What is the efficacy of preexposure prophylaxis (PrEP) for HIV?

Updated: Oct 08, 2019
  • Author: Alejandro Delgado, MD; Chief Editor: Michael Stuart Bronze, MD  more...
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ART has been shown to suppress but not eliminate the shedding of HIV in genital secretions. [10] The preventive benefits of ART have been shown in observational studies involving couples, ecologic community studies, and in a clinical trial. [11, 12, 1] Several observational studies have reported decreased acquisition of HIV-1 by sexual partners of patients receiving antiretroviral therapy. [12, 1] Ecologic studies in the community have shown a reduction in the incidence of new cases of HIV-1 after expanded use of ART. [13, 14]

In a large, randomized, controlled, multicontinental, trial that enrolled 1750 serodiscordant heterosexual and male homosexual couples, all index cases had 350-550 CD4 cells/µL at baseline and were randomly assigned to immediate ART treatment initiation or delayed treatment until 2 consecutive measurements of 200-250 CD4 cells/µL or an AIDS-defining illness. All serodiscordant couples were given prevention and adherence counseling and provided with free condoms. In the immediate treatment arm, over 1585 person years, one HIV transmission to a partner occurred that was linked by virological genomic analysis to that of the index case.

In the delayed treatment arm, over 1567 person years, 27 linked HIV transmissions occurred, yielding a rate ratio of 0.04 (95% CI 0.00-0.27). When considering all HIV infections, 35 HIV transmissions occurred in the delayed arm and 4 transmissions in the immediate arm (rate ratio 0.11; 95% CI 0.04-0.32). [11] A Cochrane review, which included the above RCT and 7 observational studies, concluded that ART is a potent intervention for prevention of HIV in discordant couples. They estimated a summary rate ratio of 0.16 (95% CI 0.07, 0.35) for the observational studies alone in favor of using PrEP. [15]

In 2016, the HPTN 052 trial randomized serodiscordant heterosexual couples either to receive immediate ART initiation or to defer ART therapy until CD4 counts fell below 250 cells/µL or an AIDS-defining event occurred. Among 1763 couples, 886 were in the immediate arm and 877 were in the delayed arm. Couples were counseled regarding condom use and safe sexual practices. A total of 46 genetically linked transmissions were reported during the trial period, of which 43 occurred in the delayed arm versus 3 in the immediate arm. No genetically linked HIV transmissions occurred among patients who were virologically suppressed. [16]

The approval of emtricitabine/tenofovir (Truvada) was based on 2 clinical trials, the Pre-exposure Prophylaxis Initiative (iPrEx) trial and the Partners PrEP trial.

The first trial was sponsored by the US National Institutes of Health (NIH) and the Bill and Melinda Gates Foundation. The iPrEx multinational study found that once-daily emtricitabine plus tenofovir disoproxil fumarate (FTC-TDF) reduced the risk of acquiring HIV by 44% in a study population of high-risk, HIV-negative men or transgender women who have sex with men. [2]

The second trial is the Partners PrEP trial, sponsored by the University of Washington and the Bill and Melinda Gates Foundation. In this trial of heterosexual couples where 1 partner was infected and condoms were used routinely, a 75% reduction was observed in risk of acquiring HIV infection with use of emtricitabine/tenofovir. [17]

On June 12, 2013, the Thailand Ministry of Health and the CDC published results from a randomized controlled trial of a daily oral dose of 300 mg of tenofovir disoproxil fumarate (TDF, Viread) that showed efficacy in reducing the acquisition of HIV infection among injecting drug users (IDUs). [18] Based on these findings, the CDC updated its interim guidance for PrEP and now recommends that tenofovir/emtricitabine (TDF/FTC, Truvada) be considered as one of several prevention options for persons at very high risk for HIV acquisition through the injection of illicit drugs. [6]

Results showed that daily oral PrEP with tenofovir 300 mg reduced the risk of acquiring HIV by approximately 49%. Among 2400 study participants, those who took the medication consistently had higher levels of protection. In a separate analysis of participants known to be adherent, because they were observed taking their medication and had tenofovir detected in their blood, the risk of HIV acquisition was reduced by approximately 74%. [18]

Since the publication of these trials, new data have further supported the previously noted benefits of PrEP.

The PROUD trial, published in January 2016, was a pragmatic open-label study performed in 13 sexual health clinics in the United Kingdom. The study enrolled MSM who were sexually active and practicing receptive condomless anal sex during the 90 days prior to recruitment. Patients were randomized to receive immediate PrEP with daily TDF/FTC or to defer treatment for 12 months. The trial enrolled 544 patients (279 in the immediate group, 269 deferred). Early during the trial, the benefit of PrEP became overwhelmingly evident, and all patients were offered treatment. The immediate PrEP arm had a total of 3 infections, while the deferred arm had 20 new infections. This resulted in an 86% risk reduction of HIV transmission. Both groups experienced many cases of STI and showed no significant change in sexual behavior. The success of this trial, which was conducted under real-world circumstances, speaks to the practical applicability of these data. [19]

The IPERGAY trial was published in December 2015. This trial, performed in France and Canada, sought to test the efficacy of on-demand, event-driven use of TDF/FTC among high-risk MSM. It was a randomized placebo-controlled trial in which individuals were instructed to take TDF/FTC preceding and after sex versus placebo. Of 414 randomized patients, 199 were in the final treatment group and 200 were in the placebo group. Sexual education, condoms, and counseling were offered equally to both groups. On average, both groups took approximately 15 pills per months. There were 2 HIV infections in the treatment arm and 14 in the placebo group. The two patients who became infected in the treatment arm were not actively taking medications, amounting to an 86% risk reduction in the risk of HIV acquisition. [20]

While these data are certainly provocative, given how often the patients were engaging in sexual activity, the number of pills taken averages around 3 pills per week, making it difficult to fully endorse the practice of on-demand PrEP in all patients.

Recently, the novel long-acting injectable integrase inhibitor cabotegravir was tested for feasibility and acceptability as an agent for use in pre-exposure prophylaxis. A trial comparing its efficacy versus TDF/FTC is currently underway. [21]

Although most data cited above concerns adults, trial data assessing the safety and feasibility of PrEP in adolescent MSM aged 15-17 years were published in 2017. [22] In this study, 78 patients were enrolled using selection criteria similar to that used for initiating PrEP in adults and were given daily TDF/FTC. Forty-six patients (64%) completed 48 weeks of follow-up. Most participants had detectable levels of the study drug. High levels of tenofovir, consistent with reception of 4 or more doses per week, which is considered highly protective against HIV acquisition, were detected in 54% at week 4, 47% at week 8, 49% at week 12, 28% at week 24, 17% at week 36, and 22% at week 48. The study demonstrated that PrEP is feasible and safe in this patient population, although adherence seemed to decrease over time. This may justify more frequent follow-up than is expected in adults to provide more effective care and to ensure appropriate adherence and protection.

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