The Clinical Times
The Front Page of Medicine

Infectious Disease · 2025

Lenacapavir (Yeztugo), twice-yearly HIV prevention

Yeztugo; PURPOSE trials

Chemical structure of the HIV capsid inhibitor lenacapavir
Reba16 (talk) / Public domain (Wikimedia Commons)

For the first two decades after highly active antiretroviral therapy made HIV a manageable chronic disease, prevention lagged well behind treatment. Daily oral PrEP with emtricitabine-tenofovir disoproxil fumarate, approved by the FDA in 2012, worked when taken consistently, but consistency was exactly what studies repeatedly failed to achieve in the populations carrying the heaviest transmission burden. Adherence rates in young women in sub-Saharan Africa and in men who have sex with men in high-incidence settings hovered well below the threshold needed for reliable protection. The structural and behavioral barriers were well documented; what was lacking was a drug that removed adherence from the equation almost entirely.

Lenacapavir addressed that gap by exploiting its mechanism. As an HIV capsid inhibitor, it disrupts multiple stages of the viral replication cycle and has a half-life long enough to support subcutaneous dosing every six months. Gilead Sciences developed two parallel Phase 3 trials under the PURPOSE program to test it as PrEP. PURPOSE 1, led by Linda-Gail Bekker at the Desmond Tutu HIV Centre in Cape Town and colleagues across southern and eastern Africa, enrolled cisgender women in a region where HIV incidence among young women is among the highest recorded anywhere. PURPOSE 2, co-led by Colleen Kelley at Emory University, enrolled men who have sex with men, transgender women, transgender men, and gender non-binary individuals across sites in the United States, Latin America, Europe, and South Africa.

The results from PURPOSE 1 were striking enough that the trial's independent data and safety monitoring board recommended unblinding early. Not one participant receiving lenacapavir acquired HIV, compared with infections in the daily-pill control arms. Across both PURPOSE trials, lenacapavir reduced HIV incidence by a substantial margin relative to daily oral emtricitabine-tenofovir disoproxil fumarate, a drug already accepted as highly effective. Measuring a new agent against an active comparator rather than placebo is a more demanding test, and the size of the observed difference was unusual by the standards of randomized controlled trials in infectious disease prevention.

FDA approval of lenacapavir for PrEP came in June 2025 under the brand name Yeztugo, making it the first twice-yearly injectable option available for HIV prevention. Regulatory review moved relatively quickly given the strength of the efficacy signal and the clear unmet need. Moupali Das of Gilead Sciences led the clinical development program through approval. The agency's decision covered the broad at-risk population studied across both trials, not a narrowed indication.

Approval was followed immediately by a predictable debate about access. The PURPOSE 1 population, cisgender women in sub-Saharan Africa, stood to benefit most, yet they were also the group least likely to afford a drug priced for high-income markets. Gilead announced tiered pricing agreements intended to close that gap, but the history of prior HIV prevention tools, including oral PrEP itself, showed a persistent distance between licensing deals and actual dispensing at the clinic level. Manufacturing capacity, cold-chain logistics, and health system delivery infrastructure all constrained the pace of rollout in high-burden settings. The efficacy demonstrated in the trials was a ceiling; the protection delivered to living populations would depend on implementation.

Key People

Read the original — PubMed

FDA approval, June 2025

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