1. Antiretroviral Therapy Christopher Mathews, MD University of California, San Diego Perspectives for Developing Countries

7. (Perrin & Telenti. Science 1998;280:1871-1873)

8. Licensure of Antiretroviral Agents by Year 1987:zidovudine 1988:1989:1990: 1991:didanosine 1992:zalcitabine 1993: 1994:stavudine 1995:lamivudine saquinavir 1996: ritonavir indinavir nevirapine 1997: nelfinavir delavirdine 1998: efavirenz abacavir 1999: amprenavir 2000: lopinavir/ritonavir 2001: tenofovir

9. WHO Antiretroviral Guidelines Primary targets are national treatment advisory boards and senior-level policymakers Outline a public health approach to enable treatment of 3 million individuals in the next 3 years WHO placed ARVs on Essential Drug List in April 2002 –“they should be available at all times in adequate amounts, appropriate dosage forms, at a price individuals and communities can afford…” (http://www.who.int/HIV_AIDS/first.html)

10. Feasibility and Will to Use ARVs UN General Assembly Special Session (article 15) recognized that access to medication is integral to the human right to health Global Fund to Fight AIDS, Tuberculosis, and Malaria” – target $7-10 billion/year Of $174 million approved for coming year, 67% assigned to HIV 21 of 28 countries awarded Global Fund grants specifiy purchase of ARVs as central aim

11. Factors affecting success Drug acquisition costs Facility and personnel infrastructure Minimizing side effects Preventing rapid evolution of drug resistance Recognizing indirect benefit of treatment on transmission probability – “Therapy as Prevention”

12. Affordable prices Annual cost per person for triple therapy in Africa (US$) $12,000 $10,000 $8,000 $6,000 $4,000 $2,000 $0 1991 1993 1995 1997 19992001 2003 Drug Access Initiative Domestic production Accelerated access initiative February-April 2001 offers

13. Clinical Stage I: 1.Asymptomatic 2.Persistent generalized lymphadenopathy (PGL). Performance scale 1: Asymptomatic, normal activity. WHO Staging System for HIV Infection and Disease in Adults and Adolescents

14. Clinical Stage II: 3.Weight loss, < 10 % of body weight. 4.Minor mucocutaneous manifestations (seborrheic dermatitis, prurigo, fungal nail infections, recurrent oral ulcerations, angular cheilitis). 5.Herpes Zoster, within the last 5 years. 6.Recurrent upper respiratory tract infections (i.e., bacterial sinusitis). And/or Performance scale 2: symptomatic, normal activity.

15. WHO Staging System for HIV Infection and Disease in Adults and Adolescents: Clinical Stage III 7. Weight loss, > 10 % of body weight. 8.Unexplained chronic diarrhoea, > 1 month. 9.Unexplained prolonged fever (intermittent or consant), > 1 month. 10.Oral candidiasis (thrush). 11.Oral hairy leukoplakia. 12.Pulmonary tuberculosis, within the past year. 13.Severe bacterial infections (i.e., pneumonia, pyomyositis). And/or Performance scale 3: bed-ridden, < 50% of the day during the last month.

16. WHO Staging System for HIV Infection and Disease in Adults and Adolescents: Clinical Stage IV 14.HIV wasting syndrome, as defined by CDC 1. 15.Pneumocystis carinii pneumonia. 16.Toxoplasmosis of the brain. 17. Cryptosporidiosis with diarrhoea, > 1 month. 18. Cryptococcosis, extrapulmonary 19. Cytomegalovirus (CMV) disease of an organ other than liver, spleen or lymph nodes. 20. Herpes simplex virus (HSV) infection, mucocutaneous > 1 month, or visceral any duration. 21. Progressive multifocal leukoencephalopathy (PML). 21. Any disseminated endemic mycosis (i.e. histoplasmosis, coccidioidomycosis). 23. Candidiasis of the oesophagus, trachea, bronchi or lungs. 24. Atypical mycobacteriosis, disseminated. 25.Non-typhoid Salmonella septicaemia. 26. Extrapulmonary tuberculosis. 27. Lymphoma. 28.Kaposi’s sarcoma (KS 29.HIV encephalopathy, as defined by CDC2. And/or Performance scale 4: bed-ridden, > 50 % of the day during the last month.

17. CDC Classification of HIV Infection (1993)

18. Table A Recommendations for Initiating Antiretroviral Therapy in Adults and Adolescents with Documented HIV Infection If CD4 Testing Available:  WHO Stage IV disease irrespective of CD4 cell count  WHO Stage I, II or III 3 with CD4 cell counts <200/mm 3 (1) If CD4 Testing Unavailable:  WHO Stage IV disease irrespective of total lymphocyte count  WHO Stage II or III (3) disease with a total lymphocyte count <1000-1200/mm 3 – (2)

19. 1 The precise CD4 level above 200/mm 3 at which to start ARV treatment has not been established but the presence of symptoms and the rate of CD4 cell decline (if measurement available) should be factored into the decision making. 2 A total lymphocyte count of <1000-1200/mm 3 can be substituted for the CD4 count when the latter is unavailable and HIV-related symptoms exist. It is less useful in the asymptomatic patient. Thus, in the absence of CD4 cell testing, asymptomatic HIV infected patients (WHO Stage I) should not be treated because there is currently no other reliable marker available in severely resource constrained settings. 3 Treatment is also recommended for patients with advanced WHO Stage III disease including recurrent or persistent oral thrush and recurrent invasive bacterial infections irrespective of CD4 cell or total lymphocyte count.

22. When to change therapy? Intolerance leading to poor adherence Drug toxicity Occurrence of active tuberculosis Pregnancy Treatment failure –Clinical Disease progression on therapy, not due to immunologic reconsitution syndrome –Immunologic: Drop >30% CD4 from peak Return to baseline or below –Virologic Continued detectable viremia

25. Cytochrome P-450, HIV-1 Protease Inhibitors and NNRTIs

26. Abacavir Hypersensitivity Syndrome Incidence about 5% Onset within 6 weeks of initiation Definition: –A fever > 100.9  F and one of the following: Nausea greater than baseline Malaise greater than baseline With or without rash Stop the drug and do not re-challenge

27. Metabolic Abnormalities Associated with HIV Protease Inhibitor Therapy Peripheral lipodystrophy (Carr et al. AIDS 1998;12:F51-8) Hypertriglyceridemia Hypercholesterolemia & decreased HDL Hyperinsulinemia & glucose intolerance Accelerated atherosclerosis (Henry et al. Lancet 1998;351:1328) Dorsal fat pads (“Buffalo humps”)

28. Peripheral Lipodystrophy Variable definitions and prevalence (5-60%) Characteristics –Change in body habitus –Increase abdominal girth with visceral fat deposition (Miller et al. Lancet 1998;351:871-5) –Loss of appendicular fat, with thinning of legs and prominent veins –Breast hypertrophy in women

29. Treatment Adherence (Altice & Friedland. Ann Intern Med 1998;129:503-505) “…compared with therapies for other chronic diseases, which are often forgiving of lapses in adherence, HIV therapy is unforgiving.” Nonadherence may mean: –Not taking medication at all –Taking reduced amounts –Not taking doses at prescribed frequencies or intervals –Not matching medication to food requirements

31. Definitions Genotype Virus nucleotide sequence from which a protein’s amino acids can be deduced –Mutations reported as change in the deduced amino acid sequence, e.g., Met184Val –Specific mutations confer phenotypic resistance –The phenotype is always derived from the genotype Phenotype Relative growth of the virus in the presence of different drug concentrations –Usually reported as the drug concentration that inhibits virus replication by 50% (IC50), or the fold increase in IC50

32. Clinical characteristics Primary HIV infection Established HIV infection First regimen failure Multiple regimen failures Pregnancy Recommendation Consider testing Recommend testing Rationale Detect transmission of drug- resistant virus; modify therapy to optimize response and maintain HIV-specific immune responses Detect prior transmission of drug- resistant HIV although this may not always be possible with current tests Document drug(s) to which there is resistance Optimize the number of active drugs in the next regimen; exclude drugs to which response is unlikely Optimize maternal treatment and prophylaxis for the neonate IAS-USA Recommendations for Use of HIV Drug Resistance Assays Hirsch. JAMA 2000;283:2417.

33. Types of Drug Resistance Assays: Strengths and Weaknesses Availability Turnaround time 2 weeks Mutations may precede phenotypic resistance Lower cost GENOTYPE Requires expert interpretation Measures susceptibility indirectly Insensitive for detecting minor species Does not assess interactions among mutations Does not address drug levels Measures susceptibility directly Results are easier to interpret PHENOTYPE Restricted availability Turnaround time 2–4 weeks Insensitive for detecting minor species Clinically significant cutoff values may not be defined for some drugs More expensive Fast results (2 weeks) Moderate cost VIRTUAL PHENOTYPE Measures susceptibility indirectly Insensitive for detecting interactions between mutations StrengthsWeaknesses

34. Phenotype Sample Report From ViroLogic