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Update of Antiretroviral Agents in Adults and Adolescents 2008

Asso.Prof. Narin Hiransuthikul MD, MPH, PhD Dep. of Preventive & Social Medicine Faculty of Medicine Chulalongkorn UNiversity. Update of Antiretroviral Agents in Adults and Adolescents 2008. NOV 17, 2008. Management of HIV/AIDS (1).

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Update of Antiretroviral Agents in Adults and Adolescents 2008

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  1. Asso.Prof. Narin Hiransuthikul MD, MPH, PhD Dep. of Preventive & Social Medicine Faculty of Medicine Chulalongkorn UNiversity Update of Antiretroviral Agents in Adults and Adolescents 2008 NOV 17, 2008

  2. Management of HIV/AIDS (1) • During past 27 years, HIV/AIDS has been transformed from almostfatal diseasemanageable disease byAntiretroviral Therapy (ART)(12 years)and Optimal Rx of HIV-related Opportunistic Infections and Malignancies

  3. HIV/AIDS 27 years

  4. Management of HIV/AIDS (2) • Optimal ARTcan provide -durable virologic, immunologic and clinical benefits -minimal toxicities and drug resistance -potentially normal life span

  5. Recent Issues Influencing ART in HIV/AIDS2008 • Recent approval of 3 novel ARVs - CC chemokine receptor antagonist: Maraviroc (CCR5 antagonist)- Integrase strand transfer inhibitor : Raltegravir - 2nd generation NNRTI : Etravirine

  6. Recent Issues Influencing ART in HIV/AIDS2008 • Recent approval of 3 novel ARVs • New data that better inform the choice of ARV for initial Rx and Mx of treatment failure • New pathogenetic insights into the role of HIV in previously considered non-AIDS related conditions

  7. Goals of ART • Eradication of HIV? Not possible with currently available ARV medications

  8. What do we need to do to cure HIVinfection? Stop ongoing viral replication • Identify all stable reservoirs • Find a way to eliminate each one

  9. Viral dynamics in pts on HAART Start HAART t1/2 < 1 day t1/2 ~ 14 days Limit of Detection (50 copies/ml) 1000000 100000 10000 1000 Plasma HIV RNA (copies/ml) 100 10 1 Eradication in 2 to 3 years 0.1 0.01 0.001 0 100 200 300 Time on HAART (days)

  10. Viral dynamics in pts on HAART Start HAART Below limit of detection t1/2 < 1 day t1/2 ~ 14 days Limit of Detection (50 copies/ml) 1000000 100000 10000 1000 Plasma HIV RNA (copies/ml) 100 10 1 0.1 0.01 0.001 0 100 200 300 Time on HAART (days)

  11. - Slow decay of latently infected CD4+ T cells 10000 Time to eradication > 73.4 years 1000 100 10 Frequency (per 106 cells) 1 0.1 0.01 0.001 0.0001 0.00001 0 1 2 3 4 5 6 7 Time on HAART (years) Finzi et al., Science, 1997 Wong et al. Science, 1997 Chun et al., PNAS, 1997 Finzi et al., Nature Med., 1999 Siliciano et al., Nature Med., 2003 Chun et al., Nature Med., 1995 Chun et al., Nature, 1997

  12. HAART reduces viremia to below 50 copies/ml < 50 copies/ml HAART • HIV persists in a reservoir in resting T cells Ag † • Patients on HAART have residual viremia < 50 copies/ml HAART Dornadula et al., JAMA, 1999 Palmer et al., PNAS, 2008

  13. Release from stable reservoirs 0 1 2 3 Time on HAART (years) Start HAART 1000000 100000 10000 Limit of Detection (50 c/ml) 1000 Plasma HIV RNA (copies/ml) 100 10 1 0.1 0.01 0.001

  14. Maximal and durable suppression of HIV-RNA Restore CD4 number and function Reduce inflammation and immune activation Normalize survival Improve QOL Prevention of vertical transmission Prevention of transmission to sexual partners ART Goals & Tools to Achieve Them Goals

  15. Maximal and durable suppression of HIV-RNA ART Goals & Tools to Achieve Them Goals

  16. Maximal and durable suppression of HIV-RNA Restore CD4 number and function ART Goals & Tools to Achieve Them Goals

  17. Maximal and durable suppression of HIV-RNA Restore CD4 number and function Reduce inflammation and immune activation ART Goals & Tools to Achieve Them Goals

  18. SMART: Inflammatory Markers StronglyAssociated With Mortality and CVD Events

  19. Selection of ARV regimen Preservation of future treatment options Rational sequencing of therapy Maximizing adherence Use of resistance testing in selected clinical settings ART Goals & Tools to Achieve Them Goals Tools • Maximal and durable suppression of HIV-RNA • Restore CD4 number and function • Reduce inflammation and immune activation • Normalize survival • Improve QOL • Prevention of vertical transmission • Prevention of transmission to sexual partners

  20. Before Initiating ART: Baseline Evaluation • Complete History and Physical examination • Laboratory testing: • HIV antibody • CD4 cell count • Plasma HIV RNA • Resistance test (genotype) • CBC, chemistry profile, BUN, Cr, transaminase • Fasting glucose and lipids • RPR or VDRL • Hepatitis A, B, C serology • Toxoplasma IgG

  21. Tuberculin skin test Chest X ray (if clinically indicated) Gynecologic exam with Pap smear Testing for chlamydia and gonorrhea Ophthalmology exam (CD4 cell count <100 cells/µL) Before Initiating ART: Additional Tests

  22. Considerations in Initiating ART (1) • Willingness of patient to begin and the likelihood of adherence • Degree of immunodeficiency(CD4 cell count) • Plasma HIV RNA • Risk of disease progression • Potential benefits and risks of therapy

  23. Considerations in Initiating ART (2) • ART should be considered lifelong therapy • Interruption of ART is not recommended, except for serious toxicities or inability to take oral medications • Usually causes immediate virologic rebound, with CD4 decline

  24. Use of CD4 Cell Levels to Guide Therapy Decisions • CD4 count • The major indicator of immune function • Most recent CD4 count is best predictor of disease progression • CD4 count usually is the most important consideration in decision to start ART • Important in determining response to ART • Adequate response: CD4 increase 100-150 cells/µL per year • CD4 monitoring • Check at baseline (x2) and at least every 3-6 months

  25. Use of HIV RNA Levels to Guide Therapy Decisions • HIV RNA: • Less important than CD4 count, but may influence decision to start ART and determine frequency of CD4 monitoring • Critical in determining response to ART • Goal of ART: HIV RNA below limit of detection (ie, <40 to <80 copies/mL, depending on assay) • HIV RNA monitoring: • Check at baseline (x2) and at least every 3-4 months in stable patients • Immediately prior to initiating therapy • 2-8 weeks after start or change of ART

  26. Testing for Drug Resistance • Before initiation of ART: • Resistance testing (genotype) recommended for all at entry to care, and for all pregnant women • Transmitted resistance in 6-16% of HIV-infected patients • Identification of resistance mutations may optimize treatment outcomes • In absence of therapy, resistance mutations may decline over time and become undetectable by current assays, but may persist and cause treatment failure when ART is started • Patients with virologic failure: • Perform while patient is taking ART, or ≤4 weeks after discontinuing therapy • Interpret in combination with history of ARV exposure and ARV adherence

  27. CDC Survey: Patterns of Transmitted Drug Resistance Any Resistance NNRTI NRTI PI MDR 20 15 10.7 10.4 Patients with transmitted resistance (%) 8.8 7.7 10 7.1 6.9 5.1 5.5 3.6 3.0 5 2.4 2.1 1.7 1.9 1.3 1.3 0.8 0.4 0 0 0 1998[1](n = 257) 1999[1](n = 239) 2000[1](n = 299) 2003-2006[2](n = 3130) 1. Bennett D, et al. CROI 2002. Abstract 372. 2. Wheeler W, et al. CROI 2007. Abstract 648.

  28. Other Studies: Before Treatment with Specific ARVs • HLA-B 5701 screening • Recommended before starting abacavir, to reduce risk of hypersensitivity reaction (HSR) • HLA-B 5701-positive patients should not receive ABC • Positive status should be recorded as an ABC allergy • If HLA-B 5701 testing is not available, ABC may be initiated, after counseling and with appropriate monitoring for HSR • Coreceptor tropism assay • Should be performed when CCR5 antagonist is being considered* • Consider for patients with virologic failure on a CCR5 antagonist * Not FDA approved for initial ARV therapy.

  29. What is the best time to start ARV? 2008 High viral load >100,000 HIV RNA cop/μL Rapid decline in CD4 > 100/ μL DHHS guideline for use of ARVs in HIV-infected adults and adolescents, Jan 2008 ARV treatment of adult HIV infection 2008 IAS-USA panel.JAMA 2008;300:555-570

  30. Indications for ART Treat all: • CD4 counts of 200-350 cells/µL Risk ofAIDS-related eventsand Non-AIDS-defining conditions is higher in this range than at >350 cells/µL Non-AIDS cancer: lung, anal, head and neck, NHL 1,2 End organ damage: CVS 3, hepatic 4, and renal dysfunction 5,6 1 Grulich AE et al. Lancet 2007;370:59 2 Patel P et al. Ann Intern Med 2008;148:728 3 Friis-Moller N et al. N Engl J Med 2007;356:1732 4 Weber R.Arch Intern Med 2006;166:1632 5 Gupta SK, et al. CID 2005;40:1559 6 Choi AI et al. J Am Soc Nephrol 2007;18:2968

  31. WHO Classification of HIV-Associated Clinical Diseases WHO ARV Guidelines 2006

  32. WHO Clinical Staging of HIV Disease in Adults and Adolescents WHO ARV Guidelines 2006

  33. WHO Clinical Staging of HIV Disease in Adults and Adolescents(cont.)

  34. WHO ARV Guidelines 2006

  35. Major Targets of Antiretroviral Agents Protease Inhibitors SQV,RTV, IDV, NFV, AMV, LPV/rtv, TPV, DRV RT Inhibitors NRTI: AZT, ddI, ddC, d4T, 3TC, ABC NNRTI: NVP, DLV, EFV, ETV NTRTI: Tenofovir Integrase Inhibitors RAL 6 ds DNA Genomic RNA Integrase vpr Protease HIV 5 DNA 3 Proviral DNA 2 RT 1 Transcription 4 RNA mRNA Polyprotein Protein Spliced mRNA Entry Inhibitors CXCR4:AMD3100, T22 CCR5: MVC, SCH-C, D; TAK779 Fusion gp41: T20 ETV = Etravirine (Intelence ) MVC =Maraviroc (Selzentry ) RAL = Raltegravir (Isentress)

  36. Antiretroviral Drug FDA Approval: 1987 - 2004 ABV+3TCTDF+FTC LPV/r ddI-EC AZT+3TC +ABC T-20 ATV FTC EFV ABC NFV DLV SQV (s) AZT+3TC TDF APV RTV IDV NVP 3TC SQV(h) d4T ddC ddI AZT

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