Clinical trial NCT00557245: Pre-Exposure Prophylaxis to Prevent HIV-1 Acquisition Within HIV-1 Discordant Couples
Official title: Parallel Comparison of Tenofovir and Emtricitabine/Tenofovir Pre-Exposure Prophylaxis to Prevent HIV-1 Acquisition Within HIV-1 Discordant Couples
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV-1 Infections
HIV Infections
Keywords: HIV infection
HIV uninfected partners
Double Blind
Placebo
Seroconversion
TDF
FTC TDF
Safety
HIV Seronegativity
Lead sponsor: University of Washington
Sponsor class: OTHER
Collaborators: name: Bill and Melinda Gates Foundation
First posted: 2007-11-12
Enrollment: 4758
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Randomized, blinded, placebo-controlled trial to demonstrate if pre-exposure prophylaxis decreases HIV-1 acquisition among HIV-1 uninfected individuals within HIV-1 discordant couples.

Detailed description: HIV-1 uninfected individuals within HIV-1 discordant partnerships are at high-risk for HIV-acquisition. The majority of HIV-1 transmissions to adults in Africa occur within stable, HIV-1 discordant couples.

Pre-exposure chemoprophylaxis, in which an HIV-1 uninfected individual at high risk for contracting HIV-1 takes antiretroviral medications to maintain blood and genital drug levels sufficient to prevent HIV-1 acquisition, has been proposed as a potential HIV-1 prevention strategy.

This study was a randomized, blinded, placebo-controlled trial to demonstrate if pre-exposure prophylaxis decreases HIV-1 acquisition among HIV-1 uninfected individuals within HIV-1 discordant couples. The HIV-1 uninfected partner was randomized in a 1:1:1 ratio to one of three arms: once daily Tenofovir Disoproxil Fumarate (TDF), Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) or Placebo.

Couples were followed up to 36 months; the HIV uninfected partner attended monthly visits and the HIV infected partner quarterly visits. All participants received a comprehensive package of HIV prevention services including individual and couples counseling, free condoms, and male circumcision referrals.

Participants who seroconverted during follow-up stopped the study drug but continued with follow-up.

Eligibility criteria: Inclusion Criteria for HIV-1 uninfected partner:

* Partner within an HIV-1 discordant heterosexual relationship
* One partner meets study eligibility for HIV-1 uninfected study participant and the other partner meets study eligibility criteria for HIV-1 infected participant
* Plan to remain in the relationship for the duration of the study period
* Adequate renal, hepatic \& hematologic function
* Negative Hepatitis B surface antigen test
* Willing and able to provide written informed consent \& locator information

Exclusion Criteria for HIV-1 uninfected partner:

* Current pregnancy, or planning to become pregnant during the study period
* Currently breastfeeding
* Concurrent enrollment in another HIV-1 vaccine or prevention trial
* Receiving ongoing antiretroviral therapy
* Repeated positive urine dipstick tests for glycosuria or proteinuria
* Active and serious infections
* History of pathological bone fractures not related to trauma

Inclusion Criteria for HIV-1 infected partner:

* Partner within an HIV-1 discordant heterosexual relationship
* One partner meets study eligibility for HIV-1 uninfected study participant and the other partner meets study eligibility criteria for HIV-1 infected participant
* HIV-1 infected based on positive EIA
* No history of any clinical AIDS-defining diagnoses
* Plan to remain in the relationship for the duration of the study period
* Willing and able to provide written informed consent \& locator information

Exclusion Criteria for HIV-1 infected partner:

* Current use of antiretroviral therapy
* Concurrent enrollment in another HIV-1 treatment trial

Primary outcomes:
measure: Incidence of HIV-1 Seroconversion Among HIV-1 Uninfected Participants
timeFrame: Up to 36 months
measure: Number of Participants With Serious Adverse Events (SAEs)
timeFrame: Up to 36 months
Secondary outcomes:
measure: Study Drug Adherence: Total Number of Study Drug Doses Taken of the Total Dispensed Doses.
timeFrame: Up to 36 months
measure: Study Drug Adherence: Self-reported Missed Doses of Study Drug
timeFrame: Up to 36 months
measure: Number of Seroconverters With an HIV-1 Mutation Conferring Resistance to TDF or FTC
timeFrame: Up to 36 months
measure: Number of Participants With a Sexually Transmitted Infection (STI) During Follow-up
timeFrame: Up to 36 months
measure: Prevalence of Unprotected Sex During Follow-up
timeFrame: Up to 36 months
measure: Congenital Abnormalities Among Infants Born to Female Participants Taking Study Drug.
timeFrame: Up to 36 months
measure: Length Among Infants Born to Female Participants Taking Study Drug
timeFrame: up to 12 months
measure: Weight Among Infants Born to Female Participants Taking Study Drug
timeFrame: up to 12 months
measure: Head Circumference Among Infants Born to Female Participants Taking Study Drug
timeFrame: up to 12 months
Other outcomes:
Locations:
city: Eldoret
country: Kenya
facility: Moi University - Indiana University
city: Kisumu
country: Kenya
facility: CMR, Kemri-UCSF
city: Nairobi
country: Kenya
facility: Kenyatta National Hospital/University of Nairobi
city: Thika
country: Kenya
facility: Partners in Prevention - Thika
city: Bushenyi
country: Uganda
facility: Kabwohe Clinical Research Center
city: Jinja
country: Uganda
facility: Infectious Diseases Institute
city: Kampala
country: Uganda
facility: Partners House-Infectious Disease Institute Ltd
city: Mbale
country: Uganda
facility: The AIDS Support Organization (TASO)
city: Tororo
country: Uganda
facility: The AIDS Support Organization - Tororo Field Station
Study officials:
affiliation: University of Washington
name: Connie Celum,, MD, MPH
role: STUDY_CHAIR
affiliation: University of Washington
name: Jared Baeten, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Mujugira A, Baeten JM, Donnell D, Ndase P, Mugo NR, Barnes L, Campbell JD, Wangisi J, Tappero JW, Bukusi E, Cohen CR, Katabira E, Ronald A, Tumwesigye E, Were E, Fife KH, Kiarie J, Farquhar C, John-Stewart G, Kidoguchi L, Panteleeff D, Krows M, Shah H, Revall J, Morrison S, Ondrejcek L, Ingram C, Coombs RW, Lingappa JR, Celum C; Partners PrEP Study Team. Characteristics of HIV-1 serodiscordant couples enrolled in a clinical trial of antiretroviral pre-exposure prophylaxis for HIV-1 prevention. PLoS One. 2011;6(10):e25828. doi: 10.1371/journal.pone.0025828. Epub 2011 Oct 5.
citation: Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, Tappero JW, Bukusi EA, Cohen CR, Katabira E, Ronald A, Tumwesigye E, Were E, Fife KH, Kiarie J, Farquhar C, John-Stewart G, Kakia A, Odoyo J, Mucunguzi A, Nakku-Joloba E, Twesigye R, Ngure K, Apaka C, Tamooh H, Gabona F, Mujugira A, Panteleeff D, Thomas KK, Kidoguchi L, Krows M, Revall J, Morrison S, Haugen H, Emmanuel-Ogier M, Ondrejcek L, Coombs RW, Frenkel L, Hendrix C, Bumpus NN, Bangsberg D, Haberer JE, Stevens WS, Lingappa JR, Celum C; Partners PrEP Study Team. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012 Aug 2;367(5):399-410. doi: 10.1056/NEJMoa1108524. Epub 2012 Jul 11.
citation: Saha A, Escuduero J, Layouni T, Richardson B, Hou S, Mugo N, Mujugira A, Celum C, Baeten JM, Lingappa J, John-Stewart GC, LaCourse SM, Shah JA. Mycobacterium tuberculosis-Specific T-Cell Responses Are Impaired During Late Pregnancy With Elevated Biomarkers of Tuberculosis Risk Postpartum. J Infect Dis. 2022 May 4;225(9):1663-1674. doi: 10.1093/infdis/jiab614.
citation: Mugo NR, Eckert L, Magaret AS, Cheng A, Mwaniki L, Ngure K, Celum C, Baeten JM, Galloway DA, Wamalwa D, Wald A. Quadrivalent HPV vaccine in HIV-1-infected early adolescent girls and boys in Kenya: Month 7 and 12 post vaccine immunogenicity and correlation with immune status. Vaccine. 2018 Nov 12;36(46):7025-7032. doi: 10.1016/j.vaccine.2018.09.059. Epub 2018 Oct 5.
citation: Mackelprang RD, Bamshad MJ, Chong JX, Hou X, Buckingham KJ, Shively K, deBruyn G, Mugo NR, Mullins JI, McElrath MJ, Baeten JM, Celum C, Emond MJ, Lingappa JR; Partners in Prevention HSV/HIV Transmission Study and the Partners PrEP Study Teams. Whole genome sequencing of extreme phenotypes identifies variants in CD101 and UBE2V1 associated with increased risk of sexually acquired HIV-1. PLoS Pathog. 2017 Nov 6;13(11):e1006703. doi: 10.1371/journal.ppat.1006703. eCollection 2017 Nov.
citation: Mugwanya K, Baeten J, Celum C, Donnell D, Nickolas T, Mugo N, Branch A, Tappero J, Kiarie J, Ronald A, Yin M, Wyatt C; Partners PrEP Study Team. Low Risk of Proximal Tubular Dysfunction Associated With Emtricitabine-Tenofovir Disoproxil Fumarate Preexposure Prophylaxis in Men and Women. J Infect Dis. 2016 Oct 1;214(7):1050-7. doi: 10.1093/infdis/jiw125. Epub 2016 Mar 29.
citation: Mugwanya KK, Wyatt C, Celum C, Donnell D, Mugo NR, Tappero J, Kiarie J, Ronald A, Baeten JM; Partners PrEP Study Team. Changes in glomerular kidney function among HIV-1-uninfected men and women receiving emtricitabine-tenofovir disoproxil fumarate preexposure prophylaxis: a randomized clinical trial. JAMA Intern Med. 2015 Feb;175(2):246-54. doi: 10.1001/jamainternmed.2014.6786.
citation: Baeten JM, Donnell D, Mugo NR, Ndase P, Thomas KK, Campbell JD, Wangisi J, Tappero JW, Bukusi EA, Cohen CR, Katabira E, Ronald A, Tumwesigye E, Were E, Fife KH, Kiarie J, Farquhar C, John-Stewart G, Kidoguchi L, Coombs RW, Hendrix C, Marzinke MA, Frenkel L, Haberer JE, Bangsberg D, Celum C; Partners PrEP Study Team. Single-agent tenofovir versus combination emtricitabine plus tenofovir for pre-exposure prophylaxis for HIV-1 acquisition: an update of data from a randomised, double-blind, phase 3 trial. Lancet Infect Dis. 2014 Nov;14(11):1055-1064. doi: 10.1016/S1473-3099(14)70937-5. Epub 2014 Oct 7.
citation: Mugo NR, Hong T, Celum C, Donnell D, Bukusi EA, John-Stewart G, Wangisi J, Were E, Heffron R, Matthews LT, Morrison S, Ngure K, Baeten JM; Partners PrEP Study Team. Pregnancy incidence and outcomes among women receiving preexposure prophylaxis for HIV prevention: a randomized clinical trial. JAMA. 2014 Jul 23-30;312(4):362-71. doi: 10.1001/jama.2014.8735.
citation: Celum C, Morrow RA, Donnell D, Hong T, Hendrix CW, Thomas KK, Fife KH, Nakku-Joloba E, Mujugira A, Baeten JM; Partners PrEP Study Team. Daily oral tenofovir and emtricitabine-tenofovir preexposure prophylaxis reduces herpes simplex virus type 2 acquisition among heterosexual HIV-1-uninfected men and women: a subgroup analysis of a randomized trial. Ann Intern Med. 2014 Jul 1;161(1):11-9. doi: 10.7326/M13-2471.