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Care of Women with HIV Living in Limited-Resource Settings Antiretroviral Therapy

Care of Women with HIV Living in Limited-Resource Settings Antiretroviral Therapy. Joel E. Gallant, MD, MPH Johns Hopkins University, School of Medicine Jean R. Anderson, MD Johns Hopkins HIV Women’s Health Program John G. Bartlett, MD Johns Hopkins University, School of Medicine.

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Care of Women with HIV Living in Limited-Resource Settings Antiretroviral Therapy

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  1. Care of Women with HIV Living in Limited-Resource SettingsAntiretroviral Therapy Joel E. Gallant, MD, MPH Johns Hopkins University, School of Medicine Jean R. Anderson, MDJohns Hopkins HIV Women’s Health Program John G. Bartlett, MD Johns Hopkins University, School of Medicine

  2. Objectives • Review the natural history of HIV • Discuss the benefits of antiretroviral (ARV) therapy and general principles regarding their use • Discuss considerations in starting ARV therapy • Review possible adverse effects and drug interactions with ARV use • Discuss the limitations and barriers to success with the use of ARV therapy

  3. 107 106 105 104 103 102 Natural History of HIV Infection Without the Use of Antiretroviral Therapy Primary Infection Death + Acute HIV syndrome Wide dissemination of virus Seeding of lymphoid organs 1200 1100 1000 900 800 700 600 500 400 300 200 100 0 OpportunisticDiseases Clinical latency HIV/RNA Copies per ml Plasma Constitutional Symptoms CD4 + T Lymphocyte Count (cells/mmm3) 0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11 Years Weeks Source: Fauci et al 1996.

  4. 107 106 105 104 103 102 Natural History of HIV Infection Without the Use of Antiretroviral Therapy Primary Infection Death + Acute HIV syndrome Wide dissemination of virus Seeding of lymphoid organs 1200 1100 1000 900 800 700 600 500 400 300 200 100 0 OpportunisticDiseases Clinical latency HIV/RNA Copies per ml Plasma Constitutional Symptoms CD4 + T Lymphocyte Count (cells/mmm3) 0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11 Years Weeks Source: Fauci et al 1996.

  5. 107 106 105 104 103 102 Natural History of HIV Infection Without the Use of Antiretroviral Therapy Primary Infection Death + Acute HIV syndrome Wide dissemination of virus Seeding of lymphoid organs 1200 1100 1000 900 800 700 600 500 400 300 200 100 0 OpportunisticDiseases Clinical latency HIV/RNA Copies per ml Plasma Constitutional Symptoms CD4 + T Lymphocyte Count (cells/mmm3) 0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11 Years Weeks Source: Fauci et al 1996.

  6. Likelihood of Developing AIDS Within Three Years without ARV CD4+ T cells/mm3 Source: Mellors et al 1996.

  7. Benefits of ARV Therapy • Prevents opportunistic infections • Alters/reverses course of existing opportunistic infections • Decreases hospitalizations • Increases survival • Improves quality of life • Restores hope • Reduces HIV transmission • Benefits both adults and children

  8. Zidovudine (ZDV, AZT) Didanosine (ddI) Zalcitabine (ddC) Stavudine (d4T) Lamivudine (3TC) Abacavir (ABC) NRTI combinations ZDV+3TC ZDV+3TC+ABC Antiretroviral Drugs* Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Nucleotide Reverse Transcriptase Inhibitors (NtRTIs) • Tenofovir (DF) *Food and Drug Administration (FDA)-approved drugs as of March 2002

  9. Nevirapine (NVP) Delavirdine (DLV) Efavirenz (EFV) Antiretroviral Drugs* continued Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): *FDA-approved drugs as of March 2002

  10. Indinavir (IDV) Ritonavir (RTV) Nelfinavir (NFV) Saquinavir (SQV) Amprenavir (APV) Lopinavir (LPV) + Ritonavir (RTV) Antiretroviral Drugs* continued Protease Inhibitors (PIs) *FDA-approved drugs as of March 2002

  11. General Principles for the Use of ARV Therapy • The goal of therapy is to reduce viral load as much as possible and sustain that reduction as well as restore and/or preserve immune function • ARV agents, usually from different classes, must be used in combination • Several effective ARV combination regimens are available • Adherence to prescribed regimen is more important as a predictor of successful ARV treatment than the specific drug combination used

  12. General Principles for the Use of ARV Therapy continued • Continued HIV replication in the presence of ARV drugs promotes development of drug resistance • Development of resistance to a specific ARV agent may confer resistance to other drugs within the same class and can significantly limit future treatment options • Measurement of CD4+ cells and HIV RNA level reflects immunologic and virologic response to ARV treatment; these measurements are repeated at intervals and are indicators of the success or failure of therapy • Once therapy is started, long-term or generally life-long treatment may be needed

  13. When to Start ARV Therapy in HIV-Infected Adults and Adolescents in Limited-Resource Settings • If CD4 testing available: • WHO Stage IV disease (clinical AIDS) irrespective of CD4 cell count • WHO Stage I, II, III1 with CD4 cell counts 200/mm3 or lower • If CD4 testing unavailable: • WHO Stage IV disease (clinical AIDS) irrespective of total lymphocyte count • WHO Stage II or III disease with a total lymphocyte count 1200/mm3 or lower 1Treatment 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. Source: WHO 2002.

  14. Clinical Evaluation Before Start of ARV Therapy • Assess stage of infection • Identify past and current HIV-related illnesses that may require treatment (e.g., TB) • Identify other co-existing medical conditions (e.g., chronic hepatitis) • List current medications • Assess sexual and drug-using behaviors • Condom and contraceptive access and use • Menstrual history • Assess possibility of pregnancy and plans/risk for pregnancy • Assess readiness to start therapy

  15. ARV Factors in Choice of Initial Regimen • Strength of data on effectiveness • Potential for serious adverse effects and toxicity • Possible side effects • Convenience • Pill burden • Dosing frequency • Food/refrigeration requirements • Potential interaction with other drugs • Potential for alternative treatment options should initial combination fail • Cost and accessibility

  16. Patient Factors in Choice of Initial Regimen • Stage of disease • Likelihood of adherence • Pregnancy or risk of pregnancy • Concurrent TB and other illnesses (e.g., hepatitis B, C) • Opportunity for reliable followup

  17. Recommended Initial ARV Regimens * r = ritonavir Adapted from WHO 2002.

  18. Advantages Low cost Low pill burden Better tolerability Easier to monitor Disadvantages Lower antiviral potency Partially suppressive Decreased durability Emergence of NRTI resistance inevitable Advantages and Disadvantages of Regimens with 2 NRTIs Only

  19. Monitoring ARV Therapy: Effectiveness of Regimen • Clinical signs/symptoms • Weight gain • Resolution of oral thrush • Resolution or reduced frequency of other infections • CD4 count or total lymphocyte count increase • Viral load reduction (preferably to undetectable levels)

  20. Monitoring ARV Therapy: Adverse Effects and Toxicity of Regimen • Clinical signs/symptoms • Rash • Jaundice • Abdominal pain • Numbness or pain in extremities • Laboratory abnormalities

  21. Laboratory Monitoring for Toxicity and Effectiveness of ARV Therapy Adapted from WHO 2002.

  22. *Lactic acidosis/fatty liver All NRTIs Loss of subcutaneous fat All NRTIs Anemia ZDV Myopathy ZDV *Pancreatitis ddI, ddC Neuropathy ddI ddC d4T Ascending motor weakness d4T *Hypersensitivity reaction ABC Oral ulcers ddC Serious Adverse Effects of NRTIs *Potentially life-threatening

  23. Serious Adverse Effects of NNRTIs • *Hepatitis • All NNRTIs • Skin rash • All NNRTIs • Central nervous system symptoms • Efavirenz • *Stevens-Johnson syndrome • Nevirapine *Potentially life-threatening

  24. Hyperglycemia and diabetes All PIs Elevated serum lipids All PIs Changes in body fat distribution All PIs *Liver toxicity All PIs Kidney stones Indinavir Hypersensitivity rash Amprenavir Pancreatitis Lopinavir/ritonavir Serious Adverse Effects of PIs *Potentially life-threatening

  25. Antiretroviral Drug Interactions • These are of clinical importance if they: • Increase likelihood of drug toxicity • Decrease therapeutic effectiveness of an administered drug • Important interactions may be seen between ARV agents and: • Other ARV agents • Prescribed or non-prescription drugs (e.g., rifampin) • Herbal or traditional remedies • Certain foods • Certain illicit drugs

  26. Some Important ARV Drug Interactions for Limited-Resource Settings • Rifampin – PIs (except SQV/r), NNRTIs (except efavirenz) • Should not be used together • Oral contraceptives – ritonavir, nelfinavir, amprenavir, lopinavir, nevirapine, efavirenz • May decrease effectiveness of oral contraceptives • Use additional or alternative method • Anticonvulsants – PIs, NNRTIs • May decrease ARV levels • Cotrimoxazole, hydroxyurea, isoniazid, dapsone • May have overlapping toxicities with ARV agents

  27. Indications of Treatment Failure • Clinical– Clinical progression of disease (weight loss, oral thrush, etc.) • Immunologic– Decrease in CD4 cell count • Virologic– Lack of sustained decrease in viral load to below limits of detection Indicates need for change in therapy

  28. Factors Contributing to ARV Failure • Suboptimal ARV regimen • Mono/dual NRTI • Suboptimal drug level • Suboptimal dose • Bio-equivalence of generic drugs • Drug interactions • Malabsorption (e.g., intestinal parasites, nausea and vomiting) • Lack of proper adherence to therapy

  29. Factors Contributing to ARV Failure continued • Interruptions in treatment • Cost • Drug stockouts • Side effects/toxicity • Lack of proper adherence to therapy

  30. Correlation Between Lack of Adherence and Virologic Failure P = 0.00001, r = –0.554 Source: Paterson 1999.

  31. Ensuring Adherence to Therapy • Provide initial and ongoing counseling about importance of adherence • Educate patient about possible drug side effects and toxicity • Signs and symptoms • Management • Assess readiness and commitment of patient to start and to maintain therapy before beginning treatment

  32. Ensuring Adherence to Therapy continued • Assess adherence and barriers to adherence at each followup visit • Develop concrete plan for specific regimen with relation to meals and daily schedule • Encourage support for treatment from family and friends • Provide ongoing support for adherence at each clinical visit • Assure continued supply of ARV medications

  33. Reasons to Change ARV Therapy • Intolerance • Drug toxicity • Occurrence of active TB • Pregnancy • ARV treatment failure

  34. Recommended ARV Therapy After Treatment Failure with Initial Regimen * IDV/r, LPV/r, or SQV/r ** EFV or NVP

  35. Tuberculosis and ARV Therapy

  36. Special Considerations

  37. Important Reminders • ARV therapy is not a cure for HIV/AIDS – elimination of HIV from the body has not been achieved using the most powerful antiretroviral therapies available • HIV can still be transmitted, even when an individual is on ARV therapy and even when HIV RNA levels are below the limits of detection

  38. Summary • ARV therapy can significantly reduce morbidity and mortality related to HIV. • For therapy to be effective, ARV agents must be used in combination and must achieve a sustained decrease in HIV viral load to below detectable levels. • Decisions about ARV therapy are complex and require consideration of potential adverse effects, drug interactions, resistance issues and the need for proper adherence.

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