Myron S Cohen The University of North Carolina Chapel Hill, USA 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

Four Prevention Opportunities Cohen et al, JCI, 2008 Cohen IAS 2008 YEARS UNEXPOSED Behavioral, Structural Circumcision Condoms HOURS Vaccines ART PrEP Microbicides EXPOSED (precoital/coital) 72h Vaccines ART PEP EXPOSED (postcoital) INFECTED Treatment Of HIV Reduced Infectivity Vaccine – neutr antibodies YEARS

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

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

Viral Concentration Really Matters Chakraborty et al., AIDS 2001 0.016 0.012 Probability of transmission 0.008 Here, X axis is …. Y axis is …… explain three lines …… Explain the slope change after 4.5 log1- value of RNA values. 0.004 3 3.5 4 4.5 5 5.5 Log10 Seminal HIV RNA in one ejaculate

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

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 …

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

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

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

Four Prevention Opportunities Cohen et al, JCI, 2008 Cohen IAS 2008 YEARS UNEXPOSED Behavioral, Structural Circumcision Condoms EXPOSED 72h Vaccines ART PEP EXPOSED (postcoital) INFECTED (precoital/coital) Vaccines ART PrEP Microbicides Treatment Of HIV Reduced Infectivity Vaccine – neutr antibodies HOURS YEARS

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

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

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

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

Using Antiretroviral Agents for Prevention?

Pre-Exposure Prophylaxis (PrEP) in Macaques 2 4 6 8 10 12 14 25 50 75 100 Number of rectal exposures % Uninfected animals Controls (n = 18) Injectable FTC (n = 6) High-dose Injectable Truvada (n = 6) Oral Truvada (n = 6) Oral TDF (n = 4) Pre-Exposure Prophylaxis (PrEP) in Macaques Garcia-Lerma , PLoS Medicine 2008

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

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) 2 4 6 8 10 12 14 Number of rectal exposures

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

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

Topical Approaches for HIV-1 Prevention Klasse et al Annu Rev Med 2008 Current Microbicide Candidates (listed in latest stage of development) Tenofovir Gel Candidate Status - Phase PRO 2000 Ongoing – Phase 3 Tenofovir gel Ongoing – Phase 2B PRO 2000/BufferGel® Ongoing – Phase 2/2B Dapivirine Ongoing – Phase I Ethanol in Emollient Gel UC-781 VivaGel® Paused – Phase I ACIDFORM ™ Planned – Phase 3 Invisible Condom™ Planned – Phase 2/3 CAP vaginal soft tablet Planned – Phase I Duet® PC-815 Reservoir and Matrix Vaginal Rings www.microbicide.org, July 2008

Four Prevention Opportunities Cohen et al, JCI, 2008 Cohen IAS 2008 YEARS UNEXPOSED Behavioral, Structural Circumcision Condoms EXPOSED 72h Vaccines ART PEP EXPOSED (postcoital) INFECTED (precoital/coital) Vaccines ART PrEP Microbicides Treatment Of HIV Reduced Infectivity Vaccine – neutr antibodies HOURS YEARS

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

Four Prevention Opportunities Cohen et al, JCI, 2008 Cohen IAS 2008 YEARS UNEXPOSED Behavioral, Structural Circumcision Condoms HOURS Vaccines ART PrEP Microbicides EXPOSED (precoital/coital) 72h Vaccines ART PEP EXPOSED (postcoital) INFECTED Treatment Of HIV Reduced Infectivity Vaccine – neutr antibodies YEARS

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!!

The Hierarchy of Transmission Risk.. from ~36-39 Million People with HIV INCREASING RISK ? 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

ART for Secondary Prevention Cohen et al. Annals Int Med 2006 100 Strong biological plausibility for men and women Retrospective clinical studies Observational studies of couples Ecological population studies Not on ART On ART 80 60 Patients (%) with detectable HIV in genital secretions 40 20 Men Women 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)

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 As part of our ongoing deliberations we designed a study for RRS that could be used as the basis for statistical simulations to further address the feasibility of conducting a trial in RRS. This slide outlines the proposed trial, similar in initial design to a composite of the two trials proposed by the INSIGHT network. Endpoints: i) Transmission Events ii) OIs and Clinical Events iii) ART Toxicity

Prevention of the Sexual Transmission of HIV-1: Results from Randomized Controlled Trials Wasserheit, WHO, 2007 Intervention RCTs Completed RCTs Effective Behavior change Circumcision Diaphragms Microbicides PrEP STD Treatment Vaccines 9 4 1 9.5 7 2 3 1) RCT results are one measure of success 2) 15 RCTs in progress: new results each year

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?

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

Great HIV treatment success… 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

Modeling Interventions in Sub-Saharan Africa, 2004-2020 Integrating HIV Prevention and Treatment Salomon at al. PLoS Medicine, 2005 Modeling Interventions in Sub-Saharan Africa, 2004-2020 Scenario Millions of Total New Adult Infections Millions of Infections Averted vs. Baseline Millions of Total Adult Deaths Millions of Deaths Averted vs. Baseline Baseline 52.3 NA 37.4 Treatment-centered (optimal effects) 49.2 3.0 (6%) 32.4 5.0 (13%) Treatment-centered (mixed effects) 57.4 -5.1 (-10%) 33.9 3.5 (9%) Prevention-centered 33.2 19.1 (36%) 32.6 4.8 (13%) Combined response (optimistic) 23.4 28.8 (55%) 27.3 10.1 (27%) Combined response (pessimistic) 43.6 8.7 (17%) 31.6 5.8 (16%)

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