinfected subjects with total body BMD Z-scores B 2.0 was significantly increased compared to controls (7% vs. 2%, P 0.019), with the HIV-infected subjects having double the expected rates compared to normal population distributions. Moreover, in this study, most of their subjects had not yet entered their adolescent pubertal growth spurt. Adolescent years are crucial for bone health as they are associated with the greatest accumulation of bone mass, and attainment of 80% of peak bone mass occurs by 1825 years of age [129,131133]. Thus, this is a particularly vulnerable time, and any impairment of bone gain may impact lifelong bone health. For example, Jacobson et al. showed that HIV-infected adolescents, particularly boys, had lower BMD at the end of puberty compared to HIV-uninfected peers [125]. Perinatally infected adolescents have an increased risk of delayed puberty [134], which may impact their peak bone mass and their subsequent risk of osteoporosis and fractures [132,135]. To date, there are no studies investigating the rate of fractures among perinatally infected HIV patients [136]; long-term longitudinal studies are needed to fully assess this risk. Aetiology Predictors of low BMD have been evaluated in several studies. Similar to adult studies [116,137139], ART-treated HIVinfected adolescents appear to be at greater risk, with the use of protease inhibitors as a particular risk factor in some but not all studies [125,130,140]. The use of TDF has also been associated with low BMD in this population in some studies [35,139142], likely due to decreased renal tubular phosphate reabsorption leading to hypophosphatemia and subsequent decreased bone mineralization [143]. However, this finding is not consistent among all studies, including a 60month cohort study of 28 youth on TDF [144146]. In adult studies, TDF is consistently associated with decreases in BMD in both ART switch studies and studies evaluating first-line regimens [46,138,147,148]. Most of the paediatric TDF studies have included a small number of subjects relative to adult studies, and thus, must be interpreted with caution. In Hazra et al. a younger age was associated with lower BMD, suggesting that this population may be at particular risk of TDF-related bone toxicity [141]. Full dose ritonavir alone or in 6 Barlow-Mosha L et al. Journal of the International AIDS Society 2013, 16:18600 http://www.jiasociety.org/index.php/jias/article/view/18600 | http://dx.doi.org/10.7448/IAS.16.1.18600 combination with stavudine has also been associated with a low BMD in HIV-infected children and adolescents [149]. Additional HIV-related risk factors associated with low BMD vary by study and include advanced HIV stage, higher CD4 cell count, higher peak HIV-1 RNA levels and bone size [127,130,139,150] Traditional risk factors, as in adults, also contribute to lower BMD in HIV-infected adolescents, including lower weight and height Z-scores, white race and lack of multivitamin use [127,139]. Management The extent to which vitamin D deficiency contributes to low BMD in the HIV population is largely unknown, unlike in the general population where there are solid data from randomized, placebo-controlled trials that vitamin D and calcium supplementation decreases the risk of fractures and improves BMD in both adults and children [151155]. In contrast, the studies that have been published within the HIV-infected population are mostly cross-sectional, observational, or retrospective in nature and show conflicting data. [156161]. Only one study has been specifically designed to evaluate the bone effects of vitamin D supplementation in HIV-infected children and adolescents [162]. Arpadi et al. evaluated the bone mass accrual in 64 perinatally infected individuals, aged 616 years, after two years of 100,000 IU of vitamin D3 every other month plus daily calcium compared to placebo. No differences were found in bone mass parameters between the two groups after adjusting for confounding variables. However, while the intervention group increased their mean 25-hydroxyvitamin D (25(OH)D) concentrations after two years compared to the placebo group, 75% in the treatment group had at least 1 25(OH)D concentration B30 ng/mL, which is in the vitamin D insufficiency range. An important limitation of the study is that individuals with severe vitamin D deficiency ( B12 ng/mL) were ineligible for the study, thus potentially excluding the group likely to benefit the most from the intervention. More data on bone disease among perinatally infected adolescents are needed to further characterize the prevalence of and risk factors associated with low BMD. In particular, more studies are needed to determine potential interventions that may minimize this population’s long-term risk of osteoporosis and fractures. In the meantime, optimizing lifestyle choices, such as obtaining adequate nutrition and physical activity, and avoiding cigarette smoking, are crucial. Vitamin D deficiency The prevalence of vitamin D deficiency, as measured by blood concentrations of 25-hydroxyvitamin D (25(OH)D), the established marker of overall vitamin D status [163] is very high in the HIV-infected population, including in HIV-infected adolescents [13,98,164169]. In fact, in most studies the mean 25(OH)D values are well below current recommendations for both the Institute of Medicine (IOM) and The Endocrine Society [170,171]. A few studies have investigated risk factors for vitamin D deficiency in HIV-infected children and adolescents [13,165,166,168]. Non-HIV risk factors that have been identified include older age, female sex, black race, winter/ spring season, higher BMI, and IR. Risk factors among HIV variables include longer duration of HIV disease and cumulative use of ART, NNRTIs, and NRTIs. Efavirenz and some PIs have been associated with vitamin D deficiency but their role in vivo is still unclear [172,173]. Havens et al. found an association between EFV use and baseline 25(OH)D concentrations; however, after three consecutive monthly vitamin D3 supplementation doses, EFV use did not attenuate the increase in 25(OH)D concentrations as observed in adult studies [169,174]. In contrast, Eckard et al. did not find an association with EFV use, but this was likely due to the majority of subjects having very low 25(OH)D concentrations. They did, however, find a strong association with Fitzpatrick skin type, which evaluates skin pigmentation, suggesting that this may be a better method of identifying people who are most at risk compared to using race [165]. More trials are needed to define the role that vitamin D plays on immune reconstitution and metabolic and cardiovascular co-morbidities, as well as the supplementation doses required to restore and maintain vitamin D sufficiency in HIV-infected children and adolescents. Conclusions Metabolic complications of prolonged ART remain a serious and on-going problem of perinatally HIV-infected children, affecting their quality of life and long-term adherence to treatment. Longitudinal studies to document the incidence, risk factors and spectrum of disease in children are still limited. In resource-limited settings, these drug toxicities may progress unnoticed as large numbers of children initiate ART early in life and continue a lifetime of treatment with inadequate laboratory monitoring. Ethnic and lifestyle differences between children living in developed and resource-limited countries may have an impact on metabolic complications. Developing effective strategies to monitor, prevent and manage metabolic complications of ART in children and adolescents is critical. Therefore, using NRTIs with lower mitochondrial toxicity, simpler techniques for monitoring lipid profiles, identifying LD early, and promoting cardiac and bone health are priorities for improving long-term treatment outcomes. Authors’ affiliations 1 Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda; 2Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA, USA; 3Department of Pediatric Infectious Diseases and Rheumatology, Case Western Reserve University, Cleveland, OH, USA; 4Department of Paediatrics and Child Health, School of Medicine, College of health Sciences, Makerere University, Kampala, Uganda Competing interests The authors have no conflict of interest and have received no payment in preparation of this manuscript. Authors’ contributions LBM, ARE, GAM and PM participated in the writing of the manuscript. All authors have read and approved the final manuscript. References 1. Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338(13):85360. 7 Barlow-Mosha L et al. Journal of the International AIDS Society 2013, 16:18600 http://www.jiasociety.org/index.php/jias/article/view/18600 | http://dx.doi.org/10.7448/IAS.16.1.18600 2. Sutcliffe CG, van Dijk JH, Bolton C, Persaud D, Moss WJ. Effectiveness of antiretroviral therapy among HIV-infected children in sub-Saharan Africa. Lancet Infect Dis. 2008;8(8):47789. 3. Gibb DM, Duong T, Tookey PA, Sharland M, Tudor-Williams G, Novelli V, et al. Decline in mortality, AIDS, and hospital admissions in perinatally HIV-1 infected children in the United Kingdom and Ireland. Brit Med J. 2003;327(7422):1019. 4. Tsiodras S, Mantzoros C, Hammer S, Samore M. Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: a 5-year cohort study. Arch Intern Med. 2000;160(13):20506. 5. European Paediatric Lipodystrophy Group. Antiretroviral therapy, fat redistribution and hyperlipidaemia in HIV-infected children in Europe. AIDS. 2004;1810:144351. 6. Carter RJ, Wiener J, Abrams EJ, Farley J, Nesheim S, Palumbo P, et al. Dyslipidemia among perinatally HIV-infected children enrolled in the PACTSHOPE cohort, 19992004: a longitudinal analysis. J Acquir Immune Defic Syndr. 2006;41(4):45360. 7. McComsey GA, Leonard E. Metabolic complications of HIV therapy in children. AIDS. 2004;18(13):175368. 8. Dapena M, Jimenez B, Noguera-Julian A, Soler-Palacin P, Fortuny C, Lahoz R, et al. Metabolic disorders in vertically HIV-infected children: future adults at risk for cardiovascular disease. J Pediatr Endocrinol Metab. 2012;25(5,6): 52935. 9. Aldrovandi GM, Lindsey JC, Jacobson DL, Zadzilka A, Sheeran E, Moye J, et al. Morphologic and metabolic abnormalities in vertically HIV-infected children and youth. AIDS. 2009;23(6):66172. 10. World Health Organization. Antiretroviral therapy for HIV infection in infants and children Recommendations for a public health approach. Geneva, Switzerland: World Health Organization, 2010. 11. Mallewa JE, Wilkins E, Vilar J, Mallewa M, Doran D, Back D, et al. HIVassociated lipodystrophy: a review of underlying mechanisms and therapeutic options. J Antimicrob Chemother. 2008;62(4):64860. 12. Arpadi S, Shiau S, Strehlau R, Martens L, Patel F, Coovadia A, et al. Metabolic abnormalities and body composition of HIV-infected children on Lopinavir or Nevirapine-based antiretroviral therapy. Arch Dis Child. 2013;98:25864. 13. Eckard AR, Tangpricha V, Seydafkan S, O’Riordan MA, Storer N, Labbato D, et al. The relationship between vitamin D status and HIV-related complications in HIV-infected children and young adults. Pediatr Infect Dis J. 2013. [Epub ahead of print]. 14. Walker Harris V, Brown TT. Bone loss in the HIV-infected patient: evidence, clinical implications, and treatment strategies. J Infect Dis. 2012;205(Suppl 3): S3918. 15. Mora S, Zamproni I, Beccio S, Bianchi R, Giacomet V, Vigano A. Longitudinal changes of bone mineral density and metabolism in antiretroviral-treated human immunodeficiency virus-infected children. J Clin Endocrinol Metab. 2004;89(1):248. 16. Musoke PM, Fergusson P. Severe malnutrition and metabolic complications of HIV-infected children in the antiretroviral era: clinical care and management in resource-limited settings. Am J Clin Nutr. 2011;94(6):1716S 20. 17. Wedekind CA, Pugatch D. Lipodystrophy syndrome in children infected with human immunodeficiency virus. Pharmacotherapy. 2001;21(7):8616. 18. Aurpibul L, Puthanakit T, Lee B, Mangklabruks A, Sirisanthana T, Sirisanthana V. Lipodystrophy and metabolic changes in HIV-infected children on non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy. Antivir Ther. 2007;12(8):124754. 19. Ene L, Goetghebuer T, Hainaut M, Peltier A, Toppet V, Levy J. Prevalence of lipodystrophy in HIV-infected children: a cross-sectional study. Eur J Pediatr. 2007;166(1):1321. 20. Alam N, Cortina-Borja M, Goetghebuer T, Marczynska M, Vigano A, Thorne C. Body fat abnormality in HIV-infected children and adolescents living in Europe: prevalence and risk factors. J Acquir Immune Defic Syndr. 2012;59(3):31424. 21. Kinabo GD, Sprengers M, Msuya LJ, Shayo AM, van Asten H, Dolmans WM, et al. Prevalence of Lipodystrophy in HIV-infected children in Tanzania on highly active antiretroviral therapy. Pediatr Infect Dis J. 2013;32(1):3944. 22. Piloya T, Bakeera-Kitaka S, Kekitiinwa A, Kamya MR. Lipodystrophy among HIV-infected children and adolescents on highly active antiretroviral therapy in Uganda: a cross sectional study. J Int AIDS Soc. 2012;15(2):17427. 23. Kakuda TN, Brundage RC, Anderson PL, Fletcher CV. Nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity as an etiology for lipodystrophy. AIDS. 1999;13(16):23112. 24. Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet. 1999;354 (9184):11125. 25. Walker UA, Brinkman K. NRTI induced mitochondrial toxicity as a mechanism for HAART related lipodystrophy: fact or fiction? HIV Med. 2001;2 (3):1635. 26. Walker UA. Update on mitochondrial toxicity: where are we now? J HIV Ther. 2003;8(2):325. 27. Cossarizza A, Pinti M, Moretti L, Bricalli D, Bianchi R, Troiano L, et al. Mitochondrial functionality and mitochondrial DNA content in lymphocytes of vertically infected human immunodeficiency virus-positive children with highly active antiretroviral therapy-related lipodystrophy. J Infect Dis. 2002; 185(3):299305. 28. Cossarizza A, Moyle G. Antiretroviral nucleoside and nucleotide analogues and mitochondria. AIDS. 2004;18(2):13751. 29. Oh J, Hegele RA. HIV-associated dyslipidaemia: pathogenesis and treatment. Lancet Infect Dis. 2007;7(12):78796. 30. Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJ, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS. 1998;12(7):F518. 31. Bockhorst JL, Ksseiry I, Toye M, Chipkin SR, Stechenberg BW, Fisher DJ, et al. Evidence of human immunodeficiency virus-associated lipodystrophy syndrome in children treated with protease inhibitors. Pediatr Infect Dis J. 2003;22(5):4635. 32. Alves C, Oliveira AC, Brites C. Lipodystrophic syndrome in children and adolescents infected with the human immunodeficiency virus. Braz J Infect Dis. 2008;12(4):3428. 33. Barbaro G. Visceral fat as target of highly active antiretroviral therapyassociated metabolic syndrome. Curr Pharm Des. 2007;13(21):220813. 34. Zanone Poma B, Riva A, Nasi M, Cicconi P, Broggini V, Lepri AC, et al. Genetic polymorphisms differently influencing the emergence of atrophy and fat accumulation in HIV-related lipodystrophy. AIDS. 2008;22(14): 176978. 35. Taylor P, Worrell C, Steinberg SM, Hazra R, Jankelevich S, Wood LV, et al. Natural history of lipid abnormalities and fat redistribution among human immunodeficiency virus-infected children receiving long-term, protease inhibitor-containing, highly active antiretroviral therapy regimens. Pediatrics. 2004;114(2):23542. 36. McComsey GA, Walker UA. Role of mitochondria in HIV lipoatrophy: insight into pathogenesis and potential therapies. Mitochondrion. 2004;4(2,3): 1118. 37. Innes S, Levin L, Cotton M. Lipodystrophy syndrome in HIV-infected children on haart. South Afr J HIV Med. 2009;10(4):7680. 38. Innes S, Cotton MF, Haubrich R, Conradie MM, van Niekerk M, Edson C, et al. High prevalence of lipoatrophy in pre-pubertal South African children on antiretroviral therapy: a cross-sectional study. BMC Pediatr. 2012;12:183. 39. Resino S, Micheloud D, Larru B, Bellon JM, Leon JA, Resino R, et al. Immunological recovery and metabolic disorders in severe immunodeficiency HIV type 1-infected children on highly active antiretroviral therapy. AIDS Res Hum Retroviruses. 2008;24(12):147784. 40. Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIVinfected adults. N Engl J Med. 2005;352(1):4862. 41. Grunfeld C, Kotler DP, Hamadeh R, Tierney A, Wang J, Pierson RN. Hypertriglyceridemia in the acquired immunodeficiency syndrome. Am J Med. 1989;86(1):2731. 42. Jolliffe CJ, Janssen I. Distribution of lipoproteins by age and gender in adolescents. Circulation. 2006;114(10):105662. 43. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents; National Heart, Lung, and Blood Institute. Pediatrics. 2011;128(Suppl 5):S21356. 44. Hickman TB, Briefel RR, Carroll MD, Rifkind BM, Cleeman JI, Maurer KR, et al. Distributions and trends of serum lipid levels among United States children and adolescents ages 419 years: data from the Third National Health and Nutrition Examination Survey. Prev Med. 1998;27(6):87990. 45. Sax PE, Kumar P. Tolerability and safety of HIV protease inhibitors in adults. J Acquir Immune Defic Syndr. 2004;37(1):111124. 46. Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JM, Miller MD, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. J Am Med Assoc. 2004;292(2):191201. 8 Barlow-Mosha L et al. Journal of the International AIDS Society 2013, 16:18600 http://www.jiasociety.org/index.php/jias/article/view/18600 | http://dx.doi.org/10.7448/IAS.16.1.18600 47. Cheseaux JJ, Jotterand V, Aebi C, Gnehm H, Kind C, Nadal D, et al. Hyperlipidemia in HIV-infected children treated with protease inhibitors: relevance for cardiovascular diseases. J Acquir Immune Defic Syndr. 2002; 30(3):28893. 48. Bitnun A, Sochett E, Babyn P, Holowka S, Stephens D, Read S, et al. Serum lipids, glucose homeostasis and abdominal adipose tissue distribution in protease inhibitor-treated and naive HIV-infected children. AIDS. 2003; 17(9):131927. 49. Bitnun A, Sochett E, Dick PT, To T, Jefferies C, Babyn P, et al. Insulin sensitivity and beta-cell function in protease inhibitor-treated and naive human immunodeficiency virus-infected children. J Clin Endocrinol Metab. 2005;90(1):16874. 50. Vigano A, Cerini C, Pattarino G, Fasan S, Zuccotti GV. Metabolic complications associated with antiretroviral therapy in HIV-infected and HIV-exposed uninfected paediatric patients. Expert Opin Drug Saf. 2010;9(3): 43145. 51. Melvin AJ, Lennon S, Mohan KM, Purnell JQ. Metabolic abnormalities in HIV type 1-infected children treated and not treated with protease inhibitors. AIDS Res Hum Retroviruses. 2001;17(12):111723. 52. Lainka E, Oezbek S, Falck M, Ndagijimana J, Niehues T. Marked dyslipidemia in human immunodeficiency virus-infected children on protease inhibitor-containing antiretroviral therapy. Pediatrics. 2002;110(5):56. 53. Jaquet D, Levine M, Ortega-Rodriguez E, Faye A, Polak M, Vilmer E, et al. Clinical and metabolic presentation of the lipodystrophic syndrome in HIVinfected children. AIDS. 2000;14(14):21238. 54. Vigano A, Zuccotti GV, Cerini C, Stucchi S, Puzzovio M, Giacomet V, et al. Lipodystrophy, insulin resistance, and adiponectin concentration in HIVinfected children and adolescents. Curr HIV Res. 2011;9(5):3216. 55. Chantry CJ, Hughes MD, Alvero C, Cervia JS, Meyer WA 3rd, Hodge J, et al. Lipid and glucose alterations in HIV-infected children beginning or changing antiretroviral therapy. Pediatrics. 2008;122(1):e12938. 56. Vigano A, Brambilla P, Pattarino G, Stucchi S, Fasan S, Raimondi C, et al. Long-term evaluation of glucose homeostasis in a cohort of HAART-treated HIV-infected children: a longitudinal, observational cohort study. Clin Drug Investig. 2009;29(2):1019. 57. Saint-Marc T, Partisani M, Poizot-Martin I, Bruno F, Rouviere O, Lang JM, et al. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS. 1999;13(13):165967. 58. Brambilla P, Bricalli D, Sala N, Renzetti F, Manzoni P, Vanzulli A, et al. Highly active antiretroviral-treated HIV-infected children show fat distribution changes even in absence of lipodystrophy. AIDS. 2001;15(18):241522. 59. Borai A, Livingstone C, Ferns GA. The biochemical assessment of insulin resistance. Ann Clin Biochem. 2007;44(Pt 4):32442. 60. Yeckel CW, Weiss R, Dziura J, Taksali SE, Dufour S, Burgert TS, et al. Validation of insulin sensitivity indices from oral glucose tolerance test parameters in obese children and adolescents. J Clin Endocrinol Metab. 2004;89(3):1096101. 61. Arpadi SM, Cuff PA, Horlick M, Wang J, Kotler DP. Lipodystrophy in HIVinfected children is associated with high viral load and low CD4 -lymphocyte count and CD4 -lymphocyte percentage at baseline and use of protease inhibitors and stavudine. J Acquir Immune Defic Syndr. 2001;27(1):304. 62. Vigano A, Mora S, Testolin C, Beccio S, Schneider L, Bricalli D, et al. Increased lipodystrophy is associated with increased exposure to highly active antiretroviral therapy in HIV-infected children. J Acquir Immune Defic Syndr. 2003;32(5):4829. 63. Lakshmy R, Gupta R, Prabhakaran D, Snehi U, Reddy KS. Utility of dried blood spots for measurement of cholesterol and triglycerides in a surveillance study. J Diabetes Sci Technol. 2010;4(2):25862. 64. Vigano A, Brambilla P, Cafarelli L, Giacomet V, Borgonovo S, Zamproni I, et al. Normalization of fat accrual in lipoatrophic, HIV-infected children switched from stavudine to tenofovir and from protease inhibitor to efavirenz. Antivir Ther. 2007;12(3):297302. 65. Gonzalez-Tome MI, Amador JT, Pena MJ, Gomez ML, Conejo PR, Fontelos PM. Outcome of protease inhibitor substitution with nevirapine in HIV-1 infected children. BMC Infect Dis. 2008;8:144. 66. Vigano A, Mora S, Brambilla P, Schneider L, Merlo M, Monti LD, et al. Impaired growth hormone secretion correlates with visceral adiposity in highly active antiretroviral treated HIV-infected adolescents. AIDS. 2003;17 (10):143541. 67. Vigano A, Mora S, Manzoni P, Schneider L, Beretta S, Molinaro M, et al. Effects of recombinant growth hormone on visceral fat accumulation: pilot study in human immunodeficiency virus-infected adolescents. J Clin Endocrinol Metab. 2005;90(7):407580. 68. Dollfus C, Blanche S, Trocme N, Funck-Brentano I, Bonnet F, Levan P. Correction of facial lipoatrophy using autologous fat transplants in HIV-infected adolescents. HIV Med. 2009;10(5):2638. 69. Hultman CS, McPhail LE, Donaldson JH, Wohl DA. Surgical management of HIV-associated lipodystrophy: role of ultrasonic-assisted liposuction and suction-assisted lipectomy in the treatment of lipohypertrophy. Ann Plast Surg. 2007;58(3):25563. 70. Moyle GJ. Plastic surgical approaches for HIV-associated lipoatrophy. Curr HIV/AIDS Rep. 2005;2(3):12731. 71. Mobius U, Lubach-Ruitman M, Castro-Frenzel B, Stoll M, Esser S, Voigt E, et al. Switching to atazanavir improves metabolic disorders in antiretroviralexperienced patients with severe hyperlipidemia. J Acquir Immune Defic Syndr. 2005;39(2):17480. 72. McComsey G, Bhumbra N, Ma JF, Rathore M, Alvarez A. Impact of protease inhibitor substitution with efavirenz in HIV-infected children: results of the first pediatric switch study. Pediatrics. 2003;111(3):27581. 73. Vigano A, Aldrovandi GM, Giacomet V, Merlo M, Martelli L, Beretta S, et al. Improvement in dyslipidaemia after switching stavudine to tenofovir and replacing protease inhibitors with efavirenz in HIV-infected children. Antivir Ther. 2005;10(8):91724. 74. Guffanti M, Caumo A, Galli L, Bigoloni A, Galli A, Dagba G, et al. Switching to unboosted atazanavir improves glucose tolerance in highly pretreated HIV-1 infected subjects. Eur J Endocrinol. 2007;156(4):5039. 75. Obel N, Thomsen HF, Kronborg G, Larsen CS, Hildebrandt PR, Sorensen HT, et al. Ischemic heart disease in HIV-infected and HIV-uninfected individuals: a population-based cohort study. Clin Infect Dis. 2007;44(12):162531. 76. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007;92(7):250612. 77. McComsey GA, O’Riordan M, Hazen SL, El-Bejjani D, Bhatt S, Brennan ML, et al. Increased carotid intima media thickness and cardiac biomarkers in HIV infected children. AIDS. 2007;21(8):9217. 78. Farley J, Gona P, Crain M, Cervia J, Oleske J, Seage G, et al. Prevalence of elevated cholesterol and associated risk factors among perinatally HIV-infected children (419 years old) in Pediatric AIDS Clinical Trials Group 219C. J Acquir Immune Defic Syndr. 2005;38(4):4807. 79. Tassiopoulos K, Williams PL, Seage GR 3rd, Crain M, Oleske J, Farley J. Association of hypercholesterolemia incidence with antiretroviral treatment, including protease inhibitors, among perinatally HIV-infected children. J Acquir Immune Defic Syndr. 2008;47(5):60714. 80. Jacobson DL, Williams P, Tassiopoulos K, Melvin A, Hazra R, Farley J. Clinical management and follow-up of hypercholesterolemia among perinatally HIVinfected children enrolled in the PACTG 219C study. J Acquir Immune Defic Syndr. 2011;57(5):41320. 81. Ross AC, O’Riordan MA, Storer N, Dogra V, McComsey GA. Heightened inflammation is linked to carotid intima-media thickness and endothelial activation in HIV-infected children. Atherosclerosis. 2010;211(2):4928. 82. Miller TI, Borkowsky W, DiMeglio LA, Dooley L, Geffner ME, Hazra R, et al. Metabolic abnormalities and viral replication are associated with biomarkers of vascular dysfunction in HIV-infected children. HIV Med. 2012;13(5):26475. 83. Ross AC, Storer N, O’Riordan MA, Dogra V, McComsey GA. Longitudinal changes in carotid intima-media thickness and cardiovascular risk factors in human immunodeficiency virus-infected children and young adults compared with healthy controls. Pediatr Infect Dis J. 2010;29(7):6348. 84. Kaplan RC, Sinclair E, Landay AL, Lurain N, Sharrett AR, Gange SJ, et al. T cell activation predicts carotid artery stiffness among HIV-infected women. Atherosclerosis. 2011;217(1):20713. 85. Kaplan RC, Sinclair E, Landay AL, Lurain N, Sharrett AR, Gange SJ, et al. T cell activation and senescence predict subclinical carotid artery disease in HIVinfected women. J Infect Dis. 2011;203(4):45263. 86. Triant VA, Meigs JB, Grinspoon SK. Association of C-reactive protein and HIV infection with acute myocardial infarction. J Acquir Immune Defic Syndr. 2009;51(3):26873. 87. Longenecker C, Funderburg N, Jiang Y, Debanne S, Storer N, Labbato D, et al. Markers of inflammation and CD8 T-cell activation, but not monocyte activation, are associated with subclinical carotid artery disease in HIV-infected individuals. HIV Med. 2013 Jan 18. doi: 10.1111/hiv.12013. [Epub ahead of print]. 88. Ross AC, Rizk N, O’Riordan MA, Dogra V, El-Bejjani D, Storer N, et al. Relationship between inflammatory markers, endothelial activation markers, 9 Barlow-Mosha L et al. Journal of the International AIDS Society 2013, 16:18600 http://www.jiasociety.org/index.php/jias/article/view/18600 | http://dx.doi.org/10.7448/IAS.16.1.18600 and carotid intima-media thickness in HIV-infected patients receiving antiretroviral therapy. Clin Infect Dis. 2009;49(7):111927. 89. Terai M, Ohishi M, Ito N, Takagi T, Tatara Y, Kaibe M, et al. Comparison of arterial functional evaluations as a predictor of cardiovascular events in hypertensive patients: the Non-Invasive Atherosclerotic Evaluation in Hypertension (NOAH) study. Hypertens Res. 2008;31(6):113545. 90. Kullo IJ, Malik AR. Arterial ultrasonography and tonometry as adjuncts to cardiovascular risk stratification. J Am Coll Cardiol. 2007;49(13):141326. 91. Mattace-Raso FU, van der Cammen TJ, Hofman A, van Popele NM, Bos ML, Schalekamp MA, et al. Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study. Circulation. 2006;113(5):65763. 92. Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar ME, London GM. Impact of aortic stiffness on survival in end-stage renal disease. Circulation. 1999; 99(18):24349. 93. Shokawa T, Imazu M, Yamamoto H, Toyofuku M, Tasaki N, Okimoto T, et al. Pulse wave velocity predicts cardiovascular mortality: findings from the HawaiiLos Angeles-Hiroshima study. Circ J. 2005;69(3):25964. 94. Willum-Hansen T, Staessen JA, Torp-Pedersen C, Rasmussen S, Thijs L, Ibsen H, et al. Prognostic value of aortic pulse wave velocity as index of arterial stiffness in the general population. Circulation. 2006;113(5):66470. 95. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006;27(21):2588605. 96. Giuliano Ide C, de Freitas SF, de Souza M, Caramelli B. Subclinic atherosclerosis and cardiovascular risk factors in HIV-infected children: PERI study. Coron Artery Dis. 2008;19(3):16772. 97. Charakida M, Donald AE, Green H, Storry C, Clapson M, Caslake M, et al. Early structural and functional changes of the vasculature in HIV-infected children: impact of disease and antiretroviral therapy. Circulation. 2005; 112(1):1039. 98. Vigano A, Bedogni G, Cerini C, Meroni L, Giacomet V, Stucchi S, et al. Both HIV-infection and long-term antiretroviral therapy are associated with increased common carotid intima-media thickness in HIV-infected adolescents and young adults. Curr HIV Res. 2010;8(5):4117. 99. Fernhall B, Agiovlasitis S. Arterial function in youth: window into cardiovascular risk. J Appl Physiol. 2008;105(1):32533. 100. Sass C, Herbeth B, Chapet O, Siest G, Visvikis S, Zannad F. Intima-media thickness and diameter of carotid and femoral arteries in children, adolescents and adults from the Stanislas cohort: effect of age, sex, anthropometry and blood pressure. J Hypertens. 1998;16(11):1593602. 101. Jourdan C, Wuhl E, Litwin M, Fahr K, Trelewicz J, Jobs K, et al. Normative values for intima-media thickness and distensibility of large arteries in healthy adolescents. J Hypertens. 2005;23(9):170715. 102. Charakida M, Loukogeorgakis SP, Okorie MI, Masi S, Halcox JP, Deanfield JE, et al. Increased arterial stiffness in HIV-infected children: risk factors and antiretroviral therapy. Antivir Ther. 2009;14(8):10759. 103. Calza L, Manfredi R, Chiodo F. Hyperlactataemia and lactic acidosis in HIVinfected patients receiving antiretroviral therapy. Clin Nutr. 2005;24(1):515. 104. Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther. 2000;22(6): 685708. 105. Members of Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for use of Antiretroviral agents in Pediatric HIV infection. 2012 [cited 17 February 2013]; Available from: http://aidsinfo. nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf. 106. Lactic Acidosis International Group. Risk factors for lactic acidosis and severe hyperlactataemia in HIV-1-infected adults exposed to antiretroviral therapy. AIDS. 2007;21(18):245564. 107. Menezes CN, Maskew M, Sanne I, Crowther NJ, Raal FJ. A longitudinal study of stavudine-associated toxicities in a large cohort of South African HIV infected subjects. BMC Infect Dis. 2011;11:244. 108. Rey C, Prieto S, Medina A, Perez C, Concha A, Menendez S. Fatal lactic acidosis during antiretroviral therapy. Pediatr Crit Care Med. 2003;4(4):4857. 109. Shah I. Lactic acidosis in HIV infected children due to antiretroviral therapy. Indian Pediatr. 2005;42(10):10512. 110. Palmer M, Chersich M, Moultrie H, Kuhn L, Fairlie L, Meyers T. Frequency of stavudine substitution due to toxicity in children receiving antiretroviral treatment in Soweto, South Africa. AIDS. 2012 Nov 19. [Epub ahead of print]. 111. Carter RW, Singh J, Archambault C, Arrieta A. Severe lactic acidosis in association with reverse transcriptase inhibitors with potential response to L-carnitine in a pediatric HIV-positive patient. AIDS Patient Care STDS. 2004;18(3):1314. 112. Noguera A, Fortuny C, Sanchez E, Artuch R, Vilaseca MA, Munoz-Almagro C, et al. Hyperlactatemia in human immunodeficiency virus-infected children receiving antiretroviral treatment. Pediatr Infect Dis J. 2003;22(9):77882. 113. Desai N, Mathur M, Weedon J. Lactate levels in children with HIV/AIDS on highly active antiretroviral therapy. AIDS. 2003;17(10):15658. 114. Claas GJ, Julg B, Goebel FD, Bogner J. Metabolic and anthropometric changes one year after switching from didanosine/stavudine to tenofovir in HIV-infected patients. Eur J Med Res. 2007;12(2):5460. 115. Moren C, Noguera-Julian A, Garrabou G, Catalan M, Rovira N, Tobias E, et al. Mitochondrial evolution in HIV-infected children receiving first- or second-generation nucleoside analogues. J Acquir Immune Defic Syndr. 2012; 60(2):1116. 116. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS. 2006;20(17): 216574. 117. McComsey GA, Tebas P, Shane E, Yin MT, Overton ET, Huang JS, et al. Bone disease in HIV infection: a practical review and recommendations for HIV care providers. Clin Infect Dis. 2010;51(8):93746. 118. Paccou J, Viget N, Legrout-Gerot I, Yazdanpanah Y, Cortet B. Bone loss in patients with HIV infection. Joint Bone Spine. 2009;76(6):63741. 119. Triant VA, Brown TT, Lee H, Grinspoon SK. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system. J Clin Endocrinol Metab. 2008;93(9):3499 504. 120. McKay HA, Bailey DA, Mirwald RL, Davison KS, Faulkner RA. Peak bone mineral accrual and age at menarche in adolescent girls: a 6-year longitudinal study. J Pediatr. 1998;133(5):6827. 121. Gordon CM, Bachrach LK, Carpenter TO, Crabtree N, El-Hajj Fuleihan G, Kutilek S, et al. Dual energy X-ray absorptiometry interpretation and reporting in children and adolescents: the 2007 ISCD Pediatric Official Positions. J Clin Densitom. 2008;11(1):4358. 122. Schtscherbyna A, Pinheiro MF, Mendonca LM, Gouveia C, Luiz RR, Machado ES, et al. Factors associated with low bone mineral density in a Brazilian cohort of vertically HIV-infected adolescents. Int J Infect Dis. 2012;16(12):e8728. 123. Gafni RI, Hazra R, Reynolds JC, Maldarelli F, Tullio AN, DeCarlo E, et al. Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as salvage therapy: impact on bone mineral density in HIV-infected children. Pediatrics. 2006;118(3):e7118. 124. O’Brien KO, Razavi M, Henderson RA, Caballero B, Ellis KJ. Bone mineral content in girls perinatally infected with HIV. Am J Clin Nutr. 2001;73(4):8216. 125. Jacobson DL, Lindsey JC, Gordon CM, Moye J, Hardin DS, Mulligan K, et al. Total body and spinal bone mineral density across Tanner stage in perinatally HIV-infected and uninfected children and youth in PACTG 1045. AIDS. 2010;24(5):68796. 126. Puthanakit T, Saksawad R, Bunupuradah T, Wittawatmongkol O, Chuanjaroen T, Ubolyam S, et al. Prevalence and risk factors of low bone mineral density among perinatally HIV-infected Thai adolescents receiving antiretroviral therapy. J Acquir Immune Defic Syndr. 2012;61(4):47783. 127. Jacobson DL, Spiegelman D, Duggan C, Weinberg GA, Bechard L, Furuta L, et al. Predictors of bone mineral density in human immunodeficiency virus-1 infected children. J Pediatr Gastroenterol Nutr. 2005;41(3):33946. 128. Arpadi SM, Horlick M, Thornton J, Cuff PA, Wang J, Kotler DP. Bone mineral content is lower in prepubertal HIV-infected children. J Acquir Immune Defic Syndr. 2002;29(5):4504. 129. Soyka LA, Fairfield WP, Klibanski A. Clinical review 117: hormonal determinants and disorders of peak bone mass in children. J Clin Endocrinol Metab. 2000;85(11):395163. 130. DiMeglio LA, Wang J, Siberry GK, Miller TL, Geffner ME, Hazra R, et al. Bone mineral density in children and adolescents with perinatal HIV infection. AIDS. 2013;27(2):21120. 131. Theintz G, Buchs B, Rizzoli R, Slosman D, Clavien H, Sizonenko PC, et al. Longitudinal monitoring of bone mass accumulation in healthy adolescents: evidence for a marked reduction after 16 years of age at the levels of lumbar spine and femoral neck in female subjects. J Clin Endocrinol Metab. 1992; 75(4):10605. 132. Hansen MA, Overgaard K, Riis BJ, Christiansen C. Role of peak bone mass and bone loss in postmenopausal osteoporosis: 12 year study. Brit Med J. 1991;303(6808):9614. 133. Rizzoli R, Bonjour JP. Determinants of peak bone mass and mechanisms of bone loss. Osteoporos Int. 1999;9(Suppl 2):S1723. 10 Barlow-Mosha L et al. Journal of the International AIDS Society 2013, 16:18600 http://www.jiasociety.org/index.php/jias/article/view/18600 | http://dx.doi.org/10.7448/IAS.16.1.18600 134. de Martino M, Tovo PA, Galli L, Gabiano C, Chiarelli F, Zappa M, et al. Puberty in perinatal HIV-1 infection: a multicentre longitudinal study of 212 children. AIDS. 2001;15(12):152734. 135. Finkelstein JS, Klibanski A, Neer RM. A longitudinal evaluation of bone mineral density in adult men with histories of delayed puberty. J Clin Endocrinol Metab. 1996;81(3):11525. 136. Siberry GK, Li H, Jacobson D. Fracture risk by HIV infection status in perinatally HIV-exposed children. AIDS Res Hum Retroviruses. 2012;28(3):24750. 137. Duvivier C, Kolta S, Assoumou L, Ghosn J, Rozenberg S, Murphy RL, et al. Greater decrease in bone mineral density with protease inhibitor regimens compared with nonnucleoside reverse transcriptase inhibitor regimens in HIV-1 infected naive patients. AIDS. 2009;23(7):81724. 138. McComsey GA, Kitch D, Daar ES, Tierney C, Jahed NC, Tebas P, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: AIDS Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011;203(12):1791801. 139. Brown TT, McComsey GA, King MS, Qaqish RB, Bernstein BM, da Silva BA. Loss of bone mineral density after antiretroviral therapy initiation, independent of antiretroviral regimen. J Acquir Immune Defic Syndr. 2009;51(5): 55461. 140. Mora S, Sala N, Bricalli D, Zuin G, Chiumello G, Vigano A. Bone mineral loss through increased bone turnover in HIV-infected children treated with highly active antiretroviral therapy. AIDS. 2001;15(14):18239. 141. Hazra R, Gafni RI, Maldarelli F, Balis FM, Tullio AN, DeCarlo E, et al. Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as salvage therapy for pediatric HIV infection. Pediatrics. 2005;116(6):84654. 142. Purdy JB, Gafni RI, Reynolds JC, Zeichner S, Hazra R. Decreased bone mineral density with off-label use of tenofovir in children and adolescents infected with human immunodeficiency virus. J Pediatr. 2008;152(4):5824. 143. Jones S, Restrepo D, Kasowitz A, Korenstein D, Wallenstein S, Schneider A, et al. Risk factors for decreased bone density and effects of HIV on bone in the elderly. Osteoporos Int. 2008;19(7):9138. 144. Giacomet V, Mora S, Martelli L, Merlo M, Sciannamblo M, Vigano A. A 12-month treatment with tenofovir does not impair bone mineral accrual in HIV-infected children. J Acquir Immune Defic Syndr. 2005;40(4):44850. 145. Vigano A, Zuccotti GV, Puzzovio M, Pivetti V, Zamproni I, Cerini C, et al. Tenofovir disoproxil fumarate and bone mineral density: a 60-month longitudinal study in a cohort of HIV-infected youths. Antivir Ther. 2010;15(7): 10538. 146. Della Negra M, de Carvalho AP, de Aquino MZ, da Silva MT, Pinto J, White K, et al. A randomized study of tenofovir disoproxil fumarate in treatmentexperienced HIV-1 infected adolescents. Pediatr Infect Dis J. 2012;31(5): 46973. 147. Stellbrink HJ, Orkin C, Arribas JR, Compston J, Gerstoft J, Van Wijngaerden E, et al. Comparison of changes in bone density and turnover with abacavirlamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study. Clin Infect Dis. 2010;51(8):96372. 148. Martin A, Bloch M, Amin J, Baker D, Cooper DA, Emery S, et al. Simplification of antiretroviral therapy with tenofovir-emtricitabine or abacavirLamivudine: a randomized, 96-week trial. Clin Infect Dis. 2009;49(10):1591601. 149. Zuccotti G, Vigano A, Gabiano C, Giacomet V, Mignone F, Stucchi S, et al. Antiretroviral therapy and bone mineral measurements in HIV-infected youths. Bone. 2010;46(6):16338. 150. Pitukcheewanont P, Safani D, Church J, Gilsanz V. Bone measures in HIV-1 infected children and adolescents: disparity between quantitative computed tomography and dual-energy X-ray absorptiometry measurements. Osteoporos Int. 2005;16(11):13936. 151. Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. J Am Med Assoc. 2005;293(18): 225764. 152. Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med. 1997;337(10):6706. 153. Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354(7):66983. 154. El-Hajj Fuleihan G, Nabulsi M, Tamim H, Maalouf J, Salamoun M, Khalife H, et al. Effect of vitamin D replacement on musculoskeletal parameters in school children: a randomized controlled trial. J Clin Endocrinol Metab. 2006;91(2):40512. 155. Winzenberg TM, Powell S, Shaw KA, Jones G. Vitamin D supplementation for improving bone mineral density in children. Cochrane Database Syst Rev. 2010;(10):CD006944. 156. Paul TV, Asha HS, Thomas N, Seshadri MS, Rupali P, Abraham OC, et al. Hypovitaminosis D and bone mineral density in human immunodeficiency virus-infected men from India, with or without antiretroviral therapy. Endocr Pract. 2010;16(4):54753. 157. Hileman CLD, Storer N, McComsey GA. Bone Mineral Density (BMD), vitamin D levels and inflamation markers in antiretroviral-naive HIV infected and un-infected adults (absract# 880). 19th Conference on Retroviruses and Opportunistics Infections; Seattle, WA: CROI; 2012. [cited 2013 Feb 16]. 158. Dolan SE, Kanter JR, Grinspoon S. Longitudinal analysis of bone density in human immunodeficiency virus-infected women. J Clin Endocrinol Metab. 2006;91(8):293845. 159. Havens PL, Stephensen CB, Hazra R, Flynn PM, Wilson CM, Rutledge B, et al. Vitamin D3 decreases parathyroid hormone in HIV-infected youth being treated with tenofovir: a randomized, placebo-controlled trial. Clin Infect Dis. 2012;54(7):101325. 160. Mondy K, Yarasheski K, Powderly WG, Whyte M, Claxton S, De Marco D, et al. Longitudinal evolution of bone mineral density and bone markers in human immunodeficiency virus-infected individuals. Clin Infect Dis. 2003;36(4):48290. 161. Dao CN, Patel P, Overton ET, Rhame F, Pals SL, Johnson C, et al. Low vitamin D among HIV-infected adults: prevalence of and risk factors for low vitamin D Levels in a cohort of HIV-infected adults and comparison to prevalence among adults in the US general population. Clin Infect Dis. 2011;52(3):396405. 162. Arpadi S, McMahon D, Abrams E, Mahrukh B, Purswani M, Engelson E, et al. 2-year bone mass accrual in HIV children and adolescents after bi-monthly supplementation with oral cholecalciferol and calcium (abstract #707). 18th Conference on Retroviruses and Opportunistic Infections; Boston, MA: CROI; 2011. [cited 2013 Feb 16]. 163. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):26681. 164. Ross AC, Judd S, Kumari M, Hileman C, Storer N, Labbato D, et al. Vitamin D is linked to carotid intima-media thickness and immune reconstitution in HIV-positive individuals. Antivir Ther. 2011;16(4):55563. 165. Eckard AR, Judd SE, Ziegler TR, Camacho-Gonzalez AF, Fitzpatrick AM, Hadley GR, et al. Risk factors for vitamin D deficiency and relationship with cardiac biomarkers, inflammation and immune restoration in HIV-infected youth. Antivir Ther. 2012;17(6):106978. 166. Rutstein R, Downes A, Zemel B, Schall J, Stallings V. Vitamin D status in children and young adults with perinatally acquired HIV infection. Clin Nutr. 2011;30(5):6248. 167. Stephensen CB, Marquis GS, Kruzich LA, Douglas SD, Aldrovandi GM, Wilson CM. Vitamin D status in adolescents and young adults with HIV infection. Am J Clin Nutr. 2006;83(5):113541. 168. Atkinson SBL, Patel D, Monrose C, Tudor-Williams G, Foster C. Vitamin D deficiency in children with perinatally acquired HIV-1 infection living in the UK (abstract P159). 16th Conference of British HIV Association 2010; Manchester, UK: British HIV Association; 2010. [cited 2013 Feb 16]. 169. Havens PL, Mulligan K, Hazra R, Flynn P, Rutledge B, Van Loan MD, et al. Serum 25-hydroxyvitamin D response to vitamin D3 supplementation 50,000 IU monthly in youth with HIV-1 infection. J Clin Endocrinol Metab. 2012;97(11):400413. 170. Institute of Medicine (US). Dietary reference intakes for calcium and vitamin D. Washington, DC: The National Academies Press, 2011. 171. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):191130. 172. Brown TT, McComsey GA. Association between initiation of antiretroviral therapy with efavirenz and decreases in 25-hydroxyvitamin D. Antivir Ther. 2010;15(3):4259. 173. Cozzolino M, Vidal M, Arcidiacono MV, Tebas P, Yarasheski KE, Dusso AS. HIV-protease inhibitors impair vitamin D bioactivation to 1, 25dihydroxyvitamin D. AIDS. 2003;17(4):51320. 174. Longenecker CT, Hileman CO, Carman TL, Ross AC, Seydafkan S, Brown TT, et al. Vitamin D supplementation and endothelial function in vitamin D deficient HIV-infected patients: a randomized placebo-controlled trial. Antivir Ther. 2012;17(4):61321. 11 Puthanakit T and Siberry GK. Journal of the International AIDS Society 2013, 16:18575 http://www.jiasociety.org/index.php/jias/article/view/18575 | http://dx.doi.org/10.7448/IAS.16.1.18575 Review article Bone health in children and adolescents with perinatal HIV infection Thanyawee Puthanakit1,2 and George K Siberry§,3 § Corresponding author: George K Siberry, Maternal and Pediatric Infectious Disease (MPID) Branch, Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, 6100 Executive Boulevard, Room 4B11H, Bethesda, MD 20892, USA. Tel: 1-301-496-7350. Fax: 1-301496-8678. ([email protected]) This article is part of the special issue Perinatally HIV-infected adolescents - more articles from this issue can be found at http://www.jiasociety.org Abstract The long-term impact on bone health of lifelong HIV infection and prolonged ART in growing and developing children is not yet known. Measures of bone health in youth must be interpreted in the context of expected developmental and physiologic changes in bone mass, size, density and strength that occur from fetal through adult life. Low bone mineral density (BMD) appears to be common in perinatally HIV-infected youth, especially outside of high-income settings, but data are limited and interpretation complicated by the need for better pediatric norms. The potential negative effects of tenofovir on BMD and bone mass accrual are of particular concern as this drug may be used more widely in younger children. Emphasizing good nutrition, calcium and vitamin D sufficiency, weight-bearing exercise and avoidance of alcohol and smoking are effective and available approaches to maintain and improve bone health in all settings. More data are needed to inform therapies and monitoring for HIV-infected youth with proven bone fragility. While very limited data suggest lack of marked increase in fracture risk for youth with perinatal HIV infection, the looming concern for these children is that they may fail to attain their expected peak bone mass in early adulthood which could increase their risk for fractures and osteoporosis later in adulthood. Keywords: perinatal HIV infection; bone mineral density (BMD); fracture; dual-energy X-ray absorptiometry (DXA); peak bone mass (PBM). Received 1 February 2013; Revised 10 April 2013; Accepted 16 April 2013; Published 18 June 2013 Copyright: – 2013 Puthanakit T and Siberry GK; licensee International AIDS Society. This is an open access article distributed under the terms of the Creative Commons Attribution 3.0 Unported (CC BY 3.0) Licence (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction Worldwide, more than 2 million children are infected with HIV. In most of the cases, HIV infection was acquired during pregnancy or intrapartum or through breastfeeding. Effective antiretroviral therapy (ART) has dramatically reduced morbidity and mortality for children with perinatal HIV infection, many of whom are now adolescents or even young adults. Even as the prevention of AIDS-defining illnesses and of progressive immunosuppression is appropriately celebrated, the long-term impact of lifelong HIV infection and prolonged ART in growing and developing children is not yet known. An area of particular concern is the potential effect of HIV infection and ART on bone, which undergoes profound changes in size, mass and strength from foetal life through to young adulthood. This article will focus on available data and remaining questions related to bone outcomes in perinatal HIV infection in the context of normal bone development, non-HIV factors that impact bone, and composition of ART as well as an approach to detection, prevention and management of bone problems in this group. Bone assessment definitions and measurement methods Bone is composed of organic (bone matrix) and mineral components. Bone mass refers to the weight of bone. Bone mineral density (BMD) refers to the bone mass divided by its volume. In practice, BMD is not usually directly ascertainable (would require bone biopsy), and it is estimated by radiologic or other methods. Bone mineralization describes the incorporation of calcium and other minerals into organic bone matrix [1]. Low BMD may result from inadequate bone mass due to inadequate bone matrix, called osteopenia, or from undermineralization of bone matrix, termed osteomalacia [1]. Remodelling of bone is a continual process in which bone is periodically reabsorbed (resorption) and replaced (formation) by new bone; the balance of resorption and formation activity determines whether there is net gain or loss of bone mass. Bone strength is based on bone mass, bone mineralization and bone architecture. Osteoporosis is defined as bone weakness or fragility that manifests as increased susceptibility to fractures and is well correlated with low BMD, especially in older adults. Dual-energy X-ray absorptiometry (DXA) is the most commonly used modality for estimating bone mineral content (BMC) and BMD. The technique measures how much radiation (two beams emitted at different energy levels) gets absorbed while passing through bone or other body tissue to estimate the density of that region [1]. Denser (calcium-rich) tissues absorb more radiation. The output is expressed as absolute BMC in grams, and, as the ratio of BMC to a projection of three-dimensional bone onto a two-dimensional 1 Puthanakit T and Siberry GK. Journal of the International AIDS Society 2013, 16:18575 http://www.jiasociety.org/index.php/jias/article/view/18575 | http://dx.doi.org/10.7448/IAS.16.1.18575 area to produce the areal BMD (aBMD), usually in grams per square centimetre (g/cm2). The main limitation of the aBMD for children is that relatively smaller bones (e.g. in a child with short stature) can lead to lower aBMD and thus underestimates of true BMD [1]. These measures can also be expressed as T-scores, which standardize the absolute results against average results expected at peak bone mass (PBM) for someone of the same sex, and as Z-scores, which standardize the absolute results against average results expected at a population of similar age and sex (and sometimes race/ ethnicity). T-scores are primarily used for older adults and are not appropriate for children and young adults; Z-scores can be used at all ages and should be used through to the age when PBM has been achieved [2]. DXA can be used to assess BMD of the total body (with or without head) or of specific body sites; the sites best characterized for DXA assessment in children (lumbar spine and total body) are different from those in adults (lumbar spine and hip) [3]. A DXA BMD TscoreB 2.5 in older adults (especially postmenopausal women) has been sufficiently linked to risk of fracture that it can be used as the basis of an osteoporosis diagnosis in that population. The finding of a BMD Z-scoreB 2.0 in children and youth, however, should be described as ‘‘very low BMD for age’’; the diagnosis of osteoporosis in paediatrics requires clinical evidence of bone fragility (fracture) [3]. Other modalities used to estimate BMD include quantitative computed tomography (qCT) and quantitative ultrasonography (qUS) (Table 1) [4]. qCT measures bone in three dimensions for a true volumetric BMD and provides information about bone geometry, but it entails relatively high radiation exposure and the technique is not well standardized across centres. qUS measures the attenuation and speed of an ultrasound wave along a bone to estimate BMD; despite the advantages of lack of ionizing radiation and greater portability of ultrasound machines, the lack of standardization of this technique and absence of paediatric Table 1. Common methods for assessing bone mineral density Modality DXA qCT Advantages Disadvantages Norms available for Radiation (trivial) children and youth Small bone size leads to Widely used BMD underestimate High reproducibility Lack of norms for Short scanning times childrenBage 7 years Assessment of Radiation three-dimensional Lower reproducibility (volumetric) bone size Whole-body not feasible and geometry Lack of norms for children Ultrasound No radiation Lack of norms for children Machines often portable and youth Cannot be used for wholebody or axial skeleton From refs. [2,4]. DXAdual-energy X-ray absorptiometry; qCT quantitative computed tomography; BMD bone mineral density. reference norms currently limit its use in children. DXA remains the preferred method for bone density assessment in children because of its availability, reproducibility, speed, very low radiation exposure and paediatric reference norms [2,3]. Normal bone development The potential impact of HIV infection and treatment on the bone health of youth with perinatal HIV infection must be evaluated in the context of normal, physiologic bone growth and development (Table 2). The effect of HIV infection and its treatment on developing bones may well be different from that seen in adults who acquire HIV infection after bone development is complete. Furthermore, the assessment of potential effects must be made relative to normal or expected changes in bone. For instance, BMD, a commonly used measure of bone strength, normally increases throughout childhood and adolescence, peaks and stays relatively constant in healthy adults, and then begins to decline with older age and especially menopause (Figure 1). An assessment of the effect of an antiretroviral drug on BMD (or BMC) must then be considered against the normal age-related expectation for changes in these parameters. Perinatally infected youth are potentially first exposed to HIV infection and antiretroviral drugs (ARVs) during intrauterine life. The foetal period is a critical period for the development of bone mass. The foetus is entirely dependent upon its mother for calcium and other minerals necessary for normal bone development. Foetal bones accumulate about 30 g of calcium from transplacental transfer, with 80% of calcium accretion taking place in the third trimester [8]. Since calcium deposition into a foetal skeleton increases from 100 mg/day at week 28 to 250 mg/day at week 35 [8], preterm birth substantially compromises the amount of mineral transferred to the foetus and thus has a strong negative effect on newborn bone mineralization status. Maternal malnutrition and calcium deficiency may also contribute to lower foetal bone mineralization, but the effect of these factors appears less certain and less pronounced [9]. Infancy represents an equally critical period in bone growth, development and mineral accretion. In contrast to the foetus, infant bone health depends on maternal (breast milk) and non-maternal sources of calcium and other bone components and is affected by environmental factors, including nutrition, infections, drug and toxin exposures and activity level. During infancy, the increase in bone diameter by 50%, despite a concomitant increase in BMC by at least 50%, results in a decrease in bone density of about 30%. In this complex process, however, actual bone strength increases threefold because of accompanying changes in bone architecture [1]. There are no well-established normative data for BMD (as measured by DXA or other modalities) in infants. Throughout childhood, bone size, BMC and aBMD continue to increase (Figure 1). Normative DXA BMD and BMC data (based on US children) are available for children aged five years and older [5] which facilitates interpretation of BMD and BMC results in children. There may be advantages to BMC over aBMD DXA measures in children, especially for total body, but both measures are widely used [3]. Healthy children 2 Puthanakit T and Siberry GK. Journal of the International AIDS Society 2013, 16:18575 http://www.jiasociety.org/index.php/jias/article/view/18575 | http://dx.doi.org/10.7448/IAS.16.1.18575 Table 2. Normal bone development Developmental period Foetus Cardinal events Major factors impacting bone Other comments - Bone formation - Gestational age Entirely dependent on - Rapid longitudinal bone growth - Body size placental transfer of calcium - Marked bone mineral accretion - Most increase in bone mass and growth during and other minerals third trimester of pregnancy Infant - Rapid longitudinal bone growth - Gestational age and body size at birth Immediate shift to - Marked bone mineral accretion - Nutrition/breastfeeding, infections, drug and dependence on intestinal toxin exposures and activity level absorption, renal reabsorption and bone stores for calcium/minerals Child Adolescent - On-going longitudinal growth - Nutrition, infections, drug and toxin exposures and bone mineral accretion and activity level (slower pace) - BMI - 26% of bone mass in 4-year - Puberty period of peak height velocity - BMI - 60% of adult peak bone mass (PBM) is established - Age at pubertal onset as well as nutrition, infections, drug and toxin exposures, and activity level - Smoking - Alcohol use - Medroxyprogesterone and other drugs Young Adult - PBM achieved by age 2025 - BMI years (varies by body site) - Smoking - Alcohol use - Medroxyprogesterone and other drugs Later Adulthood - No net change in bone mass/ - Loss of bone with older age density for many years (balanced - Marked bone loss with menopause bone formation and resorption) - Smoking - Annual declines in BMD after - Alcohol use fifth decade, especially with - Reduced physical activity menopause - Nutrition BMIbody mass index; BMD bone mineral density; PBM peak bone mass. with low aBMD are likely to continue to have low aBMD over time [10]. Some of the biggest and most important changes in bone occur during puberty and adolescence. More than half of lifetime bone calcium is laid down during teen years, and almost half of BMC is accrued in the two years before and after attainment of peak height velocity [11,12]. Delayed puberty may have short- and long-term effects on bone mineral status. Late menarche has been shown to be associated with poorer BMC accrual [13], and the negative effects of late menarche on bone mass may persist up to 25 years [14]. PBM is attained by the end of the second or early in the third decade of life [12], generally occurs earlier at the hip and spine than at the whole body and occurs earlier in girls than in boys. PBM is an important concept for bone health because it has been linked to lifelong BMD outcomes and failing to attain normal PBM by young adulthood increases the risk of bone fragility in later adulthood [15]. In fact, up to 60% of the lifetime risk of osteoporosis may be attributable to the amount of bone mineral accrued through the first two decades of life [16]. Thus, factors that negatively impact bone development in the foetus, child and adolescent may contribute to a compromised PBM in the young adult, but the important clinical consequences may not manifest until decades later as increased risk of fractures and osteoporosis. Risk factors for poor bone health (not specific to HIV infection) Outside the context of HIV infection, there are numerous demographic, genetic, nutritional and lifestyle factors, as well as medical conditions and treatments, that are well known to impact bone health and BMD (Table 3). The relative contribution of these factors to bone health varies by age and setting. Intrauterine factors may have both short- and long-term impacts on bone health. Maternal macronutrient and micronutrient intake during pregnancy has been linked to effects on bone mass in progeny through 616 years old [17]. Some have hypothesized that this is due to early programming of later bone responses rather than direct consequence 3 Puthanakit T and Siberry GK. Journal of the International AIDS Society 2013, 16:18575 http://www.jiasociety.org/index.php/jias/article/view/18575 | http://dx.doi.org/10.7448/IAS.16.1.18575 Lumbar Spine BMD changes across the lifespan Lumbar Spine Bone Mineral Density (g/cm2) 1.4 LS-BMD 1.2 1 0.8 0.6 0.4 0.2 0 0 10 40 30 50 60 70 Age (years) Figure 1. Illustration of changes in lumbar spine bone mineral density (BMD) over the lifespan. Plot based on actual or estimated data from three different studies [5 7]. of lower bone mass in the foetus [17]. Maternal smoking, likely acting through compromising uteroplacental function, appears to result in lower bone mass in offspring that resolves by the second decade [17]. Preterm birth, low birth weight and poor growth early in life all may have a lasting negative impact on bone health [18,19]. While there is some evidence that breastfeeding, compared to replacement feeding, may result in lower bone mass in infancy, other evidence points to better bone mass and lower fracture risk in older children who were breastfed as infants [17]. Table 3. Through childhood and adolescence, major influences on bone mass accrual and bone health include genetic determinants, physical activity (or lack thereof), nutritional status and hormonal changes during puberty. Up to 80% of the variability in PBM may be explained by genetic factors [20]. Weight-bearing exercise leads to increased bone mass and BMD; in fact, the level of such exercise during childhood and adolescence may explain almost 20% of PBM attained in early adulthood [21]. Within the normal range of BMI, BMD increases with increasing BMI; however, undernutrition (low BMI, including adolescents with eating disorders) leads to Non-HIV-specific factors affecting bone health Factor Preterm birth Abnormal weight (BMI) Description Negative effect increases as gestational age decreases. Short-term fracture risk mainly for very preterm infants. Low BMI (general malnutrition and adolescents with eating disorders) associated with low BMD; high BMI (obesity) associated with increased fracture risk. Specific nutritional Inadequate vitamin D and calcium most important. Role of protein and other micronutrients less clear. deficiency Genetic factors Genetic disorders (osteogenesis imperfecta); family history of osteoporosis; blacks at low risk of osteoporosis relative to other racial/ethnic groups. Exercise Hormones Weight-bearing activity improves bone mass accrual and BMD; sedentary lifestyle and impaired mobility (as in cerebral palsy) compromise bone health. Normal pubertal increases in endogenous androgens, estrogens and growth hormone promote bone mass accrual. Lower PBM with delayed puberty. Pregnancy and lactation associated with transient BMD decline. Substantial BMD loss and fracture risk with menopause. Lifestyle factors Cigarette smoking, alcohol consumption and sedentary lifestyle all impair bone health. Endocrinopathies Hypogonadism, hypercortisolism (e.g., Cushing syndrome), hyperthyroidism and growth hormone deficiency associated with poor bone health. Medications Inflammation Well-established negative effect on BMD: corticosteroids, anticonvulsants, medroxyprogesterone. Full list at http:// www.nof.org/articles/6. Juvenile arthritis, inflammatory bowel disease and other inflammatory disorders and conditions; risk related to proinflammatory cytokines and treatment (corticosteroids). Other medical conditions Malignancy, renal failure. BMIbody mass index; BMD bone mineral density; PBM peak bone mass. 4 Puthanakit T and Siberry GK. Journal of the International AIDS Society 2013, 16:18575 http://www.jiasociety.org/index.php/jias/article/view/18575 | http://dx.doi.org/10.7448/IAS.16.1.18575 lower BMD and obesity (high BMI) increases the risk of fracture [22,23]. Maintaining adequate vitamin D levels and ensuring adequate calcium intake, especially during adolescence, are associated with better bone outcomes, and insufficiency of either can compromise final PBM [24]. Increases in endogenous androgens, oestrogens and growth hormone accompanying puberty have dramatic effects in promoting increases in bone length, mass and mineral content [23]. Cigarette smoking and drinking alcohol, often beginning in adolescence, both contribute to low BMD and poor bone health [25]. Many illnesses and medications have been associated with low BMD and/or increased fracture risk [23,26]. Osteogenesis imperfecta is a classic example of a genetic disorder associated with extreme bone fragility and high fracture risk. Malignancy and some chemotherapeutic agents used in its treatment increase the risk of fracture in children. Low BMD and fractures are important complications of cerebral palsy and other neurologic disorders associated with reduced mobility. Disorders associated with malabsorption, such as celiac disease and cystic fibrosis, have been linked to poor bone health. Proinflammatory cytokines and glucocorticoid therapy, among other factors, contribute to the elevated risk of fracture and bone structural abnormalities in children with juvenile rheumatoid arthritis and other inflammatory diseases [27]. Hormonal contraception, especially depot medroxyprogesterone, has been linked to significant BMD declines in adolescents most pronounced in the first one to two years of use and largely reversible after discontinuation [28]. Anticonvulsants, methotrexate and many other drugs have been linked to low BMD (http://www.nof.org/articles/6). Table 4. Prevalence of low BMD among HIV-infected children and adolescents Cross-sectional studies of BMD among HIV-infected youth (Table 4) suggest that the prevalence of low BMD may be lower ( B10%) in high-income settings [29,30] than in middle-income settings, such as Thailand (24%) [31] and Brazil (32%) [32]. This difference might be explained by older age, lower nadir CD4 cell, more advanced HIV stage and poorer nutritional status in Thai and Brazil cohorts compared to US and the Netherlands cohorts. In one longitudinal study, BMD increased over one year in 32 HIV-infected Italian children with a mean age of 12.4 years, but it remained significantly lower than HIV-uninfected controls [33]. Many [3437] but not all [38] studies have demonstrated an increased fracture risk in adults with HIV infection. There is no clear evidence of increased fracture risk in HIV-infected children in the United States [39] or Latin America [40], but these negative studies are not definitive. Studies of BMD and fracture risk in HIV-infected youth in low-income settings have not been published. Factors affecting BMD among HIV-infected children and adolescents Many factors contribute to low PBM in children with HIV infection, including delayed growth and puberty, low lean body mass, altered levels of hormones and inflammatory cytokines, vitamin D deficiency, malabsorption and physical inactivity. HIV-specific factors, which are important contributing factors to bone loss in children, include advanced HIV disease, uncontrolled viremia and ART initiation and type [41]. A large study of 236 HIV-infected US children aged 724 Prevalence of low bone mineral density among HIV-infected children and adolescents Reference DiMeglio [29] Bunders [30] Puthanakit [31] Schtscherbyna [32] Population Duration of ART (years) Findings Associated factors N350 9.5 years Total body Z-score B 2.0; 7% Higher peak viral load and Mean age 12.6 years Black 66%, Hispanic (IQR 9.111.3) 25% had CDC C versus 1% in HIV-negative peers LS Z-scoreB2.0; 4% versus 1% CD4% Ever used indinavir 26% and white 8% Nadir CD4 20% in HIV-negative peers N66 3.4 years (IQR 1.55.2) Spinal BMD Z-scoreB 2.08% Mean age 6.7 years 72% use PI, mainly Black 62% nelfinavir N100 7.0 years (4.38.7) Age 14.3 years Nadir CD4114 Z-scoreB1.5 Thai 100% (31226) cell/mm3 Ever have WHO stage 4 N74 11.1 years (SD 3.5) Low total body or lumbar spine Weight, BMI, nutrition, Age 17.3 (SD 1.8) 91% on ART in 32.4% of cohort use of tenofovir and years White 36.5% (19% NNRTI, 72% PI) Use of TDF is associated with lower lumbar spine Z-score: protease inhibitors Non-white 63.5% LS Z-scoreB 2.0; 24% Height-for-age 1.8 (1.1) vs. 1.3 (0.9) Use of protease inhibitor is associated with LS Z-score 1.7 (1.1) vs. 1.1 (0.9) ART antiretroviral therapy; Nnumber; IQR interquartile ratio; PI protease inhibitor; NNRTInon-nucleoside reverse transcriptase inhibitor; BMD bone mineral density; LS lumbar spine; SDstandard deviation; BMI body mass index. 5 Puthanakit T and Siberry GK. Journal of the International AIDS Society 2013, 16:18575 http://www.jiasociety.org/index.php/jias/article/view/18575 | http://dx.doi.org/10.7448/IAS.16.1.18575 years showed that HIV-infected males had significantly lower BMD at Tanner stage 5 compared to HIV-uninfected males [42]. Among HIV-infected Thai adolescents, WHO stage 4 increased by 3.4 times the risk of low BMD, and height-forage Z-scoreB 1.5 made low BMD 6.2 times more likely [31]. In adult studies, the period after ART initiation is associated with BMD loss [43,44], and lower cumulative ART use through structured treatment interruptions is associated with better BMD outcomes [45], suggesting a negative BMD effect of ART in general. Studies of BMD effect of ART initiation in treatment-naı̈ve children are not available but longer ART duration in one longitudinal study of 66 Dutch children was reassuringly associated with increases in spinal BMD Z-scores [30]. Not all antiretroviral drugs have the same effect on BMD. Protease inhibitors and tenofovir are most often associated with low BMD. Lopinavir/ritonavir [42], indinavir [29] and full-dose ritonavir [46] were associated with lower BMD in children. In trials randomizing treatment-naı̈ve adults to tenofovir- vs. abacavir-containing ART, BMD decreased in both arms, but BMD loss was significantly greater in the tenofovir arm [43,44]. Tenofovir was also associated with a yearly hazard ratio for osteoporotic fracture of 1.12 (95% CI 1.031.21) in HIV-infected adults [47]. Tenofovir was recently approved for children as young as two years but there is concern about potentially greater effects of tenofovir on developing bones in these young children. In a US study, median Z-scores of BMD of the lumbar spine, femoral neck, and total hip decreased from baseline at weeks 24 and 48, and remained stable up to week 96. The children who experienced 1% decrease in BMD were significantly younger than those with stable BMD (10.2 vs. 13.2 years, p0.003) [48]. On the other hand, some studies reported no effect of tenofovir on BMD. In 16 Italian children (618 years) receiving suppressive ART regimens, replacing stavudine and PI with tenofovir and efavirenz did not result in smaller 12-month BMC or BMD increases relative to HIV-uninfected peers [49]. Another study of 21 Italian children receiving tenofovir/ efavirenz/lamivudine documented no significant change in BMD Z-score from baseline through 60 months [50]. The lack of a negative effect on BMD observed in these studies may be explained by the use of a lower dose of tenofovir, lack of concomitant PIs and ART switch (instead of ART initiation). In a placebo-controlled US/Panama/Brazil trial of tenofovircontaining ART for 87 youth (1217 years) with virologic failure of their current ART regimen, there was no significant difference in 48-week BMD between the tenofovir and nontenofovir arms, but there was a trend for more tenofovir-arm than non-tenofovir-arm subjects to have spine BMD losses 4% (18% vs. 3%, p 0.1) [51]. There are no published studies of initiating tenofovir-containing ART in treatmentnaı̈ve children. Due to limited information regarding longterm effects on bone development in young children, the US DHHS guidelines recommend tenofovir (as part of initial ART) for adolescents in Tanner stages 45, as an alternative for those in Tanner stage 3, and only for special circumstances for children in Tanner stages 12 [52]. Pathogenesis of low BMD among HIV-infected individuals The pathogenesis of low bone mass among HIV-infected individuals is multifactorial, including traditional risk factors such as smoking, physical inactivity and vitamin D deficiency and also HIV-related factors including HIV infection itself, chronic immune activation and the direct effects of antiretroviral therapy. In vitro studies have shown that HIV viral proteins gp120 [53] and Vpr [54] stimulate osteoclast activity, and p55-gag suppresses osteoblast activity and increases osteoblast aopotosis [55]. Osteoclasts (OCs), the cells responsible for bone resorption, form from precursors that circulate within the monocytic population, and are recognized by their expression of receptor activator of NFkB (RANK). OC precursors differentiate into OCs under the influence of the key osteoclastogenic cytokine, RANK ligand (RANKL), moderated by RANKL’s physiological decoy receptor osteoprotegerin (OPG) [56]. In HIV-1 transgenic rat model, there is a significant increase in total RANKL expression concomitant with a significant decline in total OPG expression in both bone marrow and spleen [57]. HIVinfected antiretroviral naı̈ve adults with low BMD had elevated RANKL/OPG ratio [58]. Similarly, perinatally HIVinfected children had elevated RANKL/OPG ratio compared with healthy children [59]. Activation of T-cells by HIV infection may also affect bone physiology by producing RANKL and pro-inflammatory cytokines (e.g., IL-1 and TNF-a), which promote osteoclast activity and stimulate stromal cells to produce osteoclastogenic IL-7. Finally, CD4 and CD8 T-cell activation has been independently associated with low bone mineral study [60]. Further research is needed to fully characterize the pathogenic processes leading to low bone mass in the context of HIV infection. Approach to the assessment of bone health in HIV-infected children and adolescents Careful review of occurrence and circumstances of fracture can help identify children and youth with increased bone fragility. Fractures that occur after minimal trauma, vertebral compression fractures, a single instance of traumatic fracture of a lower extremity long bone, and two or more fractures of upper extremity long bones should raise suspicion of bone fragility [61]. In lower resource settings where DXA scanning is not available, fracture history and review of risk factors for poor bone health (as discussed above) may be the only means to assess potential bone fragility in HIV-infected children. In less resource-constrained settings, BMD assessment by DXA provides important information about risk of skeletal fragility. There is no consensus that all HIV-infected youth (or adults) should undergo routine DXA screening. If DXA is available, it should be considered for HIV-infected youth with a suspicious fracture history and/or multiple risk factors for poor bone health. As for children in general, lumbar spine and total body less head are the sites recommended for assessments. The hip is not a reliable site for measurement in growing children due to significant variability in skeletal development and lack of reproducibility [3]. A BMD Z-score less than 2, categorized as low BMD, can be used to corroborate a suspicious 6 Puthanakit T and Siberry GK. Journal of the International AIDS Society 2013, 16:18575 http://www.jiasociety.org/index.php/jias/article/view/18575 | http://dx.doi.org/10.7448/IAS.16.1.18575 fracture history for a diagnosis of osteoporosis; in the absence of fractures, it identifies children who are at increased risk of bone fragility and fractures. The normative databases used as a reference should be based on large samples of healthy children that are similar in gender, age and race/ethnicity [3]. For example, in the study among Thai HIV-infected children, 24% of children had a BMD Z-score 5 2.0 using Thai children normative data; this prevalence would have been 43% by the Caucasian normative data generated by the DXA scanner database [31]. Therefore, it is very difficult to interpret BMD measurements among HIV-infected children in settings where the normative data for specific ethnicity is not available. Furthermore, the DXA interpretation must be specific for each manufacturer and model of densitometer and software. There are three dominant DXA manufacturers: Hologic Inc. (Bedford, MA, USA), GE-Lunar Inc. (Madison, WI, USA) and Copper Surgical (Norland; Trumbull, CT, USA). They are different in calibration standards, proprietary algorithms to calculate the BMD and in the regions of interest (ROI). As a result, a patient scanned on different DXA systems will have substantially different BMD values, e.g. Hologic spine BMD is typically 11.7% lower than GE-Lunar BMD and 0.6% higher than Norland BMD [62]. Delay in growth and puberty is quite common among HIVinfected children. BMD interpretation should be adjusted for absolute height or height age in children with linear growth or maturational delay [3]. Substituting height age for chronological age as a means of adjusting for short stature may not be a preferred approach because it may treat as similar children with the same height who are at different stages of sexual maturation. Using height-for-age Z-score adjustment may result in the least bias, but the equation for height-for-age Z-score adjustment is developed only for healthy US children based on the Hologic system [63]. Adjusting for bone age, pubertal stage or lean mass has also been studied. In children who have a baseline BMD assessment by DXA, there is no clear recommendation for how often DXA scans should be repeated as part of monitoring bone health. Intervals shorter than six months are unlikely to yield significant changes in BMD; intervals of one to two years may be reasonable for children with low BMD at baseline or ongoing risk for skeletal losses [3]. Table 5. Prevention strategies for addressing bone health in children/adolescents with HIV infection (in high and lower income settings) Many of the approaches to maintaining good bone health in youth with perinatal HIV infection are similar to those used for youth in general (Table 5). Adolescents should receive at least 1300 mg calcium/day and at least 600 IU vitamin D/ day through their diet and/or supplementation [64]. Vitamin D deficiency is very common in youth with or without HIV infection [66]. In addition, there is evidence for interference with normal vitamin D metabolism by some ARV medications [41] and for elevation in PTH in youth who take tenofovir [67], which may mean that HIV-infected youth need higher doses of vitamin D to achieve functional vitamin D sufficiency. If the measurement of blood levels of 25-OH vitamin D is available, supplementation can be initiated and adjusted based on these measured levels. However, in many settings where 25-OH vitamin D measurement may be costly and impractical, clinicians should provide vitamin D supplementation if intake by history seems insufficient. General guidance about good nutrition and counselling to avoid or stop cigarette smoking and alcohol consumption should be routine. Regular, weightbearing exercise should be promoted. Such exercise does not require sophisticated equipment or facilities; running, jumping or playing a sport like basketball are effective and feasible options for most youth. Note that swimming does not involve weight-bearing or impact and so would not have any benefit to bone health. Minimize the use of corticosteroids and other medications with negative impact on bone health, but only after assessing relative risks and benefits. For example, the benefits of medroxyprogesterone for effective contraception in youth likely outweigh the negative effects on BMD [28]. Even though continuous ART resulted in lower BMD than intermittent BMD in adults in the SMART study [45], untreated HIV infection that results in progressive immunodeficiency, weight loss and opportunistic illnesses is likely to have a more negative effect on bone health [31,68]. For youth who have multiple other risk factors for low BMD, consideration of regimens that do not include TDF and/or boosted PIs is reasonable but only if an alternative ARV regimen is expected to achieve virologic suppression and be well tolerated. Prevention strategies to optimize bone health in perinatally HIV-infected youth Calciumvitamin D Ensure adequate intake of calcium (1300 mg/day) and vitamin D (600 IU/day) in adolescents [64]. Promote healthy lifestyle Good nutrition; avoid/stop cigarette smoking; avoid/limit alcohol consumption. Exercise Encourage high-intensity impact activities (like running, jumping, gymnastics, basketball) for 10 20 min/day at least three days/week [65]. Effective ART Regardless of the specific regimen, ART that achieves virologic suppression, preserves/restores immunologic function, and minimizes HIV-related illnesses should have a generally positive effect on bone health. Avoid bone ‘‘unfriendly’’ medications Individualized risk-benefit assessment critical. Minimize use of systemic corticosteroids. For youth with multiple risk factors for poor bone health, consider avoiding TDF, boosted PIs, medroxyprogesterone. ART antiretroviral therapy; TDFtenofovir disoproxil fumarate; PI protease inhibitor. 7 Puthanakit T and Siberry GK. Journal of the International AIDS Society 2013, 16:18575 http://www.jiasociety.org/index.php/jias/article/view/18575 | http://dx.doi.org/10.7448/IAS.16.1.18575 Table 6. Intervention strategies for perinatally HIV-infected youth with evidence of bone fragility (low BMD, fractures) Calciumvitamin D Provide routine calcium (1300 mg/day) and vitamin D (600 IU/day) supplementation for youth, unless intake history for calcium and measured 25-OH vitamin D levels, respectively, confirm sufficiency. No consensus on target 25-OH vitamin D level, but consider higher threshold ( ]30 ng/dL) / normal PTH level in youth with bone fragility. General nutrition Consider referral to nutritionist for in-depth counselling. Modify habits Emphasize importance of not smoking and avoiding alcohol consumption. Weight-bearing exercise Prescribe high-intensity impact activities (like running, jumping, gymnastics, basketball) for 10 20 min/day at least three days/ week. Consider referral to physical therapist to improve adherence to exercise regimen. Reexamine need, or potential substitutes, for non-HIV medications Avoid or minimize corticosteroids. Consider switching from medroxyprogesterone to alternative contraception. Review list of other agents with potential negative impact on BMD: http://www.nof.org/articles/6. HIV virologic suppression Review regimen and optimize adherence to ensure sustained effective ART. Bone-friendlier ARV regimen Consider replacing TDF (and/or boosted PI) with other ARV(s), if new regimen anticipated to Anti-resorptives: bisphosphonates maintain virologic suppression and be well tolerated. Proven effective (alendronate) in improving BMD in HIV-infected adults and in non-HIVinfected youth with bone fragility. Investigational in youth with HIV infection. Recommend consultation with endocrinologist or other bone specialist. Other osteoporosis agents No data for use of other osteoporosis agents (e.g. Denosumab, Teriparatide, Strontium, Raloxifene). BMD bone mineral density; ARVantiretroviral drug; ART antiretroviral therapy; TDFtenofovir disoproxil fumarate; PI protease inhibitor. Intervention/treatment strategies for HIV-infected youth with evidence of bone fragility (in high and lower income settings) For youth with perinatal HIV infection who have very low BMD (Z-score B 2.0) and/or fractures that are suspicious for bone fragility, clinicians should implement a multipronged approach (Table 6). Calcium, vitamin D and general nutritional sufficiency must be assured and may be facilitated by involving a nutritionist. Consider routine supplementation with calcium and vitamin D. If 25-OH vitamin D is measured, a reasonable target is 30 ng/dL though consensus on this target is lacking. There are several approaches to treating vitamin D deficiency in youth [69]. Weight-bearing exercise should be emphasized; consider collaboration with a physical therapist or other allied health professional to enhance adherence to the exercise regimen. Avoidance of cigarette smoking and alcohol use must be stressed. The risk-benefit of the use of medications like medroxyprogresterone should be reassessed and alternatives should be considered. Alternative ARV agents can be considered. In particular, replacing tenofovir and/or boosted PIs with agents that have not been associated with negative bone effects (e.g. ABC for TDF; NNRTI or integrase inhibitors for boosted PI) may be beneficial but evidence is lacking. Such regimen changes should only be undertaken if the new regimen is expected to be sustainable, maintain virologic suppression and be well tolerated. Drugs like bisphosphonates that inhibit bone resorption have been widely used to treat osteoporosis, especially in postmenopausal women. Alendronate, one of the most widely used oral bisphosphonates, improved BMD in HIV-infected adults with low BMD in a randomized, placebo-controlled trial [70]. This drug has also been used in children with other causes of osteoporosis but there is uncertainty about the longterm impact of anti-resorptive drugs on growing bone [71]. Trials in HIV-infected youth have not been completed. Alendronate, along with the measures described above, may be useful for the management of perinatal HIV-infected youth with persistent bone fragility, but this treatment should be undertaken in consultation with an endocrinologist or other bone specialists. There are no data to support newer classes of osteoporosis agents in children and youth. Conclusions Measures of bone health in youth must be interpreted in the context of expected developmental and physiologic changes in bone mass, size, density and strength that occur from foetal through adult life. The potential effects of HIV infection, ARV drugs and other factors on the bones of perinatally HIV-infected youth begin in utero and persist through the critical bone growth and development periods during childhood and adolescence and into young adulthood when PBM is attained. Low BMD appears to be more common in perinatally HIV-infected youth in lower resource settings, likely due to differences in genetic/ethnic and environmental factors, but data are limited and are complicated by the lack of well-characterized paediatric DXA BMD norms for each setting. The potential negative effects of tenofovir on BMD and bone mass accrual are of particular concern as this drug may be used more widely in younger children. Emphasizing good nutrition, calcium and vitamin D sufficiency, weight-bearing exercise and avoidance of drugs 8 Puthanakit T and Siberry GK. Journal of the International AIDS Society 2013, 16:18575 http://www.jiasociety.org/index.php/jias/article/view/18575 | http://dx.doi.org/10.7448/IAS.16.1.18575 (medications in addition to cigarettes and alcohol) are effective and available approaches to maintain and improve bone health in all settings. More data are needed to inform therapies and monitoring for HIV-infected youth with proven bone fragility. While very limited data (with no data from low-resource settings) suggest lack of a marked increase in fracture risk for youth with perinatal HIV infection, the looming concern for these children is that they may fail to attain their expected PBM in early adulthood which could increase their risk for fractures and osteoporosis later in adulthood. Authors’ affiliations 1 Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; 2HIVNAT, Thai Red Cross AIDS Research Center, Bangkok, Thailand; 3Maternal and Pediatric Infectious Disease (MPID) Branch, Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA Competing interests The authors declare that they have no competing interests. Authors’ contributions Both authors contributed equally to conceiving, writing and editing of this manuscript. Acknowledgements Dr. Puthanakit is funded in part by the National Research University Project of Commission of Higher Education and the Ratchadapiseksomphot Endowment Fund (HR 1161A-55) and the Senior Researcher Scholar, Thai Research Fund (TRF). References 1. Land C, Schoenau E. Fetal and postnatal bone development: reviewing the role of mechanical stimuli and nutrition. Best Pract Res Clin Endocrinol Metab. 2008;22(1):10718. 2. Bachrach LK, Sills IN, Section on Endocrinology. Clinical report*bone densitometry in children and adolescents. Pediatrics. 2011;127(1):18994. 3. Gordon CM, Bachrach LK, Carpenter TO, Crabtree N, El-Hajj Fuleihan G, Kutilek S, et al. Dual energy X-ray absorptiometry interpretation and reporting in children and adolescents: the 2007 ISCD pediatric official positions. J Clin Densitom. 2008;11(1):4358. 4. Specker BL, Schoenau E. Quantitative bone analysis in children: current methods and recommendations. J Pediatr. 2005;146(6):72631. 5. Zemel BS, Kalkwarf HJ, Gilsanz V, Lappe JM, Oberfield S, Shepherd JA, et al. Revised reference curves for bone mineral content and areal bone mineral density according to age and sex for black and non-black children: results of the bone mineral density in childhood study. J Clin Endocrinol Metab. 2011;96(10):31609. 6. Kalkwarf HJ, Zemel BS, Yolton K, Heubi JE. Bone mineral content and density of the lumbar spine of infants and toddlers: influence of age, sex, race, growth, and human milk feeding. J Bone Miner Res. 2013;28(1):20612. 7. National Osteoporosis Foundation. Clinician’s guide to prevention and treatment of osteoporosis. Washington, DC: National Osteoporosis Foundation; 2010. 8. Root AW, Diamond FB. Disorders of Mineral Homeostasis in the Newborn, Infant, Child, and Adolescent. In: Sperling MA, editor. Pediatric endocrinology. 3rd ed. Philadelphia: Saunders Elsevier; 2008. p. 686769. 9. Olausson H, Goldberg GR, Laskey MA, Schoenmakers I, Jarjou LM, Prentice A. Calcium economy in human pregnancy and lactation. Nutr Res Rev. 2012;25(1):4067. 10. Kalkwarf HJ, Gilsanz V, Lappe JM, Oberfield S, Shepherd JA, Hangartner TN, et al. Tracking of bone mass and density during childhood and adolescence. J Clin Endocrinol Metab. 2010;95(4):16908. 11. Zemel BS. Human biology at the interface of paediatrics: measuring bone mineral accretion during childhood. Ann Hum Biol. 2012;39(5):40211. 12. Baxter-Jones AD, Faulkner RA, Forwood MR, Mirwald RL, Bailey DA. Bone mineral accrual from 8 to 30 years of age: an estimation of peak bone mass. J Bone Miner Res. 2011;26(8):172939. 13. Jackowski SA, Erlandson MC, Mirwald RL, Faulkner RA, Bailey DA, Kontulainen SA, et al. Effect of maturational timing on bone mineral content accrual from childhood to adulthood: evidence from 15 years of longitudinal data. Bone. 2011;48:117885. 14. Chevalley T, Bonjour JP, Ferrrari S, Rizzoli R. Deleterious effect of late menarche on distal tibia microstructure in healthy 20-year-old and premenopausal middle-age women. J Bone Miner Res. 2009;24:14452. 15. Ferrari S, Rizzoli R, Slosman D, Bonjour JP. Familial resemblance for bone mineral mass is expressed before puberty. J Clin Endocrinol Metab. 1998; 83:35861. 16. Hui SL, Slemenda CW, Johnston CC. The contribution of bone loss to post menopausal osteoporosis. Osteoporos Int. 1990;1:304. 17. Jones G. Early life nutrition and bone development in children. Nestle Nutr Workshop Ser Pediatr Program. 2011;68:22733. 18. Hovi P, Andersson S, Järvenpää AL, Eriksson JG, Strang-Karlsson S, Kajantie E, et al. Decreased bone mineral density in adults born with very low birth weight: a cohort study. PLoS Med. 2009;6(8):e1000135. 19. Oliver H, Jameson KA, Sayer AA, Cooper C, Dennison EM, Hertfordshire Cohort Study Group. Growth in early life predicts bone strength in late adulthood: the Hertfordshire Cohort Study. Bone. 2007;41(3):4005. 20. Davies JH, Evans BA, Gregory JW. Bone mass acquisition in healthy children. Arch Dis Child. 2005;90(4):3738. 21. Welten DC, Kemper HC, Post GB, Van Mechelen W, Twisk J, Lips P, et al. Weight-bearing activity during youth is a more important factor for peak bone mass than calcium intake. J Bone Miner Res. 1994;9(7):108996. 22. Goulding A. Risk factors for fractures in normally active children and adolescents. Med Sport Sci. 2007;51:10220. 23. Loud KJ, Gordon CM. Adolescent bone health. Arch Pediatr Adolesc Med. 2006;160(10):102632. 24. Rizzoli R, Bianchi ML, Garabédian M, McKay HA, Moreno LA. Maximizing bone mineral mass gain during growth for the prevention of fractures in the adolescents and the elderly. Bone. 2010;46(2):294305. 25. Henwood MJ, Binkovitz L. Update on pediatric bone health. J Am Osteopath Assoc. 2009;109(1):512. 26. Ahmed SF, Elmantaser M. Secondary osteoporosis. Endocr Dev. 2009; 16:17090. 27. Burnham JM. Inflammatory diseases and bone health in children. Curr Opin Rheumatol. 2012;24(5):54853. 28. Isley MM, Kaunitz AM. Update on hormonal contraception and bone density. Rev Endocr Metab Disord. 2011;12(2):93106. 29. Dimeglio LA, Wang J, Siberry GK, Miller TL, Geffner ME, Hazra R, et al. Bone mineral density in children and adolescents with HIV infection. AIDS. 2013;27:21120. 30. Bunders MJ, Frinking O, Scherpbier HJ, van Arnhem LA, van Eck-Smit BL, Kuijpers TW, et al. Bone mineral density increases in HIV-infected children treated with long-term combination antiretroviral therapy. Clin Infect Dis. 2013;56(4):5836. 31. Puthanakit T, Saksawad R, Bunupuradah T, Wittawatmongkol O, Chuanjaroen T, Ubolyam S, et al. Prevalence and risk factors of low bone mineral density among perinatally HIV-infected Thai adolescents receiving antiretroviral therapy. J Acquir Immune Defic Syndr. 2012;61:47783. 32. Schtscherbyna A, Pinheiro MF, Mendonça LM, Gouveia C, Luiz RR, Machado ES, et al. Factors associated with low bone mineral density in a Brazilian cohort of vertically HIV-infected adolescents. Int J Infect Dis. 2012;16:e8728. 33. Mora S, Zamproni I, Beccio S, Bianchi R, Giacomet V, Viganò A. Longitudinal changes of bone mineral density and metabolism in antiretroviral-treated human immunodeficiency virus-infected children. J Clin Endocrinol Metab. 2004;89:248. 34. Young B, Dao CN, Buchacz K, Baker R, Brooks JT, HIV Outpatient Study (HOPS) Investigators. Increased rates of bone fracture among HIV-infected persons in the HIV Outpatient Study (HOPS) compared with the US general population, 20002006. Clin Infect Dis. 2011;52(8):10618. 35. Yin MT, Kendall MA, Wu X, Tassiopoulos K, Hochberg M, Huang JS, et al. Fractures after antiretroviral initiation. AIDS. 2012;26(17):217584. 36. Hansen AB, Gerstoft J, Kronborg G, Larsen CS, Pedersen C, Pedersen G, et al. Incidence of low and high-energy fractures in persons with and without HIV infection: a Danish population-based cohort study. AIDS. 2012;26(3): 28593. 37. Güerri-Fernandez R, Vestergaard P, Carbonell C, Knobel H, Avilés FF, Soria Castro A, et al. HIV infection is strongly associated with hip fracture risk, 9 Puthanakit T and Siberry GK. Journal of the International AIDS Society 2013, 16:18575 http://www.jiasociety.org/index.php/jias/article/view/18575 | http://dx.doi.org/10.7448/IAS.16.1.18575 independently of age, gender and co-morbidities: a population-based cohort study. J Bone Miner Res. 2013 Jan 29. [Epub ahead of print]. 38. Yin MT, Shi Q, Hoover DR, Anastos K, Sharma A, Young M, et al. Fracture incidence in HIV-infected women: results from the Women’s Interagency HIV Study. AIDS. 2010;24(17):267986. 39. Siberry GK, Li H, Jacobson D, Pediatric AIDS Clinical Trials Group (PACTG) 219/219C Study. Fracture risk by HIV infection status in perinatally HIV-exposed children. AIDS Res Hum Retroviruses. 2012;28(3):24750. 40. Hazra R, Megazzini K, Krauss M, Queiroz W, Succi R, Toibaro J, et al. Bone fractures among HIV-infected and HIV-exposed, uninfected (HEU) children in Latin America. 4th International Workshop on HIV Pediatrics (Abstract P_21), July 2021; Washington, DC; 2012. 41. McComsey GA, Tebas P, Shane E. Bone disease in HIV infection: a practical review and recommendations for HIV care providers. Clin Infect Dis. 2010; 51:93746. 42. Jacobson DL, Lindsey JC, Gordon CM, Moye J, Hardin DS, Mulligan K, et al. Total body and spinal bone mineral density across Tanner stage in perinatally HIV-infected and uninfected children and youth in PACTG 1045. AIDS. 2010; 24:68796. 43. Stellbrink HJ, Orkin C, Arribas JR, Compston J, Gerstoft J, Van Wijngaerden E, et al. Comparison of changes in bone density and turnover with abacavirlamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study. Clin Infect Dis. 2010;51(8):96372. 44. McComsey GA, Kitch D, Daar ES, Tierney C, Jahed NC, Tebas P, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011;203(12):1791801. 45. Grund B, Peng G, Gibert CL, Hoy JF, Isaksson RL, Shlay JC, et al. Continuous antiretroviral therapy decreases bone mineral density. AIDS. 2009;23(12): 151929. 46. Zuccotti G, Vigano A, Gabiano C, Giacomet V, Mignone F, Stucchi S, et al. Antiviral therapy and bone mineral measurements in HIV-infected youths. Bone. 2010;46:16338. 47. Bedimo R, Maalouf NM, Zhang S, Drechsler H, Tebas P. Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents. AIDS. 2012;26:82531. 48. Gafni RI, Hazra R, Reynolds JC, Maldarelli F, Tullio AN, DeCarlo E, et al. Tenofovirdisoproxilfumarate and an optimized background regimen of antiretroviral agents as salvage therapy: impact on bone mineral density in HIVinfected children. Pediatrics. 2006;118:e7118. 49. Giacomet V, Mora S, Martelli L, Merlo M, Sciannamblo M, Viganò A. A 12month treatment with tenofovir does not impair bone mineral accrual in HIVinfected children. J Acquir Immune Defic Syndr. 2005;40(4):44850. 50. Viganò A, Zuccotti GV, Puzzovio M, Pivetti V, Zamproni I, Cerini C, et al. Tenofovir disoproxil fumarate and bone mineral density: a 60-month longitudinal study in a cohort of HIV-infected youths. Antivir Ther. 2010;15:10538. 51. Della Negra M, de Carvalho AP, de Aquino MZ, da Silva MT, Pinto J, White K, et al. A randomized study of tenofovir disoproxil fumarate in treatmentexperienced HIV-1 infected adolescents. Pediatr Infect Dis J. 2012;31(5): 46973. 52. Panel on Antiretroviral Therapy and Medical Management of HIVInfected Children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. [cited 2012 Nov 25]. Available from: http://aidsinfo.nih.gov/ contentfiles/lvguidelines/pediatricguidelines.pdf 53. Fakruddin JM, Laurence J. HIV envelope gp120-mediated regulation of osteoclastogenesis via receptor activator of nuclear factor kappa B ligand (RANKL) secretion and its modulation by certain HIV protease inhibitors through interferon-gamma/RANKL cross-talk. J Biol Chem. 2003;278:482518. 54. Fakruddin JM, Laurence J. HIV-1 Vpr enhances production of receptor of activated NF-kappaB ligan (RANKL) via potentiation of glucocorticoid receptor activity. Arch Virol. 2005;150:6778. 55. Cotter EJ, Malizia AP, Chew N, Powderly WG, Doran PP. HIV proteins regulate born marker secretion and transcription factor activity in cultured human osteoblasts with consequent potential implications for osteoblast function and development. AIDS Res Hum Retroviruses. 2007;23:152130. 56. Teitelbaum SL. Bone resorption by osteoclasts. Sceinces. 2000;289:15048. 57. Vikulina T, Fan X, Yamaguchi M, Roser-Page S, Zayzafoon M, Guidot DM, et al. Alterations in the immunoskeletal interface drive bone destruction in HIV-1 transgenic rates. Proc Natl Acad Sci USA. 2010;107(31):1384853. 58. Gibellini D, Borderi M, De Crignis E, Cicola R, Vescini F, Caudarella R, et al. RANKL/OPG/TRAIL plasma levels and bone mass low evaluation in antiretroviral naı̈ve HIV-1 positive men. J Med Virol. 2007;79:144654. 59. Mora S, Zamproni I, Cafarelli L, Giacomet V, Erba P, Zuccotti G, et al. Alterations in circulating osteoimmune factors may be responsible for high born resorption rate in HIV-infected children and adolescents. AIDS. 2007; 21:112935. 60. Gazzola L, Bellistri GM, Tincati C, Ierardi V, Savoldi A, Del Dole A, et al. Association between peripheral T-lymphocyte activation and impaired bone mineral density in HIV-infected patients. J Transl Med. 2013;11:51. 61. Bogunovic L, Doyle SM, Vogiatzi MG. Measurement of bone density in the pediatric population. Curr Opin Pediatr. 2009;21(1):7782. 62. Fan B, Lu Y, Genant H, Fuerst T, Shepherd J. Does standardized BMD still remove differences between Hologic and GE-Lunar state-of-the-art DXA systems? Osteoporos Int. 2010;21:122736. 63. Zemel BS, Leonard MB, Kelly A, Lappe JM, Gilsanz V, Oberfield S, et al. Height adjustment in assessing dual energy x-ray absorptiometry measurements of bone mass and density in children. J Clin Endocrinol Metab. 2010; 95:126573. 64. Abrams SA. Calcium and vitamin D requirements for optimal bone mass during adolescence. Curr Opin Clin Nutr Metab Care. 2011;14(6):6059. 65. Kohrt WM, Bloomfield SA, Little KD, Nelson ME, Yingling VR, American College of Sports Medicine. American College of Sports Medicine Position Stand: physical activity and bone health. Med Sci Sports Exerc. 2004;36(11): 198596. 66. Rutstein R, Downes A, Zemel B, Schall J, Stallings V. Vitamin D status in children and young adults with perinatally acquired HIV infection. Clin Nutr. 2011;30(5):6248. 67. Havens PL, Stephensen CB, Hazra R, Flynn PM, Wilson CM, Rutledge B, et al. Vitamin D3 decreases parathyroid hormone in HIV-infected youth being treated with tenofovir: a randomized, placebo-controlled trial. Clin Infect Dis. 2012;54(7):101325. 68. Jacobson DL, Spiegelman D, Duggan C, Weinberg GA, Bechard L, Furuta L, et al. Predictors of bone mineral density in human immunodeficiency virus-1 infected children. J Pediatr Gastroenterol Nutr. 2005;41(3):33946. 69. Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M, Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics. 2008;122(2):398417. 70. McComsey GA, Kendall MA, Tebas P, Swindells S, Hogg E, Alston-Smith B, et al. Alendronate with calcium and vitamin D supplementation is safe and effective for the treatment of decreased bone mineral density in HIV. AIDS. 2007;21(18):247382. 71. Bachrach LK, Ward LM. Clinical review 1: bisphosphonate use in childhood osteoporosis. J Clin Endocrinol Metab. 2009;94:4009. 10 Bhimma R et al. Journal of the International AIDS Society 2013, 16:18596 http://www.jiasociety.org/index.php/jias/article/view/18596 | http://dx.doi.org/10.7448/IAS.16.1.18596 Review article Kidney disease in children and adolescents with perinatal HIV-1 infection Rajendra Bhimma§,1, Murli Udharam Purswani2 and Udai Kala3 § Corresponding author: Rajendra Bhimma, Department of Paediatric and Child Health, School of Clinical Medicine, Nelson R Mandela School of Medicine, Private Bag 7, Durban, 4013, South Africa. Tel: 27-31-260 4345. Fax: 27-31 260 4388. ([email protected]) This article is part of the special issue Perinatally HIV-infected adolescents - more articles from this issue can be found at http://www.jiasociety.org Abstract Introduction: Involvement of the kidney in children and adolescents with perinatal (HIV-1) infection can occur at any stage during the child’s life with diverse diagnoses, ranging from acute kidney injury, childhood urinary tract infections (UTIs), electrolyte imbalances and drug-induced nephrotoxicity, to diseases of the glomerulus. The latter include various immunemediated chronic kidney diseases (CKD) and HIV-associated nephropathy (HIVAN). Discussion: The introduction of highly active anti-retroviral therapy (HAART) has dramatically reduced the incidence of HIVAN, once the commonest form of CKD in children of African descent living with HIV, and also altered its prognosis from eventual progression to end-stage kidney disease to one that is compatible with long-term survival. The impact of HAART on the outcome of other forms of kidney diseases seen in this population has not been as impressive. Increasingly important is nephrotoxicity secondary to the prolonged use of anti-retroviral agents, and the occurrence of co-morbid kidney disease unrelated to HIV infection or its treatment. Improved understanding of the molecular pathogenesis and genetics of kidney diseases associated with HIV will result in better screening, prevention and treatment efforts, as HIV specialists and nephrologists coordinate clinical care of these patients. Both haemodialysis (HD) and peritoneal dialysis (PD) are effective as renal replacement therapy in HIVinfected patients with end-stage kidney disease, with PD being preferred in resource-limited settings. Kidney transplantation, once contraindicated in this population, has now become the most effective renal replacement therapy, provided rigorous criteria are met. Given the attendant morbidity and mortality in HIV-infected children and adolescents with kidney disease, routine screening for kidney disease is recommended where resources permit. Conclusions: This review focuses on the pathogenesis and genetics, clinical presentation and management of kidney disease in children and adolescents with perinatal HIV-1 infection. Keywords: human immunodeficiency virus; kidney; children; adolescents; anti-retroviral drug toxicity. Received 19 February 2013; Revised 14 April 2013; Accepted 16 April 2013; Published 18 June 2013 Copyright: – 2013 Bhimma R et al; licensee International AIDS Society. This is an open access article distributed under the terms of the Creative Commons Attribution 3.0 Unported (CC BY 3.0) Licence (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction It is estimated that 3.4 million children were living with (HIV) infection at the end of 2011, 91% of whom are in subSaharan Africa [1]. This region accounts for more than 70% of global HIV infections although it has only 10% of the world’s population, and thus bears an inordinate burden of this disease [2]. The widespread use of highly active anti-retroviral therapy (HAART), introduced in 1996, has dramatically decreased the incidence of HIV-associated nephropathy (HIVAN) although a clear benefit in non-HIVAN kidney disease has not been demonstrated [35]. In spite of this demonstrated effectiveness, only 28% of children in need of HAART worldwide actually receive it. With the long-term use of HAART, drug toxicity, advancing age and chronic viral infections has resulted in an increase in the overall frequency of kidney diseases in HIV-infected individuals [6,7]. Complications such as end-stage liver, kidney and heart disease are taking on prominent roles in the management of HIV-infected adults [8,9]. Nonetheless, a general lack of surveillance and reporting of kidney diseases in HIV-infected children exists in most developing regions of the world where HIV is highly prevalent [10]. In a large United States cohort, it was estimated that kidney disease complicating HIV infection is now among the ten most common non-infectious conditions occurring in perinatally HIV-infected children and adolescents in the HAART era, with an incidence rate of 2.6 per 100 patient-years [11,12]. The spectrum of kidney disease that occurs with perinatal HIV infection in children encompasses chronic glomerular disorders, such as HIVAN and HIV immune complex kidney disease (HIVICK), the thrombotic microangiopathies (including atypical forms of haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura), disorders of proximal tubular function and acute kidney injury [13]. Early reports of childhood HIVAN in African-American children were from Miami and New York [14,15], three years after the first description of this condition in adults [3]. The unique histological feature of HIVAN in children is classical focal 1 Bhimma R et al. Journal of the International AIDS Society 2013, 16:18596 http://www.jiasociety.org/index.php/jias/article/view/18596 | http://dx.doi.org/10.7448/IAS.16.1.18596 segmental glomerulosclerosis (FSGS) with or without mesangial hyperplasia in combination with microcystic tubular dilatation and interstitial inflammation [16,17]. Mesangial proliferative lesions secondary to immune complex deposits may also be present in some HIV-infected children with HIVAN [16,17]. All other forms of kidney diseases associated with HIV infection in children are collectively referred to as HIV-related kidney diseases hereafter. In this article, we review the pathogenesis, clinical presentation and management of HIVAN and other HIV-related kidney diseases, including complications of HAART therapy. Pathogenesis of HIVAN The role of HIV-1 infection of the kidney HIV viral burden and immunosuppression are wellestablished risk factors for the development of HIVAN and the main reasons behind the decline in its incidence with HAART [1821]. Consistent with this clinical evidence is the fact that infection of kidney epithelial cells by HIV-1 is now thought to result eventually in HIVAN, and that the kidney is also a reservoir for HIV-1 [22]. What is unclear is how the virus enters these epithelial cells since glomerular podocytes and renal tubular cells do not express CD4 or other co-receptors. Nevertheless, in vitro studies have demonstrated efficient transfer of HIV-1 viral nucleic acid from T-cells to renal tubular epithelial cells. It is also postulated that injured glomerular podocytes undergo proliferation and apoptosis, and that the remaining podocytes hypertrophy and leave bare segments of basement membrane that promotes the development of the sclerotic lesions that characterize HIVAN [22]. A report on the pathogenesis of childhood HIVAN by Ray et al. also discussed the role of productive mesangial cell infection by HIV-1 [23]. Three groups of investigators were able to demonstrate infection of cultured mesangial cells by the virus [2426], while two others were unable to do so [27,28]. Studies have shown that the HIV nef gene is important in the development of the glomerular lesions of HIVAN, in particular the dedifferentiation and proliferation of podocytes, which are otherwise terminally differentiated [2931]. The HIV vpr genes have been implicated in the development of tubular pathology in HIVAN, predominantly through the induction of apoptosis and cell cycle arrests [3235], and the HIV tat gene has been shown to have a potential role in podocyte dedifferentiation [36]. The role of FSGS without an accompanying collapsing glomerulopathy Histopathological findings of HIVAN vary in children compared to adults. Although collapsing glomerulopathy is a hallmark of the disease in adults, the unique microscopic features of HIVAN in children are defined as the presence of classical FSGS with or without mesangial hyperplasia in combination with microcystic tubular dilatation and interstitial inflammation. Mesangial proliferative lesions secondary to immune complex deposits may also be present in some children [16,37]. The early paediatric literature describes HIVAN without a collapsing glomerulopathy always being present on biopsy [14,15,38]. In two recent paediatric studies [13,18], the percentage of children with biopsyproven HIVAN that showed a collapsing glomerulopathy with FSGS was 14% and 32.5%. The findings on histology include classic FSGS and mesangial proliferative glomerulonephritis, both of which have been reported by Ray et al. to be consistent with a diagnosis of HIVAN in children [23,37]. The collapsing variant of FSGS is a clinically and pathologically distinct variant of FSGS. Indeed the clinical progression of the two is different, with a rapidly progressive course observed in the collapsing variant that is typically seen with adult HIVAN. In children with HIVAN, most without a collapsing glomerulopathy [39], the clinical course of disease is not as aggressive, with slower progression to eventual end-stage kidney disease [23]. The role of host genetics Several studies have identified a genetic basis explaining the increased risk for kidney disease and the occurrence of HIVAN almost exclusively in African-Americans, a population with a four-fold increased risk for end-stage kidney disease [40]. Interest initially centred around genetic variations at a locus near the MYH9 gene on chromosome 22 [41,42]. Later, two independent sequence variants G1 and G2 in the APOL-1 gene adjacent to the MYH9 gene were found to be highly associated with FSGS and HIVAN, with odds ratios of 17 and 29, respectively [43,44]. These risk alleles are present only on African chromosomes. The combined risk frequency of G1 and G2 polymorphisms in the Yoruba tribe in west Africa is 62% and the frequency of either allele in persons of west African origin is 35%, largely operating in a recessive manner. Interestingly, the heterozygous state protects the individual against Trypansoma brucei rhodesiense, whilst the homozygous state confers an increased risk for kidney disease, similar to the protective effect of sickle cell trait against malaria, at the cost of sickle cell disease in the homozygous state [43]. The percentages of one- and two-risk alleles for APOL-1 in self-identified African-Americans in a cohort of children and adolescents with perinatal HIV-1 infection followed in the Pediatric HIV/AIDS Cohort Study are 43% and 13%, respectively [45]. The two identified APOL1 risk alleles were noted to be in strong linkage disequilibrium with the MYH9 risk haplotype, and association between APOL1 and kidney disease remained significant after further adjustment for this and other combinations of the MYH9 alleles. The high frequency of APOL1 risk alleles in African populations do not provide an explanation for the biological mechanisms leading to an increased risk of FSGS associated with these variants [22]. Pathogenesis of HIVICK HIVICK is thought to arise either by the trapping or deposition of circulating immune complexes in the parenchyma, or by in situ immune complex formation, described in a detailed report on four patients by Kimmel et al. [46]. These immune complexes comprise various HIV core and envelope antigens including p24 and glycoprotein 41 and 160, respectively, bound to IgG or IgA antibodies that are part of the polyclonal immune response produced against these antigens in HIV-infected patients. Also included in this 2 Bhimma R et al. Journal of the International AIDS Society 2013, 16:18596 http://www.jiasociety.org/index.php/jias/article/view/18596 | http://dx.doi.org/10.7448/IAS.16.1.18596 category are other immune-mediated diseases such as IgA nephropathy, and a membranous or membrano-proliferative glomerulonephritis that may or may not be associated with hepatitis B and C virus infections. A ‘‘lupus-like’’ glomerulonephritis, in which light immunofluorescence and electron microscopic features of lupus glomerulonephritis in the absence of clinical systemic lupus erythematosus, and without the serologic markers that accompany this disease, is also seen in HIV-infected adults and children [47]. Although HIVICK occurs in African-Americans, this entity is more likely to be seen in Caucasians [48], and is not associated with the single-nucleotide polymorphisms implicated in the pathogenesis of HIVAN in African-Americans. HIVICK is not uncommon, and was found in 33% of kidney biopsies in children in a US cohort [18], whereas in South Africa there is a regional bias with HIVICK reported in 7% of paediatric biopsies from Cape Town and a much higher incidence of 51% in Johannesburg [49]. The reasons for the differences in the histological spectrum of the disease from these two regions remain to be explored. Clinical presentation of HIVAN and other glomerular diseases in children and adolescents with perinatal HIV-1 infection Kidney disease in children occurs at all stages of HIV infection. Anti-retroviral (ARV) agents, antibiotics such as aminoglycosides, antifungals (amphotericin B), antivirals (acyclovir), anti-tuberculosis drugs, anti-inflammatory drugs and combinations of all these contribute to kidney disease. The spectrum of kidney disease seen in HIV-infected patients is shown in Table 1. Glomerular pathology in children and adults in different countries and populations vary tremendously. In blacks from Africa, America and Europe and Hispanic populations, FSGS with or without collapsing glomeruli and microcystic tubular dilatation are common [23]. In their Caucasian counterparts, mesangial hyperplasia and immune complex-type disease predominates [50]. HIVAN is still the commonest cause of kidney disease in HIV-1infected children and adolescents in other parts of the world, as evidenced by recent reports from KwaZulu-Natal in South Africa and Nigeria, with a higher incidence in males [13,51]. The exceptions were two studies in adults and children in which HIVICK was equal to or more prevalent [52,53]. Common to both is interstitial inflammation. However, in other adult studies from Cape Town, South Africa [54,55], and paediatric studies from South Africa and other regions of the globe, FSGS was the commonest histological type [13,15,5658]. The incidence and natural history of HIVAN has been dramatically altered by HAART [21,59,60]. Once the commonest cause of kidney disease in adults and children, it is likely surpassed now by renal toxicity arising from ARV treatment in the United States. Below we describe the clinical presentation of the most common forms of HIV-related glomerular disease. Glomerular disease Haematuria and proteinuria and subsequent development of nephrotic syndrome and chronic kidney disease (CKD) represent the commonest manifestations of HIV-related Table 1. Spectrum of kidney disease in HIV-infected patients Glomerular diseases HIV-associated nephropathy-collapsing focal segmental glomerulosclerosis Non-collapsing focal segmental glomerulosclerosis Membranoproliferative glomerulonephritis (hepatitis C and cryoglobulinaemia) Lupus-like glomerulonephritis Membranous nephropathy (hepatitis B) IgA nephropathy Post-infectious glomerulonephritis Diabetic nephropathy Minimal change nephropathy Amyloidosis Nephrosclerosis Thrombotic microangiopathies Fibrillary glomerulonephritis Anti-neutrophil cytoplasmic antibody-associated vasculitis and anti-glomerular basement membrane disease (rare) Interstitial diseases Acute or chronic interstitial nephritis Lymphoma Acute tubular necrosis Pyelonephritis Medication-related Crystal nephropathy: indinavir, nelfinavir, atazanavir, intravenous acyclovir, sulfadiazine Proximal tubulopathy (Fanconi syndrome): tenofovir, lamivudine, abacavir, Didanosine Distal tubulopathy: amphotericin Reproduced with permission from Usama E, Ana MS, Stcey AR, Fernando CF. Treatment of HIV-associated nephropathies Nephron Clin Pract. 2011;118:c34654. Copyright # 2011 Karger AG, Basel. glomerular disease (Table 1) [13]. CKD in children with HIV infection usually has an insidious onset [49]. The strategy to minimize kidney damage is by screening urine for proteinuria and even microalbuminuria. The mean duration from the onset of proteinuria to developing end-stage kidney disease in children with HIVAN varied from 8 months to 3 years depending on the geographical area and associated AIDSdefining illnesses in untreated patients. Thus, prognosis prior to the introduction of HAART in patients with CKD was very poor [15,37,56,6163]. The reported rate of CKD in HIVinfected patients on presentation varied from 5 to 40% [13,51,53]. Haematuria Microscopic haematuria, with or without proteinuria was the commonest presenting symptom of kidney disease in two African studies; 75% and 50% with or without proteinuria, thus noting its importance as a sign or symptom in patients with HIVAN and other HIV-related kidney diseases [13,64]. If there is persistence of microscopic haematuria with or 3 Bhimma R et al. Journal of the International AIDS Society 2013, 16:18596 http://www.jiasociety.org/index.php/jias/article/view/18596 | http://dx.doi.org/10.7448/IAS.16.1.18596 without HAART, the patient needs to be evaluated further for the degree of kidney involvement and warrants a kidney ultrasound, serum electrolytes, creatinine measurement and urine microscopy [49]. Once urolithiasis has been excluded and there is no clear explanation for the haematuria, a kidney biopsy must be considered. Proteinuria Persistent proteinuria (]1 on urinary dipstick testing) is significant. Urine samples must be sent to the laboratory for a urine protein/creatinine ratio (uPCR) and a ratio of ]0.2 (measured as mg/dL protein divided by mg/dL creatinine) confirms underlying kidney disease, which can be used to monitor response to HAART as shown by Chaparro et al. [64]. In this study, the degree of proteinuria degree of proteinuria was proportional to loss of kidney function and mortality increased with nephritoc-range proteinuria [64]. Severe proteinuria is more prevalent in black African children [13,65,66]. It is also associated with a higher mortality rate, especially in the presence of collapsing glomerulopathy on kidney biopsy [13,51,53,67]. Thus, it is imperative to test for proteinuria in all HIVinfected patients and if persistent, to perform a kidney biopsy. This is borne out by an adult study in which even microalbuminuria correlated with renal parenchymal disease with a prevalence of 36% in HIV-infected black African patients [66]. There are no equivalent paediatric studies showing similar results. In a study from Enugu, Nigeria none of the 154 HIV-infected and 154 HIV-uninfected children screened for microalbuminuria were positive [68]. In another study of HIV-infected non-febrile children without any symptoms of renal disease at Chris Hani Baragwanath hospital situated in Johannesburg, South Africa, the prevalence of microalbuminuria was 25%, but unfortunately none of these patients had a kidney biopsy [69]. HIV-associated nephropathy HIVAN is the most aggressive kidney disease affecting up to 10% of HIV-infected patients and is the primary form of HIV nephropathy seen in adults [11,12]. The true prevalence of paediatric HIVAN is not known as kidney biopsies have not been performed regularly in all HIV-infected patients with proteinuria [13,15,37,53,56,6163,70] and haematuria, especially persistent microscopic haematuria. The following criteria were used for the diagnosis of HIVAN in children: 1) 2) 3) 4) Persistent proteinuria defined as an uPCR ]0.2 for 3 months or more, in the absence of acute infection especially in children of African descent. Urine sediment with urine microcysts (shed epithelial cells). Highly echogenic kidneys as detected by serial renal ultrasound performed 3 months apart. Black race with a clinical history of nephrotic-range proteinuria with or without oedema or hypertension. Diagnosis of HIVAN All HIV-infected children should be screened for proteinuria and microscopic haematuria annually or earlier if indicated. The initial investigations should include blood urea nitrogen, serum electrolytes and creatinine, and urine electrolytes to evaluate for tubulopathies [14]. An uPCR must be done to assess the severity of proteinuria and to determine if nephrotic-range. Urine microscopy is done to determine the presence of microcysts which are clusters of renal epithelial cells forming cyst-like structures [37,56]. Ultrasound examination of the kidneys should be performed to assess kidney size, echogenicity and to exclude any obstructive lesions. Unfortunately, currently available non-invasive diagnostic testing has limited sensitivity and specificity to distinguish HIVAN from other HIV-related kidney diseases. Therefore, kidney biopsy should be performed, if indicated, to confirm the presence of HIVAN, which is presently the only definitive way to diagnose HIVAN [37]. In most United States paediatric centres, children with perinatal HIV-1 infection and kidney disease were not biopsied either because they were felt to be too ill to undergo the procedure, or because of the perception that information gained from the biopsy would not make a significant contribution to the management of these children [15,38,61,62]. To date, HIV infection has not been associated with an increased risk of procedural complications from kidney biopsy [71]. Clinical presentation of other HIV-related kidney diseases in children and adolescents with perinatal HIV-1 infection We describe below the presentation of some of the more commonly seen non-HIVAN kidney diseases that may accompany HIV-1 infection in this population. Acute interstitial nephritis Acute interstitial nephritis (AIN) results mainly from multiple drugs used in the treatment of HIV infections and its complications. It can occur as a result of HIV infection of the kidney itself, as in 28% of autopsy findings in HIV-infected patients with AIN an inciting agent was not recognized [72]. Known agents causing AIN include non-steroidal anti-inflammatory drugs (NSAIDS), rifampicin and trimethoprim-sulfamethoxazole combinations [73,74]. It has also been reported in patients taking indinavir or ritonavir [57,75,76]. These protease inhibitors (PIs) can also cause nephrolithiasis with flank pain and renal colic [77]. Sulfadiazine crystal formation with resultant tubular obstruction and possibly ureteral obstruction has been described in volume-depleted HIV-infected patients [7880]. Children with AIN from any cause, including HIV-infection, may present with non-specific signs and symptoms of acute kidney injury. More than 30 acute kidney injury definitions exist in the literature and therefore data may not be consistent, but a standardized definition has been proposed by the Acute Dialysis Quality Initiative Group [81] termed the ‘‘RIFLE’’ criteria and this has been modified for use in children [82]. RIFLE (the acronym for Risk for renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function, and end-stage kidney disease) aims to standardize the definition of acute kidney injury by stratifying patients based on changes in serum creatinine levels from baseline and/or an abrupt decrease in urine output. 4 Bhimma R et al. Journal of the International AIDS Society 2013, 16:18596 http://www.jiasociety.org/index.php/jias/article/view/18596 | http://dx.doi.org/10.7448/IAS.16.1.18596 There may be sudden or insidious onset of nausea, vomiting, and/or malaise. Many patients are asymptomatic. A minority of patients may have proteinuria and gross haematuria may be found in 5% of patients [83]. Discontinuation of the potential causative agent is the mainstay of therapy. In severe cases where there is persistent renal dysfunction, immunosuppressive therapy has been employed. However, the optimal therapy of AIN is unknown, since there are no randomized controlled trials or large observational studies. These complications can be prevented or minimized with ample fluid intake. Electrolyte and acid-base disorders Electrolyte disturbances of hyponatraemia/hypernatraemia, hypophosphataemia, hypocalcaemia and hypomagnesaemia are common [13,53]. Hyponatraemia is often seen in HIVinfected children with gastroenteritis [8486]. The syndrome of inappropriate anti-diuretic hormone secretion (SIADH) develops mainly in hospitalized patients [86] usually due to intracranial and respiratory infections such as pulmonary tuberculosis (TB), Pneumocystis jiroveci pneumonia and toxoplasmosis. Hyponatraemia and hyperkalaemia can be caused by adrenal insufficiency due to mineralocorticoid deficiency or hyporeninemic hypoaldosteronism [87,88]. Hypokalaemia due to low body potassium from severe malnutrition and gastrointestinal losses is also commonly seen. This also occurs through renal tubular loss resulting from the use of drugs such as amphotericin B used for the treatment of severe fungal infections. Toxicity from anti-retroviral agents such as tenofovir can cause proximal tubular dysfunction and nephrogenic diabetes insipidus can manifest as glycosuria, hypophosphateemia, proteinuria, acidosis and acute kidney injury [8992]. Therefore, the dosing of nephrotoxic drugs should be adjusted to the estimated glomerular filtration rate in patients with acute kidney injury or CKD [93,94]. Acid-base disturbances are common in children with HIV infection and are due mainly to severe sepsis and drugs [13,94]. Lactic acidosis may possibly be due to drug-induced mitochondrial dysfunction reported with zidovudine, diadanosine, lamivudine and stavudine and which could be present in a mild form in 525% of patients [64]. Non-anion gap metabolic acidosis can result from intestinal loss of bicarbonate from diarrhoea or renal losses from drug toxicity, most commonly amphotericin B [73]. Urinary tract infections There is a higher prevalence of urinary tract infections (UTIs) in HIV-infected patients [53,57] ranging from lower tract involvement to pyelonephritis. UTIs in these patients seem to be due more to malnutrition than from immunosuppression due to HIV infection [95]. To prevent kidney damage, it is important to diagnose and treat UTIs appropriately. In a group of 60 children with HIV and renal involvement studied in Johannesburg, South Africa, 23% had UTIs [49]. The investigation and treatment of UTIs in HIV-infected children is based on standard guidelines used for management of HIV-uninfected children with UTIs [95]. Exclusion of associated infections Pulmonary and disseminated TB should be excluded in HIVAN. Nourse et al. demonstrated in four of their HIV-infected children with proteinuria as well as granulomatous lesions on histology compatible with TB, that proteinuria resolved on anti-TB drugs alone prior to the introduction of HAART [67]. TB was also a predominant finding in an adult Indian autopsy study in patients with AIDS [96]. The prevalence of TB in a cohort of 60 children at the Chris Hani Baragwanath Hospital was 33% [53]. The impact of other viral infections such cytomegalovirus (CMV), hepatitis B and hepatitis C on HIVAN has not been fully explored. One study of renal pathology in HIV-infected adult patients described CMV infection of the kidney as a cause of acute renal failure [97]. Hepatitis B virus resistance to lamivudine has been noted in kidney transplant recipients on HAART regimens containing lamivudine [98]. In patients with hepatitis C virus co-infection, clearance of the virus with interferon-ribavirin therapy should be attempted early, especially prior to transplantation, as immunosuppression exacerbates hepatitis C infection in kidney allograft recipients making management of HIV and hepatitis C virus co-infection particularly difficult [99]. Treatment of HIVAN Once kidney involvement is detected by renal dysfunction, proteinuria and/or haematuria, HAART needs to be commenced as soon as possible in accordance with WHO guidelines [100]. If already on HAART, it may be that their HIV disease is not well controlled, as evidenced by CD4 depletion and/or a high viral load, both being risk factors for HIVAN. In such a situation, appropriate resistance testing can guide subsequent HAART regimens. Associated infections such as TB, if present, must be appropriately treated. HAART is commenced after exclusion of tuberculosis to avoid immune reconstitution inflammatory syndrome (IRIS); however, ARVs may be started before TB is excluded in sick children [5,101 103]. This possibly arrests the rapid progression of kidney disease. NRTIs are excreted in the urine unchanged, and therefore decreased dosing is often required in CKD stage III and above [104]. The threshold for dose reduction varies for different NRTIs; most NRTIs generally require dose adjustment at creatinine clearance below 4060mL/min/ 1.73m2. The dosing for zidovudine is only reduced at creatinine clearance B15mL/min/1.73m2 whereas the dosing for abacavir remains unchanged at any level of kidney function [94]. Due to this variability, it is challenging to prescribe fixed-dose combinations of NRTIs in patients with reduced kidney function. Most non-nucleoside reverse transcriptase inhibitors (NNRTIs), PIs, fusion inhibitors, integrase inhibitors, and the b-chemokine receptor (CCR5) antagonists do not require dose modification with CKD [105,106]. HAART itself can cause acute kidney injury and progressive nephropathy [107110]. Some patients with normal kidney function at baseline still progress to CKD despite HAART [111]. Thus, patients on HAART who show progressive kidney disease or signs of acute kidney injury must undergo a kidney biopsy. This also applies to those in whom potentially 5 Bhimma R et al. Journal of the International AIDS Society 2013, 16:18596 http://www.jiasociety.org/index.php/jias/article/view/18596 | http://dx.doi.org/10.7448/IAS.16.1.18596 nephrotoxic drugs are being used and whose kidney function fails to improve upon discontinuation of the drug [112]. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blocking agents (ARB) can be used as an adjunct for decreasing proteinuria provided the patient does not have a depleted intravascular space, often due to severe gastroenteritis, fluid loss from tubulopathy and/or severe nephrotic syndrome [13,15,56]. The introduction of HAART and angiotensin II blockade reduces progression to end-stage kidney disease [94,113]. However, to date, no completed randomized controlled trials or quasi-randomized controlled trials have been done providing evidence for treatment of HIVAN using ACE inhibitors or ARBs as adjunctive to HAART, although in most centres this is presently the standard of care [102,114]. Diuretics need to be used with caution as these agents can exacerbate intravascular volume contraction, further worsening the decline in glomerular filtration. Steroid therapy has, in the short term, been shown to improve kidney function and proteinuria in HIVAN and in children treated for lymphoid interstitial pneumonitis; longterm effects of steroids on HIVAN are unknown. In resourcelimited countries with a high prevalence of TB this could potentially cause exacerbation of, and overwhelming infection with TB, particularly when compliance is always an issue [49]. Also, in the absence of HAART, corticosteroids have not been shown to prevent the progression of HIVAN in children [15,38,56]. Steroids are therefore not currently recommended for the routine management of HIVAN. The effects of other immunosuppressive agents such as cyclophosphamide, cyclosporine, azathioprine, mycophenelate mofetil, tacrolimus, are not known, but some have been utilized in a selective manner in certain patients [62]. In summary, co-morbidities such as UTIs, hypertension and electrolyte and acid-base disorders need to be treated aggressively. Avoidance of nephrotoxic drugs and combinations of ARVs that cannot be adjusted according to the patient’s estimated glomerular filtration rate will help prevent further kidney damage. Renal toxicity arising from ARV drugs Infants with perinatal HIV-1 infection are started on combination ARV therapy as soon as the diagnosis is established and will remain on medications for the rest of their life, given the current state of our knowledge on the treatment of HIV. It is therefore critically important to understand the toxicity profile of these drugs in order to be able to use them effectively and safely. Unfortunately, there is a paucity of data on such toxicity in children. A comprehensive review by Jao and Wyatt has described kidney toxicity reported with all classes of ARVs, except for the integrase inhibitors and the CCR5 antagonists [106]. Most PIs have, on rare occasions, been associated with the development of urolithiasis. This toxicity is notably most commonly reported with the use of indinavir. Crystalluria occurs in 20%, and nephrolithiasis in 3% of patients on this PI. Indinavir has also been reported to cause sterile pyuria and interstitial nephritis, as well as haematuria, renal colic, papillary necrosis, acute kidney injury and CKD. Due to the frequency of crystalluria and haematuria and the lack of a convenient paediatric formulation, this drug is rarely used in children and adolescents. The dose of atazanavir is now established in the paediatric population [115] and, along with the combination of lopinavir/ritonavir (Kaletra† ), is a frequently used PI in children. Although cases of nephrolithiasis and interstitial nephritis have been reported with its use, the incidence of such toxicity is very low [116,117]. Similarly, the NNRTIs are metabolized by the hepatic cytochrome P450 system and have minimal nephrotoxicity, with rare reports of minimal change disease and urolithiasis with the use of efavirenz, and acute hypersensitivity reactions with the use of nevirapine. Lamivudine, didanosine and abacavir are nucleoside reverse transcriptase inhibitors (NRTIs) for which there are rare reports of Fanconi syndrome, and for the latter two, nephrogenic diabetes insipidus [118122]. Tenofovir and renal toxicity Tenofovir is one of the most widely used ARV agents in the United States. Until recently, it was used only in children ]12 years, provided their body weight was ]35 kg. It is now available as a powder and a low-dose tablet, and in 2012, received approval for use in children ]2 years of age. It causes proximal renal tubular toxicity [123] and has been investigated far more extensively than other ARVs in order to better understand its renal safety profile. With acute tubular injury, there is reduced glomerular filtration rate, presenting as acute kidney injury [124]. The initial presentation of chronic tubular toxicity is the appearance of proteinuria, with glycosuria, phosphaturia and uricosuria, resulting in a complete or partial Fanconi syndrome [125]. In adult randomized controlled clinical trials, nephrotoxicity was observed in 12% of individuals [126]. It has been argued, however, that this is an artificially low estimate due to rigorous screening prior to participation in such studies. Cohort studies may better reflect the true renal safety profile of tenofovir in clinical care. There are few such studies in HIVinfected children and adolescents, and these are described in Table 2. They have shown results ranging from 86% proteinuria to no evidence of impaired glomerular or tubular function. One prospective double-blind placebo-controlled study showed no toxicity, while a recent large prospective cohort study showed a 2.5-fold increased risk of proteinuria with use of tenofovir for 3 years [134]. Thus, findings have been inconsistent. Dialysis in children with end-stage kidney disease In the pre-HAART era, dialysis was not offered to patients with HIV infection because of poor survival and concerns regarding high infection rates in these children [49]. Following the introduction of HAART, several studies have confirmed short-term survival rates in adults that are similar to non-HIV-infected patients, such as diabetics [5,107]. Predictors of poor outcome of patients on dialysis with HIV-infection include low CD4 counts, high viral load, HIVAN as the cause of end-stage kidney disease, absence of HAART and opportunistic infections. Given the improved survival of these patients with HAART, renal replacement therapy was shown to be feasible. 6 Recent pediatric studies of tenofovir toxicity in children and adolescents with perinatal HIV-1 infection Author, year, location Vigano, 2007 Italy [127] Study design and duration/follow-up Renal outcome measures Age (years) N Findings Prospective, open-label tenofovir use Serum creatinine, phosphate; proteinuria, without control group, 24 months glycosuria, urine protein, albumin and a-1 tubular renal function in tenofovir-treated microglobulin creatinine ratios and maximal subjects 4.918 27 No evidence of impaired glomerular or tubular phosphate reabsorption ratios; estimated GFR (glomerular filtration rate) Andiman, 2009 USA [128] Prospective cohort study; median follow-up Three sequentially abnormal renal of six years laboratory values in at least one Median age of 6.3 2102 Two-fold increased risk of renal dysfunction with tenofovir-based regimen 218 456 4% hypophosphataemia which was of three measures: urine protein, serum creatinine or estimated GFR Judd, 2010 UK/Ireland [129] Nested casecontrol study; median ] grade 2 hypophosphataemia or follow-up of 18 months estimated GFRB60 mL/min/1.73 m2 associated with prolonged tenofovir use; only one case of estimated GFRB60 mL/ min/1.73 m2 Soler-Palacin, 2011 Spain [130] 2 Cohort study, two-phase design, retrospective and prospective data Proteinuria 4 mg/m /h, urine osmolality 817 B800 mOsm/kg after restricted fluid intake, collection after ]6 months of tenofovir fractional Na excretion2, tubular alterations in 22%; significantly decreased treatment without control group, median phosphate reabsorption B90%; estimated serum phosphate and potassium duration of tenofovir use: 77 months GFR; renal ultrasound alterations concentrations, with negative correlation 40 Decreased tubular phosphate reabsorption in 74%; proteinuria in 89%; urine osmolality between serum phosphate and time on tenofovir Vigano, 2011 Prospective, open-label tenofovir use Same markers as 2007 study 4.918 26 Once again, no evidence of impaired Italy [131] Della Negra, 2012 without control group, 60 months Prospective double-blind and placebo Serum phosphate and creatinine; urine 12 B 18 87 glomerular or tubular renal function No significant differences in renal function USA, Brazil, controlled (tenofovir versus placebo), protein and glucose; estimated GFR 45 tenofovir, between tenofovir and placebo group; no Panama [132] 48 weeks 42 placebo graded serum creatinine observed 49 Renal function and serum phosphate Pontrelli, 2012 Prospective cohort study, two years Italy [133] Serum creatinine, phosphate and potassium 918 levels, estimated GFR decreased over time in all subjects; no significant association with use of tenofovir (9protease inhibitors) containing regimens Purswani, 2013 USA [134] Prospective cohort study, three years Urine protein/creatinine ratio ]0.2; CKD as Mean age ]2 sequential uPCR ]0.2 or estimated GFR (9SD) 11.592.5 B60 mL/min/1.73 m2 448 2.5-fold increased risk of proteinuria with duration of tenofovir use three years Bhimma R et al. Journal of the International AIDS Society 2013, 16:18596 http://www.jiasociety.org/index.php/jias/article/view/18596 | http://dx.doi.org/10.7448/IAS.16.1.18596 Table 2. 7 Bhimma R et al. Journal of the International AIDS Society 2013, 16:18596 http://www.jiasociety.org/index.php/jias/article/view/18596 | http://dx.doi.org/10.7448/IAS.16.1.18596 Currently, there is still no consensus on the modality of dialysis that is best for HIV-infected children and adults. Both peritoneal dialysis (PD) and haemodialysis (HD) are effective modes of renal replacement therapy in these patients, though there are various points of concern with both modalities. In the United States, HD is preferred over PD because of the added burden of PD for family members who are often managing their own disease as well as that of their child [37]. Presently, both PD and HD have been used in HIV-infected patients with end-stage kidney disease, and the mode of dialysis is not a determining factor in the survival of adult HIV-infected patients with end-stage kidney disease [135,136]. While those patients on PD have a 50% increased risk of peritonitis, patients on HD using tunnelled cuffed catheters have a five-fold higher risk of infection with gram negative bacteria and a seven-fold higher risk of infection with fungal species [137]. PD may also aggravate the malnutrition and hypoalbuminaemia in HIV patients with severe wasting syndrome. HD patients, on the other hand, have a higher risk of thrombosis [138,139]. In resourcelimited settings, PD may be the modality of choice mainly due to cost implications and distance from centres able to provide HD. There is little data on the outcome of children with endstage kidney disease secondary to HIV on maintenance dialysis. In the early stages of the epidemic when HAART was not available, Ortiz et al. reported that once full-blown AIDS develops in an HIV-infected patient on HD, survival was significantly decreased [140]. Following the introduction of HAART, Tourret et al. reported that the survival of HIVinfected adult patients on HD was not statistically different from non-HIV patients on HD. In this study, the factors associated with mortality were a high viral load and a history of opportunistic infections [141]. Gordillo et al. reported on 12 HIV-infected children with end-stage kidney disease on maintenance HD compared to 32 non-HIV-infected children over a five-year period [142]. Their main findings were that body mass index and cardiovascular disease were associated with increased mortality in the HIV-infected children. A negative correlation of mortality in HIV-infected children to CD8 counts was consistent with studies in adult HIV populations [141]. Children who died also had lower CD4 counts and higher viral loads, although this did not show statistical significance given the small sample size. However, this was consistent with studies in adult HIV-infected patients [141]. Given the high mortality from cardiovascular deaths in this group of children, the authors, in a subsequent report, proposed that routine echocardiography be periodically performed in HIV-infected children on renal replacement therapy. This would enable detection of subclinical increased left ventricular mass index, or reduced shortening fraction, both of which may be early predictors of mortality [143]. To date, there are no reports on the outcome of HIV-infected children with end-stage kidney disease on maintenance PD. Transplantation in HIV-infected children with end-stage kidney disease Prior to the introduction of HAART, the morbidity and mortality of HIV-infected patients was too high to justify using scarce resources in transplanting HIV-infected patients [98]. There were concerns that immunosuppression may exacerbate HIV replication in an already immunocompromised patient resulting in rapid progression of disease and increased mortality [144]. The ability to suppress HIV replication with HAART, as well as improved prophylaxis and treatment of opportunistic infections, encouraged the transplant community to reconsider this option in HIV-infected individuals. Further impetus was provided by the serendipitous finding that many of the commonly used immunosuppressive agents were also effective against HIV. Cyclosporine inhibition of interleukin-2-dependent T-cell proliferation may suppress HIV replication [145,146]. Furthermore, by binding to cyclophyllin A, cyclosporin prevents the formation of HIV gag protein/ cyclophyllin A complex necessary for nuclear transport of HIV DNA [147,148]. A prospective study showed more rapid immune reconstitution in HIV-infected patients treated with cyclosporine and HAART versus cyclosporine alone [149]. Mycophenolate mofetil (MMF) inhibits inosine monophosphate dehydrogenase, a rate-limiting enzyme in the synthesis of guanosine nucleotides, markedly decreasing intracellular nucleotides in lymphocytes and monocytes as these cells lack a salvage pathway for generating purines, and thereby preventing replication of these cells [150152]. Hence, MMF can provide synergistic action with nucleotide analogues such as abacavir and didanosine, which are often integral components of HAART therapy [152,153]. Of potential concern is the in vitro antagonism with stavudine and zidovudine that may inhibit the action of MMF. However, this has not been demonstrated in vivo [144]. Sirolimus inhibits the mammalian target of the rapamycin (mTOR) pathway by directly binding the mTOR Complex1 (mTORC1) that down-regulates the CCR5 receptor, which is the T-cell co-receptor for the HIV virion [154]. Transplants performed in HIV-infected patients on HAART show one-year graft and patient survival rates comparable to HIV-uninfected patients, although acute rejections are seen more frequently in the former, at a rate double that seen in those that are uninfected [144]. It has been postulated that this may be the result of immune dysregulation, but could also represent incomplete immunosuppression due to changes in overall drug exposure. Higher acute rejection rates have been observed in patients of African descent [155157]. The ‘‘Transplant Study for People with HIV’’ (www. HIVtransplant.com) has proposed selection criteria that continue to evolve as more experience accumulates in this group of transplant patients [158]. The inclusion criteria for selecting a suitable kidney transplant recipient with HIVinfection include, inter alia: . Meeting the standard criteria for kidney transplantation. . In children, the percentage of CD4T-cell is better than an absolute CD4T-cell count in defining an intact immune system, hence modification of criteria to include a T-cell percentage. For children 12 years of age, the T-cell percentage must be 30%, and in children 210 years of age it must be 20%. 8 Bhimma R et al. Journal of the International AIDS Society 2013, 16:18596 http://www.jiasociety.org/index.php/jias/article/view/18596 | http://dx.doi.org/10.7448/IAS.16.1.18596 . Undetectable viral load (B50 copies/mL) for more than . . . . . 6 months. No change in the HAART regimen for at least 3 months prior to kidney transplantation. There must be compliance to treatment for at least 6 months and caregivers and/or recipients must demonstrate willingness and an ability to comply with the immunosuppression protocol, ARV therapy and prophylaxis for opportunistic infections. In the case of pulmonary coccidiodomycosis, the recipient must be disease-free for at least 5 years prior to kidney transplantation and in the case of neoplasms, for at least 2 years. Female candidates of child-bearing potential must have a negative serum human chorionic gonadotropin pregnancy test 14 days prior to transplantation. All candidates must practice barrier contraception. The ability to provide informed consent and, for children between 7 and 12 years, signed assent. In the case of minors between the ages of 13 and 18 years, the minor and parent(s) must both provide informed consent. These ages may vary according to the laws and Institutional Review Boards of various regions. Exclusion criteria include, inter alia, the following: . Advanced-cardio-pulmonary disease. . Active uncontrolled malignancy with reduced life span; . Significant infection which may flare or reactivate with . . . . immunosuppression, such as tuberculosis, aspergillosis and other fungal infections, severe bacterial infections and active human papilloma virus infection. Documented progressive multifocal leukoencephalopathy. Epstein-Barr virus and human herpes virus 8 associated lymphoproliferative disease. Documented poor compliance. Failure to obtain informed consent or where required, assent. Pharmacokinetic interactions between immunosuppresants and HAART agents can be profound with the most notable drug interactions occurring between ARV agents and immunosuppressive agents that induce or inhibit the Pglycoprotein 1 flux transporters and the cytochrome P450 3A (CYP3A4)-metabolizing enzymes found in the gut and liver [98]. Interactions can lead to unexpected increases or decreases in drug plasma levels and result in organ rejection, toxic adverse reactions of drugs and possible exacerbation of HIV replication. Patients on PIs and cyclosporine require only about 20% of the immunosuppressant dose of the latter drug normally administered to renal transplant recipients without HIV [98]. Patients on a ritonavir-boosted PI regimen require even lower doses of calcineurin inhibitors than patients on other HAART regimens [159]. In patients on tacrolimus or sirolimus using PIs as part of HAART, not only is the dose of these immunosuppresive drugs markedly decreased, but the interval of dosing needs to be increased more than five-fold [98]. Azole antifungal and macrolide antibiotics also inhibit the CYP3A4 system, increasing immunosuppressant levels of calcineurin inhibitors and sirolimus [160]. Patients taking steroids usually need proton-pump inhibitors for gastric ulcer prophylaxis. Since proton pump inhibitors can reduce intestinal absorption of Atazanavir, this PI must always be used in conjunction with a boosting dose of ritonavir. Zidovudine as a component of HAART used in combination with MMF could lead to additive myelosuppressive effects [161]. Post-transplant prophylaxis used in HIV-infected kidney transplant recipients is the same as that in HIV-uninfected recipients [98]. These regimens include prophylaxis for CMV and fungal infections (including Pneumocystis jiroveci) in the early postoperative period. For those patients with acute rejection treated with lymphocyte-depleting agents, prophylaxis regimen should be resumed for 36 months after discontinuation of the anti-rejection treatment. Although HIV-infected adults are at increased risk for cancers such as Kaposi’s sarcoma and non-Hodgkin’s lymphoma, the rates of these cancers have declined with the introduction of HAART [162,163]. In adults, however, hepatocellular carcinoma rates have increased and this is probably related to increased longevity of patients with HIV co-infected with hepatitis B or C [164]. There are no similar reports in children. In summary, kidney transplantation in HIV-infected patients treated with HAART has shown excellent graft and patient survival rates at 35 years [156,157,165]. Most issues revolve around interactions between ARV agents and the immunosuppressive agents used to prevent rejection. Opportunistic infections in these patients do not seem to have considerably increased although these patients have higher rates of acute rejection. Hepatitis B and C co-infection in adults remain a major concern, both in terms of treatment options and long-term effects on progression of liver disease [98]. Based on the current evidence, exclusion of children with HIV-infection from receiving a kidney transplant can no longer be justified. Screening for kidney disease in children and adolescents with HIV-1 infection The life expectancy of HIV-infected patients with kidney disease has greatly improved following the introduction of HAART [105]. Progression to end-stage kidney disease with its attendant complications still remains a significant comorbidity. Thus, early detection of kidney disease would enable clinicians to intervene in a timely manner. Routine screening for kidney disease is therefore recommended, where resources permit. The guidelines implemented by the New York State Department of Health AIDS Institute include measuring estimated glomerular filtration rate, blood urea nitrogen and urinalysis at baseline and every six months in HIV-infected patients. For those on a tenofovircontaining regimen, this needs to be performed at baseline, one month and thereafter at least every four months (www. hivguidelines.org) [166]. It is important that this be tailored to the resources and facilities available in different parts of the world and is consistent with local guidelines. Additional screening evaluations, urine microalbumin/creatinine 9 Bhimma R et al. Journal of the International AIDS Society 2013, 16:18596 http://www.jiasociety.org/index.php/jias/article/view/18596 | http://dx.doi.org/10.7448/IAS.16.1.18596 ratios for example, may be indicated with additional risk factors such as concomitant diabetes mellitus. All HIVinfected patients, even if asymptomatic for kidney disease, should be educated on the importance of ARV therapy in preventing HIVAN and monitoring for other causes of kidney disease, including medication-related nephrotoxicity, hypertension and diabetes [54,167]. Conclusions The differential diagnosis of the kidney diseases that are associated with HIV has expanded well beyond HIVAN. It includes toxicity from ARV and other therapeutic agents, immune complex-mediated kidney disease, and other comorbid unrelated kidney diseases. Given the broad differential diagnosis and inadequate sensitivity and specificity of non-invasive diagnostic testing, kidney biopsy is the gold standard for the diagnosis of HIVAN. There is increasing evidence that HAART improves kidney function in HIVAN although a clear benefit in non-HIVAN kidney disease has not been demonstrated. Kidney transplantation is now a viable alternative to dialysis in HIV-infected patients with endstage kidney disease. Expanding access to HAART and further insights into the pathogenesis of HIVAN will help curb the devastating projected epidemic of kidney diseases, especially in the developing world. However, the most lasting impact on the epidemiology of this disease remains the prevention of new HIV infections. Authors’ affiliations 1 Department of Paediatrics and Child Health, School of Clinical Medicine, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa; 2Division of Pediatric Infectious Disease, Albert Einstein College of Medicine, Bronx-Lebanon Hospital Center, Bronx, NY 10457, USA; 3Chris Hani Baragwanath Hospital, University of Witwatersrand, Johannesburg, South Africa Competing interests The authors have no competing interests to declare. Authors’ contributions All authors have contributed equally to the work. References 1. WHO. Treatment of children living with HIV. Global Health Sector Strategy in HIV/AIDS, 20112015 2013 September 2012 [cited 2013 Feb 19]. Available from: http://www.unaids.org/en/media/unaids/contentassets/documents/ epidemiology/2012/gr2012/JC2434_WorldAIDSday_results_en.pdf. 2. UNAIDS. Global report: UNAIDS report on the global AIDS epidemic 2010. 2010 [cited 2013 Feb 5]. Available from: http://www.unaids.org/globalreport/ Global_report.htm. 3. Rao TK, Filippone EJ, Nicastri AD, Landesman SH, Frank E, Chen CK, et al. Associated focal and segmental glomerulosclerosis in the acquired immunodeficiency syndrome. N Engl J Med. 1984;310(11):66973. 4. Ross MJ, Klotman PE. Recent progress in HIV-associated nephropathy. J Am Soc Nephrol. 2002;13(12):29973004. 5. Szczech LA, Gupta SK, Habash R, Guasch A, Kalayjian R, Appel R, et al. The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection. Kidney Int. 2004;66(3):114552. 6. Selik RM Jr, Byers RH, Dworkin MS. Trends in diseases reported on U.S. death certificates that mentioned HIV infection, 19871999. J Acquir Immune Defic Syndr. 2002;29(4):37887. 7. Trullas JC, Barril G, Cofan F, Moreno A, Cases A, Fernandez-Lucas M, et al. Prevalence and clinical characteristics of HIV type 1-infected patients receiving dialysis in Spain: results of a Spanish survey in 2006: GESIDA 48/05 study. AIDS Res Hum Retroviruses. 2008;24(10):122935. 8. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338(13):85360. 9. Kaplan JE, Hanson D, Dworkin MS, Frederick T, Bertolli J, Lindegren ML, et al. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis. 2000;30(Suppl 1):S514. 10. Naicker S, Fabian J. Risk factors for the development of chronic kidney disease with HIV/AIDS. Clin Nephrol. 2010;74(Suppl 1):S516. 11. Shahinian V, Rajaraman S, Borucki M, Grady J, Hollander WM, Ahuja TS. Prevalence of HIV-associated nephropathy in autopsies of HIV-infected patients. Am J Kidney Dis. 2000;35(5):8848. 12. Daugas E, Rougier JP, Hill G. HAART-related nephropathies in HIV-infected patients. Kidney Int. 2005;67(2):393403. 13. Ramsuran D, Bhimma R, Ramdial PK, Naicker E, Adhikari M, Deonarain J, et al. The spectrum of HIV-related nephropathy in children. Pediatr Nephrol. 2012;27(5):8217. 14. Pardo V, Meneses R, Ossa L, Jaffe DJ, Strauss J, Roth D, et al. AIDS-related glomerulopathy: occurrence in specific risk groups. Kidney Int. 1987; 31(5):116773. 15. Strauss J, Abitbol C, Zilleruelo G, Scott G, Paredes A, Malaga S, et al. Renal disease in children with the acquired immunodeficiency syndrome. N Engl J Med. 1989;321(10):62530. 16. Fauci AS. The AIDS epidemic–considerations for the 21st century. N Engl J Med. 1999;341(14):104650. 17. Mitsuya H, Weinhold KJ, Furman PA, St Clair MH, Lehrman SN, Gallo RC, et al. 3’-Azido-3’-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/ lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci USA. 1985;82(20):7096100. 18. Purswani MU, Chernoff MC, Mitchell CD, Seage GR, 3rd, Zilleruelo G, Abitbol C, et al. Chronic kidney disease associated with perinatal HIV infection in children and adolescents. Pediatr Nephrol. 2012;27(6):9819. 19. Estrella M, Fine DM, Gallant JE, Rahman MH, Nagajothi N, Racusen LC, et al. HIV type 1 RNA level as a clinical indicator of renal pathology in HIVinfected patients. Clin Infect Dis. 2006;43(3):37780. 20. Winston JA. HIV and CKD epidemiology. Adv Chronic Kidney Dis. 2010; 17(1):1925. 21. Kalayjian RC, Lau B, Mechekano RN, Crane HM, Rodriguez B, Salata RA, et al. Risk factors for chronic kidney disease in a large cohort of HIV-1 infected individuals initiating antiretroviral therapy in routine care. AIDS. 2012; 26(15):190715. 22. Wyatt CM, Meliambro K, Klotman PE. Recent progress in HIV-associated nephropathy. Annu Rev Med. 2012;63:14759. 23. Ray PE. Taking a hard look at the pathogenesis of childhood HIV-associated nephropathy. Pediatr Nephrol. 2009;24(11):210919. 24. Conaldi PG, Bottelli A, Wade-Evans A, Biancone L, Baj A, Cantaluppi V, et al. HIV-persistent infection and cytokine induction in mesangial cells: a potential mechanism for HIV-associated glomerulosclerosis. AIDS. 2000;14(13): 20457. 25. Green DF, Resnick L, Bourgoignie JJ. HIV infects glomerular endothelial and mesangial but not epithelial cells in vitro. Kidney Int. 1992;41(4):95660. 26. Tokizawa S, Shimizu N, Hui-Yu L, Deyu F, Haraguchi Y, Oite T, et al. Infection of mesangial cells with HIV and SIV: identification of GPR1 as a coreceptor. Kidney Int. 2000;58(2):60717. 27. Barbiano di Belgiojoso G, Genderini A, Vago L, Parravicini C, Bertoli S, Landriani N. Absence of HIV antigens in renal tissue from patients with HIVassociated nephropathy. Nephrol Dial Transplant. 1990;5(7):48992. 28. Eitner F, Cui Y, Hudkins KL, Stokes MB, Segerer S, Mack M, et al. Chemokine receptor CCR5 and CXCR4 expression in HIV-associated kidney disease. J Am Soc Nephrol. 2000;11(5):85667. 29. Husain M, Gusella GL, Klotman ME, Gelman IH, Ross MD, Schwartz EJ, et al. HIV-1 Nef induces proliferation and anchorage-independent growth in podocytes. J Am Soc Nephrol. 2002;3(7):180615. 30. Husain M, D’Agati VD, He JC, Klotman ME, Klotman PE. HIV-1 Nef induces dedifferentiation of podocytes in vivo: a characteristic feature of HIVAN. AIDS. 2005;19(17):197580. 31. Zuo Y, Matsusaka T, Zhong J, Ma J, Ma LJ, Hanna Z, et al. HIV-1 genes vpr and nef synergistically damage podocytes, leading to glomerulosclerosis. J Am Soc Nephrol. 2006;17(10):283243. 10 Bhimma R et al. Journal of the International AIDS Society 2013, 16:18596 http://www.jiasociety.org/index.php/jias/article/view/18596 | http://dx.doi.org/10.7448/IAS.16.1.18596 32. Zhong J, Zuo Y, Ma J, Fogo AB, Jolicoeur P, Ichikawa I, et al. Expression of HIV-1 genes in podocytes alone can lead to the full spectrum of HIV-1associated nephropathy. Kidney Int. 2005;68(3):104860. 33. Rosenstiel PE, Chan J, Snyder A, Planelles V, D’Agati VD, Klotman PE, et al. HIV-1 Vpr activates the DNA damage response in renal tubule epithelial cells. AIDS. 2009;23(15):20546. 34. Snyder A, Alsauskas ZC, Leventhal JS, Rosenstiel PE, Gong P, Chan JJ, et al. HIV-1 viral protein r induces ERK and caspase-8-dependent apoptosis in renal tubular epithelial cells. AIDS. 2010;24(8):110719. 35. Rosenstiel PE, Gruosso T, Letourneau AM, Chan JJ, LeBlanc A, Husain M, et al. HIV-1 Vpr inhibits cytokinesis in human proximal tubule cells. Kidney Int. 2008;74(8):104958. 36. Doublier S, Zennaro C, Spatola T, Lupia E, Bottelli A, Deregibus MC, et al. HIV-1 Tat reduces nephrin in human podocytes: a potential mechanism for enhanced glomerular permeability in HIV-associated nephropathy. AIDS. 2007;21(4):42332. 37. Ray PE, Xu L, Rakusan T, Liu XH. A 20-year history of childhood HIVassociated nephropathy. Pediatr Nephrol. 2004;19(10):107592. 38. Connor E, Gupta S, Joshi V, DiCarlo F, Offenberger J, Minnefor A, et al. Acquired immunodeficiency syndrome-associated renal disease in children. J Pediatr. 1988;113(1 Pt 1):3944. 39. Albaqumi M, Barisoni L. Current views on collapsing glomerulopathy. J Am Soc Nephrol. 2008;19(7):127681. 40. Kopp JB, Nelson GW, Sampath K, Johnson RC, Genovese G, An P, et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIVassociated nephropathy. J Am Soc Nephrol. 2011;22(11):212937. 41. Bostrom MA, Freedman BI. The spectrum of MYH9-associated nephropathy. Clin J Am Soc Nephrol. 2010;5(6):110713. 42. Nelson GW, Freedman BI, Bowden DW, Langefeld CD, An P, Hicks PJ, et al. Dense mapping of MYH9 localizes the strongest kidney disease associations to the region of introns 13 to 15. Hum Mol Genet. 2010;19(9):180515. 43. Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010;329(5993):8415. 44. Tzur S, Rosset S, Shemer R, Yudkovsky G, Selig S, Tarekegn A, et al. Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene. Hum Genet. 2010; 128(3):34550. 45. Purswani M, Patel K, Kopp J, Winkler C, Specter S, Hazra H, et al. Frequency of APOL1 risk alleles among a US cohort of children with perinatal HIV-1 infection and associations with renal phenotypes. In ESPR meeting. Philadelphia: Pediatric HIV/AIDS Cohort Study; 2013. 46. Kimmel PL, Phillips TM, Ferreira-Centeno A, Farkas-Szallasi T, Abraham AA, Garrett CT. HIV-associated immune-mediated renal disease. Kidney Int. 1993;44(6):132740. 47. Haas M, Kaul S, Eustace JA. HIV-associated immune complex glomerulonephritis with ‘‘lupus-like’’ features: a clinicopathologic study of 14 cases. Kidney Int. 2005;67(4):138190. 48. Bruggeman LA, Nelson PJ. Controversies in the pathogenesis of HIVassociated renal diseases. Nat Rev Nephrol. 2009;5(10):57481. 49. McCulloch MI, Ray PE. Kidney disease in HIV-positive children. Semin Nephrol. 2008;28(6):58594. 50. Balow JE. Nephropathy in the context of HIV infection. Kidney Int. 2005;67(4):16323. 51. Anochie IC, Eke FU, Okpere AN. Human immunodeficiency virus-associated nephropathy (HIVAN) in Nigerian children. Pediatr Nephrol. 2008;23(1): 11722. 52. Gerntholtz TE, Goetsch SJ, Katz I. HIV-related nephropathy: a South African perspective. Kidney Int. 2006;69(10):188591. 53. Kala U, Petersen K, Faller G, Goetsch S. Spectrum of severe renal disease in children with HIV/Aids at Chris Hani Baragwanath Hospital, Johannesburg. Pediatr Nephrol. 2007;22:301. 54. Wearne N, Swanepoel CR, Boulle A, Duffield MS, Rayner BL. The spectrum of renal histologies seen in HIV with outcomes, prognostic indicators and clinical correlations. Nephrol Dial Transplant. 2012;27(11):410918. 55. Okpechi I, Swanepoel C, Duffield M, Mahala B, Wearne N, Alagbe S, et al. Patterns of renal disease in Cape Town South Africa: a 10-year review of a single-centre renal biopsy database. Nephrol Dial Transplant. 2011;26 (6):185361. 56. Ray PE, Rakusan T, Loechelt BJ, Selby DM, Liu XH, Chandra RS. Human immunodeficiency virus (HIV)-associated nephropathy in children from the Washington, D.C. area: 12 years’ experience. Semin Nephrol. 1998;18(4): 396405. 57. Steel-Duncan J, Miller M, Pierre RB, Dunkley-Thompson J, Palmer P, Evans-Gilbert T, et al. Renal manifestations in HIV-infected Jamaican children. West Indian Med J. 2008;57(3):24652. 58. Nourse P, Bates W, Gajjar P, Sinclair P, Sinclair-Smith, McCulloch M. Paediatric HIV renal disease in Cape Town, South Africa. Pediatr Nephrol. 2007;22:1597. 59. Atta MG. Diagnosis and natural history of HIV-associated nephropathy. Adv Chronic Kidney Dis. 2010;17(1):528. 60. Lucas GM, Eustace JA, Sozio S, Mentari EK, Appiah KA, Moore RD. Highly active antiretroviral therapy and the incidence of HIV-1-associated nephropathy: a 12-year cohort study. AIDS. 2004;18(3):5416. 61. Tarshish P. Guidelines for the care of children and adolescents with HIV infection. Approach to the diagnosis and management of HIV-associated nephropathy. J Pediatr. 1991;119(1 Pt 2):S502. 62. Ingulli E, Tejani A, Fikrig S, Nicastri A, Chen CK, Pomrantz A. Nephrotic syndrome associated with acquired immunodeficiency syndrome in children. J Pediatr. 1991;119(5):7106. 63. Turner ME, Kher K, Rakusan T, D’Angelo L, Kapur S, Selby D, et al. A typical hemolytic uremic syndrome in human immunodeficiency virus-1-infected children. Pediatr Nephrol. 1997;11(2):1613. 64. Chaparro AI, Mitchell CD, Abitbol CL, Wilkinson JD, Baldarrago G, Lopez E, et al. Proteinuria in children infected with the human immunodeficiency virus. J Pediatr. 2008;152(6):8449. 65. Eke FU, Anochie IC, Okpere AN, Eneh AU, Ugwu RO, Ejilemele AA, et al. Microalbuminuria in children with human immunodeficiency virus (HIV) infection in Port Harcourt, Nigeria. Niger J Med. 2010;19(3):298301. 66. Han TM, Naicker S, Ramdial PK, Assounga AG. A cross-sectional study of HIV-seropositive patients with varying degrees of proteinuria in South Africa. Kidney Int. 2006;69(12):224350. 67. Nourse PJ, Cotton MF, Bates WD. Renal manifestations in children coinfected with HIV and disseminated tuberculosis. Pediatr Nephrol. 2010;25(9): 175963. 68. Esezobor CI, Iroha E, Onifade E, Akinsulie AO, Temiye EO, Ezeaka C. Prevalence of proteinuria among HIV-infected children attending a tertiary hospital in Lagos, Nigeria. J Trop Pediatr. 2010;56(3):18790. 69. Mistry BJ, Kala UK. Relevance of microalbuminuria in screening for HIVassociated nephropathy. Pediatr Nephrol. 2010;25:1870. 70. Joshi VV. Pathology of childhood AIDS. Pediatr Clin North Am. 1991;38(1): 97120. 71. Tabatabai S, Sperati CJ, Atta MG, Janjua K, Roxbury C, Lucas GM, et al. Predictors of complication after percutaneous ultrasound-guided kidney biopsy in HIV-infected individuals: possible role of hepatitis C and HIV co-infection. Clin J Am Soc Nephrol. 2009;4(11):176673. 72. Parkhie SM, Fine DM, Lucas GM, Atta MG. Characteristics of patients with HIV and biopsy-proven acute interstitial nephritis. Clin J Am Soc Nephrol. 2010;5(5):798804. 73. Berns JS, Cohen RM, Stumacher RJ, Rudnick MR. Renal aspects of therapy for human immunodeficiency virus and associated opportunistic infections. J Am Soc Nephrol. 1991;1(9):106180. 74. Bourgoignie JJ. Renal complications of human immunodeficiency virus type 1. Kidney Int. 1990;37(6):157184. 75. Olyaei AJ, deMattos AM, Bennett WM. Renal toxicity of protease inhibitors. Curr Opin Nephrol Hypertens. 2000;9(5):4736. 76. Chugh S, Bird R, Alexander EA. Ritonavir and renal failure. N Engl J Med. 1997;336(2):138. 77. Kopp JB, Miller KD, Mican JA, Feuerstein IM, Vaughan E, Baker C, et al. Crystalluria and urinary tract abnormalities associated with indinavir. Ann Intern Med. 1997;127(2):11925. 78. Carbone LG, Bendixen B, Appel GB. Sulfadiazine-associated obstructive nephropathy occurring in a patient with the acquired immunodeficiency syndrome. Am J Kidney Dis. 1988;12(1):725. 79. Dong BJ, Rodriguez RA, Goldschmidt RH. Sulfadiazine-induced crystalluria and renal failure in a patient with AIDS. J Am Board Fam Pract. 1999;12(3): 2438. 80. Simon DI, Brosius FC 3rd, Rothstein DM. Sulfadiazine crystalluria revisited. The treatment of Toxoplasma encephalitis in patients with acquired immunodeficiency syndrome. Arch Intern Med. 1990;150(11):237984. 81. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure definition, outcome measures, animal models, fluid therapy and information 11 Bhimma R et al. Journal of the International AIDS Society 2013, 16:18596 http://www.jiasociety.org/index.php/jias/article/view/18596 | http://dx.doi.org/10.7448/IAS.16.1.18596 technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8(4):R20412. 82. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31. 83. Praga M, Gonzalez E. Acute interstitial nephritis. Kidney Int. 2010;77(11): 95661. 84. Agarwal A, Soni A, Ciechanowsky M, Chander P, Treser G. Hyponatremia in patients with the acquired immunodeficiency syndrome. Nephron. 1989;53(4): 31721. 85. Glassock RJ, Cohen AH, Danovitch G, Parsa KP. Human immunodeficiency virus (HIV) infection and the kidney. Ann Intern Med. 1990;112(1):3549. 86. Tang WW, Kaptein EM, Feinstein EI, Massry SG. Hyponatremia in hospitalized patients with the acquired immunodeficiency syndrome (AIDS) and the AIDS-related complex. Am J Med. 1993;94(2):16974. 87. Marks JB. Endocrine manifestations of human immunodeficiency virus (HIV) infection. Am J Med Sci. 1991;302(2):1107. 88. Kalin MF, Poretsky L, Seres DS, Zumoff B. Hyporeninemic hypoaldosteronism associated with acquired immune deficiency syndrome. Am J Med. 1987; 82(5):10358. 89. De Beaudrap P, Diallo MB, Landman R, Gueye NF, Ndiaye I, Diouf A, et al. Changes in the renal function after tenofovir-containing antiretroviral therapy initiation in a Senegalese cohort (ANRS 1215). AIDS Res Hum Retroviruses. 2010;26(11):12217. 90. Deti EK, Thiebaut R, Bonnet F, Lawson-Ayayi S, Dupon M, Neau D, et al. Prevalence and factors associated with renal impairment in HIV-infected patients, ANRS C03 Aquitaine Cohort, France. HIV Med. 2010;11(5):30817. 91. Wever K, van Agtmael MA, Carr A. Incomplete reversibility of tenofovirrelated renal toxicity in HIV-infected men. J Acquir Immune Defic Syndr. 2010; 55(1):7881. 92. Cooper RD, Wiebe N, Smith N, Keiser P, Naicker S, Tonelli M. Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIVinfected patients. Clin Infect Dis. 2010;51(5):496505. 93. Choi AI, Rodriguez RA, Bacchetti P, Volberding PA, Havlir D, Bertenthal D, et al. Low rates of antiretroviral therapy among HIV-infected patients with chronic kidney disease. Clin Infect Dis. 2007;45(12):16339. 94. Gupta SK, Eustace JA, Winston JA, Boydstun II, Ahuja TS, Rodriguez RA, et al. Guidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2005;40(11):155985. 95. Asharam K, Bhimma R, Adhikari M. Human immunodeficiency virus and urinary tract infections in children. Ann Trop Paediatr. 2003;23(4):2737. 96. Lanjewar DN, Ansari MA, Shetty CR, Maheshwari MB, Jain P. Renal lesions associated with AIDS–an autopsy study. Indian J Pathol Microbiol. 1999; 42(1):638. 97. Nadasdy T, Miller KW, Johnson LD, Hanson-Painton O, DeBault LE, Burns DK, et al. Is cytomegalovirus associated with renal disease in AIDS patients? Mod Pathol. 1992;5(3):27782. 98. Frassetto LA, Tan-Tam C, Stock PG. Renal transplantation in patients with HIV. Nat Rev Nephrol. 2009;5(10):5829. 99. Rashid A, Abboud O, Al-Kaabi S, Taha M, Ashour A, El-Sayed M. The impact of hepatitis C infection and antiviral therapy on clinical outcome in renal transplantation recipients. Saudi J Kidney Dis Transpl. 1999;10(1):315. 100. WHO. Antiretroviral therapy of HIV infection in infants and children: towards univesal access. 2006 [cited 2013 Apr 10]; 1152]. Available from: http://www.who.int/hiv/pub/guidelines/art/en/print.html 101. Wyatt CM, Klotman PE. HIV-associated nephropathy in the era of antiretroviral therapy. Am J Med. 2007;120(6):48892. 102. Smith MC, Austen JL, Carey JT, Emancipator SN, Herbener T, Gripshover B, et al. Prednisone improves renal function and proteinuria in human immunodeficiency virus-associated nephropathy. Am J Med. 1996;101(1): 418. 103. Weiner NJ, Goodman JW, Kimmel PL. The HIV-associated renal diseases: current insight into pathogenesis and treatment. Kidney Int. 2003;63(5): 161831. 104. Rao TK. Human immunodeficiency virus infection in end-stage renal disease patients. Semin Dial. 2003;16(3):23344. 105. Novak JE, Szczech LA. Management of HIV-infected patients with ESRD. Adv Chronic Kidney Dis. 2010;17(1):10210. 106. Jao J, Wyatt CM. Antiretroviral medications: adverse effects on the kidney. Adv Chronic Kidney Dis. 2010;17(1):7282. 107. Kimmel PL, Barisoni L, Kopp JB. Pathogenesis and treatment of HIVassociated renal diseases: lessons from clinical and animal studies, molecular pathologic correlations, and genetic investigations. Ann Intern Med. 2003; 139(3):21426. 108. Fine DM, Perazella MA, Lucas GM, Atta MG. Renal disease in patients with HIV infection: epidemiology, pathogenesis and management. Drugs. 2008;68(7):96380. 109. Hammer SM, Eron JJ, Jr, Reiss P, Schooley RT, Thompson MA, Walmsley S, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA. 2008;300(5):55570. 110. Cohen SD, Chawla LS, Kimmel PL. Acute kidney injury in patients with human immunodeficiency virus infection. Curr Opin Crit Care. 2008;14(6): 64753. 111. Kalayjian RC, Franceschini N, Gupta SK, Szczech LA, Mupere E, Bosch RJ, et al. Suppression of HIV-1 replication by antiretroviral therapy improves renal function in persons with low CD4 cell counts and chronic kidney disease. AIDS. 2008;22(4):4817. 112. Fine DM, Perazella MA, Lucas GM, Atta MG. Kidney biopsy in HIV: beyond HIV-associated nephropathy. Am J Kidney Dis. 2008;51(3):50414. 113. Kimmel PL, Mishkin GJ, Umana WO. Captopril and renal survival in patients with human immunodeficiency virus nephropathy. Am J Kidney Dis. 1996;28(2):2028. 114. Yahaya I, Uthman AO, Uthman MM. Interventions for HIV-associated nephropathy. Cochrane Database Syst Rev. 2009;(4):CD007183. 115. Kiser JJ, Rutstein RM, Samson P, Graham B, Aldrovandi G, Mofenson LM, et al. Atazanavir and atazanavir/ritonavir pharmacokinetics in HIV-infected infants, children, and adolescents. AIDS. 2011;25(12):148996. 116. Couzigou C, Daudon M, Meynard JL, Borsa-Lebas F, Higueret D, Escaut L, et al. Urolithiasis in HIV-positive patients treated with atazanavir. Clin Infect Dis. 2007;45(8):e1058. 117. Brewster UC, Perazella MA. Acute interstitial nephritis associated with atazanavir, a new protease inhibitor. Am J Kidney Dis. 2004;44(5):e814. 118. Nelson M, Azwa A, Sokwala A, Harania RS, Stebbing J. Fanconi syndrome and lactic acidosis associated with stavudine and lamivudine therapy. AIDS. 2008;22(11):13746. 119. Ahmad M. Abacavir-induced reversible Fanconi syndrome with nephrogenic diabetes insipidus in a patient with acquired immunodeficiency syndrome. J Postgrad Med. 2006;52(4):2967. 120. Krishnan M, Nair R, Haas M, Atta MG. Acute renal failure in an HIVpositive 50-year-old man. Am J Kidney Dis. 2000;36(5):10758. 121. Crowther MA, Callaghan W, Hodsman AB, Mackie ID. Dideoxyinosineassociated nephrotoxicity. AIDS. 1993;7(1):1312. 122. Izzedine H, Launay-Vacher V, Deray G. Fanconi syndrome associated with didanosine therapy. AIDS. 2005;19(8):8445. 123. Perazella MA. Tenofovir-induced kidney disease: an acquired renal tubular mitochondriopathy. Kidney Int. 2010;78(11):10603. 124. Herlitz LC, Mohan S, Stokes MB, Radhakrishnan J, D’Agati VD, Markowitz GS. Tenofovir nephrotoxicity: acute tubular necrosis with distinctive clinical, pathological, and mitochondrial abnormalities. Kidney Int. 2010;78(11): 11717. 125. Fernandez-Fernandez B, Montoya-Ferrer A, Sanz AB, Sanchez-Nino MD, Izquierdo MC, Poveda J, et al. Tenofovir nephrotoxicity: 2011 update. AIDS Res Treat. 2011;2011:354908. 126. Szczech LA. Tenofovir nephrotoxicity: focusing research questions and putting them into clinical context. J Infect Dis. 2008;197(1):79. 127. Vigano A, Zuccotti GV, Martelli L, Giacomet V, Cafarelli L, Borgonovo S, et al. Renal safety of tenofovir in HIV-infected children: a prospective, 96-week longitudinal study. Clin Drug Investig. 2007;27(8):57381. 128. Andiman WA, Chernoff MC, Mitchell C, Purswani M, Oleske J, Williams PL, et al. Incidence of persistent renal dysfunction in human immunodeficiency virus-infected children: associations with the use of antiretrovirals, and other nephrotoxic medications and risk factors. Pediatr Infect Dis J. 2009;28(7): 61925. 129. Judd A, Boyd KL, Stohr W, Dunn D, Butler K, Lyall H, et al. Effect of tenofovir disoproxil fumarate on risk of renal abnormality in HIV-1-infected children on antiretroviral therapy: a nested case-control study. AIDS. 2010; 24(4):52534. 130. Soler-Palacin P, Melendo S, Noguera-Julian A, Fortuny C, Navarro ML, Mellado MJ, et al. Prospective study of renal function in HIV-infected pediatric patients receiving tenofovir-containing HAART regimens. AIDS. 2011;25(2): 1716. 12 Bhimma R et al. Journal of the International AIDS Society 2013, 16:18596 http://www.jiasociety.org/index.php/jias/article/view/18596 | http://dx.doi.org/10.7448/IAS.16.1.18596 131. Vigano A, Bedogni G, Manfredini V, Giacomet V, Cerini C, di Nello F, et al. Long-term renal safety of tenofovir disoproxil fumarate in vertically HIVinfected children, adolescents and young adults: a 60-month follow-up study. Clin Drug Investig. 2011;31(6):40715. 132. Della Negra M, de Carvalho AP, de Aquino MZ, da Silva MT, Pinto J, White K, et al. A randomized study of tenofovir disoproxil fumarate in treatmentexperienced HIV-1 infected adolescents. Pediatr Infect Dis J. 2012;31(5): 46973. 133. Pontrelli G, Cotugno N, Amodio D, Zangari P, Tchidjou HK, Baldassari S, et al. Renal function in HIV-infected children and adolescents treated with tenofovir disoproxil fumarate and protease inhibitors. BMC Infect Dis. 2012;12(1):18. 134. Purswani M, Patel K, Kopp JB, Seage GR, 3rd, Chernoff MC, Hazra R, et al. Tenofovir treatment duration predicts proteinuria in a multi-ethnic United States cohort of children and adolescents with perinatal HIV-1 infection. Pediatr Infect Dis J. 2012;32(5):495500. 135. Mandayam S, Ahuja TS. Dialyzing a patient with human immunodeficiency virus infection: what a nephrologist needs to know. Am J Nephrol. 2004;24(5):51121. 136. Panel de expertos del Grupo de Estudio de Sida y del Plan Nacional sobre el Sida (PNS). [Diagnosis, treatment and prevention of renal diseases in HIV infected patients. Recommendations of the Spanish AIDS Study Group/ National AIDS Plan]. Enferm Infecc Microbiol Clin. 2010;28(8):520. e122. 137. Mokrzycki MH, Schroppel B, von Gersdorff G, Rush H, Zdunek MP, Feingold R, et al. Tunneled-cuffed catheter associated infections in hemodialysis patients who are seropositive for the human immunodeficiency virus. J Am Soc Nephrol. 2000;11(11):21227. 138. Brock JS, Sussman M, Wamsley M, Mintzer R, Baumann FG, Riles TS, et al. The influence of human immunodeficiency virus infection and intravenous drug abuse on complications of hemodialysis access surgery. J Vasc Surg. 1992;16(6):90410; discussion 9112. 139. Mitchell D, Krishnasami Z, Young CJ, Allon M. Arteriovenous access outcomes in haemodialysis patients with HIV infection. Nephrol Dial Transplant. 2007;22(2):46570. 140. Ortiz C, Meneses R, Jaffe D, Fernandez JA, Perez G, Bourgoignie JJ. Outcome of patients with human immunodeficiency virus on maintenance hemodialysis. Kidney Int. 1988;34(2):24853. 141. Tourret J, Tostivint I, du Montcel ST, Bragg-Gresham J, Karie S, Vigneau C, et al. Outcome and prognosis factors in HIV-infected hemodialysis patients. Clin J Am Soc Nephrol. 2006;1(6):12417. 142. Gordillo R, Kumar J, Del Rio M, Flynn JT, Woroniecki RP. Outcome of dialysis in children with human immunodeficiency virus infection. Pediatr Nephrol. 2009;24(1):1715. 143. Gordillo R, Del Rio M, Woroniecki RP. Dialysis-associated morbidity, ultrafiltration, and cardiovascular variables in children with HIV infection. Clin Nephrol. 2011;75(5):4349. 144. Stock PG, Roland ME. Evolving clinical strategies for transplantation in the HIV-positive recipient. Transplantation. 2007;84(5):56371. 145. Andrieu JM, Even P, Venet A, Tourani JM, Stern M, Lowenstein W, et al. Effects of cyclosporin on T-cell subsets in human immunodeficiency virus disease. Clin Immunol Immunopathol. 1988;47(2):18198. 146. Groux H, Torpier G, Monte D, Mouton Y, Capron A, Ameisen JC. Activation-induced death by apoptosis in CD4 T cells from human immunodeficiency virus-infected asymptomatic individuals. J Exp Med. 1992; 175(2):33140. 147. Schwarz A, Offermann G, Keller F, Bennhold I, L’Age-Stehr J, Krause PH, et al. The effect of cyclosporine on the progression of human immunodeficiency virus type 1 infection transmitted by transplantation–data on four cases and review of the literature. Transplantation. 1993;55(1):95103. 148. Streblow DN, Kitabwalla M, Malkovsky M, Pauza CD. Cyclophilin a modulates processing of human immunodeficiency virus type 1 p55Gag: mechanism for antiviral effects of cyclosporin A. Virology. 1998;245(2): 197202. 149. Rizzardi GP, Harari A, Capiluppi B, Tambussi G, Ellefsen K, Ciuffreda D, et al. Treatment of primary HIV-1 infection with cyclosporin A coupled with highly active antiretroviral therapy. J Clin Invest. 2002;109(5):6818. 150. Samaniego M, Becker BN, Djamali A. Drug insight: maintenance immunosuppression in kidney transplant recipients. Nat Clin Pract Nephrol. 2006;2(12):68899. 151. Ciuffreda D, Pantaleo G, Pascual M. Effects of immunosuppressive drugs on HIV infection: implications for solid-organ transplantation. Transpl Int. 2007;20(8):64958. 152. Heredia A, Margolis D, Oldach D, Hazen R, Le N, Redfield R. Abacavir in combination with the inosine monophosphate dehydrogenase (IMPDH)inhibitor mycophenolic acid is active against multidrug-resistant HIV-1. J Acquir Immune Defic Syndr. 1999;22(4):4067. 153. Margolis D, Heredia A, Gaywee J, Oldach D, Drusano G, Redfield R. Abacavir and mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase, have profound and synergistic anti-HIV activity. J Acquir Immune Defic Syndr. 1999;21(5):36270. 154. Heredia A, Latinovic O, Gallo RC, Melikyan G, Reitz M, Le N, et al. Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1. Proc Natl Acad Sci U S A. 2008;105(51):2047681. 155. Roland ME, Barin B, Carlson L, Frassetto LA, Terrault NA, Hirose R, et al. HIV-infected liver and kidney transplant recipients: 1 and 3-year outcomes. Am J Transplant. 2008;8(2):35565. 156. Kumar MS, Sierka DR, Damask AM, Fyfe B, McAlack RF, Heifets M, et al. Safety and success of kidney transplantation and concomitant immunosuppression in HIV-positive patients. Kidney Int. 2005;67(4):16229. 157. Gruber SA, Doshi MD, Cincotta E, Brown KL, Singh A, Morawski K, et al. Preliminary experience with renal transplantation in HIV recipients: low acute rejection and infection rates. Transplantation. 2008;86(2):26974. 158. Peter Stock MR. Solid organ transplantation in HIV: multi-site study. San Franscisco: EMMES Corporation; 2009. p. 182. 159. Frassetto LA, Browne M, Cheng A, Wolfe AR, Roland ME, Stock PG, et al. Immunosuppressant pharmacokinetics and dosing modifications in HIV-1 infected liver and kidney transplant recipients. Am J Transplant. 2007;7(12): 281620. 160. Niwa T, Murayama N, Emoto C, Yamazaki H. Comparison of kinetic parameters for drug oxidation rates and substrate inhibition potential mediated by cytochrome P450 3A4 and 3A5. Curr Drug Metab. 2008;9(1): 2033. 161. Jain AK, Venkataramanan R, Shapiro R, Scantlebury VP, Potdar S, Bonham CA, et al. The interaction between antiretroviral agents and tacrolimus in liver and kidney transplant patients. Liver Transpl. 2002;8(9):8415. 162. Engels EA, Biggar RJ, Hall HI, Cross H, Crutchfield A, Finch JL, et al. Cancer risk in people infected with human immunodeficiency virus in the United States. Int J Cancer. 2008;123(1):18794. 163. Vajdic CM, McDonald SP, McCredie MR, van Leeuwen MT, Stewart JH, Law M, et al. Cancer incidence before and after kidney transplantation. JAMA. 2006;296(23):282331. 164. MacDonald DC, Nelson M, Bower M, Powles T. Hepatocellular carcinoma, human immunodeficiency virus and viral hepatitis in the HAART era. World J Gastroenterol. 2008;14(11):165763. 165. Roland ME, Stock PG. Review of solid-organ transplantation in HIVinfected patients. Transplantation. 2003;75(4):4259. 166. Anonymous. Kidney disease in HIV-infected patients. New York: State Department of Health AIDS Institute; 2013. 167. Lescure FX, Flateau C, Pacanowski J, Brocheriou I, Rondeau E, Girard PM, et al. HIV-associated kidney glomerular diseases: changes with time and HAART. Nephrol Dial Transplant. 2012;27(6):234955. 13 Weber HC et al. Journal of the International AIDS Society 2013, 16:18633 http://www.jiasociety.org/index.php/jias/article/view/18633 | http://dx.doi.org/10.7448/IAS.16.1.18633 Review article The challenge of chronic lung disease in HIV-infected children and adolescents Heinrich C Weber§,1, Robert P Gie2 and Mark F Cotton2 § Corresponding author: Heinrich C Weber, Rural Clinical School, School of Medicine, Faculty of Health Sciences, University of Tasmania, Burnie, Tasmania, Australia. Fax: 61-03-64306688. ([email protected]) This article is part of the special issue Perinatally HIV-infected adolescents - more articles from this issue can be found at http://www.jiasociety.org Abstract Until recently, little attention has been given to chronic lung disease (CLD) in HIV-infected children. As the HIV epidemic matures in sub-Saharan Africa, adolescents who acquired HIV by vertical transmission are presenting to health services with chronic diseases. The most common is CLD, which is often debilitating. This review summarizes the limited data available on the epidemiology, pathophysiology, clinical picture, special investigations and management of CLD in HIV-infected adolescents. A number of associated conditions: lymphocytic interstitial pneumonitis, tuberculosis and bronchiectasis are well described. Other pathologies such as HIV-associated bronchiolitis obliterans resulting in non-reversible airway obstruction, has only recently been described. In this field, there are many areas of uncertainty needing urgent research. These areas include the definition of CLD, pathophysiological mechanisms and common pathologies responsible. Very limited data are available to formulate an effective plan of investigation and management. Keywords: HIV; adolescent; children; chronic lung disease; LIP; bronchiectasis; tuberculosis (TB). Received 31 March 2013; Revised 15 April 2013; Accepted 16 April 2013; Published 18 June 2013 Copyright: – 2013 Weber HC et al; licensee International AIDS Society. This is an open access article distributed under the terms of the Creative Commons Attribution 3.0 Unported (CC BY 3.0) Licence (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction As the HIV epidemic matures in sub-Saharan Africa, adolescents with undiagnosed HIV disease may present to health services. The majority of these HIV-infected youth have severe immunosuppression and a heavy burden of chronic complications, with the most common chronic complications being growth failure, lung and cardiac disease [1]. It is postulated that this represents an emerging, previously unrecognized severe burden of disease in countries with a high HIV burden. It is estimated that 36% of perinatally infected children may be slow progressors, who would have a mean survival of 16 years without combination of antiretroviral therapy (ART) [2]. From using data collected in Zimbabwe and South Africa, modelling suggests that a substantial number of previously undiagnosed HIV-infected adolescents will present with chronic disease, with a high percentage having chronic lung disease (CLD) [2]. This problem is likely to increase over time, as currently only 30% of children requiring ART are treated in sub-Saharan Africa [3] and with increasing ART use, more children will reach adolescence and will contribute to the pool of adolescents with chronic diseases including CLD. In an excellent review of non-infectious CLD in HIV-infected children, lymphocytic interstitial pneumonitis (LIP), malignancies, immune reconstitution inflammatory syndrome (IRIS), bronchiectasis, interstitial pneumonitis and aspiration pneumonia were described [4]. That review clearly describes the available information on the pathogenesis, clinical picture, and management of these conditions and will not be the focus of this review. The aim of this review is to highlight the magnitude of the CLD in HIV-infected children and adolescents, review the diseases that contribute to the spectrum of CLD, their possible pathogenesis, clinical features and management. Methods Electronic search was done using the keywords: HIV-infected, children, adolescents, CLD, LIP, bronchiectasis and tuberculosis (TB). Only articles in English and those electronically available were selected. The search engines used were PubMed and Google Scholar. Epidemiology of CLD in children and adolescents Very few studies have extensively examined the epidemiology of CLD in children and adolescents. In a study of 301 adolescents (1018 years) hospitalized in Zimbabwe, 41% were HIV-infected. In view of a high prevalence of stunting and either being orphaned or having an HIV-infected mother, perinatal HIV acquisition was felt to be most likely in 80% of these infected youth [5]. Of 116 consecutive adolescents attending two outpatient clinics in Harare investigated for CLD, 71% were between 13 and 18 years of age, all were 1 Weber HC et al. Journal of the International AIDS Society 2013, 16:18633 http://www.jiasociety.org/index.php/jias/article/view/18633 | http://dx.doi.org/10.7448/IAS.16.1.18633 stunted and 69% were on ART [6]. The vast majority, 86%, met study definition for CLD. Similar data are now emerging from Malawi where, in a study of 79 consecutive adolescents, over 50% reported dyspnea sufficient to limit their daily activities and a third had abnormal lung function tests [7]. No gender differences have been noted for CLD disease in HIV-infected children and adolescents [614]. Due to the limited data available, the full impact of HIV-related CLD cannot at present be estimated. However, from emerging data it seems likely that adolescent survivors of perinatal HIV infection an increasing prevalence of chronic disease, of which CLD is the largest burden. Health services are unlikely to be geared up to diagnose and manage this emerging epidemic of CLD amongst HIV-infected adolescents. Defining CLD CLD is a non-specific term that does not define the underlying pathology, but only suggests that there is an underlying chronic lung condition present. The symptoms associated with CLD such as cough or breathlessness could equally be due to chronic cardiac disease. Radiological criteria to define CLD are also problematic as they are observer dependent and terminology in radiological abnormalities varies between readers. Changes associated with bronchiectasis, LIP and bronchiolitis are not precise and subject to interpretation. Many factors contributing to CLD are shown in Figure 1. Therefore, in this review we suggest that the definitions used by Ferrand et al., who have published the most extensive article on CLD in adolescents, should be used as a screening tool [6]. Suspected CLD should include two or more of the following features: 1) Chronic cough (defined as a cough present most days for three months per year in the past two years); 2) 3) 4) 5) Recurrent respiratory tract infections ( two antibiotic courses in the last year); Moderate to severe limitation in physical activity caused by breathlessness (New York Heart Association class 24); Existing diagnosis and/or signs of cor pulmonale; Hypoxia (O2 saturation 592%) at rest or desaturation (O2 saturation ]5% reduction) on exercise. The limitation of this definition is that data on all the elements are not available in primary care clinics in many parts of the world where HIV prevalence is highest. Children with the clinical elements of CLD should be referred to regional/tertiary hospitals to confirm CLD, determine its cause and exclude other possible causes such as chronic cardiac disease. Conditions associated with CLD Lymphoid interstitial pneumonitis LIP was described in the 1980s in children with (AIDS), predating diagnostic tests for HIV. The first descriptions indicate that children with LIP were older than those presenting with Pneumocystis jerovicii pneumonia (PCP) and had a better outcome, as LIP occurred in slow progressors and was associated with a relatively preserved CD4 cell count [8]. LIP is thought to be a lymphoproliferative response to HIV or Epstein-Barr virus (EBV) [15]. Children with LIP had chronic cough, tachypnoea, clubbing and accompanying hypoxia. As part of a lymphoproliferative response, an interstitial pneumonitis, generalised lymphadenopathy, parotid swelling and hepatosplenomegaly were also noted. The typical chest x-ray (CXR) and CT scan appearance is of a diffuse, symmetrical reticulonodular or nodular pattern. Bronchiectasis is a recognised complication in children in 12.5% of cases [8]. The pathogenesis of the bronchiectasis remains unclear. As children with LIP have repeated lower respiratory tract infections, it is uncertain if it is the repeated Smoking Biomass pollution Aspiration Late ART initiation CLD Other lung disease Severe infections Bronchiolitis obliterans Malnutrition Bronchiectasis LIP HIV Immotile cilia Recurrent RTI TB Colonisation Figure 1. Potential pathophysiologic mechanisms leading to CLD in HIV-infected children and adolescents. RTI, recurrent respiratory tract infection. 2 Weber HC et al. Journal of the International AIDS Society 2013, 16:18633 http://www.jiasociety.org/index.php/jias/article/view/18633 | http://dx.doi.org/10.7448/IAS.16.1.18633 infections that result in bronchiectasis or HIV itself. LIP responds well to ART [16]. Bronchiectasis Bronchiectasis is characterized by permanent and abnormal widening of bronchi due to loss of elastin and more advance disease by destruction of muscle and cartilage [17]. The first descriptions in HIV-infected children were from two retrospective case series in the United States (USA). Between 1981 and 1990, 32 out of 77 children had LIP in the first series. Four children with LIP had bronchiectasis confirmed by CT scan [8]. The second study, conducted in 1997, of HIV-infected children referred to a pulmonology clinic noted bronchiectasis in 26 (15.8%) out of 164 children. Common predisposing factors were LIP and recurrent and unresolved pneumonia [14]. In a more recent retrospective study, bronchiectasis occurred in 5.7% of children. Mean age at first presentation with HIV-disease was 2.1 years, with age 7.8 years when bronchiectasis was first diagnosed [9]. The risk factors for developing bronchiectasis were recurrent pneumonia, severe immunosuppression and LIP [9]. Bronchiectasis was not thought to be common in Africa. Cases were first described by Kiwanuka et al. who reported bronchiectasis in five out of 110 children investigated for TB [11]. Recently, data was published on 35 HIV-infected children with bronchiectasis. Median age was 6.9 years; all were already on ART, but continued to have significant morbidity [12]. The aetiology of the bronchiectasis was not explored. TB as a cause and complicating disease of CLD In adult studies, lung function impairments were noted following TB treatment, with increasing impairment occurring with recurrent episodes of TB [18]. Ehrlich et al. noted a combined obstructive/restrictive lung function pattern in adults after TB [19]. Whether this is also true for adolescent patients is uncertain. TB was commonly implicated as a cause of bronchiectasis preceding the HIV pandemic [12,20]. In HIV-infected children with symptoms and signs of CLD not responding initially to three months of ‘‘standard’’ treatment including for TB, TB was still confirmed in 29% by lung biopsy [10]. Similarly, in a case series of older HIV-infected children receiving ART complicated by bronchiectasis, 36% were previously treated for TB, with microbiological confirmation in 11% of cases. These two studies highlight the difficulty in making and confirming the diagnosis of TB in HIV-infected children with CLD [12]. The relationship between pulmonary TB and bronchiectasis remains unclear in adolescent HIV-infected patients, but a history of treatment for TB is common in such patients [6]. Regardless of the role of TB in CLD pathogenesis, the diagnosis of TB should always be considered and actively evaluated. TB can cause bronchiectasis through airways destruction and patients with HIV-related CLD can acquire TB at any time. Bronchiolitis obliterans Bronchiolitis obliterans is characterised by fibrotic constriction and/or complete obstruction of the bronchioles [21]. In children, it is usually linked to events in the first two years of life, especially severe adenoviral and mycoplasma pneumonia requiring supplemental oxygen and assisted ventilation [21,22]. These children have small airway disease with significant air trapping and wheezing. Co-existing bronchiectasis occurs commonly. The ongoing clinical course of post-infective bronchiolitis obliterans in HIV-infants and children still needs to be described. In the Zimbabwean study of HIV-infected adolescent patients with CLD, bronchiolitis obliterans was the most common cause of CLD, although many adolescents had co-existing radiological features of bronchiectasis. The authors speculate that the bronchiolitis obliterans was caused by multiple bacterial and/or viral infections. HIV immunosuppression might also contribute by facilitating ongoing small airway inflammation. A further hypothesis is that a progressive inflammatory bronchiolitis obliterans may be caused by HIV itself. Further research to delineate the cause and effective management of bronchiolitis obliterans in HIV-related CLD is needed [6]. Chronic aspiration pneumonia Children with HIV are also at increased risk for esophagitis due to Candida albicans and cytomegalovirus. In a radiological review, aspiration pneumonia was proposed as cause of CLD frequently associated with gastro-oesophageal reflux disease in HIV-infected children [23,24]. In a case series describing swallowing problems in 25 HIV-infected young children, 83% (15/18) of children referred for assessment due to recurrent respiratory tract infections had swallowing dysfunction [25]. Interstitial lung disease Other interstitial lung diseases rarely occur in HIV-infected children and adolescents. Their clinical picture would be difficult to distinguish form other causes of interstitial lung disease or infection [4]. For an accurate diagnosis, an open lung biopsy is required, but rarely performed in HIV-infected children. Special investigations Radiology In a prospective study of HIV-infected children in the United States from the pre-ART era, a progressive accumulation of chronic CXR abnormalities, defined as abnormalities lasting more than three months, was present in children by four years of age in 32.8% of 86 HIV-infected children followed from birth [13]. The most common abnormalities were increased bronchovascular markings and reticular densities. Risk factors for chronic CXR abnormalities were declining CD4 count and increasing viral load [13]. Ferrand et al. found radiological abnormalities in 51 (68%) out of 75 adolescents, of which 74% were classified as severe. The most common reported abnormalities were ring/ tramline opacities and alveolar consolidation. Predominant consolidation was associated with progressive dyspnea (odds ratio 5.6 (95% CI 1.620)) [26]. In a subsequent study, using high-resolution computer tomography (HRCT) in adolescents with suspected CLD, the major finding was decreased attenuation, consistent with small airway disease, most likely representing obliterative bronchiolitis [6]. The next most 3 Weber HC et al. Journal of the International AIDS Society 2013, 16:18633 http://www.jiasociety.org/index.php/jias/article/view/18633 | http://dx.doi.org/10.7448/IAS.16.1.18633 common findings were consistent with large airway abnormalities, i.e., bronchial wall thickening, small and large airway plugging, indicating bronchiectasis (43%). More specific radiological features, associated with specific diagnoses such as LIP, bronchiectasis, TB, interstitial lung disease and malignancies are commonly present in these patients. The interpretation of CXR findings in HIV-infected children is complicated by persistent radiological changes and an increased range of chronic respiratory tract pathologies including TB and acute lower respiratory tract infections. In a recent review, the authors appealed for greater cooperation between clinicians and radiologists to facilitate interpretation of the chest radiographic findings and to avoid unnecessary mistakes [27]. Lung function testing In the earliest report of lung function in HIV-infected children, the airway resistance in the HIV-infected children was higher when compared to that in HIV-uninfected children (0.8490.3 vs. 0.6490.08 kPa L 1s; p B0.0001) [28]. The airway resistance declined in HIV-uninfected patients over time, but increased in the HIV-infected children, suggesting ongoing pathology. The extent of airway resistance was associated with the duration of HIV infection, rather than intercurrent infections, suggesting that HIV itself might contribute to ongoing airway disease. Evidence of large airway obstruction has also been noted. In the Zimbabwean study of HIV-infected adolescents, 33% had a peak expiratory flow rate (PEFR) below 80% of predicted, and 45% had forced expiratory volume in 1 second (FEV1) below 80% of predicted [6]. In a similar study of 79 HIV-infected youth in Malawi (median age 10.8 years), abnormal spirometry was detected in 33% [7]. Of these, almost a third (31%) had non-reversible airway obstruction as demonstrated by no bronchodilator response and suggesting structural lung disease in this group. In this study, 22% had hypoxia at rest and a further 35% desaturated on walking [7]. In a study of HIV-infected children with bronchiectasis in South Africa, the median FEV1% was only 53% of predicted (range: 586%) and median mid-expiratory flow rate (FEF2575%) was 52% (range 11165%) [12]. This study suggests both large and small structural airways disease. The measurement of oxygen saturations, before and after exercise, should be included in evaluating patients suspected of CLD, as at least one third might be missed if symptombased screening is used [7]. There are no follow-up lung function studies of children or adolescents with CLD to investigate the progression of lung disease, especially in older children and adolescents receiving ART. These studies are important to follow the course of structural lung disease and investigate if early ART would prevent CLD, especially bronchiolitis obliterans, developing. A paucity of lung function data limits the predictions of the progression of disease and the response to treatment. Microbiology In investigating the organisms isolated from sputum in HIV-infected children with bronchiectasis in South Africa, Haemophilus influenzae and H. parainfluenzae accounted for 49% of the isolates while Pseudomonas aeruginosa (2%), Staphylococcus aureus (2%) and Mycobacterium tuberculosis (1%) were rarely isolated [12]. In a study of HIV-infected adolescents in Zimbabwe, sputum cultures were positive for bacteria or fungi in 18 (46%) and mycobacteria in 12 (22%) of 54 samples [6]. H. influenzae, Moraxella and S. aureus were the most common bacterial isolates. Mycobacterium tuberculosis was found in eight adolescents, of whom seven were also sputum Ziehl-Neelsen positive. In addition, the sputum was smear positive in 16% of cases from whom no Mycobacterial species was cultured. These adolescents were treated for TB [6]. This study indicates that there might be a large burden of mycobacterial disease other than TB disease in adolescents with CLD, requiring further investigation. Haemophilus influenza has been implicated as a ciliotoxic bacterium, causing secondary immotile ciliary dysfunction [17]. The role of chronic bronchial infection with this and other organisms in the progression of CLD needs to be investigated as this could have implications in the treatment of CLD in HIV-infected adolescents. Echocardiography Echocardiographic evidence of pulmonary hypertension has been documented in 7% of adolescents with CLD [6]. In a study on the echocardiographic study findings in consecutive HIV-infected Zimbabwean adolescents, abnormal left ventricular (LV) hypertrophy (67%), impaired LV relaxation or restrictive LV physiology, and right ventricular dilatation without pulmonary artery hypertension (29%) were reported [29]. This data partially explains why limited ability to exercise, breathlessness and desaturation on exercise are common in HIV-infected adolescents even with minimal changes on the chest radiograph. Of note, CLD was not reported in this study. There are no reports of obstructive sleep apnea in HIV-infected adolescents that might complicate their CLD. Adult reports suggest that this may occur [30], but studies in children and adolescents are required. The role of ART The Children with HIV Early Antiretroviral (CHER) trial, which commenced in 2005 and ended in 2011, emphasized the importance of early diagnosis and early ART initiation by seven weeks of age, which reduced the risk of death or disease progression by 76% compared to a deferred strategy with initiation of ART at a median of six months of age. The incidence of TB was 50% lower in infants on early ART than when deferred [31]. Benefits of early ART were sustained. After a median follow-up of 4.8 years, there were five cases of CLD, including two with bronchiectasis and one with LIP in 377 trial participants [32]. It is likely that early ART is important in protecting the lungs against damage from frequent intercurrent and severe infections. Data from CLD studies strongly suggest that delayed initiation of ART in older children and adolescents will not improve lung function in the short-term, even with excellent adherence [6,12]. Paradoxically, ART has been linked to deteriorating lung disease. In IRIS, pulmonary infiltrates will temporarily increase, as has been described for pulmonary TB [33,34]. 4 Weber HC et al. Journal of the International AIDS Society 2013, 16:18633 http://www.jiasociety.org/index.php/jias/article/view/18633 | http://dx.doi.org/10.7448/IAS.16.1.18633 In a cross-sectional study of adults with airways obstruction, ART was associated with increased airways obstruction [35]. These data, however, require prospective studies for confirmation. Challenges and limitations Methodological issues The major limitation of all the cross-sectional studies is that temporality cannot be determined. Also, many studies are uncontrolled. A selection bias is likely as many studies focus on patients with severe disease. Therefore, detailed prospective studies are required. Definitions of CLD At present there are no agreed definitions of CLD in HIVinfected adolescents. The definitions would require high sensitivity and be applicable in primary care clinics in rural settings. Identified children and adolescents would require referral to regional/tertiary institutions for further investigations. These should include chest radiography, saturation monitoring (at rest, during exercise and during sleep), sputum culture for bacteria and mycobacteria, lung function testing and electrocardiography (EKG). In selected cases HRCT and echocardiography will be required. An algorithm to investigate children and adolescents should be developed and scientifically tested to ensure high sensitivity and specificity. Response to therapy There are no randomized controlled studies available to guide therapy. Although it seems logical to follow the guidelines for management of non-cystic fibrosis bronchiectasis, there is no evidence to support this approach. The postulated ongoing airways inflammation in bronchiolitis obliterans might respond to immunomodulation with macrolide antibiotics and should be studied [36]. Early identification of HIV-infected infants and children and immediate initiation of ART regardless of CD4 count may be essential to prevent CLD. Justification for this approach is the lack of association between the CD4 count, duration of ART and lung function tests indicating irreversible lung damage in adolescent patients with CLD [6]. Pathogenesis A number of risk factors that commonly occur in HIV-infected children and adolescents could lead to CLD. These include repeated respiratory tract infections, LIP, pulmonary TB, poor nutrition and exposure to increased biomass pollution at home. The risk of developing CLD would be exacerbated by tobacco smoke, late initiation of ART and late recognition of the symptoms and signs suggestive of CLD. Urgent research is required to elucidate which factors are responsible for the development of CLD in adolescence and which interventions will prevent the progression of CLD. Management To initiate the correct therapy, adolescents and children with symptoms and signs suggestive of CLD should be carefully evaluated and the most appropriate treatment initiated. This requires that patients with suspected CLD be referred to regional/tertiary hospitals for evaluation and treatment. In many parts of sub-Saharan Africa, facilities to make an accurate diagnosis are lacking. Therefore, at present it seems logical to use guidelines recommended for management of children with non-cystic bronchiectasis [37]. The aims of the treatment as modified from the above guidelines should be: 1) 2) 3) 4) To identify and treat underlying cause to prevent disease progression; To maintain or improve lung function; To reduce exacerbations and improve quality of life by reducing daily symptoms; To ensure optimal ART and preventative treatment including trimethoprim-sulphamethoxazole [38,39] and isoniazid preventative treatment [40]. Briefly, this would include patient education, aggressive treatment of acute bacterial exacerbations and annual immunization against influenza and pneumococcal vaccination every five years. Home-based physiotherapy and airway clearance techniques, bronchodilators for those with reversible airway obstruction and long-term home oxygen therapy, where possible, should be prioritized. Acute bacterial exacerbations of lower airway infections should be treated with antibiotics for 14 days. The choice of antibiotics should be guided by sputum cultures. Children and adolescents should be hospitalized if the work of breathing has significantly increased, if supplementary oxygen is required, if unable to take oral antibiotics or requires intravenous antibiotics or if a complication has developed. The most common complications are respiratory failure, haemoptysis and pulmonary hypertension leading to cor pulmonale. Protocols to manage these complications, appropriate to the level of care needed should be developed. Patients requiring long-term oral antibiotics, nebulised antibiotics, inhaled corticosteroids or possible lung resection of localized disease should be referred to tertiary institutions for advice. All of the above-suggested treatment strategies require scientific validation, preferably in randomized control trials. Prior to this occurring, databases similar to those used in national cystic fibrosis registers might be helpful in identifying timely interventions that will benefit adolescents with CLD. Conclusions CLD in HIV-infected children and adolescents requires heightened awareness to clinically identify children and adolescent patients at an early stage to prevent ongoing lung function loss. Sub-clinical CLD is likely to be common and markers of early lung damage require exploration. The success of this new era in the management of HIV-infected children and adolescents will be determined by our efforts to improve quality of life, with CLD requiring urgent attention. Authors’ affiliations 1 Rural Clinical School, School of Medicine, Faculty of Health Sciences, University of Tasmania, Burnie, Tasmania, Australia; 2Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg Children’s Hospital, Tygerberg, South Africa 5 Weber HC et al. Journal of the International AIDS Society 2013, 16:18633 http://www.jiasociety.org/index.php/jias/article/view/18633 | http://dx.doi.org/10.7448/IAS.16.1.18633 Competing interests The authors declare none. Authors’ contributions HCW wrote the initial draft and undertook the literature search. RPG co-wrote this article and gave important advice. MFC contributed to the literature search and co-wrote this article. References 1. Ferrand RA, Luethy R, Bwakura F, Mujuru H, Miller RF, Corbett EL. HIV infection presenting in older children and adolescents: a case series from Harare, Zimbabwe. Clin Infect Dis. 2007;44(6):8748. 2. Ferrand RA, Corbett EL, Wood R, Hargrove J, Ndhlovu CE, Cowan FM, et al. AIDS among older children and adolescents in Southern Africa: projecting the time course and magnitude of the epidemic. AIDS. 2009;23(15):203946. 3. UNAIDS: UNAIDS report on the global AIDS epIdemIc: 2012. In. Edited by (UNAIDS) JUNPoHA; 2012. 4. Zar HJ. Chronic lung disease in human immunodeficiency virus (HIV) infected children. Pediatr Pulmonol. 2008;43(1):110. 5. Ferrand RA, Bandason T, Musvaire P, Larke N, Nathoo K, Mujuru H, et al. Causes of acute hospitalization in adolescence: burden and spectrum of HIVrelated morbidity in a country with an early-onset and severe HIV epidemic: a prospective survey. PLoS Med. 2010;7(2):e1000178. 6. Ferrand RA, Desai SR, Hopkins C, Elston CM, Copley SJ, Nathoo K, et al. Chronic lung disease in adolescents with delayed diagnosis of vertically acquired HIV infection. Clin Infect Dis. 2012;55(1):14552. 7. Rylance J, Mwalukomo T, Rylance S, Matchere P, Thindwa D, Webb E, et al. Lung Function and Bronchodilator Response in Perinatally HIV-infected Adolescents: Malawi. In: Programs and abstracts of the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012); 2012 March 5-8; Seattle, Washington, USA. 8. Amorosa JK, Miller RW, Laraya-Cuasay L, Gaur S, Marone R, L.D. F, Nosher JL. Bronchiectasis in children with lymphocytic interstitial pneumonia and acquired immunodeficiency syndrome. Pediatr Radiol. 1992;22:6037. 9. Berman DM, Mafut D, Djokic B, Scott G, Mitchell C. Risk factors for the development of bronchiectasis in HIV-infected children. Pediatr Pulmonol. 2007;42(10):8715. 10. Jeena PM, Coovadia HM, Thula SA, Blythe D, Buckels NJ, Chetty R. Persistent and chronic lung disease in HIV-1 infected and uninfected African children. AIDS. 1998;12:118593. 11. Kiwanuka J, Graham SM, Coulter JB, Gondwe JS, Chilewani N, Carty H, et al. Diagnosis of pulmonary tuberculosis in children in an HIV-endemic area, Malawi. Ann Trop Paediatr. 2001;21(1):514. 12. Masekela R, Anderson R, Moodley T, Kitchin OP, Risenga SM, Becker PJ, et al. HIV-related bronchiectasis in children: an emerging spectre in high tuberculosis burden areas. Int J Tuberc Lung Dis. 2012;16(1):1149. 13. Norton KI, Kattan M, Rao JS, Cleveland R, Trautwein L, Mellins RB, et al. Chronic radiographic lung changes in children with vertically transmitted HIV-1 infection. AJR Am J Roentgenol. 2001;176(6):15538. 14. Sheikh S, Madiraju K, Steiner P, Rao M. Bronchiectasis in pediatric AIDS. Chest. 1997;112(5):12027. 15. Andiman WA, Eastman R, Martin K, Katz BZ, Rubinstein A, Pitt J, et al. Opportunistic lymphoproliferations associated with Epstein-Barr viral DNA in infants and children with AIDS. Lancet. 1985;2(846970):13903. 16. Dufour V, Wislez M, Bergot E, Mayaud C, Cadranel J. Improvement of symptomatic human immunodeficiency virus-related lymphoid interstitial pneumonia in patients receiving highly active antiretroviral therapy. Clin Infect Dis. 2003;36(10):e12730. 17. King PT. The pathophysiology of bronchiectasis. Int J Chron Obstruct Pulmon Dis. 2009;4:4119. 18. Hnizdo E, Singh T, Churchyard G. Chronic pulmonary function impairment caused by initial and recurrent pulmonary tuberculosis following treatment. Thorax. 2000;55(1):328. 19. Ehrlich RI, Adams S, Baatjies R, Jeebhay MF. Chronic airflow obstruction and respiratory symptoms following tuberculosis: a review of South African studies. Int J Tuberc Lung Dis. 2011;15(7):88691. 20. Dickey LB. Primary pulmonary tuberculosis as a cause of bronchiectasis in children. Dis Chest. 1952;21(3):2607. 21. Moonnumakal SP, Fan LL. Bronchiolitis obliterans in children. Curr Opin Pediatr. 2008;20(3):2728. 22. Fischer GB, Sarria EE, Mattiello R, Mocelin HT, Castro-Rodriguez JA. Post infectious bronchiolitis obliterans in children. Paediatr Respir Rev. 2010; 11(4):2339. 23. Pitcher RD, Goddard E, Hendricks M, Lawrenson J. Chest radiographic pulmonary changes reflecting extrapulmonary involvement in paediatric HIV disease. Pediatr Radiol. 2009;39(6):5658. 24. Theron S, Andronikou S, George R, du Plessis J, Goussard P, Hayes M, et al. Non-infective pulmonary disease in HIV-positive children. Pediatr Radiol. 2009;39(6):55564. 25. Nel ED, Ellis A. Swallowing abnormalities in HIV infected children: an important cause of morbidity. BMC Pediatr. 2012;12:68. 26. Desai SR, Copley SJ, Barker RD, Elston CM, Miller RF, Wells AU, et al. Chest radiography patterns in 75 adolescents with vertically-acquired human immunodeficiency virus (HIV) infection. Clin Radiol. 2011;66(3):25763. 27. Dramowski A, Morsheimer MM, Frigati L, Schaaf HS, Rabie H, Sorour G, et al. Radiology services for children in HIV- and TB-endemic regions: scope for greater collaboration between radiologists and clinicians caring for children. Pediatr Radiol. 2009;39:54144. 28. de Martino M, Veneruso G, Gabiano C, Frongia G, Tulisso S, Lombardi E, et al. Airway resistance and spirometry in children with perinatally acquired human immunodeficiency virus-type 1 infection. Pediatr Pulmonol. 1997; 24(6):40614. 29. Miller RF, Kaski JP, Hakim J, Matenga J, Nathoo K, Munyati S, et al. Cardiac disease in adolescents with delayed diagnosis of vertically acquired HIV infection. Clin Infect Dis. 2013;56(4):57682. 30. Epstein LJ, Strollo PJ, Donegan RB, Hendrix C, Westbrook RB. Obstructive sleep apnea in patients with human immunodeficiency virus (HIV) disease. Sleep. 1995;18(5):36876. 31. Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med. 2008;359(21):223344. 32. Cotton M, Violari A, Gibb D, Otwombe K, Josipovic D, Panchia R, et al. Early ART followed by Interruption Is Safe and Is Associated with Better Outcomes than Deferred ART in HIV Infants: Final Results from the 6- Year Randomized CHER Trial, South Africa. In: Programs and abstracts of the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012); 2012 March 5-8; Seattle, Washington, USA. 33. Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis. 2005;5(6):36173. 34. Zampoli M, Kilborn T, Eley B. Tuberculosis during early antiretroviralinduced immune reconstitution in HIV-infected children. Int J Tuberc Lung Dis. 2007;11(4):41723. 35. George MP, Kannass M, Huang L, Sciurba FC, Morris A. Respiratory symptoms and airway obstruction in HIV-infected subjects in the HAART era. PLoS One. 2009;4(7):e6328. 36. Healy DP. Macrolide immunomodulation of chronic respiratory diseases. Curr Infect Dis Rep. 2007;9(1):713. 37. Hill AT, Pasteur M, Cornford C, Welham S, Bilton D. Primary care summary of the British Thoracic Society Guideline on the management of non-cystic fibrosis bronchiectasis. Prim Care Respir J. 2011;20(2):13540. 38. Chintu C, Bhat GJ, Walker AS, Mulenga V, Sinyinza F, Lishimpi K, et al. Cotrimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): a double-blind randomised placebo-controlled trial. Lancet. 2004;364(9448):186571. 39. Bwakura-Dangarembizi M, Kendall L, Bakeera-Kitaka S, Nahirya-Ntege P, Keishanyu R, Kekitiinwa A, et al. Randomized comparison of stopping vs continuing cotrimoxazole prophylaxis among 758 HIV children on long-term ART: the anti-retroviral research for Watoto trial. In: Programs and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013); 2013 March 3-6; Atlanta, Georgia, USA. 40. World Health Organization. Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings. Geneva: World Health Organization; 2011. 6 Journal Information About the journal The Journal of the International AIDS Society, an official journal of the Society, provides a peer-reviewed, open access forum for essential and innovative HIV research, across all disciplines. All articles published by the Journal of the International AIDS Society are freely accessible online. The editorial decisions are made independently by the journal’s editors-in-chief. Email: [email protected] Website: http://www.jiasociety.org eISSN: 1758-2652 Publisher International AIDS Society Avenue de France 23 1202 Geneva, Switzerland Tel: +41 (0) 22 710 0800 Email: [email protected] Website: http://www.iasociety.org Indexing/abstracting The Journal of the International AIDS Society is indexed in a variety of databases including PubMed, PubMed Central, MEDLINE, Science Citation Index Expanded and Google Scholar. The journal’s impact factor is 3.256 (*2011 Journal Citation Reports® Science Edition - a Thomson Reuters product). Advertising, sponsorship and donations Please contact the editorial office if you are interested in advertising on our journal’s website.We also gladly receive inquiries on sponsorship and donations to support open access publications from authors in low- and middle-income countries. Supplements The Journal of the International AIDS Society publishes supplements, special issues and thematic series on own initiative or based on proposals by external organizations or authors. Inquiries can be sent to the editorial office at [email protected]. All articles submitted for publication in supplements are subject to peer review. Published supplements are fully searchable and freely accessible online and can also be produced in print. Disclaimer The authors of the articles in this supplement carry the responsibility for the content and opinions expressed therein. The editors have made every effort to ensure that no inaccurate or misleading content or statements appear in this supplement. However, in all cases, the publisher, the editors and editorial board, and employees involved accept no liability for the consequences of any inaccurate or misleading content or statement. Copyright The content in this supplement is published under the Creative Commons Attribution-NonCommercial 3.0 Unported (http:// creativecommons.org/licenses/by-nc/3.0/) license.The license allows third parties to share the published work (copy, distribute, transmit) and to adapt it, under the condition that the authors are given credit, that the work is not used for commercial purposes, and that in the event of reuse or distribution, the terms of this license are made clear. Authors retain the copyright of their articles, with first publication rights granted to the Journal of the International AIDS Society. Editors Editors-in-Chief: Susan Kippax (Australia), Papa Salif Sow (Senegal), Mark Wainberg (Canada) Associate Editors: Martin Holt (Australia), Kayvon Modjarrad (United States) Executive Editor: Shirin Heidari (Switzerland) Managing Editor: Mirjam Curno (Switzerland) Editorial Assistant: Helen Etya’ale (Switzerland) Editorial Board Quarraisha Abdool Karim (South Africa) Laith J. Abu-Raddad (Qatar) Dennis Altman (Australia) Joseph Amon (United States) Jintanat Ananworanich (Thailand) Judith Auerbach (United States) Françoise Barré-Sinoussi (France) Chris Beyrer (United States) Andrew Boulle (South Africa) Carlos Cáceres (Peru) Elizabeth Connick (United States) Mark Cotton (South Africa) Jocelyn DeJong (Lebanon) Diana Dickinson (Botswana) Sergii Dvoriak (Ukraine) Nathan Ford (South Africa) Omar Galárraga (Mexico) Diane Havlir (United States) Aikichi Iwamoto (Japan) Adeeba Kamarulzaman (Thailand) Rami Kantor (United States) Elly Katabira (Uganda) Sukhontha Kongsin (Thailand) Kathleen MacQueen (United States) Navid Madani (United States) Jacques Mokhbat (Lebanon) Julio Montaner (Canada) Nelly Mugo (Kenya) Paula Munderi (Uganda) Christy Newman (Australia) Héctor Perez (Argentina) Sai Subhasree Raghavan (India) Renata Reis (Brazil) Linda Richter (South Africa) Jürgen Rockstroh (Germany) Naomi Rutenberg (United States) Gabriella Scarlatti (Italy) Tim Spelman (Australia) Ndèye Coumba Touré-Kane (Senegal) Ian Weller (United Kingdom) Alan Whiteside (South Africa) David Wilson (Australia) Iryna Zablotska (Australia)