1. 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 and Westminster
Imperial College

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

3. 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  ?  ?

4. Treatment FOR prevention

5. (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

6. 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 CD
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

7. 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

8. 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

9. Treatment FOR Prevention
Study
Effect size (95% CI)
96% (73; 99)
HPTN 052
0% %
Efficacy

10. Treatment AS Prevention
Study
Effect size (95% CI)
0% %
A third were infected from outside partnership
Three ongoing trials to address public health benefit
Efficacy

11. Pre-exposure prophylaxis

12. 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

13. FDA approve Truvada for PrEP
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

14. 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

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

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

17. 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

18. Several trials – but inconsistent
Effect size (95% CI)
Tenofovir/Truvada for discordant couples
73% (49; 85)
Truvada for heterosexuals
63% (22; 83)
0% %
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

19. Why didn’t PrEP work
in all the trials?

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

21. 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

22. PRe-exposure Option for HIV prevention in the UK: immediate or Deferred 22 22

23. 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

24. 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

25. 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

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

27. 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

28. 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%)

29. 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%)

30. 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

31. 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%)

32. Baseline self-reported STIs in last 12 months

33. HIV risk reduction strategies

34. Results:
HIV endpoint 34 34

35. 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 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

36. 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.

37. 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.

38. 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

39. Prescribing, Tolerability
Results:
Prescribing, Tolerability 39 39

40. 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)

41. 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.

42. Results: STI endpoints42 42

43. STIs

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

45. Results: Sexual behaviour45 45

46. 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.

47. 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.

48. 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

49. 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

50. 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

51. Treatment FOR Prevention
Study
Effect size (95% CI)
96% (73; 99)
HPTN 052
0% %
Efficacy

52. Post-exposure prophylaxis
Study
Effect size (95% CI)
0% %
But PEP and PEPSE are policy – 28 days of it, in spite of the fact that HIV is disseminated 5 days after transmission
Efficacy

53. 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!

54. 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)

55. 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

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

57. 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

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

59. 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