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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.
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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
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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
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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
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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].
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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.
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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.
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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
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Table 1. Guidelines for initiation of combination antiretroviral treatment in adolescents
3
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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
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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
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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
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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
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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
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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
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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
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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.
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77. Abadi J, Sprecher E, Rosenberg MG, Dobroszycki J, Sansary J, Fennelly G,
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Mellins CA and Malee KM. Journal of the International AIDS Society 2013, 16:18593
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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
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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
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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
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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)
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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.
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Laughton B et al. Journal of the International AIDS Society 2013, 16:18603
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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
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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
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Table 1. Summary of recent studies on general cognition in HIV-infected children
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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
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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
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Table 2 (Continued )
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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
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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
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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.
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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
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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
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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
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Table 1 (Continued )
Lipshultz SE et al. Journal of the International AIDS Society 2013, 16:18597
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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.
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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.
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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
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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
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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
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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).
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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
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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
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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
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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
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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.
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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.
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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].
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(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
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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.
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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
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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
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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.
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Puthanakit T and Siberry GK. Journal of the International AIDS Society 2013, 16:18575
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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
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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
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Puthanakit T and Siberry GK. Journal of the International AIDS Society 2013, 16:18575
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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
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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.
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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.
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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
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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.
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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
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(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).
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10
Bhimma R et al. Journal of the International AIDS Society 2013, 16:18596
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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
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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
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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
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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.
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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
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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
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Table 2.
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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
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. 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
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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.
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Weber HC et al. Journal of the International AIDS Society 2013, 16:18633
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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
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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
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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
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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
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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.
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6
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