Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Women

Abstract

BACKGROUND Maraviroc (MVC) is a candidate drug for HIV PrEP. OBJECTIVE To assess the safety/tolerability of MVC-containing PrEP in U.S. women at-risk for HIV over 48 weeks. DESIGN Phase 2 randomized, controlled, double-blinded study of four PrEP regimens (#NCT01505114). SETTING Twelve 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 ≥1 HIV-infected or unknown-serostatus man within 90 days. INTERVENTIONS MVC alone, MVC+emtricitabine (FTC), MVC+tenofovir disoproxil fumarate (TDF), and TDF+FTC (control). MEASUREMENTS At each visit, clinical and laboratory (including HIV) assessments were conducted. Primary outcomes were grade 3–4 adverse events and time to permanent regimen discontinuation. Analyses were conducted on all randomized participants, according to original regimen assignment. RESULTS Among 188 participants, 85% completed follow-up, 11% withdrew early, and 4% were lost-to-follow-up; 19% discontinued their regimen prematurely. Number discontinuing and time-to-discontinuation did not differ among regimens. Grade 3/4 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 occurred (suicide; MVC+FTC), judged not regimen-related. Of available samples at week 48 (n=126), 60% demonstrated detectable drug concentrations. No new HIV infections occurred. LIMITATIONS Participants were not necessarily high-risk for HIV. Regimen was 3 pills daily. Study was not powered for efficacy. CONCLUSIONS MVC-containing PrEP regimens were safe and well-tolerated compared to the control regimen of TDF+FTC in U.S. women. No new HIV infections occurred, although whether this was due to low risk of the population or to protection from the study regimens is not certain. MVC-containing PrEP for women may warrant further study. FUNDING SOURCE U.S. National Institutes of Health

Perspectives of US women participating in a candidate PrEP study: adherence, acceptability and future use intentions

“…HPTN069/ACTG5305 was a prospective, randomized, double‐blinded, multisite, safety and tolerability study of four antiretroviral regimens for HIV PrEP: (1) maraviroc (MVC) alone; (2) MVC + emtricitabine (FTC); (3) MVC + tenofovir (TDF); and (4) TDF + FTC (control) conducted with women in the US between March 2013 and November 2015 . As described in detail in the presentation of primary outcomes , study regimens consisted of three pills once‐daily: MVC 300 mg, FTC 200 mg and TDF 300 mg, with matching placebos. HIV‐seronegative women who reported a history of condomless vaginal or anal intercourse with >1 HIV‐seropositive male partner or man of unknown serostatus within 90 days, and had adequate safety laboratory parameters were enrolled at 12 US‐based study sites (Baltimore, MD; Boston, MA; Chapel Hill, NC; Cleveland, OH; Los Angeles, CA; Newark, NJ; New York City, NY; Philadelphia, PA; Pittsburgh, PA; San Juan, PR; Seattle, WA; and Washington, DC).…”

“…HPTN069/ACTG5305 was a prospective, randomized, double‐blinded, multisite, safety and tolerability study of four antiretroviral regimens for HIV PrEP: (1) maraviroc (MVC) alone; (2) MVC + emtricitabine (FTC); (3) MVC + tenofovir (TDF); and (4) TDF + FTC (control) conducted with women in the US between March 2013 and November 2015 . As described in detail in the presentation of primary outcomes , study regimens consisted of three pills once‐daily: MVC 300 mg, FTC 200 mg and TDF 300 mg, with matching placebos.…”

“…In response to this paucity of data, we collected quantitative and qualitative data from women participating in HIV Prevention Trials Network (HPTN) 069/AIDS Clinical Trials Group (ACTG) 5305 study to better understand reasons for adherence and/or non‐adherence to study drug, attitudes towards PrEP and intentions to use PrEP after the end of the study. Given the few PrEP trials involving US women and demonstration projects seeking to involve them, the results of this study may help develop approaches for supporting adherence in the rollout of current and future PrEP technologies.…”

No Clinical Impact of CYP3A5 Gene Polymorphisms on the Pharmacokinetics and/or Efficacy of Maraviroc in Healthy Volunteers and HIV‐1–Infected Subjects

“…The magnitude of the effect of CYP3A5 genotype on maraviroc exposures is expected to be comparable with exposures for maraviroc administered at the approved dose of 150 mg twice daily in combination with darunavir/cobicistat. In addition, maraviroc is being assessed at lower daily doses (300 mg once daily) for HIV preexposure prophylaxis, commonly referred to as PrEP, in healthy men and women at high risk for HIV infection . The impact of CYP3A5 genotype for HIV PrEP cannot be determined until maraviroc has been shown to be effective for use in PrEP and exposure‐response analyses determine what target maraviroc exposure is needed for HIV prevention.…”

“…In addition, maraviroc is being assessed at lower daily doses (300 mg once daily) for HIV preexposure prophylaxis, commonly referred to as PrEP, in healthy men and women at high risk for HIV infection. 35,36 The impact of CYP3A5 genotype for HIV PrEP cannot be determined until maraviroc has been shown to be effective for use in PrEP and exposure-response analyses determine what target maraviroc exposure is needed for HIV prevention.…”