Antiretroviral Pre-Exposure Prophylaxis

for HIV-1 Prevention among Heterosexual African Men and Women:

The Partners PrEP Study

Jared Baeten, MD PhD & Connie Celum, MD MPHon behalf of

The Partners PrEP Study TeamIAS 2011

Study Funder: Bill & Melinda Gates Foundation

Background

• The Partners PrEP Study is a phase III, randomized, double-blind, placebo-controlled, three-arm trial of daily oral tenofovir (TDF) and emtricitabine/tenofovir (FTC/TDF) PrEP for the prevention of HIV acquisition by HIV seronegative partners in heterosexual HIV serodiscordant partnerships

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- partnerCo- 1° endpoint: Safety

Follow couples for up to 36 months

FTC/TDF once daily

All receiving comprehensive HIV prevention services

Jinja,Kabwohe,Kampala,Mbale,Tororo,Uganda

Eldoret,Kisumu,Nairobi,Thika,Kenya

Partners PrEP Study: Sites

HIV- participants- Monthly HIV & pregnancy testing - Monthly symptom & 3-monthly

laboratory safety monitoring- Monthly provision of study

medication and individualized adherence counseling, including not sharing study drug

Study Procedures

HIV+ participants- 3-monthly visits- 6-monthly CD4 counts- ongoing HIV primary care- active referral for ART,

following national guidelines

HIV- participants- Monthly HIV & pregnancy testing - Monthly symptom & 3-monthly

laboratory safety monitoring- Monthly provision of study

medication and individualized adherence counseling, including not sharing study drug

Study Procedures

HIV+ participants- 3-monthly visits- 6-monthly CD4 counts- ongoing HIV primary care- active referral for ART

following national guidelines

All participants: comprehensive HIV prevention package- Risk reduction counseling (individual and couple)- Free condoms and condom counseling - Contraception counseling and provision- Screening and treatment for STIs- Counseling & referral for other HIV prevention

interventions (e.g., male circumcision), per national policies

-

Interim monitoring• Independent Data and Safety Monitoring Board (DSMB) review every 6

months

• Interim reviews of efficacy conducted August 2010 & March 2011• Monitored with Lan-DeMets modification of O’Brien-Fleming interim

monitoring• Pre-specified conservative stopping criteria, against H0=0.7

• During Closed Session in March 2011 meeting, DSMB observed strong trend for HIV protection on PrEP arms• Determined ad hoc meeting may be required before scheduled interim review• Meeting called for 10 July 2011; study team informed shortly before meeting

• DSMB meeting on 10 July 2011 reviewed data through 31 May 2011• DSMB recommended 1) study results be publicly reported & 2) the placebo

arm be discontinued, because of clear demonstration of HIV protection from PrEP

Population characteristics

Total(n=4747*)

TDF(n=1584)

FTC/TDF (n=1579)

Placebo(n=1584)

HIV- partner female / male 38% / 62% 38% / 62% 36% / 64% 39% / 61%

Age of HIV- partner, years (median/IQR)

33(28,40)

33(28,40)

33(28,40)

33(28,40)

Couple married 98% 97% 98% 98%

Duration of partnership, years (median/IQR)

7(3,14)

7(3,14)

7(3,14)

7(3,14)

Duration known HIV serodiscordant, years (median/IQR)

0.4(0.1,2.0)

0.5(0.1,2.0)

0.4(0.1,2.0)

0.4(0.1,2.0)

CD4 count, HIV+ partner, cells/mm3 (median/IQR)

495 (375,662)

491(370,661)

497(380,664)

499(375,663)

Plasma viral load, HIV+ partner, log10 copies/mL (median/IQR)

3.9(3.2, 4.5)

3.9(3.2,4.5)

3.9(3.1,4.5)

3.9(3.2,4.5)

Started ART, HIV+ partner, during follow-up

19% 20% 18% 20%

* 11 couples found after randomization to be ineligible and exited from the study

Retention

Study month (# expected) Total TDF FTC/TDF PlaceboMonth 6 (n=4738) 98% 98% 98% 98%

Month 12 (n=4052) 96% 96% 97% 96%

Month 18 (n=3055) 95% 95% 95% 95%

Month 24 (n=2027) 95% 94% 95% 95%

Month 30 (n=605) 95% 94% 94% 98%

Month 36 (n=17) 100% 100% 100% 100%

Person-years of follow-up 7,337 2,441 2,452 2,444

Adherence

Total TDF FTC/TDF PlaceboDispensed doses taken 97% 97% 97% 97%

Pill bottles returned 98% 98% 98% 98%

• Primary measure of adherence = monthly pill count of unused study product

Pregnancy

Total TDF FTC/TDF PlaceboNumber of pregnancies 272 107 76 89

Pregnancy incidence, per 100 woman-years

10.3 12.1 8.9 9.9

P-value vs. placebo p=0.12 p=0.50Time off study drug due to pregnancy

1.8% 2.6% 1.4% 1.6%

• Among HIV- women (n=1785):

Hormonal contraceptive use at most recent study visit: 10% OCP, 26% injectable, 8% implant

HIV seroconversion endpoints

12 HIV infected at enrollment

78 HIV acquisition events in primary study

(mITT) analysis

90 HIV acquisition events for ITT analysis(as of 31 May 2011)

Primary efficacy results

TDF FTC/TDF Placebo

Number of HIV infections 18 13 47

HIV incidence, per 100 person-years 0.74 0.53 1.92

HIV protection efficacy, vs placebo 62% 73%

95% CI (34-78%) (49-85%) p-value 0.0003 <0.0001

Z-score, vs. H0=0.7 -2.17 -2.99

• Primary analysis: modified intention-to-treat (mITT)• excluding infections present at randomization (3 TDF, 3 FTC/TDF, 6 placebo)

ITT analysis results similar

Primary efficacy results

TDF FTC/TDF Placebo

Number of HIV infections 18 13 47

HIV incidence, per 100 person-years 0.74 0.53 1.92

HIV protection efficacy, vs placebo 62% 73%

95% CI (34-78%) (49-85%) p-value 0.0003 <0.0001

Z-score, vs. H0=0.7 -2.17 -2.99

• Primary analysis: modified intention-to-treat (mITT)• excluding infections present at randomization (3 TDF, 3 FTC/TDF, 6 placebo)

ITT analysis results similar

Effect of TDF and FTC/TDF statistically similar (p=0.18)

Primary efficacy results

TDFFTC/TDFPlacebo

Subgroup analysis - gender

Efficacy 95% CI P-value Interaction p-value

TDF Women

Men

68%

55%

29-85%

4-79%

p=0.01

p=0.04p=0.54

FTC/TDF Women

Men

62%

83%

19-82%

49-94%

p=0.01

p=0.001p=0.24

• Both TDF and FTC/TDF significantly reduced HIV risk in both men and women

Women: 42 total infections: 8 TDF, 9 FTC/TDF, 25 placeboMen: 36 infections: 10 TDF, 4 FTC/TDF, 22 placebo

Safety

• No statistically significant difference in deaths, SAEs, key laboratory AEs

Number of participants with each safety event

Total TDF FTC/TDF Placebo

Death 24(<1%)

8 7 9

SAE 320(7%)

108 107 105

Confirmed creatinine AE 49(1%)

17 20 12

Confirmed phosphorus AE 403(9%)

138 133 132

Tolerability

% of participants reporting symptom

TDF FTC/TDF Placebo P-value TDF vs. Placebo

P-valueFTC/TDF

vs. PlaceboNausea

All visits

Month 1

1.6%

6.3%

1.7%

5.9%

1.5%

4.5%

p=0.23

p=0.03

p=0.18

p=0.07

Diarrhea

All visits

Month 1

1.6%

4.1%

1.8%

4.5%

1.4%

2.8%

p=0.18

p=0.06

p=0.02

p=0.02

• Monthly 19-item symptom questionnaire

Sexual behavior

At enrollment, 27% of couples reported unprotected sex in the past month.

Sexual behavior

At enrollment, 27% of couples reported unprotected sex in the past month. This declined during follow-up and was similar across the study arms.

Sexual behavior

One-third reported an outside partner during the study: 34% TDF, 33% FTC/TDF, 33% placebo

At enrollment, 27% of couples reported unprotected sex in the past month. This declined during follow-up and was similar across the study arms.

Ongoing testing

• Testing ongoing for the following, not yet available:

• HIV resistance in seroconverters• HIV plasma viral load in seroconverters• Plasma / intracellular drug levels in seroconverters

and subset of non-seroconverters

Summary

• TDF and FTC/TDF PrEP definitively reduced risk of HIV acquisition, by 62% & 73%, respectively,

in African men and women • Similar efficacy between TDF & FTC/TDF• HIV protection effect was robust in both women and men• Study announcing findings 1.5 years earlier than expected

• TDF and FTC/TDF PrEP were safe & well-tolerated • Mild gastrointestinal side effects, predominantly in Month 1

• No evidence of risk compensation

Next steps

• Partners PrEP Study is continuing:• DSMB strongly recommended blinded continuation of

the active PrEP arms, to continue to gather comparative information on the efficacy, safety, tolerability and resistance with TDF vs. FTC/TDF PrEP

• Placebo arm participants currently stopping study medication. Thereafter, placebo arm will be offered active PrEP at the research clinics.

• Demonstration projects for PrEP are needed, including as part of evaluations of evidence-based

combination HIV prevention

Partners PrEP Study Team• University of Washington Coordinating Center

Connie Celum (PI), Jared Baeten (Co-Chair and Medical Director), Deborah Donnell (Statistician), Justin Brantley, Tami Cloutier, Robert Coombs, Amy Dao, Shauna Durbin, Mira Emmanuel-Ogier, Lisa Frenkel, Carlos Flores, Harald Haugen, Renee Heffron, Ting Hong, Jim Hughes, Erin Kahle, Johanna Karas, Becky Karschney, Lara Kidoguchi, Meighan Krows, Matt Leidholm, Jai Lingappa, Toni Maddox, Angela McKay, Julie McElrath, Allison Mobley, Susan Morrison, Nelly Mugo, Andrew Mujugira, Vikram Nayani, Patrick Ndase, Apollo Odika, Hilda O’Hara, Dana Panteleeff, Jennifer Revall, Marothodi Semenya, John Sparkman, Kathy Thomas, Ellen Wilcox

• Sites– Eldoret, Kenya (Moi U, Indiana U): Edwin Were (PI), Ken Fife (PI), Cosmas Apaka– Jinja, Uganda (Makarere U, UW); Patrick Ndase (PI), Elly Katabira (PI), Fridah Gabona– Kabwohe, Uganda (KCRC): Elioda Tumwesigye (PI), Rogers Twesigye – Kampala, Uganda (Makarere U): Elly Katabira (PI), Allan Ronald (PI), Edith Nakku-Joloba– Kisumu, Kenya (KEMRI, UCSF): Elizabeth Bukusi (PI), Craig Cohen (PI), Josephine Odoyo– Mbale, Uganda (TASO, CDC): Jonathan Wangisi (PI), Jim Campbell (PI), Jordan Tappero (PI),

Akasiima Mucunguzi– Nairobi, Kenya (KNH/U Nairobi, UW): James Kiarie (PI), Carey Farquhar (PI), Grace John-Stewart

(PI), Harrison Tamooh, Freda Kinoti– Thika, Kenya (KNH/U Nairobi, UW): Nelly Mugo (PI), Kenneth Ngure– Tororo, Uganda (CDC, TASO): Jim Campbell (PI), Jonathan Wangisi (PI), Jordan Tappero (PI),

Aloysious Kakia• DF/Net (data center): Lisa Ondrejcek, Darryl Pahl, Jae Chong• CLS (laboratory oversight): Wendy Stevens, Charlotte Ingram, Ute Jentsch, Mukthar Kader, Nombulelo

Gqomane, Feroza Bulbulia, Jan van den Heuvel• ClinPhone/Perceptive Informatics (randomization)

• Gilead (study drug): Jim Rooney, Raj Sangha, Abboud Habr, Farideh Said• Bill & Melinda Gates Foundation (study funder): Stephen Becker• HIV serodiscordant couples who test, screen, & participate

Partners PrEP Study Team