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Role of ARV as Prevention

Role of ARV as Prevention. Martin Fisher Brighton and Sussex University Hospitals, UK. New HIV diagnoses (Adjusted) among MSM, UK, 2001-2010. Global HIV Epidemic. The number of new infections exceeds the number of new cases starting ART 5 million untreated at <200; 10 million at <350.

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Role of ARV as Prevention

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  1. Role of ARV as Prevention Martin Fisher Brighton and Sussex University Hospitals, UK 9th Advanced HIV Course Aix-en-Provence 2011

  2. New HIV diagnoses (Adjusted) among MSM, UK, 2001-2010

  3. Global HIV Epidemic The number of new infections exceeds the number of new cases starting ART 5 million untreated at <200; 10 million at <350

  4. Clinical trial evidence for preventing sexual HIV transmission –2011 Study Effect size (CI) Medical male circumcision (Orange Farm, Rakai, Kisumu) 54% (38; 66) HIV Vaccine (Thailand) 31% (1; 51) Efficacy 0% 10 20 30 40 50 60 70 80 90 100% Modified from Slim Karim 6th Transmission Workshop, 2011

  5. Clinical trial evidence for preventing sexual HIV transmission –2011 0% (-69; 41) Truvada for women (Kenya, SA, Tanzania) Study Effect size (CI) Treatment for prevention (Africa, Asia, America’s) 96% (73; 99) Tenofovir/truvada for discordant couples (Partners PrEP) 73% (49; 85) Truvada oral for heterosexuals (Botswana TDF2) 63% (21; 48) Medical male circumcision (Orange Farm, Rakai, Kisumu) 54% (38; 66) Truvada oral MSMs (America’s, Thailand, SA) 44% (15; 63) Tenofovir vaginal (SA) 39% (6; 60) HIV Vaccine (Thailand) 31% (1; 51) Efficacy 0% 10 20 30 40 50 60 70 80 90 100% Modified from Slim Karim 6th Transmission Workshop, 2011

  6. Outline and Aims • Biological rationale for use of ART as prevention • PEP, PrEP • Microbicides • Treatment as Prevention • Summarise latest key data on Prevention • HPTN052, PrEP studies • Implications for global HIV prevention strategies • Clinical implications

  7. EXPOSED 72 HRS HOURS YEARS YEARS (postcoital) Vaccines ART PEP Treatment of HIVReduced Infectivity Behavioral, Structural Four HIV-1 Prevention Opportunities Cohen et al. JCI 2008; Cohen. IAS Journal online 2008 INFECTED UNEXPOSED EXPOSED (precoital/coital) Vaccines ART PrEP Microbicides RX STDS Circumcision Condoms Cohen et al. JCI 2008; Cohen. IAS Journal online 2008

  8. NSI HIV (M-tropic) SI HIV (T-tropic) Semen Lamina propria Dendritic cell CD4+ CCR5+ DC-SIGN+ HIV-1 “swarm” CD4 DC-SIGN CCR5 T-cell Migration to lymphoid organs Transmitted HIV: 99% R5, 82% 1 variant Geijtenbeek TBH, et al. Cell 2000;100:587-597

  9. Microbicides: Efficacy trials pre-ARV

  10. Tenofovir 1% vaginal gel protects - CAPRISA 004IAS 2010Science 2010 10

  11. Science July 2011

  12. More data on microbicides to come… • Alternative agents: Delpivirine most advanced • Alternative methods of administration • Acceptability to women • Efficacy versus oral PrEP (VOICE)

  13. HIV-1 Acquisition and Acute Infection . Established Infection Window of Opportunity? 108 Symptoms 107 106 Set Point 105 104 eclipse Reservoir 103 Limit of detection for HIV RNA Virus Concentration in Extracellular Fluid or Plasma (c/ml) 102 101 Virus dissemination 100 10-1 Transit 10-2 10-3 10-4 10-5 45 50 55 60 65 70 0 5 10 15 20 25 30 35 40 Time Postexposure (days) Transmission

  14. Evidence: HCW case control study Cardo DM et al. N. Engl. J Med 1997; 337:1485

  15. Algorithm for nPEP Usage Significant exposure risk Negligible exposure risk >72 hours since exposure ≤72 hours Source patient known to be HIV+ Source patient of unknown HIV status nPEP not recommended nPEP recommended Case-by-case determination Based upon British and USA Guidelines

  16. Algorithm for nPEP Usage Significant exposure risk Negligible exposure risk >72 hours since exposure ≤72 hours Source patient known to be HIV+ Source patient of unknown HIV status nPEP not recommended nPEP recommended Case-by-case determination If “source” patient is on ART and undetectable? Based upon British and USA Guidelines

  17. Concerns with post-exposure prophylaxis • Cost and cost-effectiveness • Access issues (within 72 hours) • Poor tolerability of existing regimens • Multiple presentations • Patients ability to predict “risk” • Failure to demonstrate benefit at population level • Praca Onze project in Brazil • How to alter recommendations if “source” individual is on ART and “undetectable…”

  18. PrEP in Macaques 100 High-Dose Injectable Truvada (n = 6) 75 Oral Truvada (n = 6) 50 % Uninfected Animals Injectable FTC (n = 6) 25 Oral TDF (n = 4) Controls (n = 18) 0 0 2 4 6 8 10 12 14 Number of Rectal Exposures Garcia-Lerma et al. PLoS Med 2008

  19. iPrEX Study

  20. 44% reduction in HIV (95% CI: 15-63%) (p=0.005) • 58%reduction (95% CI: 32-74%)(p=0.01) if reported URAI in 6m preceding enrolment

  21. FEM-PREP – closed on 18 April 2011 Equal numbers of HIV seroconversions (28 each gp) • Women from Kenya, South Africa and Tanzania, many of whom were commercial sex workers • Daily truvada (tenofovir + emtricitabine) • 28 seroconversions in each group (estimated 95% CI for HR: 0.59-1.69) • Higher pregnancy rate in the women taking truvada • Self-reported adherence ~ 95% overall

  22. Antiretroviral Pre-Exposure Prophylaxis for HIV-1 Prevention among Heterosexual African Men and Women: The Partners PrEP Study Jared Baeten & Connie Celum on behalf of The Partners PrEP Study Team IAS 2011

  23. Partners PrEP Study 4758 HIV serodiscordant couples (HIV+ partner not yet medically eligible for ART) Randomize HIV- partners (normal liver, renal, hematologic function) TDF once daily FTC/TDF once daily Placebo once daily Follow couples for up to 36 months 1° endpoint: HIV infection in HIV- partner Co- 1° endpoint: Safety All receiving comprehensiveHIV prevention services

  24. Primary efficacy results • Primary analysis: modified intention-to-treat (mITT) • excluding infections present at randomization (3 TDF, 3 FTC/TDF, 6 placebo) Effect of TDF and FTC/TDF statistically similar (p=0.18) ITT analysis results similar

  25. Subgroup analysis - gender • Both TDF and FTC/TDF significantly reduced HIV risk in both men and women Women: 42 total infections: 8 TDF, 9 FTC/TDF, 25 placebo Men: 36 infections: 10 TDF, 4 FTC/TDF, 22 placebo

  26. Daily oral antiretroviral use for the prevention of HIV infection in heterosexually active young adults in Botswana: results from the TDF2 study MC Thigpen, PM Kebaabetswe, DK Smith, TM Segolodi, FA Soud, K Chillag, LI Chirwa, M Kasonde, R Mutanhaurwa, FL Henderson, S Pathak, R Gvetadze, CE Rose, LA Paxton for the TDF2 Study Team 27

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  29. TDF-2: Efficacy – Intention-to-Treat Analysis 30 9 HIV-infected in TDF-FTC group and 24 HIV-infected in placebo group Overall protective efficacy 62.6% (95% CI 21.5 to 83.4, p=0.0133)

  30. TDF-2: HIV Infection By Gender 31

  31. Maraviroc as PrEP? Cervicovaginal Fluid Vaginal Tissue Blood Plasma N = 12 Protein-free IC90 = 0.5 ng/ml N=12 Dumond et al. CROI 2008

  32. Why only 3 of 4 studies show a benefit? • Multiple researchers working on: • Adherence • Pharmacokinetics • Sexual behaviour • Further studies still to report

  33. Future PrEP Studies: ethical considerations • Is it ethical to have a placebo? • ANRS Study: Coital PrEP in MSM • UK: Immediate versus deferred PrEP • Will it be acceptable not to have a placebo? • “pill parties”

  34. Issues with implementing PrEP • Which drug(s)? • maraviroc, raltegravir • How often? • Daily, coitally? • Who to target? • How often to monitor? • HIV test, toxicity screening • Population impacts: condom displacement, resistance

  35. Proportion MSM in the community reporting having had an HIV test, London: 2000-2008 University College London/Health Protection Agency

  36. Thai Study: no transmissions < 1049; Tovanabutra, JAIDS 2002

  37. Meta-analysis: ART and viral load and transmission Attia, AIDS, 2009

  38. Partners in Prevention StudyDonnell, Lancet, 2010 92% reduction in HIV transmission with ART

  39. HPTN 052 Study Design Stable, healthy, serodiscordant couples, sexually active CD4 count: 350 to 550 cells/mm3 Randomization Immediate ART CD4 350-550 Delayed ART CD4 <250 Primary Transmission Endpoint Virologically-linked transmission events Primary Clinical Endpoint WHO stage 4 clinical events, pulmonary tuberculosis, severe bacterial infection and/or death

  40. HPTN 052 Enrollment 10,838 Individuals Screened Major reasons for exclusion: 3058 HIV+ but CD4 count out of range 2565 HIV- but HIV+ partner ineligible 308 Seroconcordant couples 155 Ineligible due to sexual history 1763 Couples (3526 Individuals) Randomized Immediate Arm 886 Couples Delayed Arm 877 Couples

  41. HPTN 052 Enrollment (Total Enrollment: 1763 couples) U.S. Thailand India Americas 278 Kenya Malawi Asia 531 Brazil Zimbabwe Botswana South Africa Africa 954

  42. HPTN 052: HIV-1 Transmission Total HIV-1 Transmission Events: 39 Immediate Arm 4 Delayed Arm 35 p < 0.0001

  43. HPTN 052: HIV-1 Transmission Total HIV-1 Transmission Events: 39 Linked Transmissions: 28 Unlinked or TBD Transmissions: 11 • 18/28 (64%) transmissions from infected participants with CD4 >350 cells/mm3 • 23/28 (82%) transmissions in sub-Saharan Africa • 18/28 (64%) transmissions from female to male partners Immediate Arm: 1 Delayed Arm: 27 p < 0.001

  44. 1980 2000 2020 2040 ART for Prevention: The WHO Model • Annual testing by all >15 year old individuals • All HIV+ individuals started on ART immediately • 99% decrease in infectiousness • High adherence with ART • Low failure with first line ART • 95% reduction in new HIV cases in 10 years • HIV Incidence reduced from • 15-20,000 to 1000 per million • Prevalence decreases to less than 1% by 2050 Granich et al, Lancet 2009 Granich et al Lancet 2009; 373:48-57

  45. Models of ART and transmission Impact may be different for MSM and heterosexuals?

  46. Spectrum of Engagement in HIV Care - USA The authors estimated that only about 19% of HIV infected individuals in the USA have an undetectable HIV-1 RNA level Gardner E, McLees M, Steiner J, del Rio C, Burman W, Clin Infect Dis. (2011) 52 (6): 793-800

  47. Might test-and-treat work differently in different contexts? • Heterosexual epidemic • Lower partner change rate • Less concurrency • Most transmissions occur from established infection • Homosexual epidemic • High rates of partner change • More concurrency • High rates of onward transmission from acute infection

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