Transcript Identifying Priority Research Questions

Timothy Mastro
Family Health International
XVII International AIDS Conference
Mexico City
7 August 2008
Rationale for ARV PrEP for HIV Prevention
Data suggesting that ARV PrEP may be effective
•
•
•
ARVs for PMTCT
Post-exposure prophylaxis for HIV
Monkey models for SHIV transmission
Available ARVs appear safe
Available ARVs can be used once daily
•
•
•
TDF: tenofovir disoproxil fumarate: Viread ®
FTC: emtricitibine: Emtriva ®
TDF/FTC: Truvada ®
Data from Monkey Studies at CDC:
Prevention of Rectal SHIV Transmission by Chemoprophylaxis with ARVs
% Uninfected animals
100
FTC/Tenofovir (subcut, n = 6)
75
FTC/TDF (oral, n = 6)
p = 0.0075, [HR = 7.8]
50
FTC (subcut, n = 6)
p = 0.021, [HR = 3.9]
25
TDF (oral, n = 4)*
p = 0.3
Control (n = 18)
0
0
2
4
6
8
10
12
14
Number of rectal exposures
Laboratory Branch, DHAP, CDC
One Completed Clinical Trial
West Africa Phase II PrEP Trial (FHI/BMGF)
RCT: daily TDF 300mg and placebo
Women (n=936) in Ghana, Cameroon, Nigeria
Conducted June 2004 - March 2006
No evidence of increased clinical or laboratory
adverse effects
No evidence of risk compensation
Inadequate power to assess efficacy
•
8 HIV seroconversions: 2 TDF, 6 placebo
• RR = 0.35, p=0.24
Ongoing PrEP Trials
Tenofovir Extended Safety Study (CDC)
Bangkok Tenofovir Study (CDC)
Botswana TDF2 (TDF/FTC) Trial (CDC)
iPrEX (UCSF/NIAID/BMGF)
Partners PrEP (UW/BMGF)
Planned PrEP Trials
FEM-PrEP (FHI/USAID/BMGF)
VOICE (MTN 003) (NIAID)
ONGOING PREP TRIALS
U.S. Extended Tenofovir Safety Trial
Sponsor
CDC
Objective
To assess clinical, laboratory and
behavioral safety; and adherence
and acceptability
Design
Randomized double-blind placebo
controlled phase II extended safety
study with 1:1 TDF : placebo
Duration
24 months with DSMB review of
data every 6 months
U.S. Extended Tenofovir Safety Trial
400 HIV-neg MSM (Atlanta, San Francisco, Boston)
9 month delay in enrollment of 200 men to assess
behavioral changes once drug prophylaxis started
Close monitoring of seroconverters for resistance
and clinical outcomes
Adverse events, and access to HIV care if infected,
managed through physician referral
Started February 2005; fully enrolled July 2007;
follow-up to end August 2009
Bangkok Tenofovir Study (BTS)
BMA Drug Treatment Clinics
Sponsor: CDC
TUC Lab
(Nonthaburi)
BMA Lab
Thailand
Bangkok
Bangkok Tenofovir Study (BTS)
Bangkok Tenofovir Study (BTS)
Design
•Phase II/III
•Randomized
•double-blind
•placebo controlled trial
Study Population
HIV-neg IDUs aged 20-60
Enrollment Target Initially 1600, now 2,400
Follow-Up
•All, for one year after enrollment
complete
•Participants choose daily DOT or
monthly visits
Status
90% enrolled (7/08)
Event driven review
BTS Objectives
Botswana TDF-2 Study
Sponsor:
CDC
Botswana TDF-2 Study
Trial started in 2005 with TDF;
halted enrollment (at N=71) in
March 2006 to prepare for
switch to Truvada (TDF/FTC).
New trial (TDF-2) started in
February 2007
Study population originally
1200 heterosexual men and
women aged 18-29
Now planning to expand age
range to 18-39 and increase N
to 1800-2000 through addition
of new site
Botswana TDF-2 Study
Design
•Phase II/III
•Randomized
•Double-Blind
•Placebo-Controlled Trial
End Points •HIV Seroconversion
•Adverse Events
•Risk Behaviors
•Adherence
•Altered Viral Load Set
Point in Seroconverters
The iPrEx Study:
Safety, Efficacy, Behavior, and Biology
Sponsored by NIH/NIAID/DAIDS
with co-funding by the
Bill and Melinda Gates Foundation
and drug donated by
Gilead Sciences
The iPrEX Study
Plans to enroll 3000 high-risk MSM
Randomized 1:1 daily oral PrEP
FTC/TDF vs Placebo
Followed on drug for:
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HIV seroconversion
Adverse events (especially renal & liver)
Metabolic effects (Bone, Fat, Lipids)
HBV flares among HBsAg+
Risk behavior & STIs
Adherence
If infected
– Drug resistance
– Viral load
– Immune responses & CD4 count
The iPrEX Study
Ju
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Se 7
pDe 0 7
cM 07
ar
-0
Ju 8
n0
Se 8
pDe 0 8
cM 08
ar
Ju 09
n0
Se 9
pDe 0 9
cM 09
ar
-1
Ju 0
n1
Se 0
pDe 1 0
c10
Enrollment
After 3 Years of Preparation,
iPrEx is Enrolling as Planned
3500
3000
2500
2000
1500
1000
500
0
Why MSM?
MSM bear a major burden of the epidemic
•
•
•
Throughout the Americas
In some parts of Asia
The burden in Africa is increasingly appreciated
Efficacy could be different after rectal exposure
•
•
Higher efficiency of transmission
Possibly different tissue penetration of virus and drug
iPrEx is the only efficacy trial of PrEP in MSM
Partners PrEP
Multisite trial of pre-exposure prophylaxis against
HIV in HIV discordant couples
Parallel comparison of TDF and TDF/FTC PrEP to
prevent HIV-1 acquisition within HIV-1 discordant
couples
Jared Baeten, MD, PhD
Connie Celum, MD, MPH
University of Washington
Where Partners PrEP Study
Fits into the PrEP Research Landscape
When considering possible wide-spread implementation, HIV
discordant couples would be a priority target
•
More than half of new HIV transmissions occur in stable couples
3 Arm Trial: side-by-side evaluation of TDF and FTC/TDF
Will enroll and follow HIV+ partners
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Assess PrEP efficacy vs. HIV+ partner characteristics (e.g., high viral load)
Drug levels to test for drug sharing (in context of counseling re: sharing)
Assess baseline and longitudinal resistance in HIV+ partners
–
–
marker / impact of sharing
transmitted vs. acquired resistance in seroconverters
Partners PreP: Design
Partners PrEP: Statistical Power
Sample size = 3900 HIV discordant couples
• 1:1:1 randomization (common placebo arm)
• estimated HIV incidence in placebo arm of 3.25%
 With 191 endpoints, >80% power to detect 60%
efficacy of each arm against placebo and ‘rule out’
<30% efficacy
Partners PrEP: Timeline
Funding awarded from BMGF: mid-2007
Protocol development and pre-IND: May 2007
IND approved: September 2007
Site preparedness, stakeholder sessions, IRB & national drug
authority approvals: October 2007-present
First 2 sites activated: May & June 2008
Additional 6 sites to be activated: Q3-Q4 2008
Target enrollment period: 2 years
Completion of follow-up and results: 2011
PLANNED PREP TRIALS
FHI FEM-PrEP: Trial Overview
FHI FEM-PrEP Trial Overview
Design
Phase 3: Double-Blind, Randomized, Placebo-Controlled,
Effectiveness and Safety Study
Sponsor
Funders
FHI
USAID, BMGF
Sites
4 Countries and 6 Sites:
South Africa, Malawi, Kenya, Tanzania
Number
3900 Women at High-Risk of HIV Infection
Approach
Integrated, Interdisciplinary Approach
•Socio-Behavioral Preparatory and Ongoing
•Pilot Intervention Development
Regimen
Daily Oral Truvada (or Placebo)
Follow -Up
Follow-Up on Drug: 52 weeks
Seroconverters followed for 52 weeks
FHI FEM-PrEP: Trial Objectives
FEM PrEP: Timeline
Jun 2007 Initiation of non-research community activities
(i.e., CABs)
Aug 2007 Initiation of site preparedness activities
Oct 2007 Investigators’ meeting (Nairobi)
Mar 2008 FHI PHSC approval
May 2008 IND submission
Jul 2008 1st training (Kenya)
Q4 2008 1st screening
Q3 2011 Trial completion (primary objective)
Q3 2012 Trial completion (seroconverter objectives)
VOICE
Vaginal and Oral Interventions to Control the Epidemic
Sponsor: NIAID/NIH
VOICE Study Objectives
The VOICE Study
Safety and effectiveness study of tenofovir gel, tenofovir
tablet and Truvada tablet for prevention of HIV infection in
4,200 women
Randomized trial with 5 study groups. Two sequential
randomizations. Women will use product for average of 21
months
TOTAL SAMPLE
(4200)
Oral Pill
(2520)
Truvada
(840)
Tenofovir
(840)
Vaginal Gel
(1680)
Oral Placebo
(840)
Tenofovir Gel
(840)
Placebo Gel
(840)
VOICE Study Hypothesis
>25% difference in effectiveness
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Between tenofovir 1% gel and placebo gel
Between TDF and oral placebo
Between FTC/TDF and oral placebo
No difference in safety
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Between daily regimens of tenofovir 1% gel and placebo gel
Between daily regimens of TDF and oral placebo
Between daily regimens of FTC/TDF and oral placebo
VOICE Study Sites
South Africa
Malawi
Uganda
Zambia
Zimbabwe
VOICE Study Timeline
SWG*
Develop
protocol
NIAID
PSRC**
DAIDS
approval***
IRB/EC
approval
Start
accrual
Complete
accrual
Complete
follow-up
June
2007
Q3 2007
Q4 2007
Q2 2008
Q3 2008
Q4 2008
Q3 2010
Q3 2011
Select
protocol
co-chairs
and write
protocol
Revise
Submit
protocol as
protocol to needed for
Prevention Medical
Science
Officer and
Review
Regulatory
Committe approval
Obtain
IRB/EC
approval
at study
sites
Recruit,
screen and
enroll study Follow-up
subjects
period
Present
study
concept to
SWG
*Strategic Working Group, Division of AIDS, National Institute of Allergy and Infectious Diseases (NIAID)
** Prevention Sciences Review Committee, NIAID
***Division of AIDS, NIAID
Summary of Ongoing PrEP Studies - I
Sponsor/
Funder
Study
Product/
Population
N
Sites
Expected
Results
CDC
TDF
MSM
400
USA
2009
CDC
BTS
TDF
M&F IDUs
2400
Thailand
2009?
CDC
TDF-2
TDF/FTC
M&F
Heterosexuals
1800-2000
Botswana
2010?
Summary of Ongoing PrEP Studies - II
Sponsor/
Funder
Study
Product/
Population
N
Sites
Expected
Results
UCSF
NIH
BMGF
iPREX
TDF/FTC
MSM
3000
Peru
Equador
Brazil
U.S.
Other
2010
UW
BMGF
Partners
PrEP
TDF
TDF/FTC
Discordant
Heterosexual
Couples
3900
Kenya
Uganda
2011
Summary of Planned PrEP Studies
Sponsor/
Funder
Study
Product/
Population
N
Sites
Expected
Start/ Results
FHI
USAID/BMGF
FEM-PrEP
TDF/FTC
Women
3900
Kenya
Malawi
South Africa
Tanzania
2008/2012
MTN
NIAID
VOICE
TDF
TDF/FTC
TDF Gel
Women
4200
Malawi
South Africa
Uganda
Zambia
Zimbabwe
2009/2012
Total Participants in 7 Trials
Total Participants in 7 Trials
Women – Hetero
11,050
Men – Hetero
2,950
MSM
3,400
IDU
2,400
TOTAL
19,800
Next Steps
Intermittent vs. daily PrEP
New ARVs and combinations
Formulations: oral, injectable, gel, vaginal ring
Adolescents
Program implementation
Acknowledgements
Lynn Paxton
CDC
J Gerardo Garcia-Lerma
CDC
Walid Heneine
CDC
Bob Grant
University of California, San Francisco
Connie Celum
University of Washington
Lut Van Damme
Amy Corneli
Family Health International
Family Health International
Sharon Hillier
Magee Hospital, University of Pittsburgh
Ward Cates
Family Health International
Mitchell Warren
AIDS Vaccine Advocacy Coalition