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  1. ART Advances-into the Next Decade James Hakim MB MMed MSc FRCP Professor of Medicine, University of Zimbabwe AIDS 2010 Vienna-Austria 18-23 July 2010

  2. Antiretroviral Therapy Into the Next Decade

  3. Historical PerspectivesART Milestones Vancouver 1996 Durban 2000 Barcelona 2002

  4. Key ART Initiatives National & Regional Initiatives NGO & Other Initiatives

  5. When/What is the next Milestone • ? Universal Access

  6. Status of ART Roll-Out 2009 • 5.2m PLH on ART • Most - MLIC • Infection outstrips Treatment by 5:2 • 5m more need treatment • 2010 WHO Guidelines takes this to 10 Mill

  7. Achievements of ART Kim J, Farmer P. NEJM 2006 • Improved survival • Decreased opportunistic infections • Improved quality of life Restores Hope & Dignity

  8. Mortality RLS vs RRS Braitstein P. Lancet 2006;367;817 • ART-LINC vs ART-CC comparisons Adjusted HR 1-6 mths - 4.3 (95%CI 1.6-11.8) 7-12 mths-1.5 (95% CI 0.7-3.0) Mortality

  9. Mortality in RRS • Resource rich settings • Increasing importance of non-AIDS illnesses beyond second year ART-CC CID 2010;50:1387

  10. Mortality in RLS Lawn S. AIDS 2008;22:1897 Lawn S. AIDS 2009;23:335 • High early mortality after initiation of ART • Causes • Tuberculosis • Acute sepsis • Cryptococcal disease • Malignancy (KS) • P jiroveci • Others Impact of time spent on various CD4 strata on mortality

  11. Other Achievements of ART • Impact: • Tuberculosis • Maternal and child mortality • Hogan M, et al. Lancet 2010;375:1609 • Improves school attendance & workforce • Zivin J, et al. J Publ Econ 2009;93:1008 • Thirumurthy H, et al. J Hum Res 2008;43:511 • HIV transmission • Donnell D, et al. Lancet 2010;375:2092

  12. Impact on Tuberculosis Middelkoop K, et al. IAS C Town 2009; Am J Resp Crit Care 2010; Jun 25 Severe P, et al. NEJM 2010;363:257 • Ecological analysis • Fall in TB prevalence in HIV patients • 1,250 pts in S. Africa • RCT • Early vs Delayed ART • 816 participants • TB cases: • 18 vs 36 p=0.0125

  13. ART in the Developing World • Implementation has been greatly helped by WHO guidelines • 2002 • 2003 • 2006 • 2010 2010 WHO ART Guidelines for Adults & Adolescents Guidelines

  14. Early Initiation of ART CD4 threshold 350c/mm3 • CIPRA-HT-001 • Severe P, et al. NEJM 2010;363:257 • 816 participants • Deaths: • 6 vs 23 p=0.0011 • Cohort Analysis • Even higher thresholds • 350-500 • >500 • Kitahata MM, et al. NEJM 2009;360:1815

  15. Guidelines-CD4 Thresholds

  16. Treat Earlier-2010 WHO Guidelines To start earlier is the right thing to do “Harmonize treatment guidelines” CD4<350 c/mm3 Seek and Treat (earlier diagnosis)

  17. Public Health Approach DART CIPRA S. Africa Jinja Uganda

  18. Survival 0.95 0.94 0.55 0.92 0.90 0.18 164 events LCM: 2.2/100 PY 0.90 0.87 0.08 1.0 CDM: 2.9/100 PY 218 events 0.8 0.6 Proportion alive 0.4 Entebbe Cohort(Uganda): pre-ART 1996-2000, median CD4 75 at enrolment: 57.7/100 PY 0.2 0.0 0 1 2 3 4 5 Years from enrolment Survival at 5 yrs: LCM-90%, CDM-87%

  19. Trained Lay Workers-monitoring ART Jaffar S, et al. Lancet 2009;374:2080 • Home-based vs Facility based care • End point-Virologic Failure (RNA >500c/ml) • 859 participants • (HBC-729 vs FBC-483) • Rate Ratio: • 1.04 (95%CI 0.78-1.4) HBC is as effective as FBC

  20. CIPRA South Africa Sanne I, et al. Lancet 2010;376:33 • Nurse monitored vs Doctor monitored • Randomized non-inferiority trial • Follow up-120 wks Nurse vs Doctor monitoring is non-inferior HR 1.09 (95% CI 0.89-1.33)

  21. Antiretroviral Drugs • NRTIs • Zidovudine • Lamuvudine • Stavudine • Didanosine • abacavir • Tenofovir • Emtricitabine • NNRTIs • Nevirapine • Efavirenz • Etraverine • Integrase Inhibitors • Raltegravir • Protease inhibitors • Lopinavir • Atazanvir • Tipranavir • Darunavir • Indinavir • Ritonavir • Nelfinavir • Saquinavir • Amprenavir • Fosamprenavir • Fusion Inhibitors • Enfuvertide • CCR5 antagonists • Maraviroc

  22. First-Line ART • Harmonized to include TB and pregnant women • ART to all TB and HBV patients • Preferred-NNRTI based regimen • Preferred use of TDF or AZT • d4T withdrawal and elimination WHO 2010 Guidelines

  23. Second-Line ART • Boosted PI-based regimens • Poor evidence of efficacy of NRTI backbone in public health approach • High resistance mutations when failure is clinically or immunologically diagnosed • Hosseinipour M, et al. AIDS 2009;23:1127 • ? Immediate use of new classes/drugs immediately (RAL, ETV, Darunavir)

  24. Second-Line ART • Need for studies to provide evidence for public health approach to second line regimens • EDCTP trial-EARNEST (enrolling) • ACTG trial • Other • The place of PI/r monotherapy

  25. Third-Line ART • Real need to treat those failing second-line ART • Can this be addressed with public health approach principles? • ? Need for resistance testing • WHO 2010 recommends drugs eg DRV, ETV, RLV • Does this obviate resistance testing?

  26. Monitoring • Issues • Efficacy tests (CD4, RNA VL) • Cost • Lab capacity • Impact on pace of roll-out • Need for evidence-based monitoring • Evidence for RNA VL monitoring is good-but availability to date is limited • Need for roll-out of low-cost point-of-care tests • CD4, RNA VL, resistance testing

  27. Monitoring • Toxicity tests • CBC • Chronic illness, AZT, malignancies, malnutrition, etc • Renal function test (which? creatinine, urine) • TDF • Other • Tropism tests, HLAB5701 (ABC)

  28. Into the Next Decade • Pipeline for new antiretroviral drugs • The pace of development has slowed in this area

  29. Into the Next Decade Treatment 2.0 • Current drugs are efficacious with good safety and tolerance • But there is still need for drugs that are: • More efficacious • Better tolerated (Better adherence) • More safe (Less monitoring) • More forgiving (Less resistance) • Compatible with TB, pregnancy, hepatitis, malaria, etc...

  30. Into the Next Decade SMART. NEJM 2006;355:2283 DAD NEJM 2007;356:1723 Bone Cardiovascular Address long- term non-AIDS complications Renal Neuro-congnitive Hepatic

  31. Into the Next Decade • Non-AIDS outcomes • unmitigated HIV replication or ART • cardiovascular, hepatic, renal, bone, neuro-cognitive effects, cancer • Aging/senescence Limited data from RLS More research required

  32. Into the Next DecadeLaboratory Monitoring • Accelerate roll-out of Point-of-care technology • CD4 counts • RNA Viral Load • Resistance • Other

  33. HIV Eradication • A preventive HIV vaccine is an important intermediate step • The eradication and cure of HIV remains the only victory that we can celebrate • The science and strategy required to achieve this is of the highest priority • Granich R. Lancet 2009;373:48 • Hütter G. NEJM 2009;360:692 • Carter C. Nature Med 2010;16:446

  34. Conclusions-Current • The last decade has seen a momentous expansion of ART in LMIC • We continue to see the benefits of ART in improved survival, reduction in disease progression & improved quality of life • ART impacts non-AIDS conditions in both negative and positive ways. This must continue to be a focus of research

  35. ConclusionsInto the Next Decade • The quest for more efficacious, better tolerated, safer and more forgiving antiretroviral drugs must continue • Better delivery modes of ART are needed to improve access to all • Preventive value of ART has come of age-pMTCT and beyond... • HIV cure remains the ultimate prize in the response to AIDS

  36. Acknowledgements • UCSF • Diana Havlir • ARASA • Michaela Clayton • Univ of Zimbabwe • Anthony Chisada • Nehemiah Nhando • Wadzanai Samaneka • Mike Chirenje • YRG-Care • Kumar Kumarasamy • University of Denver • Thomas Campbell • WHO • Marco Vitoria • Slides & Comments • Many

  37. Thank You