Intermittent (vs daily) pre-exposure prophylaxis in men who have unprotected sex with men yielded an 86% relative reduction in new HIV infections in a new study. The caveats?
I have written previously for this site on preexposure prophylaxis (PrEP) as a way of reducing the risk of acquiring HIV1.1 I pointed out both the successes and failures of PrEP, as discussed in various presentations at the 2015 Conference on Retroviruses and Opportunistic Infections (CROI). One of the presentations at that meeting recently was published in The New England Journal of Medicine,2 and warrants further discussion.
Molina and colleagues2 randomized 400 men who have unprotected anal sex with men to receive the combination of tenofovir disoproxil fumarate plus emtricabine (Truvada) versus placebo before and after sexual activity. All participants received risk reduction counseling and condoms. The study was conducted at sites in Montreal and France. Participants were instructed to take two pills (Truvada or placebo) with food 2 to 24 hours before anticipated sexual activity, a third pill 24 hours after the first one, and a fourth pill 24 hours after the third pill. In the circumstance of multiple days of sexual activity, participants were instructed to take one pill per day until the last day of intercourse, followed by the two postexposure pills (given at 24 hour intervals).
The rationale for a placebo-controlled trial was that previous trials of PrEP in both men and women have not consistently shown a benefit of Truvada, and the largest trial of PrEP in men who have sex with men (iPrex) showed only a modest (40%) reduction in new cases of HIV. The authors hypothesized that intermittent PrEP would not be as limited by “adherence fatigue” as daily PrEP regimens are, and that intermittent PrEP would be safer (eg, less nephrotoxicity) than daily PrEP.3 Participants were enrolled between February 2012 and October 2014, when the trial was stopped early by the data and safety monitoring board. At that time, participants had been followed for a median of 9.3 months.
The main findings:
. Overall, there was an 86% relative reduction in new infections in the Truvada group compared to the placebo group (2 infections versus 14). Study drug was not detected in the plasma of the 2 individuals from the Truvada group at the time they were found to be HIV-infected.
. Adherence in the Truvada group was good: over 80% had detectable serum levels of the drug when tested. This result corresponds to ingestion of the drug within the previous 1 week. The drug also was detected in 8 participants (4%) assigned to placebo. Participants took a median of 15 pills (Truvada or placebo) per month.
. Sexual activity did not change during the trial compared to baseline. At baseline, participants reported a median of 10 episodes of sexual intercourse in the previous 4 weeks, with a median of 8 different sexual partners in the previous 2 months.
. Forty-one percent of persons in the Truvada group and 33% of those in the placebo group developed a new sexually transmitted infection (STI) of the throat, anus, and/or urethra during the trial. Specifically, 20% acquired chlamydia, 22% acquired gonorrhea, 10% acquired syphilis, and 1% acquired hepatitis C.
. There was no difference in the number of serious adverse events between the two groups. However, GI adverse events were reported more frequently in the Truvada group than in the placebo group (14% versus 5%). In addition, elevations in serum creatinine were observed in 18% of participants in the Truvada group vs 10% in the placebo group. All but one of these elevations were “Grade 1,” and none led to study drug discontinuation.
My interpretation of the results of the trial are generally positive. An 86% reduction in new infections is impressive, and among the highest reduction rates associated with PrEP reported in the literature. However, the short duration of follow-up may have contributed to this effect. It also is discouraging (but not surprising) that the 2 individuals who seroconverted in the Truvada group did not have detectable plasma levels of the drug. This highlights the importance of adherence with any PrEP strategy. Furthermore, the high number of new HIV infections that occurred in the placebo group (14) equates to an infection rate of 6.6 per one hundred person years, and highlights the need for earlier detection of HIV infection in high risk groups and the importance of “treatment as prevention” approaches to HIV transmission reduction.
Clearly, there remains much to be done from a public health perspective before we are likely to see any large and meaningful reduction in the annual number of new HIV infections and other STIs attributable to high-risk sexual behavior.
1. MacArthur RD. PrEP: progress against HIV? ConsultantLive 25 February 2015.
2. Molina J-M, Capitant C, Spire B, et al. On-demand preexposure in men at high risk for HIV-1 infection. N Engl J Med. 2015;373:2237-2246.
3. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363:2587-2599.