Treatment as prevention - The PROUD study and implications for future HIV prevention 18th March 2015 Sheena McCormack MRC Clinical Trials Unit at UCL 56 Dean Street@Chelsea and Westminster Imperial College

Disclaimers Grants Gilead Sciences contributed drug and a grant for diagnostics for PROUD

Definitions Treatment FOR prevention = an individual care decision to take treatment in order to become undetectable with negligible risk for onward transmission to sexual partners Treatment AS prevention = a public health strategy to offer treatment to HIV positive individuals at the point of diagnosis in order to reduce community viral load Pre-exposure prophylaxis = taking treatment BEFORE AND AFTER exposure to HIV Post-exposure prophylaxis = starting treatment AFTER the exposure to HIV  ?  ?

Treatment FOR prevention

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

Primary Transmission Endpoint Primary Clinical Endpoint HPTN 052 Study Design Stable, healthy, serodiscordant couples, sexually active CD4 count: 350 to 550 cells/mm3 Immediate ART CD4 350-550 Delayed ART CD4 <250 Randomization 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 Enrollment Immediate Arm 886 Couples Delayed Arm 877 Couples 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 We screened 10, 838 infected people to enroll 1763 couples. Note that the couples were equally distributed in groups. 50% of the infected participants were men Immediate Arm 886 Couples Delayed Arm 877 Couples

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

Treatment FOR Prevention Study Effect size (95% CI) 96% (73; 99) HPTN 052 0% 10 20 30 40 50 60 70 80 90 100% Efficacy

Treatment AS Prevention Study Effect size (95% CI) 0% 10 20 30 40 50 60 70 80 90 100% A third were infected from outside partnership Three ongoing trials to address public health benefit Efficacy

Pre-exposure prophylaxis

What is PrEP? How might it work? Drug given to HIV uninfected individuals before and after exposure to HIV Pills, topical (in a gel, pessary or released from intravaginal ring) or injectable HIV is thought to cross into cells within 60 minutes, and evidence that the virus is multiplying can be detected after 4-5 hours HIV virus can be detected in the blood as early as 5 days after exposure So the window for active drug is 30 minutes – 5 days

FDA approve Truvada for PrEP FDA NEWS RELEASE For Immediate Release: July 16, 2012 Media Inquiries: Erica Jefferson, 301-796-4988, erica.jefferson@fda.hhs.gov 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

Fully enrolled as of December 2009 Sites 11 Participants 2499 San Francisco Boston Chiang Mai Iquitos Guayaquil Sao Paulo Lima Rio de Janeiro Cape Town New England Journal of Medicine, online Nov 23, 2010

The iPrEx Study MSM and Trans Women Comprehensive Prevention Package Randomized 1:1 Daily Oral PREP FTC/TDF vs Placebo Followed Monthly

Partners PrEP Study: Sites Eldoret, Kisumu, Nairobi, Thika, Kenya Jinja, Kabwohe, Kampala, Mbale, Tororo, Uganda

Partners PrEP Study 4758 HIV serodiscordant couples (HIV+ partner not yet medically eligible for ART) TDF once daily Placebo once daily Randomize HIV- partners (normal liver, renal, hematologic function) 1° endpoint: HIV infection in HIV- partner Co- 1° endpoint: Safety Follow monthly for up to 36 months FTC/TDF once daily All receiving comprehensive HIV prevention services 17

Several trials – but inconsistent Effect size (95% CI) Tenofovir/Truvada for discordant couples 73% (49; 85) Truvada for heterosexuals 63% (22; 83) 0% 10 20 30 40 50 60 70 80 90 100% Tenofovir for IVDUs 49% (10; 72) 39% (6; 60) Tenofovir vaginal (coital) Truvada for MSMs 44% (15; 63) Truvada for women 0% (-69; 41) Truvada for women 0% (-50; 30) Tenofovir for women 0% (-99; 3) Tenofovir gel (daily) for women 15% (-20; 40) Efficacy

Why didn’t PrEP work in all the trials?

Why so different? Adherence… PrEP is approximately 90% effective when drug (tenofovir) is detected

UK stakeholder concerns, 2011 PrEP could change condom behaviour Choice of partner Type of sex Increasing exposure to those who are very infectious (and don’t know it because their last test was HIV negative) Increase in other STIs How can we pay for it? Toxicity, resistance

PRe-exposure Option for HIV prevention in the UK: immediate or Deferred http://www.proud.mrc.ac.uk/ 22 22

Rationale To determine whether PrEP worked as well as iPrEx in this setting (44% reduction in HIV) Why might effectiveness be less in real world? Adherence less trial schedules monthly well resourced for adherence support Behaviour riskier For these reasons, the study design needs to be open-label with a ‘no-PrEP’ control

PROUD Pilot GMSM reporting UAI last/next 90days; 18+; and willing to take a pill every day Randomize HIV negative MSM (exclude if treatment for HBV/Truvada contra-indicated) Risk reduction includes Truvada NOW Risk reduction includes Truvada AFTER 12M We created a randomised PrEP versus no-PrEP situation in the first year of follow-up. In the second year of follow-up, everyone has access to PrEP. Follow 3 monthly for up to 24 months Main endpoints in Pilot: recruitment and retention From April 2014: HIV infection in first 12 months 24 24

Designed to mimic real-world Eligibility: routine clinic data and p24Ag/Ab serology at enrolment (no PCR) Safety: serum creatinine when starting and annually; additional tests if 1+ protein on dipstick STIs: (mainly) quarterly HIV, syphilis, HCV, gonorrhoea and chlamydia according to routine clinic Behaviour change interventions according to routine clinic (sexual risk, adherence, addiction) Study procedures: web-randomisation, data entry, participant-completed questionnaires

Participant randomization 545 enrolled 276 assigned to IMMEDIATE (IMM) 269 assigned to DEFERRED (DEF)

Baseline demographics (n=539) Characteristics Immediate Deferred Median Age 35 (IQR: 30 – 43) 35 (29 – 42) Age N (%) 18-30 70 (26%) 79 (30%) 30-40 111 (41%) 101 (38%) >40 92 (34%) 86 (32%) Ethnicity White 211 (77%) 210 (79%) Irish 9 (3%) 8 (3%) Indian, Pakistani, Bangladeshi Black Caribbean, African, other 11 (4%) 10 (4%) Mixed ethnic group 15 (6%) Chinese 5 (2%) 6 (2%) Other 19 (7%) Missing 0 (0%) 2 (0%) Born UK No 110 (40%) 107 (40%) Yes 162 (59%) 159 (60%) 1 (0%) 539/545 (99%) CRFs returned

Baseline demographics Characteristics Immediate Deferred Maximum Education   No qualifications 9 (3%) 5 (2%) O-levels/GCSEs/Equivalent 31 (11%) 29 (11%) A-levels/Equivalent 41 (15%) 45 (17%) University Degree or above 162 (59%) 165 (62%) Still in full-time education 7 (3%) 12 (5%) Vocational training 15 (5%) Other qualifications 3 (1%) Missing 1 (0%) 0 (0%) Employment Full time 191 (70%) 195 (73%) Part-time 26 (10%) Students (fulltime) Unemployed 24 (9%) 20 (8%) Retired Other 8 (3%)

Baseline demographics Characteristics Immediate Deferred Sexuality Gay/homosexual 262 (96%) 250 (94%) Bi-sexual 5 (2%) 11 (4%) Straight/heterosexual 3 (1%) Missing 2 (1%) Current Relationship Status Yes and living with partner 88 (32%) 72 (27%) Yes and not living with partner 49 (15%) 46 (17%) No ongoing relationship 145 (53%) 147 (55%) 0 (0%) 1 (0%)

Baseline demographics Drug use in last 3 months Immediate Deferred Mephedrone 35% 38% GHB/GBL (liquid ecstasy) 32% 30% Crystal meth (methamphetamine) 19% 17% Poppers (amyl nitrate) 49% Viagra 44% 39% Cocaine (coke) 26% 25% Cannabis (marijuana, grass) 24% Ecstasy (E) 15% 18% Ketamine (K) Other 8% 5% Speed (amphetamine) 6% 4% Anabolic steroids 3% 74% in immediate and 72% in deferred arm used recreational drugs

Baseline behaviour Immediate Deferred Clinic visits in last 12 months Median (IQR) HIV testing 3 (IQR 2-4) STI testing Immediate Deferred PEP use in last 12 months Number (%) At least once 92 (33%) 92 (34%) More than once 36 (13%) 35 (13%)

Baseline self-reported STIs in last 12 months

HIV risk reduction strategies

Results: HIV endpoint 34 34

Calculation of person-years: 545 enrolled 276 assigned to IMMEDIATE 269 assigned to DEFERRED 2 HIV +ve at enrolment 7 no HIV test after enrolled 1 HIV +ve at enrolment 12 no HIV test after enrolled 267 contribute to effectiveness analysis 256 contribute to effectiveness analysis Participants could contribute the following to the person years of data for the main analysis, depending on which of these three timepoints came first. A full year before the protocol was changed The time up until they accessed PrEP which could be less than a year after the protocol change, as 139 participants on the deferred arm had not reached month 12 when we were advised to change to study protocol and offer everyone PrEP in October 2014. It could also be more than a year if they were in the deferred group and had defaulted from follow-up so came after 12 months to access PrEP The time up to their first HIV positive test. Calculation of person-years: From enrolment to the first of the following HIV test at m12, or HIV test at the time of access to PrEP, or diagnosis of HIV infection

Individual incident HIV infections Individual incident infections with the most recent HIV negative result, and the first positive HIV result The red bar indicates the time at which the window opened for the month 12 visit. There were 2 infections in the immediate and 6 in the deferred diagnosed at the first follow-up visit, all of whom could have caught HIV before enrolment. If they were all dropped the effectiveness there would still be a huge difference between the groups. Of the three immediate infections, one participant had a significant exposure in the week before enrolment which was too late for PEP. He took 15 doses of truvada before his HIV positive test. Although a sample taken 5 days later was negative for tenofovir in the plasma, this was as expected and the fact that he had the 184 minority mutation supports his story of taking Truvada. The second individual did not return after enrolment and was diagnosed at a different clinic. The third individual defaulted after three months and was later admitted to another hospital with a seroconversion illness. He told that hospital staff that he had not been taking PrEP for months and had no mutations.

HIV Incidence Efficacy =86% (90% CI: 58 – 96%) P value =0.0002 Group No. of infections Follow-up (PY) Incidence (per 100 PY) 90% CI Overall 22 453 4.9 3.4–6.8 Immediate 3 239 1.3 0.4–3.0 Deferred 19 214 8.9 6.0–12.7 Efficacy =86% (90% CI: 58 – 96%) P value =0.0002 Rate Difference =7.6 (90% CI: 4.1 – 11.2) Number Needed to Treat =13 (90% CI: 9 – 25) 86% reduction is greater than seen in placebo-controlled HIV prevention trials. The 90% confidence interval gives us 95% confidence around the lower bound of 58% reduction. The 95% lower bound is 52% - both exceed the 50% reduction we considered would make a useful impact on our epidemic. Rate difference is important for public health as it informs the number who would need to be treated. The number of gay men who need to be treated for one year to avert one infection is very low – only 13.

Drug Resistance 3 of 6 individuals who were seroconverting around baseline (immediate group) or month 12 (deferred group) developed M184V/I mutations (as a mixture with wild type) K65R was not detected

Prescribing, Tolerability Results: Prescribing, Tolerability 39 39

Prescriptions of PrEP and PEP Immediate Deferred 14 (5%) never started PrEP 156 (56%) prescribed sufficient drug for 100% daily dosing Overall, drug prescribed covered 86% of days in follow-up Anecdotally, rare use of PrEP These data are taken from the prescribing data on the visit case record form SORT OUT LINE THICKNESS 13 (5%) prescribed PEP (total 15 prescriptions) 83 (31%) prescribed PEP (total 174 prescriptions)

PrEP interruptions for medical event PrEP interrupted by 28 participants (both groups) but only 13 had events considered related to drug: Nause alone or with diarrhoea/abdominal pain/aches and fatigue (n=5) Decline in creatinine clearance (n=2) Headache (n=2) Joint pain, with fatigue in one case (n=2) Sleep disturbance (n=1) Flu-like illness (n=1) PrEP re-started: by 11 of 13 participants above This is taken from the larger dataset We are still chasing missing AE forms so this could be an underestimate.

Results: STI endpoints 42 42

STIs

STIs Caveat Number of screens differed between the groups: e.g. Rectal gonorrhoea 974 in the IMM group and 749 in the DEF

Results: Sexual behaviour 45 45

Reported sexual behaviour Anal sex partners in last 90 days BASELINE (n=539) ImmediateMedian (IQR) Deferred Median (IQR) Total number of partners 10.5 (5-20) 10 (4-20) Condomless partners, participant receptive 3 (1-5) 2 (1-5) Condomless partners, participant insertive 2.5 (1-6) 3 (1-7) Ongoing analyses as we are still collecting month 12 questionnaires, but with this preliminary dataset the picture at month 12 is very similar to baseline. There is some suggestion of a change in the upper quartile between the groups. If there is a question, the most important point to emphasise is that we don’t have all the data yet.

Reported sexual behaviour Anal sex partners in last 90 days BASELINE (n=539) ImmediateMedian (IQR) Deferred Median (IQR) Total number of partners 10.5 (5-20) 10 (4-20) Condomless partners, participant receptive 3 (1-5) 2 (1-5) Condomless partners, participant insertive 2.5 (1-6) 3 (1-7) Anal sex partners in last 90 days MONTH 12 (n=358) ImmediateMedian (IQR) Deferred Median (IQR) Total number of partners 10 (3-25) 8 (3-15) Condomless partners, participant receptive 2 (1-7) 2 (1-5) Condomless partners, participant insertive 3 (1-8) 2 (1-6) Ongoing analyses as we are still collecting month 12 questionnaires, but with this preliminary dataset the picture at month 12 is very similar to baseline. There is some suggestion of a change in the upper quartile between the groups. If there is a question, the most important point to emphasise is that we don’t have all the data yet.

Conclusions from PROUD HIV incidence in the population who came forward to access PrEP was much higher than predicted based on all MSM attending sexual health clinics, despite extensive use of PEP in the deferred period Our concerns about PrEP being less effective in the real world were unfounded MSM incorporated PrEP into existing risk reduction strategies which continued to include condom use There was no difference in STIs, which were common in both groups Clinics were able to adapt routine practice to incorporate PrEP

Policy activities PrEP policy sub-group of National HIV Clinical Reference Group established September 2014 Evidence review completed for published trials, reviewed December 2014 Cost-effectiveness underway and Clinical pathway drafted – for review 30 March 2015 BHIVA/BASHH Position Statement being updated On target for a decision that could be implemented in April 2016

Evidence required for policy Size of effect and strength of evidence Cost-effectiveness Also takes account of.. Value for money in comparison to other interventions, affordability Stakeholder opinion

Treatment FOR Prevention Study Effect size (95% CI) 96% (73; 99) HPTN 052 0% 10 20 30 40 50 60 70 80 90 100% Efficacy

Post-exposure prophylaxis Study Effect size (95% CI) 0% 10 20 30 40 50 60 70 80 90 100% But PEP and PEPSE are policy – 28 days of it, in spite of the fact that HIV is disseminated 5 days after transmission Efficacy

We can’t afford to ignore this! Summary PrEP works if you take it – extremely well PROUD has addressed the main concerns raised by UK stakeholders, in a cohort that was Already engaged with SH clinics providing integrated service and motivated to reduce their risk, but Unable to use condoms consistently Overwhelming evidence base for PrEP – especially when compared to PEP Cost effectiveness inevitable as the number that need to be treated to avert one infection is only 13 We can’t afford to ignore this!

Acknowledgements (1) Study participants MRC CTU at UCL Sarah Banbury, Liz Brodnicki, Christina Chung, Yolanda Collaco-Moraes, Monica Desai, David Dolling, David Dunn, Mitzy Gafos, Sajad Khan, Brendan Mauger, Sheena McCormack, Yinka Sowunmi, Gemma Wood HIV & STI Dept, PHE Monica Desai, Sarika Desai, Noel Gill, Anthony Nardone, GUMCAD team, HIV team Clinics Vanessa Apea (Barts Health NHS Trust), Christine Bowman (Sheffield Teaching Hospitals NHS Foundation Trust), Michael Brady (Kings College Hospital NHS Foundation Trust), Martin Fisher (Claude Nichol Centre), Julie Fox (Guy’s and St Thomas’s NHS Foundation Trust), Richard Gilson (The Mortimer Market Centre), Charles Lacey (York Hospitals NHS Foundation Trust), Nicola Mackie (St Mary’s Hospital), Alan McOwan (56 Dean Street), Iain Reeves (Homerton University Hospital NHS Foundation Trust), Gabriel Schembri (Manchester Centre for Sexual Health), Ann Sullivan (John Hunter Clinic for Sexual Health), Steve Taylor (Heart of England NHS Foundation Trust)

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 Gilead: Matt Bosse, Rich Clarke, Jim Rooney, Murad Ruf University of Liverpool: Saye Khoo Independent Data Monitoring Committee: Anton Pozniak, Simon Collins, Fiona Lampe Community Engagement Group Community: Yusef Azad (NAT), Gus Cairns (NAM), Rob Cookson (LGF), Tom Doyle (Mesmac), Justin Harbottle (THT), Marion Wadibia (NAZ), Matthew Hodson (GMFA), Cary James (THT), Roger Pebody (NAM) Clinics: Anthony Bains, Alan McOwan (Lead), MRC CTU at UCL: Sheena McCormack, Mitzy Gafos, Annabelle South Social Science Advisory Group Interviewers: Caroline Rae, Gill Bell, Michael Rayment, Sonali Wayal, Will Nutland, Mitzy Gafos Advisors: Ingrid Young, Ford Hickson, Lisa McDaid, Marsha Rosengarten, Nicolas Lorente, Agata Pacho, Elizabeth Poliquin, Anthony Nardone, Catherine Dodds, Adam Bourne, David Dolling, Sheena McCormack, Rob Horne

Ipergay : Event-Driven iPrEP 2 tablets (TDF/FTC or placebo) 2-24 hours before sex 1 tablet (TDF/FTC or placebo) 24 hours later 1 tablet (TDF/FTC or placebo) 48 hours after first intake Friday Saturday Sunday Monday Tuesday Wednesday Thursday

HIV-1 Infection (mITT Population) KM Estimates of Time to HIV-1 Infection (mITT Population) Figure 2. Kaplan–Meier Estimates of Time to HIV Infection (Modified Intention-to-Treat Population). The cumulative probability of HIV acquisition is shown for the two study groups. The efficacy of preexposure prophylaxis with emtricitabine and tenofovir disoproxil fumarate (FTC–TDF) was 44%, as compared with placebo (P=0.005). The inset graph shows a more detailed version of the overall graph up to a probability of 0.10. Mean follow-up of 13 months: 16 subjects infected 14 in placebo arm (incidence: 6.6 per 100 PY), 2 in TDF/FTC arm (incidence: 0.94 per 100 PY) 86% relative reduction in the incidence of HIV-1 (95% CI: 40-99, p=0.002) NNT for one year to prevent one infection : 18 57 57

Adherence by Pill Count TDF/FTC Nb pills/month Placebo Nb pills/month

Conclusions In this population of high risk MSM, incidence of HIV-1 infection in the placebo arm was higher than expected “On Demand” oral PrEP with TDF/FTC was very effective with a 86% (95% CI: 40-99) reduction in HIV-incidence Adherence to PrEP was good supporting the acceptability of “on demand” PrEP Safety of “on demand” TDF/FTC was overall similar to placebo except for gastrointestinal AEs No evidence of risk compensation On demand PrEP: attractive alternative to daily PrEP in high risk MSM who do not use condoms consistently 59