Twice-yearly lenacapavir prevents HIV more effectively than daily F/TDF

1. In this randomized controlled trial, among men and gender-diverse persons who have sex with men, it was found that twice-yearly lenacapavir resulted in a significantly lower human immunodeficiency virus (HIV) incidence than with daily F/TDF.

2. The incidence of adverse events and laboratory abnormalities was similar between the two groups.

Evidence Rating Level: 1 (Excellent)

Study Rundown: While the overall number of new HIV infections has been declining globally, new diagnoses among cisgender men who have sex with men and transgender women have increased. Global preexposure prophylaxis (PrEP) use remains low, especially in the populations most disproportionately affected by HIV, highlighting the need for new PrEP options that do not rely on daily oral adherence or frequent injection visits. Lenacapavir is a multistage HIV-1 capsid inhibitor with a long half-life, allowing for twice-yearly subcutaneous administration, and is effective for HIV prevention among cisgender women. The present trial assessed the efficacy and safety of twice-yearly subcutaneous lenacapavir compared with daily oral F/TDF for HIV prevention among cisgender men and gender-diverse persons who have sex with men. Lenacapavir reduced HIV incidence by 96% compared with background HIV incidence and by 89% compared with F/TDF. Additionally, with regards to safety, the incidence of both adverse events and laboratory abnormalities was similar between the two groups. The study was limited by its lack of longitudinal follow-up, with the risk of lenacapavir eliciting resistant virus when used broadly remaining a concern that requires careful monitoring. Nevertheless, these findings show that twice-yearly lenacapavir could overcome current challenges with respect to PrEP uptake and adherence among men and gender-diverse persons who have sex with men.

Click to read the study in NEJM

In-Depth [randomized controlled trial]: This phase randomized trial compared the efficacy and safety of twice-yearly subcutaneous lenacapavir for HIV prevention with that of daily oral F/TDF among men and gender-diverse persons who have sex with men. Cisgender men and gender-diverse persons 16 years of age or older who had condomless receptive anal sex with male partners, were not using PrEP, and had unknown HIV status with no HIV testing within the previous three months were included. All participants underwent HIV testing, with HIV-negative participants randomly assigned in a 2:1 ratio to receive lenacapavir or F/TDF. The primary efficacy outcome was the incidence of HIV infection. The safety outcomes were adverse events and clinical laboratory abnormalities. A total of 3,271 participants were included in the study, with 2,183 assigned to the lenacapavir group and 1,088 to the F/TDF group. Two new HIV infections were observed in the lenacapavir group (0.10 per 100 person-years; 95% Confidence Interval [CI], 0.01 to 0.37) compared with nine in the F/TDF group (0.93 per 100 person-years; 95% CI, 0.43 to 1.77). HIV incidence with lenacapavir was 96% lower than the background incidence (incidence rate ratio, 0.04; 95% CI, 0.01 to 0.18) and 89% lower than with F/TDF (incidence rate ratio, 0.11; 95% CI, 0.02 to 0.51). With regards to safety, the incidence of adverse events was similar overall between the two groups. Laboratory abnormalities occurred in 84.6% of participants in the lenacapavir group compared with 87.5% of participants in the F/TDF group, with most being grade one or two in severity. In summary, twice-yearly lenacapavir was both safe and more effective compared with daily oral F/TDF for preventing HIV infection among men and gender-diverse persons who have sex with men.

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