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Three Maraviroc PrEP Regimens Largely Protective in US MSM Study
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Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston
Mark Mascolini
WEBCAST link: http://www.croiwebcasts.org/console/player/29578?mediaType=audio&
Five of 404 men who have sex with men (MSM) or transgender women taking a maraviroc-containing preexposure prophylaxis (PrEP) regimen or tenofovir/emtricitabine (TDF/FTC) picked up HIV infection in the 48-week HPTN 069/ACTG A5305 trial [1]. All infected men had no, low, or variable drug levels at HIV seroconversion. But results of a substudy suggested maraviroc alone may be less potent than maraviroc/TDF or maraviroc/FTC [2].
Maraviroc is a reasonable PrEP candidate because it concentrates in the genital tract and rectum and can be taken once daily. To explore maraviroc's potential as PrEP alone or with TDF or FTC, HPTN and ACTG collaborators recruited HIV-negative men or transgender women who did not inject drugs and who had condom-free anal sex with one or more HIV-positive or serostatus-unknown men in the past 90 days. The researchers randomized them to 48 weeks of maraviroc alone, maraviroc/FTC, maraviroc/TDF, or TDF/FTC, all once daily. Thus each man took 3 pills daily (including matching placebo).
The trial enrolled 406 people, all male at birth and 7 (2%) transgender women. Median age stood at 30 years and ranged from 18 to 70. Most participants (62%) were white, while 28% were black and 22% Latino. Two thirds of the group had at least some college education. Of the 406 people randomized, 404 started study drugs and 340 (84%) completed the study. Thirty-seven participants (9%) stopped study drugs early, with no differences by study arm. Time to permanent drug discontinuation did not differ between arms.
Analysis of 18 men per study arm showed that TDF or FTC did not affect maraviroc concentrations. In a random subset of 160 participants, all drugs could be detected in 83% of participants at week 24 and 77% at week 48, with no difference between arms.
Ninety men (22%) had 115 sexually transmitted infections diagnosed during follow-up, a finding indicating a high rate of continuing sex. Five men became infected during follow-up for an annual incidence of 1.4% (95% confidence interval 0.8% to 2.3%). Four were taking maraviroc alone and one was taking maraviroc/TDF. Their ages ranged from 20 to 61. (The study was not powered to evaluate efficacy.)
At HIV seroconversion, the man taking maraviroc/TDF had undetectable levels of both drugs. One man on maraviroc alone had no detectable maraviroc at seroconversion, while the other three had levels of 0.7, 6.7, and 145 ng/mL. The expected predose maraviroc level is 32 ng/mL, so only one man had good maraviroc levels at seroconversion. But in all 3 men with detectable maraviroc at seroconversion, levels were highly variable throughout the study, indicating off-and-on PrEP use. All 5 men got infected with virus using the R5 receptor (which maraviroc blocks) and none had genotypic resistance to maraviroc.
Pairwise comparisons showed no difference between study arms in occurrence or rate of 67 grade 3 or 4 adverse events. The only grade 2 or higher adverse events affecting more than 5% of the study group were hypophosphatemia (17%) and upper respiratory infection (11%). Diarrhea affected 2% taking maraviroc alone, 8% on maraviroc/FTC, 7% on maraviroc/TDF, and 4% on TDF/FTC.
The HPTN/ACTG team proposed that "maraviroc-containing regimens should be considered for testing in clinical efficacy trials." Whether to go ahead with solo maraviroc or maraviroc plus TDF remains an open question. A substudy in which researchers tested the four regimens in colorectal tissue explants of 55 study participants found significantly less viral suppression with maraviroc alone than with the three combination regimens [2]. But the HPTN/ACTG team noted that they have yet to correlate those results with pharmacokinetic adherence data. Also, the same regimens are being tested in women, so decisions on future trials must await those results.
References
1. Gulick R, Wilkin TJ, Chen Y, et al. HPTN 069/ACTG 5305: phase II study of maraviroc-based regimens for HIV PrEP in MSM. Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 103.
2. McGowan I, Nikiforov A, Young A, et al. PrEP impact on T-cell activation and explant infection: HPTN 069/ACTG 5305 substudy. Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 104.
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