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

New HIV diagnoses (Adjusted) among MSM, UK,

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

Clinical trial evidence for preventing sexual HIV transmission –2011 Efficacy Study Effect size (CI) Medical male circumcision (Orange Farm, Rakai, Kisumu) 54% (38; 66) HIV Vaccine (Thailand) 31% (1; 51) 0% % Modified from Slim Karim 6 th Transmission Workshop, 2011

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

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

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

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

Microbicides: Efficacy trials pre-ARV ProductEffectConfidence interval Interpretation at the time N ?harm Savvy too few events Carraguard poor adherence CS ?pH ?osmolality 0.5% PRO % PRO reduced activity after coitus Buffer Gel lack of potency

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

Science July 2011

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

Transmission Virus Concentration in Extracellular Fluid or Plasma (c/ml) Time Postexposure (days) Set Point Limit of detection for HIV RNA Reservoir Symptoms Virus dissemination Window of Opportunity? Established Infection Transit. eclipse 10 0 HIV-1 Acquisition and Acute Infection

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

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

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

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…

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) PrEP in Macaques Garcia-Lerma et al. PLoS Med 2008

iPrEX Study

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

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: ) Higher pregnancy rate in the women taking truvada Self-reported adherence ~ 95% overall

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

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

Primary efficacy results TDFFTC/TDFPlacebo Number of HIV infections HIV incidence, per 100 person-years HIV protection efficacy, vs placebo 62%73% 95% CI(34-78%)(49-85%) p-value0.0003< Z-score, vs. H 0 = Primary analysis: modified intention-to-treat (mITT) excluding infections present at randomization (3 TDF, 3 FTC/TDF, 6 placebo) ITT analysis results similar Effect of TDF and FTC/TDF statistically similar (p=0.18)

Subgroup analysis - gender Efficacy95% CIP-valueInteraction p-value TDF Women Men 68% 55% 29-85% 4-79% p=0.01 p=0.04 p=0.54 FTC/TDF Women Men 62% 83% 19-82% 49-94% p=0.01 p=0.001 p=0.24 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

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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TDF-2: Efficacy – Intention-to-Treat Analysis 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 Using 33 Seroconverters TDF-FTCPlaceboEfficacy95% CIP-value Female , Male , Using 23 Seroconverters TDF-FTCPlaceboEfficacy95% CIP-value Female , Male ,

Dumond et al. CROI 2008 N=12 Maraviroc as PrEP? Vaginal Tissue Blood Plasma N = 12Protein-free IC 90 = 0.5 ng/ml Cervicovaginal Fluid

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

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

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

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

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

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

Partners in Prevention Study Donnell, Lancet, % reduction in HIV transmission with ART

Stable, healthy, serodiscordant couples, sexually active CD4 count: 350 to 550 cells/mm 3 Primary Transmission Endpoint Virologically-linked transmission events Primary Clinical Endpoint WHO stage 4 clinical events, pulmonary tuberculosis, severe bacterial infection and/or death HPTN 052 Study Design Immediate ART CD Delayed ART CD4 <250 Randomization

10,838 Individuals Screened Immediate Arm 886 Couples Delayed Arm 877 Couples 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 HPTN 052 Enrollment 1763 Couples (3526 Individuals) Randomized

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

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

Total HIV-1 Transmission Events: 39 HPTN 052: HIV-1 Transmission Linked Transmissions: 28 Unlinked or TBD Transmissions: 11 p < Immediate Arm: 1 Delayed Arm: 27 18/28 (64%) transmissions from infected participants with CD4 >350 cells/mm 3 23/28 (82%) transmissions in sub-Saharan Africa 18/28 (64%) transmissions from female to male partners

Granich et al Lancet 2009; 373: % 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 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 ART for Prevention: The WHO Model

Models of ART and transmission San FranciscoKatz, Am J Pub Health, 2002 Increase in risk behaviour in MSM will outweigh benefit of ART AustraliaClements, JAIDS, 2004ART benefits outweighed by increased risk in MSM South AfricaBertran, JAIDS, 2004WHO guidelines: 12% reduction in incidence US guidelines: 72% AmsterdamBezemer, AIDS, 2008Benefits of ART outweighed by increased risk behaviour in MSM British ColumbiaLima, JID, % reduction in incidence if 100% treated at CD4 <350 AustraliaWilson, Lancet, 2008ART rather than condoms may increase incidence 4 fold WHOGranich, Lancet, 2009Annual testing and universal ART could reduce prevalence of HIV to <1% Impact may be different for MSM and heterosexuals?

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

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

Role of undiagnosed and primary HIV in onward transmission Undiagnosed HIV: US: 54% of new infections come from 25% undiagnosed Marks, AIDS 2006 Amsterdam: 90% from 24% Bezemer, AIDS 2008 Brighton: 76% from 30% Fisher, AIDS 2010 Primary HIV Infection: High viral load Infectivity increased ? x PHI accounts for 10-50% of onward infections

Is the World ready yet for test-and-treat? Treating for public rather than individual health Recruitment to START has been slow… Costs associated with this £241million/year for the UK alone Ability to support infrastructure: High testing rates High uptake of treatment rates Maintenance within treatment and care Virological monitoring

Controlling the epidemic_17Jul LCM (n=590) CDM (n=617) LCM (n=109) CDM (n=78) < First-line ART Second-line ART N.B. 149 values of <400 c/ml imputed as <199 c/ml Percentage LCM (n=590) CDM (n=617) LCM (n=109) CDM (n=78) < First-line ART Second-line ART N.B. 149 values of <400 c/ml imputed as <199 c/ml Percentage LCM (n=590) CDM (n=617) LCM (n=109) CDM (n=78) < First-line ART Second-line ART N.B. 149 values of <400 c/ml imputed as <199 c/ml Percentage LCM (n=590) CDM (n=617) LCM (n=109) CDM (n=78) < First-line ART Second-line ART N.B. 149 values of <400 c/ml imputed as <199 c/ml Percentage VL at 5y in DART, by monitoring strategy C Kityo, D Dunn, R Kasirye et al CROI 2011

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

Funding HIV with comprehensive prevention The Economist, June 2011

Clinical Management Serodiscordant couples Heterosexual: good data for reduced transmission MSM no data but plausible Early ART supported by all treatment guidelines Seronegative persons with multiple partners Inform of PEP Inform of PrEP – if study available Reinforce multifaceted approach to prevention Increased testing, increased frequency of testing, and reducing undiagnosed infection central to any benefit of ART on transmission

Behavioural Intervention -Abstinence -Be Faithful HIV Counselling and Testing Coates T, Lancet 2000 Male Condoms Female Condoms Treatment of STIs Grosskurth H, Lancet 2000 Male circumcision Auvert B, PloS Med 2005 Gray R, Lancet 2007 Bailey R, Lancet 2007 Microbicides for women Abdool Karim Q, Science 2010 Treatment for prevention Donnell D, Lancet 2010 Cohen M, NEJM 2011 Behavioural positive prevention Fisher J, JAIDS 2004 Grant R, NEJM 2010 (MSM) Baeten J, 2011 (Couples) Paxton L, 2011 (Heterosexuals) Oral pre-exposure prophylaxis Post Exposure prophylaxis (PEP) Scheckter M, 2002 Vaccines Rerks-Ngarm S, NEJM 2009 COMBINATION HIV PREVENTION

Thanks Sarah Fidler Sheen MacCormack Nicky Mackie Laura Waters