Timothy Mastro

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• Timothy Mastro
• Family Health International
• XVII International AIDS Conference
• Mexico City
• 7 August 2008

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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

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Data from Monkey Studies at CDCPrevention of
Rectal SHIV Transmission by Chemoprophylaxis with
ARVs

• Laboratory Branch, DHAP, CDC

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One Completed Clinical Trial

• West Africa Phase II PrEP Trial (FHI/BMGF)
• RCT daily TDF 300mg and placebo
• Women (n936) 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, p0.24

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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)

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Planned PrEP Trials

• FEM-PrEP (FHI/USAID/BMGF)
• VOICE (MTN 003) (NIAID)

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OnGOING PrEP TRIALS
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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 11 TDF placebo
• Duration 24 months with DSMB review of data
  every 6 months

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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

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Bangkok Tenofovir Study (BTS)BMA Drug Treatment
Clinics
Sponsor CDC
TUC Lab (Nonthaburi)
BMA Lab
Thailand
Bangkok
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Bangkok Tenofovir Study (BTS)

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BTS Objectives
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Botswana TDF-2 Study
Sponsor CDC
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Botswana TDF-2 Study

• Trial started in 2005 with TDF halted enrollment
  (at N71) 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

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The iPrEx StudySafety, 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

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The iPrEX Study

• Plans to enroll 3000 high-risk MSM
• Randomized 11 daily oral PrEP
• FTC/TDF vs Placebo
• Followed on drug for
• 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

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The iPrEX Study
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After 3 Years of Preparation, iPrEx is Enrolling
as Planned
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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

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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

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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
• 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

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Partners PreP Design
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Partners PrEP Statistical Power

• Sample size 3900 HIV discordant couples
• 111 randomization (common placebo arm)
• estimated HIV incidence in placebo arm of 3.25
• ? With 191 endpoints, gt80 power to detect 60
  efficacy of each arm against placebo and rule
  out lt30 efficacy

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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

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Planned PREP TRIALS
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FHI FEM-PrEP Trial Overview
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FHI FEM-PrEP Trial Objectives
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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)

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VOICE
Vaginal and Oral Interventions to Control the
Epidemic
Sponsor NIAID/NIH
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VOICE Study Objectives
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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

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VOICE Study Hypothesis

• gt25 difference in effectiveness
• Between tenofovir 1 gel and placebo gel
• Between TDF and oral placebo
• Between FTC/TDF and oral placebo
• No difference in safety
• 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

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VOICE Study Sites

• South Africa
• Malawi
• Uganda
• Zambia
• Zimbabwe

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VOICE Study Timeline

• Strategic Working Group, Division of AIDS,
  National Institute of Allergy and Infectious
  Diseases (NIAID)
• Prevention Sciences Review Committee, NIAID
• Division of AIDS, NIAID

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Summary of Ongoing PrEP Studies - I
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Summary of Ongoing PrEP Studies - II
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Summary of Planned PrEP Studies
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Total Participants in 7 Trials
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Next Steps

• Intermittent vs. daily PrEP
• New ARVs and combinations
• Formulations oral, injectable, gel, vaginal ring
• Adolescents
• Program implementation

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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 Family Health International
• Amy Corneli Family Health International
• Sharon Hillier Magee Hospital, University of
  Pittsburgh
• Ward Cates Family Health International
• Mitchell Warren AIDS Vaccine Advocacy Coalition