Transcript Document

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
HPTN 052 Enrollment
(Total Enrollment: 1763 couples)
U.S.
Thailand
Americas
278
India
Kenya
Malawi
Brazil
Zimbabwe
Botswana
South Africa
Africa
954
Asia
531
HPTN 052 Study Design
Stable, healthy, serodiscordant couples, sexually active
CD4 count: 350 to 550 cells/mm3
Randomization
Immediate ART
CD4 350-550
Delayed ART
CD4 <250
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
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
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
Immediate
Arm: 1
Delayed
Arm: 27
• 23/28 (82%) transmissions in sub-Saharan
Africa
• 18/28 (64%) transmissions from female to
p < 0.001
male partners
Treatment FOR Prevention
Study
Effect size (95% CI)
HPTN 052
96% (73; 99)
Efficacy
0%
10
20
30
40
50
60
70
80
90 100%
Treatment AS Prevention
Effect size (95% CI)
Study
A third were infected from outside partnership
Three ongoing trials to address public health benefit
Efficacy
0%
10
20
30
40
50
60
70
80
90 100%
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,
[email protected]
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
Participants
11
2499
San Francisco
Boston
Chiang Mai
Iquitos
Guayaquil
Lima
Sao Paulo
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)
Randomize HIV- partners
(normal liver, renal, hematologic function)
TDF once daily
FTC/TDF once daily
All receiving comprehensive
Placebo once daily
HIV prevention services
Follow monthly for up to 36 months
1° endpoint: HIV infection in HIV- partner
Co- 1° endpoint: Safety
Several trials – but inconsistent
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
15% (-20; 40)
Efficacy
0%
10
20
30
40
50
60
70
80
90 100%
Why didn’t PrEP work
in all the trials?
Why so different? Adherence…
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/
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
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
Follow 3 monthly for up to 24 months
Main endpoints in Pilot: recruitment and retention
From April 2014: HIV infection in first 12 months
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
Median Age
Age
18-30
30-40
>40
Immediate
35 (IQR: 30 – 43)
N (%)
70 (26%)
111 (41%)
92 (34%)
Deferred
35 (29 – 42)
N (%)
79 (30%)
101 (38%)
86 (32%)
211 (77%)
9 (3%)
210 (79%)
8 (3%)
9 (3%)
9 (3%)
11 (4%)
10 (4%)
9 (3%)
5 (2%)
19 (7%)
0 (0%)
15 (6%)
6 (2%)
6 (2%)
2 (0%)
110 (40%)
162 (59%)
1 (0%)
107 (40%)
159 (60%)
0 (0%)
Ethnicity
White
Irish
Indian, Pakistani,
Bangladeshi
Black Caribbean,
African, other
Mixed ethnic group
Chinese
Other
Missing
Born UK
No
Yes
Missing
539/545 (99%) CRFs returned
Baseline demographics
Characteristics
Maximum Education
No qualifications
O-levels/GCSEs/Equivalent
A-levels/Equivalent
University Degree or above
Still in full-time education
Vocational training
Other qualifications
Missing
Employment
Full time
Part-time
Students (fulltime)
Unemployed
Retired
Other
Missing
Immediate
Deferred
9 (3%)
31 (11%)
41 (15%)
162 (59%)
7 (3%)
15 (5%)
7 (3%)
1 (0%)
5 (2%)
29 (11%)
45 (17%)
165 (62%)
12 (5%)
7 (3%)
3 (1%)
0 (0%)
191 (70%)
26 (10%)
15 (5%)
24 (9%)
9 (3%)
8 (3%)
0 (0%)
195 (73%)
26 (10%)
12 (5%)
20 (8%)
7 (3%)
3 (1%)
3 (1%)
Baseline demographics
Characteristics
Immediate
Sexuality
Gay/homosexual 262 (96%)
5 (2%)
Bi-sexual
3 (1%)
Straight/heterosexual
3 (1%)
Missing
Current Relationship Status
Yes and living with partner 88 (32%)
Yes and not living with partner 49 (15%)
No ongoing relationship 145 (53%)
0 (0%)
Missing
Deferred
250 (94%)
11 (4%)
3 (1%)
2 (1%)
72 (27%)
46 (17%)
147 (55%)
1 (0%)
Baseline demographics
Drug use in last 3 months
Mephedrone
GHB/GBL (liquid ecstasy)
Crystal meth (methamphetamine)
Poppers (amyl nitrate)
Viagra
Cocaine (coke)
Cannabis (marijuana, grass)
Ecstasy (E)
Ketamine (K)
Other
Speed (amphetamine)
Anabolic steroids
Immediate
Deferred
35%
32%
19%
49%
44%
26%
24%
15%
18%
8%
6%
4%
38%
30%
17%
49%
39%
25%
24%
18%
15%
5%
4%
3%
Baseline behaviour
Immediate
Deferred
Median (IQR)
Median (IQR)
HIV testing
3 (IQR 2-4)
3 (IQR 2-4)
STI testing
3 (IQR 2-4)
3 (IQR 2-4)
Immediate
Deferred
Number (%)
Number (%)
At least once
92 (33%)
92 (34%)
More than once
36 (13%)
35 (13%)
Clinic visits in last 12 months
PEP use in last 12 months
Baseline self-reported STIs in last
12 months
70%
64%
60%
50%
40%
30%
20%
10%
0%
36%
26% 25%
23% 21%
17%
13%
10% 10%
5%
HIV risk reduction strategies
38%
% of positive response
40%
30%
26%
26%
15%
use condoms sero-sort neg
strategic
ask partners sero-sort pospositioning to use condom
tx
don't think
about risk
reduction
Results:
HIV endpoint
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
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
Immediate PrEP
0
12
24
36
48
N=3
60 0
N=19
Deferred PrEP
12
24
Weeks since enrolment
36
48
60
HIV Incidence
Group
No. of
Follow- Incidence
infections up (PY) (per 100 PY)
90% CI
Overall
22
453
4.9
3.4–6.8
Immediate 3
Deferred
19
239
214
1.3
8.9
0.4–3.0
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)
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
Results:
Prescribing, Tolerability
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
• 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
Results:
STI endpoints
STIs
60
p=0.08
% ever diagnosed
50
40
30
p=0.44
p=0.44
p=0.08
Immediate
20
p=0.32
10
0
Deferred
STIs
60
p=0.08
% ever diagnosed
50
40
30
Caveat
Number of p=0.44
screens differed between the groups:
p=0.44
e.g. Rectal gonorrhoea
974 in the IMM group and 749 in the DEF
p=0.08
Immediate
20
p=0.32
10
0
Deferred
Results:
Sexual behaviour
Reported sexual behaviour
Anal sex partners in last 90 days
BASELINE (n=539)
Total number of partners
Immediate
Deferred
Median (IQR) Median (IQR)
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)
Reported sexual behaviour
Anal sex partners in last 90 days
BASELINE (n=539)
Total number of partners
Immediate
Deferred
Median (IQR) Median (IQR)
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)
Total number of partners
Immediate
Deferred
Median (IQR) Median (IQR)
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)
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)
HPTN 052
96% (73; 99)
Efficacy
0%
10
20
30
40
50
60
70
80
90 100%
Post-exposure prophylaxis
Effect size (95% CI)
Study
But PEP and PEPSE are policy – 28 days
of it, in spite of the fact that HIV is
disseminated 5 days after transmission
Efficacy
0%
10
20
30
40
50
60
70
80
90 100%
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
Friday
Saturday
Sunday
KM Estimates of Time to
HIV-1 Infection (mITT Population)
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
Adherence by Pill Count
TDF/FTC
Placebo
Nb pills/month
Nb pills/month
4.00
0 or missing
4.00
]1 – 4]
0 or missing
]1 – 4]
2.00
]4 – 11]
2.00
]4 – 11]
3.00
]11 – 18]
3.00
]11 – 18]
4.00
]18 – 25]
4.00
]18 – 25]
]25 – 30]
]25 – 30]
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