Emtricitabine/Tenofovir Disoproxil Fumarate for HIV Prevention in Men (iPrEx)

Chemoprophylaxis for HIV Prevention in Men

The purpose of this study is to determine whether daily use of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) can prevent HIV infection in men who also receive HIV counseling, condoms, and treatment for other sexually transmitted infections (STIs).

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: daily TDF/FTC; Drug: Placebo

Detailed Description

The Joint United Nations Programme on AIDS estimates that 14,000 persons are newly infected with HIV every day worldwide; one half of these infections occur in people between the ages of 15 and 24. New infections occur despite widespread awareness of the modes of HIV transmission and the protection afforded by condom use. Effective interventions for HIV prevention are urgently needed. This study will evaluate the safety and efficacy of chemoprophylaxis for HIV prevention in men who have sex with men (MSM) who are at high risk for HIV infection despite using condoms, receiving HIV counseling, and receiving treatment for STIs, particularly hepatitis B virus (HBV) infection. A daily combination dose of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) has been selected for evaluation because it has a well-established safety record in previous studies and was demonstrated to be effective for HIV prevention in primate models. These medications have long half-lives that allow daily dosing and do not have known interactions with hormonal contraception, methadone, or tuberculosis therapies.

Once on the study drug, participants will be followed for a variable length of time, starting within 4 weeks of their screening visit and lasting up to 144 weeks. All participants will be followed for at least 8 weeks after stopping study drug. Participants who are reactive to a Hepatitis B surface antigen (HBsAg) test will be followed for hepatic flares for 16 additional weeks for a total of 24 weeks after stopping study drug. If enrolled in the optional substudy of bone mineral density, fat distribution, and fasting lipids, the participant will be asked to return for one additional visit 24 weeks after stopping study drug. Participants who HIV seroconvert during their participation will also be followed until the end of the study.

All study visits will be at 4 week intervals. At study entry, high risk, HIV uninfected MSM will be randomly assigned to receive either daily FTC/TDF or placebo, in addition to standard HIV counseling, condoms, and sexually transmitted infection (STI) management. The study will closely monitor biological and behavioral safety, including careful analysis of drug resistance, kidney and liver function, and risk behavior.

At the screening visit, participants will undergo HIV antibody and HBV testing, a medical history, a medical exam, blood and urine collection, risk behavior assessment, and STI testing. At study entry, participants will be given study medication; tested for HCV; and offered the HBV vaccine, if applicable. At all study visits, there will be HIV antibody testing, pill counts, adherence checks, study medication distribution, HIV counseling, and condom distribution. A medical history and blood will be taken on selected visits, along with STI testing and treatment if needed. Testing and treatment of STIs will be provided at no cost to the participant.

All study participants will be encouraged to join a substudy that will assess interactions between HBV infection, bone mineral density and fat distribution, and immune function. If enrolled in the substudy, the participant will be asked to return for one additional visit 24 weeks after stopping the study medication. All participants in the substudy will undergo dual energy x-ray absorptiometry (DEXA) scans, and HIV infected participants will undergo additional blood collection.

Sites will have the option of participating in the following four substudies:

The Hair Substudy: Participants who are receiving FTC/TDF will be eligible to enroll. At each 12-week follow-up study visit, hair samples will be collected and questionnaires will be completed.

The Urine Substudy: For all participants who elect to enroll in this substudy, additional testing will occur on blood and urine samples collected at each 24-week follow-up visit. An additional urine collection will occur 8 weeks after participants stop receiving FTC/TDF.

The Semen Substudy: Participants who seroconvert during the study may elect to participate in this substudy. One semen sample will be collected at participants' next study visit when plasma viral load testing is performed.

The Gonorrhea and Chlamydia Substudy: Participants in this substudy will undergo rectal and oropharyngeal swab procedures and urine collection at the 24-week study visit.

After the randomized phase ends, if the daily oral FTC/TDF arm is shown to be beneficial and safe, participants will be given the option of participating in an open label extension phase. During this extension phase, study participants will receive daily oral open-label FTC/TDF, in addition to standard counseling, condoms, and STI management.

• Study Type: Interventional
• Enrollment (Actual): 2499
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Rio de Janeiro, Brazil, 21040-900
    • IPEC/FIOCRUZ iPrEx CRS
  • Rio de Janeiro, Brazil, 21941.590
    • Projeto Praca Onze, Universidade Federal do Rio de Janeiro iPrEx CRS
  • Sao Paulo, Brazil, 05403
    • Universidade de Sao Paulo iPrEx CRS
• Ecuador
  • Guayas
    • Guayaquil, Guayas, Ecuador
      • Fundación Ecuatoriana Equidad, Guayaquil, iPrEx CRS
• Peru
  • Lima, Peru
    • Investigaciones Médicas en Salud (INMENSA), Lince, iPrEx CRS
  • Maynas
    • Iquitos, Maynas, Peru
      • Asociación Civil Selva Amazónica, Iquitos, iPrEx CRS
• South Africa
  • Cape Town, South Africa, 7925
    • Desmond Tutu HIV Ctr. iPrEx CRS
• Thailand
  • Chiang Mai, Thailand, 50200
    • Research Institute for Health Sciences iPrEx CRS
• United States
  • California
    • San Francisco, California, United States, 94102
      • San Francisco Dept. of Public Health iPrEx CRS
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Stroger Hospital of Cook County/Core Center IPREX CRS
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Fenway Community Health iPrEx CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Male sex (at birth)
• HIV uninfected
• Age having reached the local age of consent
• High risk for HIV infection including any of the following: 1) No condom use during anal intercourse with a male HIV-positive partner or a male partner of unknown HIV status during the last 6 months; (2) anal intercourse with more than 3 male sex partners during the last 6 months; (3) exchange of money, gifts, shelter, or drugs for anal sex with a male partner during the last 6 months; (4) sex with a male partner and STI diagnosis during the last 6 months or at screening, or (5) sexual partner of an HIV-infected man with whom condoms are not consistently used in the last 6 months.
• Able to provide a street address of residence for themselves and one personal contact who would know their whereabouts during the study period
• Healthy enough to work, as indicated by score of 80 or greater on the Karnofsky scale
• Certain laboratory values
• A urine dipstick with a negative or trace result for both glucose and protein within 28 days of enrollment.
• Ability to understand and local language for which an informed consent form has been approved by a local IRB and registered with the study sponsor.

Inclusion Criteria for Open-Label Extension:

• Participated in a randomized, placebo-controlled, PrEP trail
• Has been unblinded
• Has provided informed consent

Exclusion Criteria:

• Previously diagnosed active and serious infections, including tuberculosis infection, osteomyelitis, or infections requiring parenteral antibiotic therapy
• Active clinically significant medical problems including heart disease (e.g., symptoms of ischemia, congestive heart failure, arrhythmia), lung disease (steroid-dependent chronic obstructive pulmonary disease), diabetes requiring hypoglycemic medication, or previously diagnosed cancer expected to require further treatment
• Acute HBV infection at the screening visit or presence of treatment indications for hepatitis B based on local practice standards; or clinical signs of hepatic cirrhosis
• History of pathological bone fractures not related to trauma
• Receiving ongoing therapy with certain HIV/AIDS-related medications or other medications as determined by the investigator
• Definitely or possibly received an anti-HIV vaccine while participating in a blinded clinical trial
• Current alcohol or drug use that, in the opinion of the investigator, may interfere with the study
• Current participation in a clinical trial or cohort study other than sub-studies of this protocol
• Any condition at enrollment that, in the opinion of the investigator, would make participation in the study unsafe or would interfere with the study
• Sites may utilize additional criteria that restrict enrollment to a subset of people who meet the protocol-defined enrollment criteria.

Exclusion Criteria for Open-Label Extension:

- Site leadership believes participant will have difficulty completing requirements

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TDF/FTC; Drug. Daily oral tablet of co-formulated 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate (TDF/FTC).	Drug: daily TDF/FTC; daily oral medication; Other Names: truvada
Placebo Comparator: Placebo; Drug. Daily oral placebo	Drug: Placebo; daily oral medication

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HIV Seroconversion	Confirmed HIV infection	Monthly follow-up through a median of 1.2 years
Grade 1 or Higher Creatinine Toxicity	Creatinine which reach grade 1 (mild, 1.1 to 1.3 local upper limit of normal) or higher by the US Division of AIDS grading table (version 1) or a 50% increase in creatinine from the baseline value. The DAIDS table can be found at https://rsc.tech-res.com/docs/default-source/safety/table_for_grading_severity_of_adult_pediatric_adverse_events.pdf	Duration of follow-up, median 1.2 years
Grade 3 or Higher Phosphorous Toxicity	Grade 3 or higher phosphorous toxicity (hypophosphatemia) by the Division of AIDS Grading Table (severe, level at or below 1.9 mg/dL)	The entire follow-up period, median 1.2 years
Grade 2, 3, or 4 Laboratory Adverse Events	Number of participants with at least one Grade 2, 3, or 4 laboratory adverse events (moderate, severe of life threatening based one the US Division of AIDS Grading of adverse events, version 1.0). The table can be found at https://rsc.tech-res.com/docs/default-source/safety/table_for_grading_severity_of_adult_pediatric_adverse_events.pdf	Entire follow-up, median 1.2 years
Grade 2, 3, or 4 Clinical Adverse Events	Number of participants with at least 1 Grade 2, 3, or 4 clinical adverse events (moderate, severe of life threatening based one the US Division of AIDS Grading of adverse events, version 1.0). The table can be found at https://rsc.tech-res.com/docs/default-source/safety/table_for_grading_severity_of_adult_pediatric_adverse_events.pdf	Entire follow-up, median 1.2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hepatitis Flares Among Hepatitis B Virus (HBV) Infected Persons During and After Chemoprophylaxis	A hepatic flare is defined as an increase in alanine transaminase or aspartate transaminase to >5 fold upper limit of normal at any visit, or an increase to >2.5 fold upper limit of normal for 3 months, within 24 weeks of permanently stopping study drug. More details in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752387/	Quarterly lab tests through a median follow-up of 1.2 years
Percentage Change in Bone Mineral Density	% Change from baseline in bone mineral density (100 * [(value at 24 weeks- value at baseline)/ (value at baseline)]) in in hip and L1-L4 spine by dual-energy x-ray absorptiometry	baseline and week 24.
Percentage Change in Body Fat	Percentage Change (100 * [(value at 24 weeks- value at baseline)/ (value at baseline)]) in Body Fat from Baseline by dual-energy x-ray absorptiometry	Baseline and Week 24
Percentage Change in Fasting Triglycerides	Percentage Change (Percentage Change (100 * [(value at 24 weeks- value at baseline)/ (value at baseline)]) in Triglycerides from Baseline from a fasting sample.	Baseline and Week 24
Percent Change in Total Cholesterol	Percent change (100 * [(value at 24 weeks- value at baseline)/ (value at baseline)]) in fasting total cholesterol from baseline	Baseline and Week 24
Viral Load Among HIV Infected Participants	HIV-RNA in log10 units among HIV infected participants at the time closest to HIV detection	At the time closest to HIV detection
Among HIV Infected Participants Drug Resistance	Genotypic resistance by clinical assays among the seroconverters from baseline to the end of the study treatment period	at the time of HIV acquisition
CD4 Count Among HIV Infected Participants	CD4 cell count for HIV infected participants during the trial	at the time infection was detected
Proportion of Missed Doses by Pill Count	Estimated proportion of missed doses by pill count (assuming pills taken in unreturned bottles)	At 24 weeks
Percentage of Missed Doses by Estimate During CASI Interview	Percentage of missed doses by estimate during computer assisted structured interview	Week 24
Number of Condomless Sexual Partners With HIV Positive or Unknown Status	Participants self-report of the number of sexual partners with HIV positive or unknown status in the previous 12 weeks with whom they had condomless anal sex	At 24 weeks
Total Number of Sexual Partners	Self-reported total number of sexual partners in the previous 12 weeks.	24 weeks
Condomless Receptive Anal Intercourse in the Previous 12 Weeks With Any Partners Regardless of Status.	Self-reported condomless receptive anal intercourse in the previous 12 weeks with any partners regardless of status.	At 24 weeks
Incidence of Confirmed Syphilis During Follow-Up	Number of participants who have at least 1 confirmed syphilis infection during the study	All Follow-Up median of 1.2 years of follow-up
Incidence of HSV-2 During the Follow-up Period	Incidence of HSV-2 during the follow-up period among those HIV-2 negative at baseline	Total study follow-up, a median of 1.2 years
Diagnosis of Gonorrhea During the Follow-up Period	Diagnosis of gonorrhea during the follow-up period by PCR	All of follow-up period, median of 1.2 years

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Bill and Melinda Gates Foundation
• Investigators: Principal Investigator: Robert M. Grant, MD, MPH, J. David Gladstone Institutes, University of California San Francisco

Publications and helpful links

General Publications

• Castillo-Mancilla J, Seifert S, Campbell K, Coleman S, McAllister K, Zheng JH, Gardner EM, Liu A, Glidden DV, Grant R, Hosek S, Wilson CM, Bushman LR, MaWhinney S, Anderson PL. Emtricitabine-Triphosphate in Dried Blood Spots as a Marker of Recent Dosing. Antimicrob Agents Chemother. 2016 Oct 21;60(11):6692-6697. doi: 10.1128/AAC.01017-16. Print 2016 Nov.
• Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, Goicochea P, Casapia M, Guanira-Carranza JV, Ramirez-Cardich ME, Montoya-Herrera O, Fernandez T, Veloso VG, Buchbinder SP, Chariyalertsak S, Schechter M, Bekker LG, Mayer KH, Kallas EG, Amico KR, Mulligan K, Bushman LR, Hance RJ, Ganoza C, Defechereux P, Postle B, Wang F, McConnell JJ, Zheng JH, Lee J, Rooney JF, Jaffe HS, Martinez AI, Burns DN, Glidden DV; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010 Dec 30;363(27):2587-99. doi: 10.1056/NEJMoa1011205. Epub 2010 Nov 23.
• Mehrotra ML, Westreich D, McMahan VM, Glymour MM, Geng E, Grant RM, Glidden DV. Baseline Characteristics Explain Differences in Effectiveness of Randomization to Daily Oral TDF/FTC PrEP Between Transgender Women and Cisgender Men Who Have Sex With Men in the iPrEx Trial. J Acquir Immune Defic Syndr. 2019 Jul 1;81(3):e94-e98. doi: 10.1097/QAI.0000000000002037. No abstract available.
• Glidden DV, Mulligan K, McMahan V, Anderson PL, Guanira J, Chariyalertsak S, Buchbinder SP, Bekker LG, Schechter M, Grinsztejn B, Grant RM. Metabolic Effects of Preexposure Prophylaxis With Coformulated Tenofovir Disoproxil Fumarate and Emtricitabine. Clin Infect Dis. 2018 Jul 18;67(3):411-419. doi: 10.1093/cid/ciy083.
• Glidden DV, Mulligan K, McMahan V, Anderson PL, Guanira J, Chariyalertsak S, Buchbinder SP, Bekker LG, Schechter M, Grinsztejn B, Grant RM. Brief Report: Recovery of Bone Mineral Density After Discontinuation of Tenofovir-Based HIV Pre-exposure Prophylaxis. J Acquir Immune Defic Syndr. 2017 Oct 1;76(2):177-182. doi: 10.1097/QAI.0000000000001475.
• Gandhi M, Glidden DV, Mayer K, Schechter M, Buchbinder S, Grinsztejn B, Hosek S, Casapia M, Guanira J, Bekker LG, Louie A, Horng H, Benet LZ, Liu A, Grant RM. Association of age, baseline kidney function, and medication exposure with declines in creatinine clearance on pre-exposure prophylaxis: an observational cohort study. Lancet HIV. 2016 Nov;3(11):e521-e528. doi: 10.1016/S2352-3018(16)30153-9. Epub 2016 Aug 31.
• Glidden DV, Amico KR, Liu AY, Hosek SG, Anderson PL, Buchbinder SP, McMahan V, Mayer KH, David B, Schechter M, Grinsztejn B, Guanira J, Grant RM. Symptoms, Side Effects and Adherence in the iPrEx Open-Label Extension. Clin Infect Dis. 2016 May 1;62(9):1172-7. doi: 10.1093/cid/ciw022. Epub 2016 Jan 20.
• Mulligan K, Glidden DV, Anderson PL, Liu A, McMahan V, Gonzales P, Ramirez-Cardich ME, Namwongprom S, Chodacki P, de Mendonca LM, Wang F, Lama JR, Chariyalertsak S, Guanira JV, Buchbinder S, Bekker LG, Schechter M, Veloso VG, Grant RM; Preexposure Prophylaxis Initiative Study Team. Effects of Emtricitabine/Tenofovir on Bone Mineral Density in HIV-Negative Persons in a Randomized, Double-Blind, Placebo-Controlled Trial. Clin Infect Dis. 2015 Aug 15;61(4):572-80. doi: 10.1093/cid/civ324. Epub 2015 Apr 23.
• Liu A, Glidden DV, Anderson PL, Amico KR, McMahan V, Mehrotra M, Lama JR, MacRae J, Hinojosa JC, Montoya O, Veloso VG, Schechter M, Kallas EG, Chariyalerstak S, Bekker LG, Mayer K, Buchbinder S, Grant R; iPrEx Study team. Patterns and correlates of PrEP drug detection among MSM and transgender women in the Global iPrEx Study. J Acquir Immune Defic Syndr. 2014 Dec 15;67(5):528-37. doi: 10.1097/QAI.0000000000000351.
• Liegler T, Abdel-Mohsen M, Bentley LG, Atchison R, Schmidt T, Javier J, Mehrotra M, Eden C, Glidden DV, McMahan V, Anderson PL, Li P, Wong JK, Buchbinder S, Guanira JV, Grant RM; iPrEx Study Team. HIV-1 drug resistance in the iPrEx preexposure prophylaxis trial. J Infect Dis. 2014 Oct 15;210(8):1217-27. doi: 10.1093/infdis/jiu233. Epub 2014 Apr 16.
• Buchbinder SP, Glidden DV, Liu AY, McMahan V, Guanira JV, Mayer KH, Goicochea P, Grant RM. HIV pre-exposure prophylaxis in men who have sex with men and transgender women: a secondary analysis of a phase 3 randomised controlled efficacy trial. Lancet Infect Dis. 2014 Jun;14(6):468-75. doi: 10.1016/S1473-3099(14)70025-8. Epub 2014 Mar 7.
• Amico KR, Mansoor LE, Corneli A, Torjesen K, van der Straten A. Adherence support approaches in biomedical HIV prevention trials: experiences, insights and future directions from four multisite prevention trials. AIDS Behav. 2013 Jul;17(6):2143-55. doi: 10.1007/s10461-013-0429-9.

Helpful Links

• Primary Manuscript

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: April 6, 2007
• First Submitted That Met QC Criteria: April 6, 2007
• First Posted (Estimate): April 10, 2007

Study Record Updates

• Last Update Posted (Actual): November 2, 2021
• Last Update Submitted That Met QC Criteria: October 29, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: HIV Seronegativity; HIV; Hepatitis; Chemoprophylaxis; Viral human hepatitis
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
• Other Study ID Numbers: CO-US-104-0288; 10445 (Other Identifier: CTEP); 1U01AI064002 (U.S. NIH Grant/Contract); iPrEx (Other Identifier: Study team)