Pre-exposure prophylaxis regimens containing maraviroc were safe and well-tolerated in women at risk for HIV infection compared with emtricitabine-tenofovir disoproxil fumarate, according to results from a phase two trial. “More than 2m new HIV infections occur annually worldwide, with about half in women,” Dr Roy M Gulick, from Weill Cornell Medicine, and colleagues wrote. “Effective strategies to prevent HIV acquisition among women are urgently needed, yet studies of HIV pre-exposure prophylaxis (PrEP) in women have shown conflicting results.”
Maraviroc, a CCR5 antagonist HIV entry inhibitor approved for HIV treatment, is a viable candidate drug for HIV PrEP, according to the researchers.
Gulick and colleagues conducted a phase-2 controlled, double-blinded study to determine the safety and tolerability of maraviroc-containing PrEP in women at risk for HIV infection from one of 12 US clinical research sites of the HIV Prevention Trials Network and AIDS Clinical Trials Group. They enrolled 188 HIV-negative women (median age, 35 years; 65% black; 17% Latina; 27% white; 8% other) who reported having vaginal or anal intercourse without a condom with at least one man infected with HIV or with unknown serostatus within 90 days. Participants were randomly assigned to one of four PrEP regimens for 48 weeks: maraviroc only, maraviroc-emtricitabine, maraviroc-tenofovir disoproxil fumarate and emtricitabine-tenofovir disoproxil fumarate (control). They took three pills including matching placebos once per day.
Follow-up was completed by 85% of enrollees, 11% withdrew early and 4% were lost to follow-up. 19% of participants halted their regimen prematurely. There was no difference among regimens in the number of women discontinuing treatment or the time to discontinuation. Five women receiving maraviroc, 13 receiving maraviroc-emtricitabine, nine receiving maraviroc-tenofovir disoproxil fumarate and eight receiving emtricitabine-tenofovir disoproxil fumarate experienced grade 3 or grade 4 adverse events.
There was no difference in rates of adverse events among regimens. One participant in the maraviroc-tenofovir disoproxil fumarate group died by suicide; however, this event was not related to the study drugs. Detectable drug concentrations were seen in 60% of plasma samples at week 48. New HIV infections did not occur.
“We found that [maraviroc]-containing PrEP regimens were generally safe and well-tolerated compared with the standard-of-care regimen of [emtricitabine-tenofovir disoproxil fumarate] in US women who were at risk for HIV infection … Although no HIV infections occurred in this study, it was not designed to assess efficacy,” Gulick and colleagues concluded.
“Given concerns about suboptimal [tenofovir] levels in the female genital tract, additional PrEP choices are needed. Maraviroc-containing oral PrEP regimens, with demonstrated safety and tolerability similar to that of [emtricitabine-tenofovir disoproxil fumarate], may warrant further study in fully powered efficacy studies for HIV PrEP.”
Background: Maraviroc (MVC) is a candidate drug for HIV preexposure prophylaxis (PrEP).
Objective: To assess the safety and tolerability of MVC-containing PrEP over 48 weeks in U.S. women at risk for HIV infection.
Design: Phase 2 randomized, controlled, double-blinded study of 4 antiretroviral regimens used as PrEP. (ClinicalTrials.gov: NCT01505114)
Setting: 12 clinical research sites of the HIV Prevention Trials Network and AIDS Clinical Trials Group.
Participants: HIV-uninfected women reporting condomless vaginal or anal intercourse with at least 1 man with HIV infection or unknown serostatus within 90 days.
Intervention: MVC only, MVC–emtricitabine (FTC), MVC–tenofovir disoproxil fumarate (TDF), and TDF–FTC (control).
Measurements: At each visit, clinical and laboratory (including HIV) assessments were done. Primary outcomes were grade 3 and 4 adverse events and time to permanent discontinuation of the study regimen. All randomly assigned participants were analyzed according to their original assignment.
Results: Among 188 participants, 85% completed follow-up, 11% withdrew early, and 4% were lost to follow-up; 19% discontinued their regimen prematurely. The number discontinuing and the time to discontinuation did not differ among regimens. Grade 3 or 4 adverse events occurred in 5 (MVC), 13 (MVC–FTC), 9 (MVC–TDF), and 8 (TDF–FTC) participants; rates did not differ among regimens. One death (by suicide) occurred in the MVC–TDF group but was judged not to be related to study drugs. Of available plasma samples at week 48 (n = 126), 60% showed detectable drug concentrations. No new HIV infections occurred.
Limitations: Participants were not necessarily at high risk for HIV infection. The regimen comprised 3 pills taken daily. The study was not powered for efficacy.
Conclusion: Maraviroc-containing PrEP regimens were safe and well-tolerated compared with TDF–FTC in U.S. women. No new HIV infections occurred, although whether this was due to study drugs or low risk in the population is uncertain. Maraviroc-containing PrEP for women may warrant further study.
Roy M Gulick; Timothy J Wilkin; Ying Q Chen; Raphael J Landovitz; K Rivet Amico; Alicia M Young; Paul Richardson; Mark A Marzinke; Craig W Hendrix; Susan H Eshleman; Ian McGowan; Leslie M Cottle; Adriana Andrade; Cheryl Marcus; Karin L Klingman; Wairimu Chege; Alex R Rinehart; James F Rooney; Philip Andrew; Robert A Salata; Marc Siegel; Yukari C Manabe; Ian Frank; Ken Ho; Jorge Santana; Joanne D Stekler; Shobha Swaminathan; Marybeth McCauley; Sally Hodder; Kenneth H Mayer