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 100

FTC/Tenofovir (subcut, n = 6)

75 50 25 0 0 2 4 6 8 10 12

Number of rectal exposures

14

FTC/TDF (oral, n = 6) p = 0.0075, [HR = 7.8] FTC (subcut, n = 6) p = 0.021, [HR = 3.9] TDF (oral, n = 4)* p = 0.3

Control (n = 18)

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 Objective Design Duration

CDC To assess clinical, laboratory and behavioral safety; and adherence and acceptability Randomized double-blind placebo controlled phase II extended safety study with 1:1 TDF : placebo 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)

Design Bangkok Tenofovir Study (BTS)

•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

Design Botswana TDF-2 Study

•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: • 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

After 3 Years of Preparation, iPrEx is Enrolling as Planned

3500 3000 2500 2000 1500 1000 500 0 Ju n -0 7 S ep -0 7 D ec -0 7 M ar -0 8 Ju n -0 8 S ep -0 8 D ec -0 8 M ar -0 9 Ju n -0 9 S ep -0 9 D ec -0 9 M ar -1 0 Ju n -1 0 S ep -1 0 D ec -1 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 • 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

Design Sponsor Funders Sites Number Approach Regimen Follow -Up FHI FEM-PrEP Trial Overview

Phase 3: Double-Blind, Randomized, Placebo-Controlled, Effectiveness and Safety Study FHI USAID, BMGF 4 Countries and 6 Sites: South Africa, Malawi, Kenya, Tanzania 3900 Women at High-Risk of HIV Infection Integrated, Interdisciplinary Approach •Socio-Behavioral Preparatory and Ongoing •Pilot Intervention Development Daily Oral Truvada (or Placebo) 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

1 st training (Kenya)

Q4 2008

1 st screening

Q3 2011 Q3 2012

Trial completion (primary objective) 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) Truvada (840) Oral Pill (2520) Tenofovir (840) Oral Placebo (840) Vaginal Gel (1680) Tenofovir Gel (840) Placebo Gel (840)

VOICE Study Hypothesis

• • •

>25% 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

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

Present study concept to SWG

Select protocol co-chairs and write protocol Submit protocol to Prevention Science Review Committe Revise protocol as needed for Medical Officer and Regulatory approval Obtain IRB/EC approval at study sites Recruit, screen and enroll study subjects Follow-up period Q3 2011

*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

CDC CDC

BTS

CDC

TDF-2

Product/ Population

TDF MSM

N

400 TDF M&F IDUs 2400 TDF/FTC M&F Heterosexuals 1800-2000

Sites

USA Thailand Botswana

Expected Results

2009 2009?

2010?

Summary of Ongoing PrEP Studies - II

Sponsor/ Funder

Study

UCSF NIH BMGF

iPREX

UW BMGF

Partners PrEP

Product/ Population

TDF/FTC MSM TDF TDF/FTC Discordant Heterosexual Couples

N

3000 3900

Sites

Peru Equador Brazil U.S.

Other Kenya Uganda

Expected Results

2010 2011

Summary of Planned PrEP Studies

N Sponsor/ Funder

Study

FHI USAID/BMGF

FEM-PrEP

Product/ Population

TDF/FTC Women 3900

Sites

Kenya Malawi South Africa Tanzania

Expected Start/ Results

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 IDU 3,400 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 J Gerardo Garcia-Lerma Walid Heneine Bob Grant Connie Celum Lut Van Damme Amy Corneli Sharon Hillier Ward Cates Mitchell Warren

CDC CDC CDC University of California, San Francisco University of Washington Family Health International Family Health International Magee Hospital, University of Pittsburgh Family Health International AIDS Vaccine Advocacy Coalition