1 / 34

Antiretroviral Therapy

Antiretroviral Therapy. Perspectives for Developing Countries. Christopher Mathews, MD University of California, San Diego. (Perrin & Telenti. Science 1998;280:1871-1873). 1987: zidovudine 1988: 1989: 1990: 1991: didanosine 1992: zalcitabine 1993: 1994: stavudine

annevans
Download Presentation

Antiretroviral Therapy

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

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

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

  3. 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 Licensure of Antiretroviral Agents by Year

  4. 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)

  5. 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

  6. 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”

  7. Annual cost per person for triple therapy in Africa (US$) $12,000 $10,000 $8,000 $6,000 $4,000 $2,000 $0 Drug Access Initiative Domestic production Accelerated access initiative February-April 2001 offers 1991 1993 1995 1997 1999 2001 2003 Affordable prices

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

  9. WHO Staging System for HIV Infection and Disease in Adults and Adolescents • 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.

  10. 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. WHO Staging System for HIV Infection and Disease in Adults and Adolescents: Clinical Stage III

  11. 14. HIV wasting syndrome, as defined by CDC1. 15. Pneumocystis carinii pneumonia. 16. Toxoplasmosis of the brain. Cryptosporidiosis with diarrhoea, > 1 month. Cryptococcosis, extrapulmonary Cytomegalovirus (CMV) disease of an organ other than liver, spleen or lymph nodes. Herpes simplex virus (HSV) infection, mucocutaneous > 1 month, or visceral any duration. Progressive multifocal leukoencephalopathy (PML). Any disseminated endemic mycosis (i.e. histoplasmosis, coccidioidomycosis). Candidiasis of the oesophagus, trachea, bronchi or lungs. Atypical mycobacteriosis, disseminated. 25. Non-typhoid Salmonella septicaemia. Extrapulmonary tuberculosis. 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. WHO Staging System for HIV Infection and Disease in Adults and Adolescents: Clinical Stage IV

  12. CDC Classification of HIV Infection(1993)

  13. 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 III3 with CD4 cell counts <200/mm3 (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/mm3 – (2)

  14. 1The precise CD4 level above 200/mm3 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. 2A total lymphocyte count of <1000-1200/mm3 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. 3Treatment 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.

  15. 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

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

  17. 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

  18. 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”)

  19. 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

  20. 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

  21. Definitions Genotype • Virus nucleotide sequence from which a protein’samino 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 presenceof different drug concentrations • Usually reported as the drug concentration that inhibits virus replication by 50% (IC50), or the fold increase in IC50

  22. IAS-USA Recommendations for Use of HIV Drug Resistance Assays Clinical characteristics Primary HIV infection Established HIV infection First regimen failure Multiple regimen failures Pregnancy Recommendation Consider testing Consider testing Recommend testing Recommend 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 Hirsch. JAMA 2000;283:2417.

  23. Types of Drug Resistance Assays:Strengths and Weaknesses Strengths Weaknesses

  24. Phenotype Sample Report From ViroLogic

More Related