The New England Journal of MedicineTwice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women

Long-Acting Injectables May Address Adherence Challenges in HIV Prevention

A phase 3 trial evaluated the efficacy of twice-yearly lenacapavir injections and daily oral emtricitabine–tenofovir alafenamide (F/TAF) for HIV prevention in cisgender women, compared to daily oral emtricitabine–tenofovir disoproxil fumarate (F/TDF). The study, conducted in South Africa and Uganda, aimed to address challenges in preexposure prophylaxis uptake and adherence among this population.

Study Design:

• Participants: 5,338 adolescent girls and young women in South Africa and Uganda
• Randomization: 2:2:1 ratio to receive subcutaneous lenacapavir every 26 weeks, daily oral F/TAF, or daily oral F/TDF (active control)
• Blinding: Double-blind, with participants receiving alternate subcutaneous or oral placebo
• Primary outcome: Incidence of HIV infection compared to estimated background incidence in the screened population

Key Findings:

• Lenacapavir group: 0 HIV infections (0 per 100 person-years; 95% CI, 0.00 to 0.19)
• F/TAF group: 39 HIV infections (2.02 per 100 person-years; 95% CI, 1.44 to 2.76)
• F/TDF group: 16 HIV infections (1.69 per 100 person-years; 95% CI, 0.96 to 2.74)
• Background HIV incidence: 2.41 per 100 person-years (95% CI, 1.82 to 3.19)
• Lenacapavir significantly reduced HIV incidence compared to background (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.04; P<0.001) and F/TDF (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.10; P<0.001)
• F/TAF did not significantly differ from background HIV incidence (incidence rate ratio, 0.84; 95% CI, 0.55 to 1.28; P=0.21)
• No significant difference between F/TAF and F/TDF (incidence rate ratio, 1.20; 95% CI, 0.67 to 2.14)
• Low adherence observed in F/TAF and F/TDF groups
• No major safety concerns identified
• Injection-site reactions more common with lenacapavir (68.8%) than placebo injections (34.9%)
• 0.2% of lenacapavir group discontinued due to injection-site reactions

HCN Medical Memo
The striking efficacy of long-acting lenacapavir in preventing HIV infection among cisgender women suggests a potentially game-changing approach to PrEP. However, the lower-than-expected efficacy of oral medications only further pushes the need for continued research into adherence support strategies and diverse prevention options to meet individual patient needs and preferences.

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