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Chief, Division of HIV Medicine
Harbor-UCLA Medical Center
Professor of Medicine
David Geffen School of Medicine at UCLA
Los Angeles, California
Eric S. Daar, MD, has disclosed that he has received consulting fees from Genentech, Gilead Sciences, and ViiV Healthcare and funds for research support from Gilead Sciences, Merck, and ViiV Healthcare.
A key pillar for ending HIV/AIDS in the United States is the use of pre-exposure prophylaxis (PrEP) for preventing new infections among high-risk HIV-uninfected individuals. The first study demonstrating the efficacy of PrEP was iPrEx, which included HIV-uninfected men who have sex with men (MSM) and transgender women (TGW) and showed slightly greater than a 40% reduction in risk of acquiring HIV among those randomized to tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) vs placebo. Among those documented to be taking more than 90% of their doses, the preventive efficacy exceeded 70%. There have been several studies also assessing the efficacy of TDF/FTC in high-risk heterosexual men, heterosexual women, and intravenous drug users. Although several studies in women did not show efficacy, it was subsequently shown that this was because of poor adherence. At this time, it is generally accepted that when taken appropriately, TDF/FTC likely confers in excess of 95% protection from HIV acquisition. TDF/FTC was approved by the FDA in 2012.
Evolving PrEP Strategies
Subsequent research has focused on strategies to enhance adherence and simplify treatment. Based on nonhuman primate data, another strategy studied in HIV-uninfected MSM and TGW is the potential of on-demand PrEP using 2 TDF/FTC tablets given between 2 and 24 hours before a sexual exposure and then a single tablet at 24 and 48 hours after the pre-exposure dose—the so called 2-1-1 regimen. This approach was shown to be highly effective when compared with placebo, resulting in early termination of the pivotal IPERGAY trial conducted in Paris. Post hoc analyses showed that even in those with less frequent sexual exposures, the strategy remained highly effective, and these results have been further supported by a large observational study in Paris. Although the 2-1-1 regimen is increasingly used outside the United States, in the United States, it is not approved by the FDA or currently recommended by the CDC; however, it is supported by the International Antiviral Society-USA guidelines as an alternative option for MSM having relatively infrequent sex. At this time, based on the data available, this regimen should only be recommended for prevention of transmission via anal intercourse.
Another recent advance came from the DISCOVER study that randomized HIV-uninfected MSM and TGW at high risk of HIV infection to either daily TDF/FTC or tenofovir alafenamide (TAF)/FTC, containing a newer prodrug of tenofovir that has been shown in individuals with HIV to be as effective at suppressing HIV as TDF with less adverse events on the bone and kidneys. This regimen was shown to be an effective form of PrEP and was approved by the FDA in 2019 for HIV-uninfected MSM and TGW. Studies are underway to assess the effectiveness of this medication to prevent HIV transmission associated with vaginal intercourse.
Two nonenteral strategies are in advanced stages of development for PrEP. The first is the dapivirine vaginal ring, designed to protect women from HIV acquisition through vaginal sex. It is inserted into vagina every 28 days and reduced HIV transmission in the Ring and ASPIRE studies by approximately 30% vs placebo. Among those with highest adherence to the ring, its efficacy was closer to 75%. In July 2020, the dapivirine ring received a positive scientific opinion from the European Medicine Agency in cooperation with the WHO on the public health benefits for women in low- and middle-income countries outside of the European Union.
New PrEP Data From AIDS 2020: Virtual
The second nonenteral PrEP strategy is long-acting cabotegravir (LA-CAB). At AIDS 2020: Virtual, investigators presented results from the randomized, double-blind phase IIb/III HPTN 083 study comparing daily oral TDF/FTC vs intramuscular LA-CAB injections administered every 8 weeks. This trial included 4566 HIV-uninfected MSM and TGW at high risk of HIV infection. Individuals randomized to the LA-CAB arm initially received oral CAB 30 mg once daily until Week 5 before switching to intramuscular LA-CAB 600 mg every 4 weeks for 2 doses, then every 8 weeks thereafter. The study was stopped early by the data and safety monitoring board due to a highly significant reduction in HIV acquisition in the LA-CAB group compared with the oral TDF/FTC group, with 13 vs 39 HIV infections, respectively (HR: 0.34; 95% CI: 0.18-0.62; P = .0005). Among 1256 dried blood spot samples assayed from a random set of 372 participants receiving daily oral TDF/FTC, nearly 25% overall had tenofovir diphosphate levels associated with receipt of 4 or fewer doses per week. The LA-CAB injections were generally well tolerated, with 2.2% of LA-CAB recipients permanently discontinuing for injection-related adverse events. Several grade ≥ 2 adverse events occurred at a significantly higher rate in the LA-CAB arm vs the oral TDF/FTC arm, including decreased creatinine clearance rate, nasopharyngitis, increased blood glucose level, and pyrexia. A parallel study, HPTN 084, in HIV-uninfected heterosexual women at high risk for HIV infection is currently underway.
Current Status of PrEP and Anticipated Future Data
In summary, since the original approval of TDF/FTC for PrEP, there have been several advances that will enhance tolerability, convenience, and possibly efficacy. Of most importance, a wider array of options will give individuals at risk great choice and a higher likelihood of finding an approach that is right for them and their lives. As with most medical interventions, one size does not fit all. At this point, there remain fewer options for those at risk for HIV acquisition by vaginal sex, but hopefully data with daily TAF/FTC and LA-CAB will be available for these groups in the near future. An ongoing priority remains to enhance the number of eligible individuals who are using these highly effective prevention regimens.
What are your thoughts about what new and emerging HIV prevention options offer for your at-risk patients? Join the discussion by posting a comment and share your experiences of what your patients are telling you they would most like to see in future HIV prevention strategies.