Pre-Exposure Prophylaxis to Prevent HIV-1 Acquisition Within HIV-1 Discordant Couples (Partners PrEP)

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ClinicalTrials.gov Identifier: NCT00557245

Recruitment Status : Completed

First Posted : November 12, 2007

Results First Posted : November 27, 2014

Last Update Posted : April 19, 2019

Sponsor:

Collaborator:

Bill and Melinda Gates Foundation

Information provided by (Responsible Party):

Connie Celum, University of Washington

Study Description

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.

Condition or disease	Intervention/treatment	Phase
HIV-1 Infections HIV Infections	Drug: Tenofovir Disoproxil Fumarate (TDF) Drug: Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) Drug: Placebo	Phase 3

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	4758 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Prevention
Official Title:	Parallel Comparison of Tenofovir and Emtricitabine/Tenofovir Pre-Exposure Prophylaxis to Prevent HIV-1 Acquisition Within HIV-1 Discordant Couples
Study Start Date :	May 2008
Actual Primary Completion Date :	October 2013
Actual Study Completion Date :	October 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Drug Information available for: Emtricitabine Tenofovir Tenofovir Disoproxil Tenofovir Disoproxil Fumarate

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Tenofovir Disoproxil Fumarate (TDF) TDF 300 mg tablet, once daily + Placebo FTC/TDF orally, once daily.	Drug: Tenofovir Disoproxil Fumarate (TDF) TDF 300 mg tablet, once daily + Placebo FTC/TDF orally, once daily. Other Name: Viread + Placebo Truvada
Active Comparator: Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) FTC/TDF - 200 mg tablet, once daily + Placebo TDF orally, once daily	Drug: Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) FTC/TDF - 200 mg tablet, once daily + Placebo TDF orally, once daily Other Name: Truvada + Placebo Viread
Placebo Comparator: Placebo Placebo TDF + Placebo FTC/TDF orally, once daily.	Drug: Placebo Placebo TDF & Placebo FTC/TDF, 1 tablet each daily. Other Name: Placebo + Placebo

Outcome Measures

Primary Outcome Measures :

Incidence of HIV-1 Seroconversion Among HIV-1 Uninfected Participants [ Time Frame: Up to 36 months ]
The efficacy of once daily PrEP in preventing HIV-1 acquisition among uninfected heterosexuals in HIV-1 discordant partnerships, measured by calculating the HIV incidence per 100 person-years in each of three arms.
Number of Participants With Serious Adverse Events (SAEs) [ Time Frame: Up to 36 months ]
Safety of daily TDF or FTC/TDF among HIV-1 uninfected individuals randomized to TDF or FTC/TDF compared to those randomized to placebo measured as the number of participants with Serious Adverse Events (SAEs) during follow-up.

Secondary Outcome Measures :

Study Drug Adherence: Total Number of Study Drug Doses Taken of the Total Dispensed Doses. [ Time Frame: Up to 36 months ]
Adherence to study medication as assessed by pill count at follow-up visits. We assessed the total number of doses taken of the total dispensed doses.
Study Drug Adherence: Self-reported Missed Doses of Study Drug [ Time Frame: Up to 36 months ]
Adherence to study drug measured as the percentage of visits when participants reported missing 1) any dose of study drug in the prior month and 2) 2 or more consecutive doses of study drug.
Number of Seroconverters With an HIV-1 Mutation Conferring Resistance to TDF or FTC [ Time Frame: Up to 36 months ]
HIV-1 resistance as measured by the number of seroconverters who had an HIV-1 reverse transcriptase mutation (K65R, K70E, M184I, or M184V) conferring resistance to TDF or FTC. These mutation types were pre-defined. Plasma samples for resistance testing were collected at the visit seroconversion was first detected and again at a visit within 1 month of seroconversion. Mutations detected at either of those visits are reported.

Both seroconverters found to have a resistance mutation had been HIV infected at enrollment (TDF arm: n=1; FTC-TDF arm: n=1).
Number of Participants With a Sexually Transmitted Infection (STI) During Follow-up [ Time Frame: Up to 36 months ]
Prevalence of STIs measured as the number of participants with a positive test result for N. gonorrhoeae, C. trachomatis, or T. vaginalis during follow-up. Participants were tested for STIs at annual follow-up visits and at intervening visits at which the participant presented with symptoms of an STI. Assessment for symptomatic sexually transmitted infections was conducted quarterly.

N. gonorrhoeae and C. trachomatis testing were by APTIMA Combo 2 (Gen-Probe) or COBAS Amplicor (Roche Diagnostics). T. vaginalis testing was by APTIMA TV TMA (Gen-Probe) or In Pouch TV (Biomed Diagnostics).
Prevalence of Unprotected Sex During Follow-up [ Time Frame: Up to 36 months ]
Sexual risk behavior of participants, measured as the percentage of visits when participants reported having unprotected sex during follow-up.
Congenital Abnormalities Among Infants Born to Female Participants Taking Study Drug. [ Time Frame: Up to 36 months ]
Infant outcomes measured as the number of live-born infants born to female participants taking study drug that had any congenital anomalies.
Length Among Infants Born to Female Participants Taking Study Drug [ Time Frame: up to 12 months ]
The slope of the linear model of the growth of infants (length) during the entirety of follow-up. The length of the infant was measured as a z-score, in terms of standard deviations from the age and gender specific median using the World Health Organization growth curve, accounting for skewness. The slope, representing the change over time of the z-score, was calculated using all available z-scores over 12 months and regressing against study month.
Weight Among Infants Born to Female Participants Taking Study Drug [ Time Frame: up to 12 months ]
The slope of the linear model of the growth of infants (weight) during the entirety of follow-up. The weight of the infant was measured as a z-score, in terms of standard deviations from the age and gender specific median using the World Health Organization growth curve, accounting for skewness. The slope, representing the change over time of the z-score, was calculated using all available z-scores over 12 months and regressing against study month.
Head Circumference Among Infants Born to Female Participants Taking Study Drug [ Time Frame: up to 12 months ]
The slope of the linear model of the growth of infants (head circumference) during the entirety of follow-up. The head circumference of the infant was measured as a z-score, in terms of standard deviations from the age and gender specific median using the World Health Organization growth curve, accounting for skewness. The slope, representing the change over time of the z-score, was calculated using all available z-scores over 12 months and regressing against study month.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	18 Years to 65 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

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

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00557245

Locations

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Kenya
Moi University - Indiana University
Eldoret, Kenya
CMR, Kemri-UCSF
Kisumu, Kenya
Kenyatta National Hospital/University of Nairobi
Nairobi, Kenya
Partners in Prevention - Thika
Thika, Kenya
Uganda
Kabwohe Clinical Research Center
Bushenyi, Uganda
Infectious Diseases Institute
Jinja, Uganda
Partners House-Infectious Disease Institute Ltd
Kampala, Uganda
The AIDS Support Organization (TASO)
Mbale, Uganda
The AIDS Support Organization - Tororo Field Station
Tororo, Uganda

Sponsors and Collaborators

University of Washington

Bill and Melinda Gates Foundation

Investigators

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Study Chair:	Connie Celum,, MD, MPH	University of Washington
Study Director:	Jared Baeten, MD, PhD	University of Washington

More Information

Publications of Results:

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.

Other Publications:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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. Erratum in: PLoS Pathog. 2019 Feb 11;15(2):e1007588.

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.

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.

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.

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.

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. Erratum in: Ann Intern Med. 2016 Dec 6;165(11):832.

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Responsible Party:	Connie Celum, Professor, School of Medicine, Global Health, University of Washington
ClinicalTrials.gov Identifier:	NCT00557245
Other Study ID Numbers:	STUDY00000172 IND 75,365; 07-7454-A-01
First Posted:	November 12, 2007 Key Record Dates
Results First Posted:	November 27, 2014
Last Update Posted:	April 19, 2019
Last Verified:	April 2019

Keywords provided by Connie Celum, University of Washington:


HIV infection HIV uninfected partners Double Blind Placebo Seroconversion	TDF FTC TDF Safety HIV Seronegativity

Additional relevant MeSH terms:

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Infection Communicable Diseases HIV Infections Lentivirus Infections Retroviridae Infections RNA Virus Infections Virus Diseases Sexually Transmitted Diseases, Viral Sexually Transmitted Diseases Immunologic Deficiency Syndromes Immune System Diseases	Tenofovir Emtricitabine Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination Antiviral Agents Anti-Infective Agents Reverse Transcriptase Inhibitors Nucleic Acid Synthesis Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Anti-Retroviral Agents Anti-HIV Agents

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