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National Medicines Information Centre VOLUME 18 NUMBER 4 2012 ST. JAMES’S HOSPITAL • DUBLIN 8 TEL 01-4730589 or 1850-727-727 • FAX 01-4730596 • www.nmic.ie HUman immunodeficiency virus infection Human immunodeficiency virus (HIV) is transmitted by sexual contact (heterosexual and male to male), by blood and blood products and by infected mothers to infants Delayed diagnosis of HIV is associated with increased morbidity and mortality, therefore testing of HIV should be undertaken for all patients at risk of HIV infection and for pregnant women; increased targeted testing in areas of high prevalence shoud be considered Antiretroviral therapy (ART) is very effective at reducing morbidity and mortality in patients infected with HIV and results in patients having a normal quality of life and attaining life goals Healthcare professionals should be aware of the potential for drug-drug interactions in patients on ART INTRODUCTION Acquired Immune Deficiency Syndrome (AIDS) was first recognised in the US in 1981, with cases of Pneumocystis jiroveci pneumonia and/or Kaposi’s sarcoma being reported in previously healthy men who have sex with men (MSM). The disease subsequently became recognised in injection drug users (IDUs), in recipients of blood transfusions and in haemophiliacs.1 In 1983 human immunodeficiency virus (HIV) was isolated from a patient with lymphadenopathy and in 1984 it was demonstrated to be the causative agent of AIDS, which had a high mortality.1,2 With the arrival of highly active antiretroviral therapy (ART), the mortality from HIV reduced; it is now considered a chronic medical condition. The majority of patients living with HIV in developed countries, remain fit and well.2,3 However many HIV-infected people remain unaware of their HIV status, continue to transmit HIV to others and when diagnosed have very advanced and often difficult to treat late stage disease.1-3 This bulletin will provide an overview of HIV infection. EPIDEMIOLOGY HIV infection/AIDS is a global pandemic, with an estimated 34.2 million individuals living with HIV in 2011, of which 2.5 million people were newly diagnosed.1,4 The most common HIV infection in the world is HIV-1; HIV-2 is mainly found in West Africa but remains less common overall.1 HIV is transmitted primarily by sexual contact (both heterosexual and in MSM), by blood and blood products and by infected mothers to infants.1 Maternal transmission of HIV to the foetus occurs most commonly in the perinatal period. Risk factors associated with an increased risk of sexual transmission of HIV include: behavioural changes associated with alcohol consumption and illicit drug use, and unsafe sexual behaviour. The risk of HIV transmission is highest in the first weeks of HIV infection, before and around seroconversion, when plasma HIV RNA levels are high and in advanced disease as the viral load increases.1 There is a small but definite occupational risk of HIV transmission to healthcare workers and laboratory personnel, which is reduced with use of ART following exposure, i.e. post exposure prophylaxis (PEP). In Ireland, it is estimated that the diagnosed prevalence of HIV in adults aged 17-78 years is approximately 1 in 1,000 nationally and 2 in 1,000 in Dublin.5 In 2011, there were 320 people (74% male) newly diagnosed with HIV, 46 patients diagnosed with AIDS and 7 reported deaths among AIDS cases.6 Of those newly diagnosed with HIV, 43% were MSM, 34% were heterosexuals, 5% were IDUs and 1% (n=3) were reported as mother to child transmission. Overall the largest number of new HIV cases occurred in those aged 30-39 years, and people ≥50 years accounted for 10 % of new diagnoses. Pathophysiology HIV is a single stranded RNA retrovirus. Extracellular virions enter their target cell through a complex three-step process, (1) attachment to the CD4 receptor, (2) binding to the CCR5 or CXCR4 co-receptors, or both and (3) membrane fusion.2 The hallmark of HIV disease is a profound immunodeficiency resulting primarily from a progressive quantitative and qualitative deficiency of the subset of T lymphocytes referred to as helper T cells. HIV binds to CD4 receptors on helper T lymphocytes, monocytes, macrophages and neural cells.7 CD4 infected cells migrate to the lymphoid tissue where the virus replicates producing billions of new virions. These are released and in turn infect new CD4 cells. The progressive and severe depletion of CD4 helper lymphocytes has profound repercussions for the functioning of the immune system. Cell-mediated immune deficiency, which is the major consequence, leaves the host open to infections with intracellular pathogens, while the coexisting antibody abnormalities predispose to infections with encapsulated bacteria. HIV also has a direct effect on certain tissues, including the nervous system. Clinical presentation Primary HIV infection is often asymptomatic and the majority of patients are unaware of seroconversion. It is estimated that 1050% of patients experience an acute retroviral syndrome characterised by fever, malaise, generalised lymphadenopathy, pharyngitis, diarrhoea and rash typically 2-4 weeks after infection, which resolves spontaneously within 2-3 weeks.1,2 All patients will develop some degree of viraemia during infection, which contributes to virus dissemination throughout the lymphoid tissue, even though they may be asymptomatic or not recall experiencing symptoms.1 In primary infection, plasma HIV RNA concentrations can be very high, making secondary transmission a high risk if the newly infected person continues to engage in unprotected sexual activity or needle sharing.2,3 Up to 50% of all transmission events in MSM are thought to occur in the context of acute infection, therefore identification, treatment and counselling of affected individuals is a key public health focus.2 Clinically asymptomatic disease: After the symptoms of primary HIV infection resolve, the infected person enters a phase of clinically asymptomatic disease, which may persist for a median of 10 years.1 Rapid progression may also occur, which is more commonly associated with older age.2 The virus continues to replicate and the person remains infectious. Symptomatic disease often emerges as the peripheral CD4 cell count falls to <350 cells per µL.2 Advanced HIV disease: As HIV infection progresses, the viral load rises, the CD4 count falls and the patient becomes highly susceptible to opportunistic disease.1 Although the CD4 lymphocytes are the principal targets of HIV, virtually any cell that expresses the CD4 molecule can potentially be infected with HIV.1 HIV-associated diseases include cytomegalovirus (CMV) infection, Kaposi’s sarcoma, HIV encephalopathy, herpes simplex and recurrent or multiple bacterial infections. The risk of HIV-associated disease becomes apparent at low CD4 cell counts, with many occurring at <200 cells per µL (e.g. Pneumocystis pneumonia, cerebral toxoplasmosis).1,2 However serious complications including bacterial pneumonia, Kaposi’s sarcoma, nonHodgkins lymphoma and tuberculosis (TB) may occur in patients with higher CD4 cell counts.2 Diagnosis It is important to diagnose patients with HIV early, as late diagnosis has been associated with increased transmission of HIV, increased morbidity and mortality, impaired response to ART and increased cost to healthcare services.3 A recent UK study found that 24% of deaths occurring amongst HIV positive patients were directly attributable to the diagnosis of HIV being made too late for effective treatment.3 Of interest, many of these patients had previously been seen by healthcare professionals, prior to the diagnosis of HIV being made. Universal routine (‘opt-out’) strategies have been adopted in healthcare settings, whereby all individuals attending specific settings are offered and recommended HIV testing as part of routine care, but an individual has the option to refuse a test.3 These settings include antenatal clinics, sexual health clinics and patients diagnosed with conditions including TB, hepatitis B and lymphoma. The adoption of universal testing in the antenatal setting has resulted in a significant reduction in the proportion of patients with HIV that remain undiagnosed prior to delivery.3 Voluntary antenatal HIV testing in Ireland was introduced in 1999, and since then all women who attend for antenatal services are offered screening.8 Testing of HIV is recommended for other patients as outlined in Table 1. As with any other medical investigation, the patient should be informed that a HIV test is being performed; however lengthy HIV counselling is not a requirement unless requested by the patient.3 Table 1: Settings in which HIV testing should be undertaken or considered3 Universal HIV testing is recommended in all the following settings: • Sexual health clinics • Antenatal services • Drug dependency services • Healthcare services for those diagnosed with TB, hepatitis B, hepatitis C and lymphoma HIV testing should be routinely offered and recommended to the following group of patients • All patients presenting to healthcare settings where HIV, including primary HIV is part of the differential diagnosis • All patients diagnosed with a sexually transmitted infection • All sexual partners of men and women known to be HIV positive • All men who have disclosed sexual contact with other men • All female sexual contacts of men who have sex with men • All patients reporting a history of injecting drug abuse • All men and women known to be from a country of high HIV prevalence (>1%)* • All men and women who report sexual contact abroad or at home with individuals from countries of high HIV prevalence HIV testing should be routinely performed in the following groups • Blood donors • Dialysis patients • Organ transplant donors and recipients HIV testing may be considered in the following settings where the diagnosed HIV prevalence in the local population exceeds 2 in 1,000 of the population** • All men and women visiting their general practitioner • All general medical admissions The introduction of universal HIV testing in these settings should be evaluated for acceptability and feasibility and the resultant data made available to inform the ongoing development of guidelines. *for an up-to-date list see http://www.unaids.org/en/knowledgeCentre/HIVData/Epidemiology/LatestEpiData.esp, ** - e.g. greater Dublin area according to 2010 figures HIV is diagnosed by a positive result of a HIV screening antibody test or a combined screening test (HIV antibody and HIV p24 antigen) and confirmed by a more specific antibody test (e.g. Western blot).9 HIV antibody might be initially negative following recent infection (usually 1-3 weeks after exposure) and in this case checking HIV nucleic acid (HIV-RNA, HIV-DNA) or repeating antibody tests at 6 weeks and 3 months can confirm the diagnosis. Confirmation of HIV requires two positive results on two separate samples. In Ireland, confirmatory tests are undertaken by The National Virus Reference Laboratory (NVRL). Since 1st January 2012, all confirmed cases of HIV must be notified to the Department of Public Health.9 Management of hIV The aims of management of patients with HIV infection are (1) to maintain physical and mental health, (2) to avoid transmission of the virus and (3) to maximise quality of life. The complexity of HIV infection means that patients should be managed by physicians with HIV expertise and via a multidisciplinary team approach. Contact tracing is an important aspect of the non-pharmacological management of a patient with HIV, which should be undertaken by a trained health advisor.9 Managing patients with sensitivity and taking care to address their fears which may be heightened due to the stigma associated with HIV, are central elements to effective contact tracing and secondary prevention. Patients must be educated about the potential transmissibility of their infection and they should be counselled with regard to sexual practices and needle sharing.1 Psychological and emotional support of the infected patient, the family and friends are also vital aspects of the management. Pharmacological Management Combination ART, also referred to as highly active ART (HAART), is the cornerstone of management of patients with HIV.1 Successful ART is associated with dramatic decreases in the development of HIV-related conditions and their associated mortality.1,10 Widespread use of ART during pregnancy has almost eliminated mother to child transmission in the developed world.10 Recent data from the UK has shown that life expectancy in people treated for HIV infection has increased by over 15 years during 1996-2008, but is still about 13 years less than that of the UK population.11 It is considered that earlier diagnosis and subsequent timely treatment with ART may further increase life expectancy. There is ongoing research as to the most appropriate time to start ART,2,12,13 however recent evidence increasingly supports earlier initiation of ART.13 Studies have shown a decrease in AIDS-free survival as the CD4 count threshold for initiation of therapy decreases and the higher the CD4 cell count achieved after commencing ART, the greater the survival benefit.13 The British HIV Association guidelines currently recommend ART for patients including those with chronic HIV infection presenting with CD4 cell count ≤350 cells per µL; those presenting with HIV-associated disease (e.g. Kaposi’s sarcoma) irrespective of CD4 cell count; patients presenting with primary HIV infection and with one of the following criteria: neurological involvement; and patients with HIV presenting either with an AIDS-defining infection, or a serious bacterial infection and a CD4 cell count <200 cells per µL.12 In addition, to reduce the risk of mother to child transmission, pregnant women should be treated at least by the second trimester and therapy continued after birth.10 The early initiation of ART also reduces the rate of transmission in serodiscordant relationships of HIV by up to 96%, which is another indication to consider treatment with ART.14 Virological treatment failure is generally defined as persistently detectable plasma HIV RNA concentrations after 16-24 weeks of ART. Nearly all first regimen virological failures can be attributed to non-adherence or pre-existing drug resistance.2 The treatment goal is to reduce viral load to undetectable ranges.2 Virological failure should trigger a thorough review of drug side-effects (a common cause of non-adherence) and a search for other drugs and medical conditions that may be affecting absorption or metabolism of ART. Patients with HIV also require treatment for opportunistic infections which may occur e.g. CMV, TB, herpes simplex and any co-existing co-morbidities. Antiretroviral agents used in hiv ART drugs are classified by the viral life-cycle step they inhibit and/or by their chemical structure.2 Due to concerns regarding resistance, three active drugs are usually used in combination for the treatment of HIV. Initial therapy usually consists of a backbone of two nucleoside/nucleotide reductase inhibitors (NRTIs) and a third drug (either a protease inhibitor [PI], or a non-nucleoside reductase inhibitor [NNRTI] or an integrase inhibitor).2,13 Irish figures estimate that 43% of patients on ART are on first-line NRTIs and a NNRTI and another 43% are on NRTIs and a PI.5 The most popular regimen in terms of convenience, is a coformulation of three drugs in a single pill take once daily.2 Table 2 summarises the ART drugs used in clinical practice. Table 2: Antiretroviral drugs used in clinical practice12,13,15-38 Class Drugs Precautions for use * Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine All NRTIs are associated with potential risk of severe lactic acidosis and hepatic steatosis; should be used with caution in patients at risk of or with hepatic dysfunction. Dose adjustments are recommended in renal impairment, apart from abacavir Abacavir is associated with hypersensitivity reactions in at risk individuals (i.e. HLA B5701 positive patients) and some studies show an association with its use and myocardial infarction Tenofovir is associated with renal dysfunction and a decrease in bone mineral density Zidovudine is associated with haematological adverse reactions Stavudine has been associated with peripheral neuropathy and lipoatrophy Didanosine has been associated with peripheral neuropathy and pancreatitis Efavirenz, etrevirine and nevirapine are associated with development of maculopapular rash and also the development of Stevens’ Johnson syndrome (SJS) Efavirenz can cause CNS toxicity (which is usually time limited) and has teratogenic potential Etravine is associated with severe hypersensitivity reactions Nevirapine can cause hepatotoxicity when used in patients with higher CD4 cell counts. Rilpivirine has substantial food interactions Non-nucleoside reverse Efavirenz transcriptase inhibitors Etravirine (NNRTIs) Nevirapine Rilpivirine Protease inhibitors (PIs) Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir Most PIs are associated with hyperlipidaemia and other metabolic abnormalities such as insulin resistance. Long term PI exposure has been associated with an increased risk of cardiovascular disease Atazanavir is associated with QT prolongation, increased bilirubin and occasionally causes reversible jaundice Darunavir has been associated with drug induced hepatitis and skin rash which may be severe (including SJS) Fosamprenavir is associated with a rash Indinavir is associated with an increased risk of nephrolithiasis Lopinavir is associated with an increased risk of pancreatitis Nelfinavir should be used with caution in patients with liver disease Ritonavir has been associated with prolonged QT interval and pancreatitis Saquinivir is associated with dose-dependent QT and PR prolongations; contraindicated in patients with QT prolongation and in patients on drugs which prolong QT and/or PR interval Tipranavir has been associated with drug induced hepatitis and an increased risk of bleeding including reports of intracranial haemorrhage Integrase inhibitors Raltegravir Severe skin and hypersensitivity reactions have been reported Other agents: CCR5 inhibitors Maraviroc Entry inhibitors Enfuvirtide Cases of hepatotoxicity and hepatic failure with allergic features have been reported. Caution in severe cardiovascular disease Injection site reactions and hypersensitivity reactions occur with enfuvirtide * This list is not exhaustive; the individual Summary of Product Characteristics should be consulted for full prescribing information including further information on precautions, adverse effects and drug interactions for each medicine Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) block the action of reverse transcriptase thereby preventing further synthesis of viral DNA, resulting in inhibition of HIV replication.1,39,40 The currently available NRTIs are nucleoside RTIs, apart from tenofovir, which is a nucleotide RTI.1,40 NRTIs are not metabolised by the CYP450 system, however drug interactions can occur as many of the NRTIs are exclusively eliminated by the kidneys.40 Abacavir should only be used in HIV patients who have been screened for HLA-B5701, due to hypersensitivity reactions which occur more commonly in patients who are HLA-B5701 positive.1,10,16 Lamivudine, emtricitabine and tenofovir also have activity against hepatitis B (Hep B) virus.1,10,15 Recurrent hepatitis in patients with Hep B may occur on discontinuation of these NRTIs, therefore patients require liver function monitoring.15 The combination of tenofovir and emtricitabine or abacavir and lamivudine as alternatives are the preferred ‘backbone’ first-line treatment in most regions.2,12,13 Non-nucleoside reverse transcriptase inhibitors (NNRTIs) inhibit HIV-1 reverse transcriptase, by binding to the enzyme outside the active site and causing changes in the enzyme that render it inactive.39 They are used as combination ART for the treatment of HIV-1 infected patients. A limitation to their use is that they are metabolised by the CYP450 system which leads to potential numerous drug-drug interactions (DDIs).39 All NNRTIs are substrates for CYP3A4 and can act as inducers, inhibitors or mixed inducers and inhibitors. Efavirenz is the most common NNRTI used as a third agent in combination ART.12 Protease inhibitors (PIs) prevent the processing of viral proteins into functional conformations, resulting in immature, noninfectious viral particles.39 PIs are used as combination ART for the treatment of HIV-1 infected patients.1 All the PIs are extensively metabolised by CYP3A4 and there is enormous potential for DDIs with other ART and other commonly used medications.39 Ritonavir has the most pronounced inhibitory CYP450 effect. This effect is used to clinical advantage to “boost” the levels of other PI agents (by inhibiting their metabolism). Boosted atazanavir (i.e. combined with ritonavir) or darunavir may be used as the ‘third agent’ in initial combination ART.12 Integrase inhibitors which inhibit the viral enzyme integrase are the newest class of ART. Raltegravir is authorised for use as combination therapy for HIV-1 patients.36 Raltegravir does not affect the CYP450 system.36 It can be used as the ‘third agent’ in initial ART.2 Other ART agents used: A number of other ART agents are used in highly specialised settings including CCR5 antagonists (interfere with HIV binding at the stage of co-receptor engagement) and entry (fusion) inhibitors (interfere with HIV binding to its receptor or co-receptor).1 Maraviroc (CCR5 antagonist) is authorised in combination therapy for treatment experienced patients infected with CCR5-tropic HIV-1 infection.37 It is a substrate for CYP3A4 and requires adjustment in the presence of drugs that interact with these enzymes.37 Enfuvirtide (entry inhibitor), which is administered twice daily subcutaneously, is authorised for use as combination therapy in HIV-1 patients who have failed or have intolerance of other regimes.38 No clinically significant DDIs are expected between enfuvirtide and concurrently given medicinal products metabolised by CYP450 enzymes.38 drug interactions associated with Antiretroviral therapy Clinically significant DDIs between ART and other drugs occur frequently in clinical practice, primarily due to induction or inhibition of the CYP450 system. It is estimated that approximately 25-33% of patients receiving ART are at risk of a clinically significant DDI.12 HIV specialists are responsible for initiating and monitoring HIV patients on ART, however HIV patients are increasingly being managed by non-HIV specialists for co-morbid conditions.41 Studies suggest that physicians may only be able to correctly identify a third of clinically significant DDIs involving ART.12,41 This emphasises the importance of being aware of what medications the patient is taking, the possibility of DDIs occurring in patients on ART and of good communication amongst healthcare professionals. It is important that patients are educated on the risks of DDIs including over-the-counter or recreational drugs. Patients should be encouraged to check with their healthcare professionals before commencing any new drugs. Evidence suggests that HIV patients receiving ART take between 6-10 medications and that the risk of a clinically significant DDI is higher among patients using > 5 non-antiretroviral agents.41 Clinically important DDIs to consider when co-administering with ART include interactions with the following drugs: methadone, oral contraceptives, anti-epileptics, antidepressants, lipidlowering agents, acid-reducing agents, certain antimicrobials (e.g. clarithromycin, minocycline and fluconazole), some anti-arrhythmics, TB therapy, anti-cancer drugs, immunosuppressants, phosphodiesterase inhibitors and anti-hepatitis C virus therapy. Most of these interactions can be managed safely (i.e. with/without dosage modification, together with enhanced clinical vigilance) but in some cases the nature of the interaction is such that co-administration must be avoided (e.g ribavirin and zidovudine, atazanavir and proton pump inhibitors, PIs and rifampicin, PIs and dabigatran/rivaroxaban, PIs and triazolam).42 An excellent resource for healthcare professionals, developed by the University of Liverpool, is www.hiv-druginteractions.org, which provides clinically useful, reliable, up-to-date, evidence-based information on DDIs in HIV treated patients.41 The website has interaction charts for the different types of ART, which are also available as a mobile phone app. Practical issues in managing a patient with HIV It is important that there are clear procedures for patients to receive a confirmed diagnosis of HIV.3 A newly-diagnosed patient should be immediately linked into appropriate HIV treatment and care.3 Patients need to be assessed for other co-morbidities including cardiovascular disease. Modifiable cardiovascular risk factors should be addressed in all patients with HIV infection.10 Drug adherence: Poor adherence to ART can affect HIV-related outcomes such as viral load, progression to AIDS and survival and can be improved by various interventions.43,44 For most patients on ART, near perfect adherence of >95% is required to achieve full and durable viral suppression.45 Studies have shown that educating patients about ART (including necessity, efficacy and sideeffects) all affect adherence.12 Depression is significantly associated with low adherence and some studies report an independent association between depression and mortality in people with HIV. Additional factors which have a negative effect on adherence include problematic alcohol and recreational drug use, poverty, youth and female gender. Adverse effects: It is important to consider adverse effects of ART; all presently used ARTs are generally well tolerated and safe, but none are without adverse effects.2 Improvement in immune function as a result of ART may provoke a marked inflammatory reaction against residual opportunistic organisms, i.e. immune restitution syndrome (IRIS). Metabolic effects associated with ART include fat redistribution, insulin resistance and dyslipidaemia (lipodystrophy syndrome).15 Fat redistribution is associated with regimens containing PIs and NRTIs. Dyslipidaemia is associated with ART, particularly PIs and insulin resistance and hyperglycaemia is associated with PIs and some NRTIs.15 Osteonecrosis has been reported in patients with advanced HIV diseases or following longterm exposure to combination ART. Monitoring: Baseline investigations will depend on the clinical setting, but should include a full blood count, urea and electrolytes, liver function tests, lipid profile, lymphocyte subsets, HIV viral load and a screen for other sexually transmitted infections. Plasma lipids and blood glucose should be monitored 3 to 6 months after starting ART and annually.15 The average CD4 cell count in uninfected adults is usually >500 cells per µL. Most opportunistic infections and cancers occur as the CD4 cell count falls <200 cells per µL.2 Once treatment has begun, CD4 cells typically increase rapidly for the first three months and then slowly increase. The viral load is measured before ART begins, but its primary value is in monitoring the treatment response or failure. The treatment goal is to reduce viral load to undetectable ranges. CVD risk factors should be assessed in all patients annually and fracture risk in patients ≥50 years every 3 years.46 Drug resistance testing: Most guidelines recommend obtaining a baseline genotypic resistance test once HIV infection is diagnosed and in patients who experience virological failure while on ART.2 Each ART drug and to some degree each drug class, varies in its ability to generate drug resistance. Full resistance to some drugs follows the selection of one mutation (e.g. most NNRTIs), while other drugs retain some activity even after some mutations have emerged (e.g. NRTIs). PIs typically have a high genetic barrier and need long-term exposure before resistance emerges. SUMMARY Delayed diagnosis of HIV is associated with increased morbidity and mortality, therefore testing of HIV should be undertaken for all patients at risk of HIV infection and for pregnant women; increased targeted testing in areas of high prevalence should be considered • Confirmation of a diagnosis of HIV requires two positive results on two separate samples • Patients with HIV should be referred to a HIV specialist and multidisciplinary team • The use of ART in a patient with HIV is associated with reduced morbidity and mortality • Poor adherence to ART can have an impact on the outcome of a patient with HIV and patients should be educated on the importance of adherence to ART regimens • Many of the ART agents used to treat patients with HIV have the potential to cause significant DDIs • Many patients will have co-morbid conditions requiring additional co-medication with the potential increased risk for a DDI • www.hiv-druginteractions.org is an excellent resource, which provides clinically useful, reliable, up-to-date, evidence-based information on DDIs in patients with HIV on ART FOR PERSONAL USE ONLY. NOT TO BE REPRODUCED WITHOUT PERMISSION OF THE EDITOR • List of references available on request. Date of preparation: November 2012 Every effort has been made to ensure that this information is correct and is prepared from the best available resources at our disposal at the time of issue. Prescribers are recommended to refer to the individual Summary of Product Characteristics (SmPC) for specific information on a drug. References for HIV Bulletin Vol 18 No 4 2012 1. Human Immunodeficiency Virus Disease: AIDS and Related Disorders, Section 14, chapter 189, Harrison’s Principles of Internal Medicine, Edited by Longo D. Fauci A, Kasper D, Hauser S et al, 18th Edition published by the McGraw Hill companies 2012 2. Volberding P, Deeks S, Antiretroviral therapy and management of HIV infection, Lancet 2010;376:49-62 3. British HIV Association & British Association of Sexual Health and HIV British Infection society, UK National Guidelines for HIV testing 2008, downloaded from www.bashh.org on the 9th August 2012 4. WHO factsheet, Global summary of the AIDS epidemic 2011, downloaded from www.who.int on the 10th October 2012 5. Tuite H et al, Antiretroviral treatment and viral responses in HIV-infecetd patients accessing specialist care in Ireland, in 22nd European Congress of Clinical Microbilogy and Infectious Diseases (ECCMID), 31.03.2012 – 03.04.2012 available at http://registration.akm.ch/einsicht.php?XNABSTRACT_ID=145623&XNSPRACHE_ID=2 &XNKONGRESS_ID=161&XNMASKEN_ID=900 6. HPSC, HIV in Ireland 2011 Report, published May 2012, downloaded from www.hpsc.ie on the 3rd October 2012 7. Oxford textbook 8. Epi-Insight Voluntary Antenatal HIV testing in Ireland: Results of the screening programme 2002-2008 April 2010, downloaded from www.hpsc.ie on the 10th October 2012 9. A working group of the National AIDS Strategy Committee, HIV notification – Information for professionals, published June 2012, downloaded from www.hpsc.ie on the 15th October 2012 10. Thompson M, Aberg J, Cahn P et al, Antiretroviral treatment of adult HIV infection, 2012 recommendations of the international AIDS Society-USA panel, JAMA 2010;304 (3):321333 11. Mat M et al, Impact of late diagnosis and treatment on life expectancy in people with HIV1: UK Collaborative HIV Cohort (UK CHIC) Study, BMJ Oct 2011;343:d6106 12. BHIVA guidelines for the treatment of HIV-1 positive adults with antiretroviral therapy April 2012 13. Thompson M et al, Antiretroviral Treatment of Adult HIV Infection, JAMA 2012;308(4):387-402 14. Cohen M et al, Prevention of HIV-1 infection with early antiretroviral therapy, NEJM 2011;365(6):493-505 15. BNF September 2012, Section 5.3.1 HIV infection 16. SmPC of Ziagen® (abacavir) downloaded from www.medicines.ie on the 4th October 2012 17. SmPC of Videx® (didanosine) downloaded from www.medicines.ie on the 4th October 2012 18. SmPC of Emtriva® (emtricitibine) downloaded from www.medicines.ie on the 4th October 2012 19. SmPC of Epivir® (lamivudine) downloaded from www.medicines.ie on the 4th October 2012 20. SmPC of Zerit® (stavudine) downloaded from www.medicines.ie on the 4th October 2012 21. SmPC of Viread® (tenofovir) downloaded from www.medicines.ie on the 4th October 2012 22. SmPC of Retrovir® (zidovudine) downloaded from www.medicines.ie on the 4th October 2012 23. SmPC of Sustiva® (efavirenz) downloaded from www.medicines.ie on the 4th October 2012 24. SmPC of Intelence® (etravirine) downloaded from www.medicines.ie on the 4th October 2012 25. SmPC of Viramune ® (nevirapine) downloaded from www.medicines.ie on the 5th October 2012 26. SmPC of Edurant® (rilpivirine) downloaded from www.medicines.ie on the 5th October 2012 27. SmPC of Reyataz® (atazanavir) downloaded from www.medicines.ie on the 5th October 2012 28. SmPC of Prezista® (darunavir) downloaded from www.medicines.ie on the 5th October 2012 29. SmPC of Telzir® (fosamprenavir) downloaded from www.medicines.ie on the 5th October 2012 30. SmPC of Crixivan® (indinavir) downloaded from www.imb.ie on the 19th October 2012 31. SmPC of Kaletra® (lopinavir/ritonavir) downloaded from www.medicines.ie on the 5th October 2012 32. SmPC of Viracept® (nelfinavir) downloaded from www.imb.ie on the 19th October 2012 33. SmPC of Norvir® (ritonavir) downloaded from www.medicines.ie on the 6th October 2012 34. SmPC of Invirase® (saquinivir) downloaded from www.medicines.ie on the 3rd October 2012 35. SmPC of Aptivus® (tipranavir) downloaded from www.medicines.ie on the 3rd October 2012 36. SmPC of Isentress® (raltegravir) downloaded from www.medicines.ie on the 3rd October 2012 37. SmPC of Celsentri® (maraviroc) downloaded from www.medicines.ie on the 3rd October 2012 38. SmPC of Fuzeon® (enfuratide) downloaded from www.medicines.ie on the 3rd October 2012 39. Basic & clinical pharmacology / edited by Bertram G. Katzung ; associate editors, Susan B. Masters, Anthony J. Trevor, McGraw Hill Medical 2012 40. Akanbi M, Scarsi K, Taiwo B, Murphy R, Combination nucleoside/nucleotide reverse transcriptase inhibitors for treatment of HIV infection, Expert Opinion Pharmacotherapy 2012;13(1):65-79 41. Patel N et al, Predictors of clinically significant drug-drug interactions among patients treated with nonnucleoside reverse transcriptase inhibitors-, protease inhibitors-, and raltegravir-based antiretroviral regimens, The Annals of Pharmacotherapy 2011;45:317-324 42. University of Liverpool, Interactions with antiretroviral drugs, www.hivdruginteractions.org on the 3rd October 2012 43. Wong W, Luk C, Kidd M, Is there a role for primary care clinicians in providing shared care in HIV treatment? A systematic literature review, Sex Transm Infect 2012;88:125-131Role for primary care 44. Al-Dakkak I et al, The impact of specific HIV-treatment related adverse events on adherence to antiretroviral therapy: A systematic review and meta-analysis, AIDS Care 2012:1-15 45. Paterson DL, Swindells S, Mohr J, Brester M, Vergis EN, Squier C, Wagener MM, Singh N.,Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med. 2000 Jul;133(1):21-30 46. Asboe D et al, British HIV Association guidelines for the routine investigation and monitoring of adult HIV-1 infected individuals 2011, HIV Medicine 2012;13:1-44