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HIV Care 2010: The 3 rd Revolution in HIV treatment

HIV Care 2010: The 3 rd Revolution in HIV treatment. Chris Farnitano, MD Noon Conference February 11, 2010. Learning Objectives. Be familiar with recent advances in anti-HIV medications Know the new threshold for initiating HIV treatment according to the December, 2009 DHHS guidelines

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HIV Care 2010: The 3 rd Revolution in HIV treatment

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  1. HIV Care 2010:The 3rd Revolution in HIV treatment Chris Farnitano, MD Noon Conference February 11, 2010

  2. Learning Objectives • Be familiar with recent advances in anti-HIV medications • Know the new threshold for initiating HIV treatment according to the December, 2009 DHHS guidelines • Be able to discuss the reasons for these more aggressive treatment guidelines

  3. Case Study: D.T. • Ms. D. T. is a 51 y.o. woman diagnosed HIV+ in 1994 with T cells=232 at that time • Long history of antiviral therapy:

  4. Case Study: D.T. • Antiviral History: • Nukes tried: • zidovudine, lamivudine, stavudine, • didanosine, abacavir • Non-nukes tried: • nevirapine

  5. Case Study: D.T. • Antiviral History: • Protease inhibitors tried: • saquinavir, indinavir, nelfinavir, ritonavir, amprenavir, lopinavir, azatanavir, • Novel agents tried: • hydroxyurea

  6. Case Study: D.T. • Genotype/Phenotype testing results: • Resistant to all nukes except tenofovir • Resistant to non-nukes • Multiple PI mutations, resistant to all protease inhibitors unless boosted with ritonavir

  7. Case Study: D.T. • June, 2008: • T cells = 62 • HRNA = 6320 • On dialysis for HIV nephropathy • Patient absolutely refuses to take even the lowest dose of ritonavir due to diarrhea and nausea • “Even looking at the Norvir pill makes me vomit”

  8. Case Study: D.T. • What to do now?

  9. The first revolution in HIV care: Slowing the damage to the immune function, delaying death from AIDS: • 1987:AZT (zidovudine) becomes the first FDA-approved anti-HIV drug • 1989: FDA approves aerosolized pentamidine for PCP prophylaxis • 1989: CDC recommends use of TMP/SMZ (Septra/Bactrim) for PCP prophylaxis • PCP prophylaxis adds 2 years to HIV+ pt lifespan • 1991:DDI (didanosine) approved by FDA

  10. US AIDS Cases and Deaths

  11. The 2nd revolution in HIV care:Restoring the damaged immune system,Improving health of HIV+s • 1995: lamivudine approved by FDA • 1995: saquinavir approved as first protease inhibitor • 1996: nevirapine approved as first non-nuke drug • 1996: ritonavir, indinavir approved

  12. The 3rd revolution in HIV care:Preventing immune related damage • June, 06: Darunavir, protease inhibitor with efficacy against highly PI-resistant virus, approved by FDA • August, 07: Maravaroc, first CCR5 co-receptor blocker approved • October, 07: Raltegravir, first integrase inhibitor approved • January, 08: Etravirine, first of 2nd generation non-nukes approved

  13. The 3rd revolution in HIV care:Preventing immune related damage December, 09: DHHS revises guidelines on when to start therapy:

  14. 2009 guidelines

  15. Why the change? • Better, less toxic drugs • Increased recognition of harms of uncontrolled viral replication • Accumulating data showing better outcomes with earlier therapy • (Public health benefit?)

  16. Better, less toxic drugs June, 2006: Darunavir, protease inhibitor with efficacy against highly PI-resistant virus, approved by FDA August, 07: Maravaroc, first CCR5 co-receptor blocker approved October, 07: Raltegravir, first integrase inhibitor approved January, 08: Etravirine, first of 2nd generation non-nukes approved

  17. Better, less toxic drugs: darunavir • Prezista (darunavir) protease inhibitor -1 tablet (600 mg) twice a day with food • Take with 1 tablet Norvir (ritonavir 100mg) twice a day • Works against protease inhibitor resistant virus • SE: rash, abd pain, constipation, headache

  18. Better, less toxic drugs: maraviroc • Selzentry (maraviroc) CCR5 co-receptor blocker • Take 1 tablet (300mg) with or without food twice a day • 150mg bid c ritonavir boosted protease inhibitors • 600 mg bid c etravarine or efavarenz • 150 mg bid c ritonavir and etravarine • dose adjustment also needed with clarithromycin, itraconazole

  19. Better, less toxic drugs: maraviroc • Selzentry (maraviroc) CCR5 co-receptor blocker • need CCR5 tropism assay to see if will respond • 80% of treatment experienced patients with Tcells<100 have CXCR4 virus • SE: uncommon: cough 5-10%, dizziness, fever, rare liver toxicity

  20. HIV tropism assay

  21. Better, less toxic drugs: raltegravir • Isentress (raltegravir) integrase inhibitor • 1 tablet (400 mg) twice a day with or without food • SE: uncommon: nausea, dizziness • Avoid dosing with metal ions (calcium, ant-acids)

  22. Better, less toxic drugs: raltegravir

  23. Better, less toxic drugs: etravirine • Intelence (etravirine) non-nucleoside reverse transcriptase inhibitor • 2 tablets (100 mg each) twice a day with food • Effective against 1st gen NNRTI resistant virus (K103N, Y181C) • SE: 10-18% of men and 34% women get transient rash • Contraindicated with atazanavir, fosamprenavir, tipranavir (levels markedly incr or dec.)

  24. New drugs darunavir and raltegravir move into preferred first line therapy

  25. Options for Once-daily Therapy • Options with evidence of QD efficacy: • TDV + FTC* • TDV + DDI • TDV + 3TC • DDI + 3TC • ABC + 3TC • EFV* • ATV/rtv* • DRV/rtv* • NVP • F-AMP/rtv • SQV/rtv • LPV/rtv + *indicates preferred regimen for initial therapy, DHHS guidelines

  26. Most patients can control their virus

  27. Why the change? • Better, less toxic drugs • Increased recognition of harms of uncontrolled viral replication • Accumulating data showing better outcomes with earlier therapy • (Public health benefit?)

  28. Increased recognition of harms of uncontrolled viral replication • Neuropathy • Nephropathy • Acceleration of liver disease in Hep B/C co-infected • Increased risk of many different cancers • Accelerated atherosclerosis • CNS dysfunction • Malaise, fatigue, lipodystrophy

  29. Increased recognition of harms of uncontrolled viral replication

  30. Why the change? • Better, less toxic drugs • Increased recognition of harms of uncontrolled viral replication • Accumulating data showing better outcomes with earlier therapy • (Public health benefit?)

  31. NA-ACCORD analysis • Analysis of 17,517 asymptomatic HIV+ US and Canada • Antiretroviral naive • Compare mortality between those starting ART at: • <350 (deferred) vs • CD4 350-500 • CD4 >500 • Kitahata, NEJM, 2009

  32. NA-ACCORD analysis: Retrospective case control study • Higher risk of death in deferred ART group vs >350 CD4 • CD4 <350 vs 350-500 N=8362 • Relative risk 1.69 (95% CI 1.26-2.26) of death • CD4 <500 vs >500 N=9155 • Relative risk 1.94 (95% CI 1.37-2.79) of death • Other predictors of mortality: older age, injection drug use and HCV

  33. When to Start Consortium: Prospective case matched study

  34. When to Start Consortium

  35. Why the change? • Better, less toxic drugs • Increased recognition of harms of uncontrolled viral replication • Accumulating data showing better outcomes with earlier therapy • (Public health benefit?)

  36. Can more aggressive treatment break the back of the epidemic?

  37. Can more aggressive treatment break the back of the epidemic? Model for Elimination of HIV Transmission: Generalized epidemic in South Africa (17% prevalence): Developed model to predict outcomes Population aged 15 and above Annual HIV testing Treat for all newly identified cases Assume infectiousness falls to 1% of pre-ART HIV elimination defined as reduction in incidence <1/1000 people/year Granich, Lancet, 2009

  38. Can more aggressive treatment break the back of the epidemic?

  39. Can more aggressive treatment break the back of the epidemic?

  40. Can more aggressive treatment break the back of the epidemic? Universal HIV testing and immediate ART combined with other prevention interventions • 95% reduction in new HIV cases in 10 years • Incidence reduced from 15-20,000 to 1000 per million • Prevalence less than 1% by 2050 • Initial resources higher but over time, given the reduction in HIV incidence, this approach may provide cost savings • Estimated costs are within UNAIDS estimates for Universal Access for a population this size.

  41. Case Study: D.T. • Genotype/Phenotype testing results: • Resistant to all nukes except tenofovir • Resistant to all 1st gen. non-nukes • Multiple PI mutations, resistant to all protease inhibitors unless boosted with ritonavir

  42. Case Study: D.T. June, 2008: T cells = 62 HRNA = 6320 On dialysis for HIV nephropathy Patient absolutely refuses to take even the lowest dose of ritonavir due to diarrhea and nausea “Even looking at the Norvir pill makes me vomit”

  43. Case Study: D.T. What to do now?

  44. Case Study: D.T. • Started on tenofovir/lamivudine, etravarine, raltegravir • Tolerates well with no noticeable side effects

  45. Case Study: D.T. • 3 months later: • T Cells= 148 • Viral load <48 • 18 months later: • T Cells= 382 • Viral load <48 • Patient in UCSF transplant program, awaiting donation of living related donor kidney (cousin)

  46. It’s an infection, stupid, so treat it!

  47. Hope!

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