NEXT PrEP:  The Next Chapter in PrEP

By Kenneth Mayer, MD
Medical Research Director, Co-Chair of The Fenway Institute

& Christopher Chianese
Clinical Study Coordinator

Oral PrEP is a novel HIV prevention approach in which at risk HIV-uninfected individuals take antiretroviral medication to prevent them from acquiring HIV. Globally there have been multiple  PrEP  studies either recently completed or currently underway in 13 countries involving over 20,000 individuals with diverse risk behaviors (HIV serodiscordant couples, at risk heterosexual persons in high HIV prevalence areas, intravenous drug users (IDUs) and men who have sex with men (MSM). All of these clinical trials have evaluated PrEP using either tenofovir disoproxil fumarate (TDF) or the fixed-dose combinations of TDF/emtricitabine (FTC).

In late 2010, results became available from the first efficacy trial of an antiretroviral-based PrEP, known as “iPrEx.” Close to 2,500 HIV-negative MSM and transgendered women who have sex with men were randomized to daily oral TDF/FTC or placebo. The Fenway Institute was one of 2 US sites involved in this study. Overall 44% fewer incident HIV infections occurred in the TDF/FTC group compared to the placebo group. A key finding of the study was that drug detection in blood was highly correlated with protection where among those whose data indicated use of TDF/FTC on 90% or more days, an estimated 73% level of protection was demonstrated. The drug combination was also found to be generally safe and well-tolerated.

Despite these encouraging findings, some concerns about the use of TDF exist. TDF/FTC is used commonly in ARV regimens for treatment of HIV-infected individuals and viral strains that are resistant to  FTC, and less commonly to TDF, exist and have been transmitted. In addition, although TDF with or without FTC is generally well-tolerated in both HIV-infected individuals and healthy participants using PrEP, concerns remain about longer-term side effects of these drugs, including renal toxicity and decreased bone mineral density (BMD). Given the 44% overall efficacy of TDF/FTC demonstrated in iPrEx, which appeared to be influenced by poor adherence, as well as concerns about drug resistance and long term toxicity, further options for  PrEP regimens using alternative agents are needed.

Maraviroc (MVC) is a CCR5 antagonist that was approved by the US Food and Drug Administration (FDA) in 2007 for treatment of people infected with HIV. Its mechanism of action is  that it blocks  the CCR5 co-receptor that HIV uses for cell entry. MVC has a number of potential advantages for use as a PrEP agent. It acts early in the life cycle of HIV by preventing viral binding to the CCR5 co-receptor. In addition, MVC has a number of favorable pharmacological properties (high concentrations in the genital and anorectal areas), and drug resistance characteristics. Recent animal  data has demonstrated that MVC can protect against retroviral challenges.. The longer-term safety and tolerability of MVC as a PrEP agent in healthy, HIV-uninfected individuals requires further assessment.

The Fenway Institute will be one of 12 US sites involved in HPTN 069: A Phase II Randomized, Double-Blind, Study of the Safety and Tolerability of Maraviroc (MVC), Maraviroc + emtricitabine (MVC + FTC), Maraviroc + Tenofovir disoproxil fumarate (MVC+TDF), or Tenofovir disoproxil fumarate + Emtricitabine (TDF +FTC) For Pre-Exposure Prophylaxis (PrEP) To Prevent HIV Transmission in At-Risk Men Who Have Sex With Men.

The primary objective is to assess the safety and tolerability of MVC, MVC+FTC, MVC+TDF and TDF+FTC over 48 weeks. This will be measured by  comparing the occurrence of serious or severe adverse events  and time to permanent drug discontinuation (tolerability) in each of the four study arms. Participants will be assessed for eligibility, by reviewing their medical and sexual history,  and then  testing them for HIV, as well as renal, liver, and hematologic function. Eligible participants will be randomized to receive MVC, MVC+FTC, MVC+TDF, or TDF+FTC in a 1:1:1:1 ratio. All participants will receive HIV testing with pre-and post-test counseling, in addition to risk reduction counseling and condoms. Accrual will occur over approximately 9 months, and each participant will be followed for approximately 12 months. Four hundred (400) HIV uninfected MSM will be included in this study.

HPTN 069 is sponsored by the Division of AIDS (DAIDS) and the US National Institute of Allergy and Infectious Diseases (NIAID). Pharmaceutical support will be provided by Gilead Sciences, Inc. and ViiV Healthcare. The Protocol Chair is Roy M. Gulick, MD, MPH from the Weill Medical College of Cornell University. Protocol Co-chairs are Kenneth Mayer, MD from Fenway Health and Timothy Wilkin, MD from the Weill Medical College of Cornell University. The core clinical and recruitment team members for the Fenway site include Lori Panther, MD, MPH, Marcy Gelman, RN, MSN, MPH, Ariel Watriss, MSN, NP-C, Christopher Chianese, M.ED, Daniel Jones, RN, Benny Vega and Paul Fletcher. HPTN 069 is expected to start enrollment in March 2012.