1. HIV Care 2010: The 3 rd 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 2 nd 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 2 nd 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 1 st 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 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. 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?

40. 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 1 st 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!