HIV/AIDS Antiretroviral Newsletter 2000

World Health Organization Regional Office for the Western Pacific The aim of this biannual newsletter is to provide health workers in the Region with a brief, up-to-date summary of the latest developments in antiretroviral therapies. June 2000 Issue No. 3 SPECIAL FOCUS: COMPLICATIONS OF ANTI-RETROVIRAL THERAPY Introduction Recognized complications associated with antiretroviral (ARV) therapy now include a diverse group of abnormalities, which include bone marrow suppression, hepatic, renal and pancreatic inflammation, body- composition changes (lipodystrophy), skin and nail abnormalities diabetes hypersensitivity reactions, hyperlipidaemia, osteopenia, avascular bone necrosis, hypertension, atherosclerosis, hypothyroidism, hypogonadism and gout. Increasingly, decisions concerning the timing of the introduction of ARV are balanced between the clearly demonstrated benefit of therapy and the potential for numerous, sometimes life threatening, side effects. The safe use of antiretroviral therapy requires careful clinical and laboratory monitoring. The focus of this newsletter is on the complications of ARV, in particular lipodystrophy, and recent developments in the understanding of mitochondrial toxicity. Class Specific Toxicities Nucleoside reverse transcriptase inhibitors mitochondrial DNA toxicity Nucleotide reverse transcriptase inhibitors proximal renal tubular dysfunction Non-nucleoside reverse transcriptase inhibitors hypersensitivity reactions Protease inhibitors multiple metabolic disorders Drug Specific Toxicities Zidovudine anaemia, leucopenia, skin hyperpigmentation, gastro-intestinal intolerance, headache, myopathy, alopecia Didanosine pancreatitis, gastro-intestinal intolerance Zalcitabine mouth ulcers Abacavir hypersensitivity reaction (can be severe or fatal if rechallenged) Efavirenz CNS toxicity (drowsiness, dizziness, confusion, abnormal dreaming) Ritonavir peri-oral parasthesiae, taste perversion, gastro-intestinal intolerance Indinavir renal calculi and crystaluria, hyperbilirubinaemia, alopecia Nelfinavir diarrhoea Amprenavir rash IN THIS ISSUE: INTRODUCTION 1 PROXIMAL RENAL TUBULAR DYSFUNCTION 3 LIPODYSTROPHY 2 HYPERSENSITIVITY REACTIONS 4 MITOCHONDRIAL DYSFUNCTION 3 ABACAVIR HYPERSENSITIVITY 4 MITOCHONDRIAL TOXICITY OF PERINATALLY ADMINISTERED ZIDOVUDINE 3 BONE MINERAL DENSITY 4 2 Antiretroviral Newsletter Issue no. 3 Lipodystrophy No generally accepted case definition exists for lipodystrophy. However, researchers attending The First International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV (San Diego, June 1999) produced a working definition that included increased waist size, increased breast size, 'buffalo hump' (fat accumulation around the neck and upper back), fat accumulation around the neck and jaw ('moon face'), fat deposits in other locations, facial wasting, especially of the cheeks, wasting of the buttocks, thinning of arms and legs, and prominent leg veins. The syndrome of lipodystrophy is also associated with insulin resistance and hyperlipidaemia. Pathogenesis Lipodystrophy is no longer regarded as a direct consequence of protease inhibitors (PIs) alone. The causes of body fat changes are multi-factorial and more complex than first thought. Despite a number of emerging theories, the exact mechanisms that result in body fat and metabolic changes in patients taking ARV have not been identified. Rare forms of genetically inherited lipodystrophy have been identified and acquired forms of lipodystrophy, which resemble those reported in HIV, have also been reported in uninfected individuals. The syndrome has also been reported in HIV-negative people taking ARV as post-exposure prophylaxis. Recently, it has become clear that both nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors play a role in the development of body fat and metabolic changes perhaps via different mechanisms One theory is that protease inhibitors interfere with two human proteins involved in fat metabolism, the low- density lipoprotein-receptor-related protein (LRP) and the cytoplasmic retinoic-acid binding protein type 1 (CRABP-1). Researchers have found that the active site of HIV protease bears a close resemblance to a string of amino acids on the low-density lipoprotein receptor- related protein (LRP). A further theory suggests that body fat and metabolic disorders may result from PI- induced disruption of steroid hormone production. In one French study, serum cortisol levels were reported to be significantly higher in 37 patients taking highly active antiretroviral therapy (HAART) compared to 20 HIV- negative controls. In the same study, patients with lipodystrophy had lower levels of DHEA (which plays a role in regulating cortisol, lipid and insulin levels). Higher cortisol/DHEA ratios were associated with lipodystrophy. The mechanism of nucleoside analogue-induced body fat changes is thought to relate to the mitochondrial toxicity caused by this class of ARV. The role of mitochondrial dysfunction in the pathogenesis of many of the complications seen in association with ARV is discussed later. Prevalence Estimates of the prevalence of lipodystrophy in patients taking protease inhibitors vary widely. Australian researchers reported that 83% of the PI treated patients experienced some symptoms of lipodystrophy after 21 months of therapy, while 11% experienced severe body fat changes. Other studies have reported a lower incidence of between 5%-30%. Spanish and French studies have also reported that a majority of patients experienced lipodystrophy after two years of treatment. A review of 624 French patients who had been taking at least one PI for an average of 18 months found that 85% had experienced at least one physical change during that time. In the Spanish study, of 158 patients treated with protease inhibitors for more than six months, 22% showed signs of lipodystrophy. Statistical analysis performed as part of this study suggested a 75% chance of developing lipodystrophy after two years of treatment. Risk factors for the development of lipodystrophy Increasing patient age (especially >40 years) Duration and type of PI therapy (ritonavir reported as more likely) Duration and type of NRTI therapy (d4T reported as more likely) Advanced HIV disease Diagnosis and monitoring The diagnosis of lipodystrophy/lipo-atrophy can be made clinically with the typical body composition changes clearly visible to the physician and patient. Attempts have been made to quantify these changes using DEXA and CT scanning, BIA (bio-impedance assay) anthropometry and measurement of hip/waist ratio. Abnormal liver enzymes, serum lactate and anion gap are associated with mitochondrial toxicity. Protease inhibitors may cause elevated serum lipids and glucose and glycosuria. Management Rational decision making in the management of lipodystrophy, lipo-atrophy, hyperlipidaemia and insulin resistance is difficult, in the absence of a known aetiology. There is no known treatment for the body composition changes. Stopping and/or switching therapy have produced variable results in clinical studies. Therefore, it is essential the patients are fully informed about lipodystrophy and that the changes may be permanent even if ARV is ceased. It is uncertain whether there will be clinical benefits from drug therapy for hyperlipidaemia and insulin resistance. The clinical options include the following: ? ? doing nothing ? ? switching the PI Antiretroviral Newsletter Issue no. 3 3 ? ? switching the NRTI(s) ? ? prescribing diet or exercise ? ? treating specific abnormalities with medications Switching from a PI to non-PI regimen has not demonstrated significant improvement in lipodystrophy in studies to date. The use of efavirenz may itself be associated with hyperlipidemia. Researchers report that diet and exercise may reduce triglyceride levels by 20%. There are drug-interaction issues with the use of lipid-lowering drugs because all of the statins except pravastatin are metabolised by cytochrome P450. The fibrates are indicated for the treatment of hypertriglyceridemia and are reasonably effective. Treatment of hyperglycaemia is more difficult. Sulfonylureas may lead to hepatic or renal toxicity. Metformin is contraindicated in the presence of renal or liver dysfunction. Insulin may be the safest therapy for symptomatic hyperglycemia. Mitochondrial dysfunction Mitochondria generate cellular energy by the process of oxidative phosphorylation. Most cells contain hundreds of mitochondria that perform multiple cellular functions. They contain their own extra-chromosomal DNA. The enzyme DNA polymerase is responsible for mitochondria DNA replication. Genetic mutations that disrupt mitochondrial oxidative phosphorylation occur naturally in humans. Such disruption results in a reduced cellular energy capacity and signs and symptoms of disease covering a wide clinical spectrum may appear. Clinical presentations of nucleoside reverse transcriptase inhibitor mitochondrial Body as a whole progressive weight loss, fatigue, elevated serum lactate, elevated anion gap Muscle myopathy, myalgia, muscle wasting, weakness, fatigue, elevated CPK Heart cardiomyopathy Nerve pain, parasthesiae, sensory loss, areflexia, muscle weakness Liver hepatomegaly, elevated liver enzymes, lactic acidosis Pancreas pancreatitis, elevated serum amylase Adipose tissue lipoatrophy (typically peripheral) Recently, nucleoside analogue reverse transcriptase inhibitors have been recognised as causing mitochondrial disruption, particularly following long- term therapy. Nucleoside analogues inhibit DNA polymerase resulting in decreased mitochondria DNA synthesis and increased mitochondrial DNA mutation. They also inhibit oxidative metabolism as the final common pathway. Whether NRTI-induced mitochondrial toxicity is reversible, at least in part, after cessation of the drug is unknown. The role of supplementation with thiamine, riboflavin and co- enzyme Q (all involved in the process of oxidative phosphorylation) is being investigated. Mitochondrial toxicity of perinatally administered zidovudine In February, 1999, French clinical investigators reported two cases of severe, fatal mitochondrial neurological disease in neonates born to 7 HIV-infected mothers who had been exposed perinatally to ZDV plus 3TC. The children were not HIV-infected. Theoretically, the mechanisms of NNRTI-induced mitochondrial toxicity could result in damage, which could persist after cessation of the drugs. Following the reported deaths, 6 further infants were discovered with mitochondrial metabolic abnormalities measured in muscle biopsy tissue. In a review of five large databases at the National Institutes of Health and CDC, covering over 20,000 HIV-infected women, 227 deaths in HIV-uninfected or indeterminate children were analysed retrospectively. While none of these children died of illnesses resembling the two fatal cases in France, three had symptoms or signs that were suggestive of mitochondrial disease. However, none of these three children had known perinatal exposure to NRTIs. An extensive review of living, HIV-uninfected children is being conducted. At this stage there is insufficient evidence concerning mitochondrial toxicity in NRTI-exposed neonates to warrant a change in recommendations for perinatal prophylaxis. Proximal renal tubular dysfunction Adefovir, which belongs to the nucleotide reverse transcriptase inhibitor class of ARV drugs, was recently withdrawn from clinical development due to the high incidence of proximal renal tubular dysfunction in clinical studies to date. This syndrome presents with reversible elevation of creatinine, associated with glycosuria, proteinuria, decrease serum bicarbonate and (variably) hypophosphataemia. Onset of the syndrome is typically after 20 weeks of adefovir therapy. The aetiology may relate to mitochondrial toxicity and/or inhibition of organic anion transport protein by adefovir in proximal tubule cells. Hypersensitivity reactions Drug hypersensitivity reactions are 100 times more common in HIV infected patients. Typically, such reactions are seen following therapy with non-nucleoside RTIs (nevirapine, efavirenz, delavirdine), cotrimoxazole, 4 Antiretroviral Newsletter Issue no. 3 abacavir and amprenavir. Clinical features include rash, hepatitis, mucosal inflammation, and constitutional symptoms such as fever and malaise. Non-nucleoside RTI hypersensitivity reactions are often self-limiting and may be managed with a 'treat through' approach, involving frequent clinical review of the patient and antihistamines. The incidence of nevirapine-induced rash is reduced by the recommended introduction of a reduced initial dose (200mg/day) escalating to 400mg/day after two weeks. Severe reactions may necessitate withdrawal of the drug. The special case of abacavir is discussed below in more detail. Abacavir hypersensitivity Approximately 3% of patients treated with abacavir develop an idiosyncratic hypersensitivity reaction that resolves on discontinuation, but returns with greater severity of symptoms on reintroduction of abacavir. The median time to onset of the hypersensitivity is 11 days, with 94% of cases occurring within 6 weeks of initiation of abacavir therapy. The most frequent symptoms are fever (80%), rash (70%), gastrointestinal symptoms (50%), and malaise (40%). Respiratory symptoms have been reported in approximately 20% of patients and include dyspnoea, pharyngitis and cough. Wheezing is infrequently reported. Approximately half of patients have 3 or 4 symptoms, and an additional 20% have fever and rash. Fever and/or rash are present in 98% of cases. An important clue to the diagnosis is the evolution of the symptoms (over several days) and evidence for multi- organ system involvement. The rash can be mild. Gastrointestinal symptoms without either fever or rash are more likely to indicate common adverse events to antiretroviral therapy and not hypersensitivity. Laboratory abnormalities reported in association with abacavir hypersensitivity reaction included lymphopenia, thrombocytopenia, elevated ALT and CPK. If abacavir is re-introduced, the resultant reaction may develop within hours and is more severe. Rechallenge with abacavir following initial hypersensitivity reaction has been associated with death and should never be undertaken. Death has also been reported from the acute respiratory symptoms associated with an abacavir hypersensitivity reaction. The diagnosis of abacavir hypersensitivity must always be considered in patients presenting with acute respiratory symptoms in addition to other symptoms associated with abacavir hypersensitivity and the drug must be ceased immediately. Bone mineral density Two abstracts presented at the 7th Conference on Retroviruses and Opportunistic Infections reported small studies of bone mineral density (BMD) in HIV-infected subjects with lipodystrophy who were receiving HAART. Both studies showed that a substantial proportion of subjects taking PIs had decreased bone mineral density, which led to diagnoses of osteopenia or osteoporosis; this was 21% of 64 persons taking a PI in one study, and 28% of 74 patients in the other study. Men receiving protease inhibitors have been reported as having a higher incidence of osteopenia and/or osteoporosis compared to women. Osteopenia and osteoporosis are unique metabolic complications associated with protease inhibitor containing potent antiretroviral regimens that appear to be independent of adipose tissue maldistribution. References and further reading (1) Saint-Marc T et al. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long term nucleoside therapy. AIDS 1999,13:1659-1667 (2) Blanche, S., Tardieu, M., Rustin, P., et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 354: 1084- 89 1999 (3) Brinkmann K, Smeitinik, Burton et al. Mitochondrial toxicity induced by nucleoside analogue reverse transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral therapy related lipodystrophy. Lancet 199: 354: 1112-5. (4) Carr A, Samaras K, Burton S et al, A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance inpatients receiving protease inhibitors. AIDS 1998, 12: F51-58 (5) www.aidsmap.com Treating body fat and metabolic changes,March 2000 Body fat changes on HAART, March 2000 Metabolic changes on HAART, March 2000 (6) www.medscape.com Many review articles (7) www.natap.org Many review articles Sexually transmitted infections, including HIV/AIDS World Health Organization Regional Office for the Western Pacific United Nations Avenue, (P.O. Box 2932), 1000 Manila, Philippines Fax no. (632) 521-1036, (632) 526-0279, (632) 526-0362 Tel. No.: (632) 528-8001 Email: HSI@wpro.who.int Website: www.wpro.who.int World Health Organization Regional Office for the Western Pacific The aim of this biannual newsletter is to provide health workers in the Region with a brief, up-to-date summary of the latest developments in antiretroviral therapies. Nov 2000 Issue No. 4 Clinical and Laboratory Monitoring of Antiretroviral Therapy in Resource-Limited and Unlimited Settings Introduction Monitoring commences prior to the initiation of antiretroviral therapy (ARV), with the clinical status of the patient and laboratory markers guiding when to recommend commencement of therapy. Traditionally, this decision is based on the predictive values for disease progression and death of CD4 lymphocyte count and HIV- RNA. The presence or absence of HIV-related signs and symptoms also significantly influences the decision to initiate therapy. Increasingly, concerns related to drug toxicities, pill burden and the ability of patients to adhere to strict and complicated treatment regimens have complicated the decision-making process for physicians and patients alike. Despite promised price-reductions and increased availability of generic drugs in some counties, cost remains a major factor in deciding when to start therapy in many parts of the world. Guidelines vary from country to country. Early intervention in an asymptomatic patient is commencement of ARV if the CD4 lymphocyte count is less than 500 cells/ml3. A less aggressive approach is to recommend therapy when the count is below 350 cells/ml3. In Thailand, depending on the financial resources of the patient, treatment typically is delayed until the CD4 count is 200 cells/ml3. In addition to these guidelines, a declining CD4 count and/or rising viral load over time may be considered reasons to initiate therapy. Most physicians would recommend therapy for patients with symptomatic HIV conditions, such as the presence of recurrent oral candida, oral hairy leukoplakia (OHL) or unexplained weight loss. The commitment of the patient to commencing therapy, an understanding of the lifelong nature of such treatment and of the importance of adherence to drug regimens on a daily basis all affect the timing of the recommendation. Once treatment begins, the clinical progress of the patient needs to be reviewed regularly. Laboratory monitoring is focused on markers of efficacy of the regimen and drug toxicities. The frequency of review is dictated by the drugs selected, the development of adverse events and the available resources Efficacy Monitoring Virological markers Quantification of HIV-1 RNA in plasma is the basis of ARV efficacy monitoring. The ultimate goal of combination ARV is undetectable plasma HIV-RNA (viral load). This should be achievable in most treatment-naive patients receiving highly active ARV therapy (HAART). The "gold standard" remains a triple drug combination of two nucleoside reverse transcriptase inhibitors (NRTI) plus a protease inhibitor. However, some studies have shown that a triple nucleoside combination or a combination of two NRTIs plus a non- nucleoside reverse transcriptase inhibitor (NNRTI) can result in a similar ("or even higher") percentage of patients achieving undetectable viral load as regimens containing two NRTIs and a PI. Latest generation ultrasensitive HIV-1 RNA assays are recommended if available. There are three commercially available assays; Amplicor HIV-1 Monitor, Quantiplex HIV-RNA bDNA and the nucleic acid sequence base amplification (NASBA) assay. They are similar in terms of sensitivity, specificity, cost and laboratory personnel training requirements. The Amplicor HIV-1 Monitor is the only commercial assay licensed by the US Food and Drug Administration. The ability of the assay to detect all HIV subtypes with equivalent accuracy is important in South-east Asia where subtype E (and A/E mosaic) predominates. IN THIS ISSUE INTRODUCTION 1 INDICATIONS FOR CHANGING THERAPY 4 EFFICACY MONITORING 1 CLINICAL MONITORING 4 LABORATORY TOXICITY MONITORING 3 2 Antiretroviral Newsletter Issue no. 4 *The addition of primer sets (SK145 and SK151) improves accuracy of detection of subtypes E and A/E Case Study: Interpretation of viral load results This ARV-naive patient had a viral load of 130,000 copies on two occasions, one month apart and CD4 count of 320 cells/mm3. He commenced zidovudine, lamivudine and indinavir at standard doses and had a typical decline in viral load to below 50 copies (undetectable) at 3-month review. At 12 months, there was an unexpected "bleep", which persisted when rechecked one month later. This may have been due to poor adherence, intercurrent infection or vaccination. In this case it was incorrect timing of drug doses and, with indinavir dosing corrected to every 8 hours and AZT/3TC to every 12 hours, his viral load returned to undetectable at the next visit. After two years, he had a sustained rebound in viral load. The principle of management here is to change as many drugs in the combination as possible with new drugs, based on a thorough understanding of ARV cross-resistant patterns. Genotypic and phenotypic viral resistance assays (if available) may be useful tools in guiding drug choices following failure of the initial regimen. The monitoring in this case is typical of a patient being managed in a resource unlimited setting. In situations where the high cost of these assays is prohibitive, it is reasonable to perform baseline viral load followed by repeat testing every 3-6 months. In some countries viral load measurement is unavailable and monitoring of therapy is by CD4 count changes only. However, it is possible to adequately manage a patient on ARV therapy with regular clinical assessment for signs of disease progression and body weight. In resource unlimited countries, a typical monitoring schedule for a patient on triple therapy is monthly visits for the first 3 months then every 3 months, with clinical examination and re-enforcement of adherence. Recommended laboratory tests at each visit are full haematology and clinical chemistry, T-cell subsets and HIV-RNA. In resource limited settings, a clinical review 1 month after commencing ARV, followed by assessments every 3-6 month, if the patient experiences no problems, is sufficient. Clinically, the efficacy of the ARV regimen may be evident with weight gain and regression of CDC B symptoms such as OHL and oral candida. The treating physician will need to prioritize laboratory monitoring depending on available resources. Useful and inexpensive tests are haemoglobin, total lymphocyte count and liver enzymes. T-cells subsets are affordable in many middle income countries in the Asia Pacific region and should be performed every 3-6 month. Viral load testing is often unavailable. Immunological markers Following successful initiation of HAART, a rise in CD4 lymphocyte count of 90-150 cells would be expected. To some extent, this rise is dependent on the CD4 count at the time of commencement of therapy, with a lesser response expected with a lower initial count. There is often a biphasic response with an initial rise in CD4 count after 1-2 months of therapy as cells are redistributed from bone marrow. This may be followed by a decline in CD4 cell numbers followed by a second, slower rise with continued suppression of viral replication. This second-phase rise in CD4 cell numbers may continue for more than 12 months. As HIV disease progression is unlikely in a patient with a CD4 count above 350 cells/mm3, this should be the minimum immunological goal of therapy. However, risk of disease progression is significantly reduced if the CD4 cell count can be maintained above 200 cells/mm3 ASSAY Method Lower Limit of Detection Standard Lower Limit of Detection Ultrasensitive Ability to detect all HIV subtypes Amplicor HIV-1 Monitor (v1.5) Target amplification 400 copies/ml 50 copies/ml YES* Quantiplex HIV-RNA bDNA Signal amplification 500 copies/ml 50 copies/ml YES NASBA Target amplification 400 copies/ml 40 copies/ml False low results reported with subtypes A and E 50 20,050 40,050 60,050 80,050 100,050 120,050 0 3 9 13 21 27 Months HIV-RNA Antiretroviral Newsletter Issue no. 4 3 Laboratory Toxicity Monitoring Drug Class Drug Laboratory Abnormality Laboratory Tests zidovudine anaemia, leucopenia, neutropenia myopathy full haematology CPK didanosine pancreatitis amylase lamivudine few nil specific stavudine hepatotoxicity pancreatitis liver enzymes amylase abacavir hepatotoxicity hypersensitivity liver enzymes CPK, creatinine, haematology nucleoside reverse transcriptase inhibitors zalcitabine pancreatitis amylase nevirapine hepatotoxicity liver enzymes efavirenz hepatotoxicity hypercholesterolaemia liver enzymes serum cholesterol non-nucleoside reverse transcriptase inhibitors delavirdine hepatotoxicity liver enzymes indinavir renal calculi, crystalluria, haematuria nephrotoxicity hepatotoxicity, hyperbilirubinaemia hyperglycaemia, diabetes hyperlipidaemia urinalysis serum creatinine liver enzymes urinalysis, BSL serum lipids saquinavir hepatotoxicity hyperglycaemia, diabetes hyperlipidaemia liver enzymes urinalysis, BSL serum lipids nelfinavir hepatotoxicity hyperglycaemia, diabetes hyperlipidaemia liver enzymes urinalysis, BSL serum lipids ritonavir hepatotoxicity hyperglycaemia, diabetes hyperlipidaemia elevated CPK, uric acid liver enzymes urinalysis, BSL serum lipids CPK, uric acid protease inhibitors amprenavir hepatotoxicity hyperglycaemia, diabetes hyperlipidaemia liver enzymes urinalysis, BSL serum lipids This list covers the more important and clinically relevant laboratory adverse events associated with ARV, some class-specific and some peculiar to individual drugs. Prior to the commencement of ARV in a resource-unlimited clinic, it is recommended that the following set of laboratory tests at baseline and each follow-up visit be performed: • full blood count (FBC) and differential • liver enzymes • serum creatinine and serum amylase • fasting serum glucose • fasting serum cholesterol / triglycerides • electrolytes • CPK • T-cell subsets • HIV RNA Where resources are limited, regular FBC, serum AST (or ALT) and amylase are the minimum requirements for safety monitoring. Toxicities associated with ARV may appear soon after the commencement of therapy. An NNTRI-induced rash or an abacavir hypersensitivity reaction may present within days. A clinically significant decline in haemoglobin, sufficient to require interruption of therapy, may occur within the first month of zidovudine therapy. Some toxicities appear in the medium term. Lipodystrophy and significant hyperlipidaemia associated with PI therapy typically present following 6- 18 months of therapy. Adverse reactions to ARV are not always typical and can be unpredictable. Renal colic associated with indinavir and pancreatitis caused by ddI can occur at any time. Further, laboratory monitoring is not always helpful in predicting such events. 4 Antiretroviral Newsletter Issue no. 4 Indications for changing therapy Changing therapy may be necessary due to treatment failure, toxicity, patient intolerance to the combination or inability of the patient to adhere to the treatment regimen. Clinical disease progression is a marker of treatment failure and necessitates a review of the patient's therapy. Virological treatment failure can be defined as a failure to achieve undetectable HIV-RNA or at least a 2 log10 decline in viral load from baseline, after a reasonable time on therapy, typically 1-2 months. A viral load rebound to detectable levels or a rebound of 0.5 log10 from the nadir (preferably repeated and in the absence of an identifiable cause such as recent infection) also indicates failing therapy. Immunological failure is less easily defined, as individual CD4 count responses to ARV are less predictable. The response is dependent on such variables as disease stage, prior ARV and the drugs taken. As stated above, a patient with a CD4 count of less than 200 cells/mm3 is at significant risk of HIV disease progression and a failure to achieve this level indicates the need to review the therapy. A declining CD4 count over time is also a marker of treatment failure. The situation can present where a patient has well- preserved CD4 count (>350 cells/mm3) but evidence of virological failure with a persistently elevated viral load (>10,000 copies/ml). This clinical picture may be seen in patients on therapy with two ARV drugs (as in many countries in the Asia Pacific region) or in a heavily pre- treated patient on a salvage combination of drugs. In this scenario, a partially suppressive regimen may be reducing viral fitness sufficiently to maintain the CD4 count at a level that makes disease progression unlikely. Decisions to change therapy can be straightforward or, as in this example, require a thorough review of the patient's clinical status, immunological and virological markers, treatment history and available, useful drugs. The role of resistance assays in guiding therapy changes is still being developed. Clinical Monitoring As stated above, laboratory monitoring cannot always predict the development of complications and a patient taking ARV requires regular clinical evaluation. Probably the most common long-term side effects of combination ARV are NRTI-associated lipo-atrophy and PI-associated lipodystrophy (and the related abnormalities in serum lipids and glucose). The exact aetiology of these metabolic complications remains uncertain. However, it is clear that NRTIs cause mitochondrial toxicity resulting in multiple end-organ damage. The clinical picture includes peripheral fat loss, hepatic and pancreatic toxicity and peripheral neuropathy. Treatment with protease inhibitors can result in a similar, but quite distinct syndrome, of fat redistribution and metabolic abnormalities. It is critical that patients be clinically assessed for the early development of these side effects, particularly the body composition changes. To date, there is no definite evidence that these are reversible. In fact, the changes may be permanent in many patients, even if the drugs are stopped. While serum lipids and liver enzymes may help predict those patients at risk, the best method of monitoring these newly emerged toxicities is regular clinical review. References and further reading (1) Dept. of Health and Human Services (DHHS) and Henry J. Kaiser Family Foundation guidelines for the Use of Antiretroviral Agents in HIV-infected adults and adolescents. January 2000. Available at: www.hivatis.org (2) British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy. Available at :www.aidsmap.com/bhiva (3) WHO Guidance Modules on ARV Treatments. Module 4: Safe and Effective Use of ARV Module 5: Laboratory Requirements for Safe and effective use of ARV. www.who.int/HIV_AIDS/antiretroviral_modules/indexa r.htm Order copies by emailing: publications@who.ch New publication: Safe and effective use of antiretroviral treatments in adults with particular reference to resource-limited settings Based on experiences with the use of antiretroviral therapies in resource-limited settings where the capacity of health systems and the profile of patients seeking ART differs from that in industrialized countries. It discusses the universal principles of antiretroviral therapy which are the standard of care, and outlines the health system requirements as well as the counseling needs, clinical evaluation and monitoring needs of patients that will enable safe and effective use of antiretroviral drugs in resource-limited settings. www.who.int/HIV_AIDS/WHO_HSI_2000.04_1.04/ind ex.htm Free copies can be obtained on request HIV,AIDS and Sexually Transmitted Infections (HSI) Focus World Health Organization Regional Office for the Western Pacific United Nations Avenue, (P.O. Box 2932), 1000 Manila, Philippines Fax no. (632) 521-1036, (632) 526-0279, (632) 526-0362 Tel. No.: (632) 528-8001 Email: HSI@wpro.who.int Website: www.wpro.who.int