Dr Monica Desai. MRC Clinical Trials Unit at UCL, London. Science of PrEP. Monica Desai

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1 8 th Annual Conference of the Children s HIV Association Closing the Gap: Treatment and Prevention Dr Monica Desai MRC Clinical Trials Unit at UCL, London 8 th Annual Conference, Friday 16 th May 2014 Science of PrEP Monica Desai Public Health SpR, Public Health England Trial Physician, PROUD trial, Medical Research Council 1

2 Number of persons with diagnosed HIV infection Overview Context Rationale and proof Unanswered questions Demonstration projects PROUD pilot study HIV epidemic in the UK to date 80,000 75,000 70,000 65,000 60,000 55,000 50,000 New HIV diagnoses AIDS Deaths Total living with diagnosed HIV infection 128,805 diagnosed with HIV New diagnoses concentrated in men who have sex with men (MSM), people from sub- Saharan Africa and people who inject drugs (PWID) 27,798 first AIDS diagnoses 45,000 40,000 35,000 30,000 25,000 20,000 21,117 deaths among people living with HIV People living with HIV can now expect a near normal life expectancy with the introduction of effective ART. 15,000 10,000 5,000 0 Ageing cohort as of 2012, 1 in 4 adults accessing care were aged 50 and older. PHE HIV/STI Dept - HIV Epidemiology

3 Number of new HIV diagnoses New HIV diagnoses by exposure group: United Kingdom, ,000 5,000 Sex between men (adjusted) Heterosexual contact (adjusted) Injecting drug use (adjusted) Not reported Sex between men (observed) Heterosexual contact (observed) Other (adjusted) 4,000 3,000 2,000 1, Year of first HIV diagnosis in the UK PHE HIV/STI Dept - HIV Epidemiology Recently acquired infections among new HIV diagnoses by exposure group: England and Northern Ireland, 2012 PHE HIV/STI Dept - HIV Epidemiology

4 Treatment cascade of adults living with HIV: United Kingdom, % 100% 90% 80% 77% 73% 70% 60% 64% 58% 50% 40% 30% 20% 10% 0% HIV infected (n=94,900) HIV diagnosed (n=72,900) Retained in care (n=69,200) On treatment (n=60,700) Undetectable VL (n=52,200) PHE HIV/STI Dept - HIV Epidemiology Distribution of infectives* among HIV-infected MSM, UK: 2010, Brown et al 4

5 Why do we need new prevention strategies in the UK? # of new HIV diagnoses in MSM has surpassed new diagnoses in heterosexuals Majority of transmission from those undiagnosed NHS costs: 762 million in 2010 Life-time cost: 280, ,000 What is PrEP? Antiretroviral given before (and after) exposure to HIV negative persons to reduce HIV susceptibility and risk of infection Oral or topical Analagous to prophylaxis for malaria and use of ARV as prophylaxis to prevent transmission to HIVexposed infants 5

6 Slide from K Fenton Esacaide 2011 How might PrEP work? 6

7 ART and Male Genital Tract Exposure (percent of blood plasma) Dumond et al. The PRN Notebook 2006; 2(11) % 400% 600% IDV (100%) TDF (500%) 3TC (600%) SQV(3%) ZDV (200%) EFV (3%) ABC (150%) d4t (2%) RTV (3%) LPV (5%) NVP (70%) NRTI PI NNRTI Female Genital Tract Exposure (percent of blood plasma) Dumond et al. JAIDS 2009; 51(5): % 400% 600% ABC (40%) ddi (100%) IDV (200%) 3TC (400%) FTC (600%) SQV(ND) ZDV (200%) TDF (400%) EFV (0.6%) d4t (4%) RAL (93%) RTV (20%) DLV (20%) MVC (400%) ATV (30%) LPV (30%) ABC (40%) APV (50%) NVP (80%) Integrase CCR5 NRTI PI NNRTI 7

8 PrEP and Microbicide Studies Effect size (95% CI) Tenofovir/Truvada for discordant couples 73% (49; 85) Truvada for heterosexuals 63% (22; 83) Tenofovir for IVDUs 49% (10; 72) Truvada for MSMs 44% (15; 63) Tenofovir vaginal (coital) 39% (6; 60) Truvada for women 0% (-69; 41) Truvada for women 0% (-50; 30) Tenofovir for women 0% (-99; 3) Tenofovir gel (daily) for women Efficacy 0% % 15% (-20; 40) Trials demonstrating PrEP efficacy Study, population Drug PrEP efficacy (95% CI) Reference Partners PrEP Hetersexual couples Kenya, Uganda (n=4758) TDF 2 Heterosexuals Botswana (n=1219) BTS IDUs Thailand (n=2413) iprex MSM Brazil, Ecuador, Peru, South Africa, Thailand, US (n=2499) FTC/TDF TDF 75% (55-87%) 67% (44-81%) FTC/TDF 62% (16-83%) TDF 49% (10-72%) FTC/TDF 44% (15-63%) Baeten et al. N Engl J Med 2012 Thigpen et al. N Eng J Med 2012 Choopanya et al. Lancet 2013 Grant et al. N Engl J Med

9 Consistent adherence to daily drug = High level of protection Early adherence Those who had no tenofovir at month 1 had no tenofovir throughout Donnell et al CROI

10 Donnell et al CROI 2012 Factors associated with low adherence in oral PrEP trials Younger age (Partners PrEP, VOICE) Not in partnership (VOICE, FEM-PrEP) Low perception of risk (FEM-PrEP, iprex) Less sex (Partners PrEP, iprex) Alcohol use (Partners PrEP) Not engaging in follow up (Partners PrEP, VOICE) 10

11 HIV prevention with high adherence ART for HIV prevention PrEP for HIV prevention Estimate of HIV prevention effect with high adherence 96% (HPTN 052, near perfect adherence) -90% (When tenofovir detected) Both very powerful prevention strategies- but require high adherence Less than daily dosing May still be protective (animal and human modelling studies) Anderson et al Sci Transl Med

12 Adherence and risk of antiretroviral resistance Placebo-controlled trial- no resistance in those acquiring HIV during follow-up. Resistance only seen HIV positive at baseline. PrEP+ART: Mathematical model estimates marginal increase in resistance if add PrEP roll-out to ART roll-out (Abbas JID 2013) Key message PrEP is NOT prevention PrEP IS risk reduction It is NOT going to protect everyone that takes it every day Adherence is key, but imperfect in reality. There is some forgiveness for less than perfect adherence 12

13 PrEP questions Real world effectiveness Risk compensation Adherence Monitoring and optimisation Alternative regimens PrEP delivery and monitoring Who will pay? Who wants it? Risk behaviour Concern regarding risk compensation No evidence to support this in placebo controlled RCTs No evidence to date in open label studies (Mugwanya Lancet ID 2013) Frequency of unprotected sex acts with HIV infected partner 13

14 FDA approve Truvada FDA NEWS RELEASE For Immediate Release: July 16, 2012 Media Inquiries: Erica Jefferson, , Consumer Inquiries: 888-INFO-FDA FDA approves first drug for reducing the risk of sexually acquired HIV infection Evidence-based approach enhances existing prevention strategies Today, the U.S. Food and Drug Administration approved Truvada (emtricitabine/tenofovir disoproxil fumarate), the first drug approved to reduce the risk of HIV infection in uninfected individuals who are at high risk of HIV infection and who may engage in sexual activity with HIV-infected partners Project Pop. Design/key questions Status The Demo Project MSM/TGW East Bay Consortium LAC PATH PrEP Demo Project Active Linkage, Engagement & Retention to Reduce HIV (ALERT) CDC Foundation Demonstration Project SPARK Project NYC Project PrEPare USA Demonstration Studies (8) Young MSM of color MSM/TGW MSM MSM and heterosexual woman MSM/TGW Young MSM (15-17 years) 600 HIV-negative MSM/TGW at clinics in 3 cities. Test and link YMSM of color to services; A customized prevention package that may include PrEP. Randomized to evaluate text messaging based adherence 1200 participants in health clinic settings Identify social/behavioral factors associated with disparities in access PrEP among YMSM who are at risk for HIV infection Oct 12; Aug 14 April 2013; 2017 May 13; May 17 Jan 13; Oct 15 Pending funding. Oct 2013 Nov 12; Nov 15 HPTN 073 Black MSM Assess the initiation/acceptability/ July 13; 14

15 Project Country Pop. Design/key questions Status iprex OLE Br, Pe, Eq, SA, Th, US MSM/TGW Open Label extension Enrolled; Nov13 TDF2 FU Bots Hetero Open Label extension Nov12; Nov13 Bangkok FU Partners PrEP CHAMPS Thailand Kenya & Uganda People who inject drugs South Africa Hetero adol Open Label extension Q4 13; Q4 14 SD PrEP as bridge to ART. Aug 13; Prevention menu for adolescents WRHI South Africa FSW PrEP and TasP as combined prevention and care LVCT and SWOP National Agency Durbar & Ashodaya PrEP Demonstration Studies (10) Kenya Women, FSW, MSM Introduce PrEP into combination prevention Nigeria SD PrEP and TasP as combined prevention and care July 11; June 15 Feb 14; Sep 16 Feasibility results Dec Formative India FSW&T PrEP intro Feasibility results Oct Alternative PrEP IPERGAY (phase III) France, Canada, Germany Randomized to "on demand" (pre/post sex) Truvada versus placebo ADAPT (HPTN 067 ) (phase II) - SA, Thailand, US Randomized to daily, time-driven (twice week/post), and event-driven (BAT24) dosing NEXT-PrEP (HPTN 069/ACTG 5305 ) (phase II) - USA Randomized to different combinations Maraviroc, Maraviroc + FTC, Maraviroc + tenofovir, Tenofovir + FTC (+placebo match) 15

16 In the pipeline Vaginal gels Tenofovir FACTS 001 Dapivrine MIV150/Zn/Carrageenan Rectal Gels Tenofovir CHAARM, MTN014, 017 Silicon Rings Dapivirine Aspire, The Ring Maraviroc + Dapivirine MTN 013/IPM 026 Tenofovir CONRAD MIV150/Zn Pop Council Oral Injectable Truvada, TMC278 LA Maraviroc, S/GSK 744 Maraviroc + FTC Phase I Maraviroc + tenofovir HPTN 069 DAIDS/PSP/PMPRB Adapted from Jim Turpin s IRMA presentation PROUD Pilot Study PRe-exposure Option for reducing HIV in the UK: an open-label randomisation to immediate or Deferred daily Truvada for HIV negative gay men 16

17 PROUD Pilot MSM reporting UAI Willing to take a pill now or in 12M Randomize 500 HIV negative eligible MSM (exclude if on treatment for hepb) Risk reduction includes Truvada NOW Risk reduction includes Truvada in 12M Follow 3 monthly for up to 24 months Main endpoints: recruitment and retention 17

18 Sexually transmitted infections Comparison data: 1. Public Health England: STI data tables for England 2012; 2. Centers for Disease Control 2010 STDs in Men who have sex with men Conclusions PrEP has the potential to reduce HIV infection by -90% if taken daily and with high adherence Several real world questions remain, in particular about effectiveness, cost and implementation and delivery PrEP will not work alone to reduce HIV incidence; it is part of a broader prevention toolkit 18

19 Acknowledgements (1) Study participants MRC CTU at UCL David Dolling, David Dunn, Mitzy Gafos, Gemma Wood, Liz Brodnicki, Yolanda Collaco- Moraes, Sarah Banbury, Brendan Mauger, Yinka Sowunmi, Christina Chung, Sheena McCormack HIV & STI Dept, PHE Anthony Nardone, Noel Gill, Sarika Desai, GUMCAD team, HIV team Clinics Vanessa Apea (Barts Health NHS Trust), Nicola Mackie (St Mary s Hospital), Alan McOwan (56 Dean Street), Amanda Clarke (Claude Nichol Centre), Christine Bowman (Sheffield Teaching Hospitals NHS Foundation Trust), Charles Lacey (York Hospitals NHS Foundation Trust), Gabriel Schembri (Manchester Centre for Sexual Health), Richard Gilson (The Mortimer Market Centre), Ann Sullivan (John Hunter Clinic for Sexual Health), Iain Reeves (Homerton University Hospital NHS Foundation Trust), Michael Brady (Kings College Hospital NHS Foundation Trust), Julie Fox (Guy s and St Thomas s NHS Foundation Trust), Steve Taylor (Heart of England NHS Foundation Trust), Saye Khoo (University of Liverpool) Acknowledgements (2) Trial Steering Committee Independent members: Mike Adler (Co-Chair), Gus Cairns (Co-Chair), Dan Clutterbuck, Rob Cookson, Claire Foreman, Stephen Nicholson, Tariq Sadiq, Matthew Williams Investigator members: Brian Gazzard, Noel Gill, Anne Johnson, Sheena McCormack, Andrew Phillips Community Engagement Group Alan McOwan (Lead), Yusef Azad (NAT), Anthony Bains, Gus Cairns (NAM), Rob Cookson (LGF), Tom Doyle (Mesmac), Mitzy Gafos (MRC CTU at UCL), Justin Harbottle (THT), Matthew Hodson (GMFA), Cary James (THT), Ben McClelland (THT), Sheena McCormack (MRC CTU at UCL), Francesa McNeil (PHE), Roger Pebody (NAM), Annabelle South (MRC CTU at UCL) Gilead Jim Rooney, Rich Clarke, Matt Bosse, Murad Ruf Academia: Social media: Press: Will Nutland (LSHTM) Darren Clapich (Grindr), Simon Johnson (Gaydar) David Rowlands (Baseline), Robert Fieldhouse (Baseline), Chris O Connor (Baseline), Patrick Cash (QX) 19

20 Supplementary slides PrEP and microbicides in context Study Treatment for prevention Effect size (95% CI) 96% (73; 99) Tenofovir/Truvada for discordant couples 73% (49; 85) Truvada for heterosexuals 63% (22; 83) Medical male circumcision 54% (38; 66) Truvada for MSMs 44% (15; 63) Tenofovir vaginal (coital) 39% (6; 60) Prime boost Vaccine 31% (1; 51) 0% % Efficacy 20

21 PROUD PROUD 12 NHS Trusts led by C&W Integrated qualitative data collection led by UCL PK led by University of Liverpool Who is enrolling? Key demographics at baseline Fully enrolled as of April 2014 Data based on 494 enrolled, 443 baseline CRFs Number (N= ) Percentage (%) Age Median 35.5 IQR: Ethnicity White % Black 14 4% S Asian 27 6% Other 48 10% Maximum education University degree or above % A-levels/equivalent 73 17% No qualifications 11 3% Other 97 23% Enrolled as partners 17 (+1 triplet) 21

22 Sexual risk at baseline Median IQR Sexual partners Total Condomless receptive anal sex Condomless insertive anal sex Partnerships Number (N=440) In ongoing partnership % Living with partner % Percentage (%) Partner serostatus at last anal sex 22

23 Sexual healthcare providers knowledge of, attitudes to and practice of pre-exposure prophylaxis (PrEP) for HIV prevention: PrEP KAP Cross-sectional survey of 328 participants Recruited from professional societies, GUMNet clinics and conferences Based on currently available evidence, do you think that PrEP should be available in the UK outside of a clinical trial? 80% 70% Attitude to PrEP availability in UK 73% 66% 60% 50% 40% 30% 20% 10% 54% 41% 0% Overall Doctors Health advisers SH Nurses P<