Twice-Yearly Subcutaneous Lenacapavir Injection Prevents HIV Infection

By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

SYNOPSIS: Subcutaneous injection of lenacapavir every 26 weeks had 100% efficacy in preventing human immunodeficiency virus (HIV) infection in a high-risk population.

SOURCE: Bekker LG, Das M, Abdool Karim Q, et al; PURPOSE 1 Study Team. Twice-yearly lenacapavir or daily F/TAF for HIV prevention in cisgender women. N Engl J Med 2024; Jul 24. doi: 10.1056/NEJMoa2407001. [Online ahead of print].

Bekker and colleagues evaluated the efficacy of preventive therapies, including the long-acting capsid inhibitor, lenacapavir, in the prevention of human immunodeficiency virus (HIV) infection in adolescent girls and young women in Uganda and South Africa. HIV-negative subjects who were sexually active with male partners were randomized (2:2:1) to receive lenacapavir subcutaneously every 26 weeks, daily oral emtricitabine–tenofovir alafenamide (F/TAF), or daily oral emtricitabine–tenofovir disoproxil fumarate (F/TDF; active control). Appropriate oral or subcutaneous placebos also were administered.

The modified intent-to-treat analysis included 5,338 participants (median age 21 years), with 2,134 receiving lenacapavir, 2,136 receiving F/TAF, and 1,068 receiving F/TDF. One-fourth had a sexually transmitted infection at baseline. Adherence to the oral medications, assessed in 10% by detection of tenofovir in red blood cells, was low and decreased over time.

A total of 55 new HIV infections occurred over the two years of the trial, including 39 in the F/TAF group (2.02 per 100 person-years), 16 in F/TDF recipients (1.69 per 100 person years), and 0 infections in those assigned lenacapavir — a 100% reduction (P < 0.001) compared to both background incidence and incidence in F/TAF recipients. The medications were well tolerated except for frequent injection site reactions in the lenacapavir group (68.8% vs. 34.9% with placebo injections) and nausea in those receiving an oral medication. Headache was reported by approximately 15% in each group. There was no sign of a problem with use in pregnancy.

Commentary

Currently approved interventions for HIV pre-exposure prophylaxis (PrEP) include oral tenofovir-based regimens administered either daily or on-demand, use of a one-month dapivirine vaginal ring, and long-acting injections of cabotegravir.¹ Daily F/TDF, which was approved in 2012, provided 44% protection against incident HIV infection in men who have sex with men (MSM) in a six-country study.² The monthly dapivirine ring was associated with a 31% lower infection incidence compared to placebo in a study in sub-Saharan Africa.³ Cabotegravir injections given every eight weeks reduced incident infections relative to daily F/TDF (hazard ratio, 0.34) in at-risk cisgender men and transgender women in the United States, Latin America, Asia, and Africa.⁴ Similar results with injections given every eight weeks were found in a study in Africa.⁴

While the serum half-life of orally administered lenacapavir is approximately 41 hours, after intramuscular injection it is 5.6 to 12.5 weeks and possibly longer after subcutaneous injection. This prolonged exposure allows its infrequent administration. Thus, in the PrEP study reviewed here, lenacapavir was 100% efficacious, while the daily oral regimens were inferior. Much of this inferiority was associated with the difficulty of adherence to the required daily regimen. A twice-a-year injection clearly overcomes this problem. Until we get an effective HIV vaccine, lenacapavir by injection twice a year is the answer.

References

1. Liegeon G, Delaugerre C, Molina JM. HIV pre-exposure prophylaxis. Infect Dis Clin North Am 2024;38:453-474.
2. Grant RM, Lama JR, Anderson PL, et al; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010;363:2587-2599.
3. Nel A, van Niekerk N, Kapiga S, et al. Safety and efficacy of a dapivirine vaginal ring for HIV prevention in women. N Engl J Med 2016;375:2133-2143.
4. Landovitz RJ, Donnell D, Clement ME, et al. Cabotegravir for HIV prevention in cisgender men and transgender women. N Engl J Med 2021;385:595-608.
5. Delany-Moretlwe S, Hughes JP, Bock P, et al. Cabotegravir for the prevention of HIV-1 in women: Results from HPTN 084, a phase 3, randomised clinical trial. Lancet 2022;399:1779-1789.