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Prevention of the Sexual Transmission of HIV-1: A view from the 21st century

This article discusses prevention strategies for the sexual transmission of HIV-1, including behavioral interventions, structural interventions, vaccines, antiretroviral therapy, post-exposure prophylaxis, and pre-exposure prophylaxis.

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Prevention of the Sexual Transmission of HIV-1: A view from the 21st century

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  1. Prevention of the Sexual Transmission of HIV-1: A view from the 21st century Myron S Cohen The University of North Carolina Chapel Hill, USA

  2. EXPOSED UNEXPOSED EXPOSED (precoital/coital) (postcoital) Behavioral, Structural Vaccines ART PEP Vaccines ART PrEP Microbicides Circumcision Condoms YEARS HOURS 72h Four Prevention Opportunities Cohen et al, JCI, 2008 Cohen IAS 2008 INFECTED Treatment Of HIVReduced Infectivity YEARS

  3. Let’s Accept the Idea that …Coates et al Lancet 2008 • Abstinence or total monagomy in a SERONEGATIVE couple are effective, but difficult to achieve (…and beware concurrency) • Barrier Methods Work • Condoms (serve as a reversible barrier) • Circumcision ( form an irreversible and imperfect barrier) • HIV prevalence has fallen in many communities so some behavioral interventions work • Combination multilevel behavioral and structural approaches may ultimately prove very effective, and they certainly need continued effort

  4. But When Primary Prevention Fails… Risk of a Transmission Event Develops Cohen and Galvin, Nat Micro Rev 2004 Infectious Susceptible Inoculum (concentration) Hereditary resistance Phenotypic factors Innate resistance Acquired resistance

  5. Viral Concentration Really Matters Chakraborty et al., AIDS 2001 0.016 0.012 Probability of transmission 0.008 0.004 3 3.5 4 4.5 5 5.5 Log10 Seminal HIV RNA in one ejaculate

  6. Donor (variable) Mucosa Recipient Abortive Abortive Abortive Less fit or attenuated Time (days) 7 0 14 21 28 A Single R5 Virus from “A SWARM” Infects Keele et al., PNAS 2008

  7. Estimating HIV Transmission: Have the methods confused the message? Powers et al Lancet ID, 2008 HIV Transmission is often estimated as 1/500-1000 episodes of intercourse but only when… • Acute transmission in couples cannot be measured • STDs are RARE in the study population(s) • Condom usage cannot be readily measured • Anal intercourse is not generally practiced SEXUAL TRANSMISSION MUST ON MANY OCCASIONS BE FAR MORE EFFICIENT …

  8. HIV Transmission Efficiency By Cofactor Powers et al Lancet ID, 2008

  9. 10 8 6 4 2 0 1/30 or greater odds of transmission to a susceptible partner per coital act HIV RNA In Semen (Log10 copies/mL) AIDS Acute HIV Infection & STD Co-infection STD Episode STD Episode Amplified Transmission of HIV

  10. What about…“The STD Paradox”? Gray and Wawers, Lancet 2008 • Only 1/7 STD intervention RCTs have led to reduced transmission of HIV • So… either STDs do not “amplify” HIV transmission OR (MORE LIKELY) the interventions are inadequate?? • BUT Successful intervention requires that….. • The “RIGHT” STD(S) are treated • At JUST the right time • In JUST the right people (HIV positive or negative) • With VERY EFFECTIVE drugs(s) • For the RIGHT duration of time And treating STDs has a benefit far BEYOND the effects of HIV prevention

  11. EXPOSED UNEXPOSED (postcoital) Behavioral, Structural Vaccines ART PEP Circumcision Condoms YEARS 72h Four Prevention Opportunities Cohen et al, JCI, 2008 Cohen IAS 2008 INFECTED EXPOSED (precoital/coital) Treatment Of HIVReduced Infectivity Vaccines ART PrEP Microbicides HOURS YEARS

  12. HIV-1 Transmission Event Adapted from Johnston and Fauci, NEJM,2007. Window of Opportunity?? Established Infection 8 Symptoms 7 6 5 Set Point 4 eclipse Reservoir 3 Virus Concentration in Extracellular Fluid or Plasma (Log10 Copies/ml) Limit of detection for HIV RNA 2 1 HIV-1 Integration and Viral Dissemination 0 -1 Transit -2 -3 -4 -5 45 50 55 60 65 70 0 5 10 15 20 25 30 35 40 Time Post Exposure (days) Transmission

  13. Biological prevention options at exposure…… When Transmission is Imminent • Modification of Innate Immunity • Acquired Immunity (A VACCINE) • Neutralizing antibodies • Cell mediated immunity • Antiretroviral therapy

  14. Strategies for an HIV Vaccine Vaccine Success Transmission Cell-Mediated Immunity protection against HIV sterilizing immunity! protection against disease A reduced HV peak and “set point” no protection HIV Infection and RNA set point initial infection “controlled” chronic infection with low set point Infection prevented

  15. HIV Vaccines: Summary Walker and Burton, Science, 2008 • We do not know how to generate neutralizing antibodies • Cell mediated (CTL) vaccines lower peak viremia and set point in macaques But, human studies have not yet controlled viremia (STEP Trial) control treated Letvin, Science, 2006 WE HAVE ABSOLUTELY NO CHOICE BUT TO CONTINUE TO DEVELOP THE SCIENCE REQUIRED FOR AN HIV VACCINE…NO MATTER HOW LONG IT TAKES

  16. Using Antiretroviral Agents for Prevention?

  17. 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 Pre-Exposure Prophylaxis (PrEP) in Macaques Garcia-Lerma , PLoS Medicine 2008

  18. Current and Proposed PrEP Trials Daily TNF Daily Truvada Daily TNF Gel Coitally-dependent TNF Gel

  19. Efficacy of Oral Truvada PrEP Garcia-Lerma & Heneine (in progress) 100 -72h/+2h (n=6); p=0.01 -22h/+2h (n=6); p=0.008 75 -2h/+22h (n=6); p=0.04 50 % Uninfected animals 25 Untreated controls (n=27) 0 0 2 4 6 8 10 12 14 Number of rectal exposures

  20. Maraviroc (CCR5 blockade) as PrEP? Dumond et al. CROI 2008 Vaginal Tissue Cervicovaginal Fluid Blood Plasma protein-free IC90 = 0.5ng/mL N=12 N=12

  21. TRUVIROC T T Truviroc …fighting the viral swarm THE ULTIMATE IN PrEP??? Thinking Ahead Truvada + Maraviroc

  22. Topical Approaches for HIV-1 Prevention Klasse et al Annu Rev Med 2008 Current Microbicide Candidates (listed in latest stage of development) Tenofovir Gel Reservoir and Matrix Vaginal Rings www.microbicide.org, July 2008

  23. EXPOSED UNEXPOSED (postcoital) Behavioral, Structural Vaccines ART PEP Circumcision Condoms YEARS 72h Four Prevention Opportunities Cohen et al, JCI, 2008 Cohen IAS 2008 INFECTED EXPOSED (precoital/coital) Treatment Of HIVReduced Infectivity Vaccines ART PrEP Microbicides HOURS YEARS

  24. Post Exposure Prophylaxis Roland, 2008 • A clinical trial to PROVE that PEP works cannot be developed • PEP requires emergent usage and a full 28 days of therapy, and multiple agents • Human failures have occurred, especially after anal exposure and with delayed initiation of ART • In several reports health care providers seem to demonstrate ambivalence about the PEP strategy

  25. EXPOSED UNEXPOSED EXPOSED (precoital/coital) (postcoital) Behavioral, Structural Vaccines ART PEP Vaccines ART PrEP Microbicides Circumcision Condoms YEARS HOURS 72h Four Prevention Opportunities Cohen et al, JCI, 2008 Cohen IAS 2008 INFECTED Treatment Of HIVReduced Infectivity YEARS

  26. Secondary HIV Prevention • Transmission from those who do not know their status is important (Marks, AIDS 2006) • Transmission in HIV discordant couples represents an ongoing challenge (Dunkle, Lancet 2008) HIV TESTING REMAINS A CRITICAL LINK!!

  27. INCREASING RISK The Hierarchy of Transmission Risk..from ~36-39 Million People with HIV ? Acute HIV Infection (only 8 weeks) ? AIDS (untreated) Established infection (untreated + STDs) ? 30,000,000 people (Fraser et al, PNAS, 2007) Established infection (unrecognized) Established infection (on ART) 2.5 million people

  28. Men Women ART for Secondary Prevention Cohen et al. Annals Int Med 2006 100 Not on ART On ART • Strong biological plausibility for men and women • Retrospective clinical studies • Observational studies of couples • Ecological population studies 80 60 Patients (%) with detectable HIV in genital secretions 40 20 0 Vernazza, al., AIDS, 2000 Cu-Uvin et al., JAIDS, 2006 BUT WE DO NOT KNOW THE DEGREE OR DURABILITY OF BENEFIT FROM ART AS AN HIV-1 PREVENTION WITHIN A COUPLE (Wilson et al. Lancet, 2008)

  29. HPTN 052…AN RCT UNDERWAY(www.hptn.org/research_studies/hptn052.asp) HIV-infected subjects with 350 to 550 CD4 T cells Randomization Immediate ART 350-550cells/uL Deferred ART CD4 <250>200 AZT+3TC+EFV Endpoints: i) Transmission Events ii) OIs and Clinical Events iii) ART Toxicity

  30. Prevention of the Sexual Transmission of HIV-1:Results from Randomized Controlled Trials Wasserheit, WHO, 2007 1) RCT results are one measure of success 2) 15 RCTs in progress: new results each year

  31. HIV Prevention and Public Health Potts et al. Science, 2008 • Resources must match opportunities? • Failure to implement ideas that work? • Failure to undertake combined multi-pronged and multilevel approaches?

  32. Highly Active HIV Prevention Coates, Richter et al., 2008

  33. The Big Challenge NOW Great HIV treatment success… 22 antiretroviral agents available More than 2 million people receiving ART But 2.5 million new HIV infections/yr HIV prevention lags behind and has not married treatment except for MTCT!! HIV prevention MUST marry treatment NOW: With the community…a unified strategy

  34. Integrating HIV Prevention and TreatmentSalomon at al. PLoS Medicine, 2005 Modeling Interventions in Sub-Saharan Africa, 2004-2020

  35. THANK YOU • To the organizers • To many collaborators over 25 years • To faculty and staff at UNC-CH, and UNC Projects in Malawi, China, Madagascar and other countries • To patients and volunteers who participated in many clinical trials • To NIH, CDC, USAID, and others for funding

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