Lenacapavir Twice-Yearly Injection Achieves 96% Efficacy for HIV PrEP: PURPOSE Trials Transform Prevention in 25,000 Participants

What Is Lenacapavir and How Does Its Capsid Inhibitor Mechanism Work?

Lenacapavir (brand name Sunlenca for HIV treatment, Yeztugo for PrEP, developed by Gilead Sciences) represents an entirely new class of antiretroviral agent that targets the HIV-1 capsid protein (CA, also known as p24). The HIV capsid is a cone-shaped protein shell composed of approximately 1,500 copies of the CA protein arranged in hexameric and pentameric lattices. It plays essential roles at multiple stages of the viral replication cycle: protecting the viral RNA genome during cytoplasmic transport, mediating nuclear import of the pre-integration complex through nuclear pore interactions, facilitating reverse transcription, and directing the assembly and release of new viral particles from the host cell membrane.

Lenacapavir binds to the interface between CA hexamers at a site that is structurally constrained by the requirement for proper capsid geometry. This binding disrupts capsid function at multiple stages: it accelerates premature capsid disassembly (uncoating) during early infection, blocks the interaction between the capsid and nuclear transport factors needed for nuclear entry, and inhibits the assembly of new capsid structures during virion maturation. This multistage mechanism of action is unique among antiretrovirals and provides an exceptionally high genetic barrier to resistance — resistance mutations typically require multiple simultaneous changes in the CA gene that impair capsid function, making them fitness-costly for the virus. In vitro studies have shown that lenacapavir maintains activity against HIV-1 strains resistant to NRTIs, NNRTIs, protease inhibitors, integrase inhibitors, and entry inhibitors.

What Were the Results of the PURPOSE PrEP Trials?

PURPOSE 1 was a randomized, double-blind, controlled Phase 3 trial enrolling approximately 5,338 cisgender women and adolescent girls aged 16–25 years across sites in South Africa and Uganda — regions with among the highest HIV incidence globally. Participants were randomized 2:2:1 to subcutaneous lenacapavir every 26 weeks, daily oral emtricitabine/tenofovir alafenamide (F/TAF, Descovy), or daily oral emtricitabine/tenofovir disoproxil fumarate (F/TDF, Truvada). The primary endpoint was HIV incidence in the lenacapavir arm compared to a pre-specified background incidence rate.

Results were unequivocal: zero HIV infections occurred among the approximately 2,134 participants randomized to lenacapavir, achieving 100% efficacy. HIV infections did occur in the oral PrEP comparator arms, though at rates lower than the background incidence, confirming oral PrEP effectiveness. However, the zero infections in the lenacapavir arm — in a population with high HIV exposure — represents an unprecedented level of protection. The trial's Data Safety Monitoring Board recommended unblinding and offering lenacapavir to all participants. The results were published in the New England Journal of Medicine in 2024.

PURPOSE 2 enrolled approximately 3,267 cisgender men who have sex with men, transgender women, transgender men, and non-binary individuals across sites in the Americas, Europe, Southeast Asia, and Africa. The trial compared lenacapavir every 26 weeks to daily oral F/TDF. Two HIV seroconversions occurred among approximately 2,179 participants in the lenacapavir arm, yielding an efficacy of 96% compared to background HIV incidence. These results were also published in the New England Journal of Medicine in 2024, confirming the benefit of twice-yearly lenacapavir across diverse populations at risk of HIV.

Why Is Long-Acting Injectable PrEP a Game-Changer for Global HIV Prevention?

The global HIV epidemic persists with approximately 1.3 million new infections annually (UNAIDS 2024), despite the availability of highly effective oral PrEP since 2012. The fundamental problem is adherence: while daily oral PrEP (emtricitabine/tenofovir) provides over 99% protection when taken consistently, real-world effectiveness is substantially lower due to inconsistent pill-taking, particularly among the populations at highest risk. In sub-Saharan Africa, which accounts for the majority of all new HIV infections, daily oral PrEP uptake remains limited among eligible individuals, constrained by stigma, pill fatigue, supply chain disruptions, and the challenge of maintaining daily medication adherence in resource-limited settings.

Lenacapavir's twice-yearly injection addresses this adherence gap directly. Two clinic visits per year is achievable within existing healthcare infrastructure even in low-resource settings, and eliminates the daily behavioral commitment that undermines oral PrEP. Health authorities including the WHO have recognized that long-acting injectable PrEP could significantly accelerate progress toward the UNAIDS targets for epidemic control by achieving higher population-level PrEP coverage, which in turn reduces community viral transmission.

The principal barrier to global implementation is cost. Lenacapavir for PrEP (marketed as Yeztugo) is priced at approximately $28,218 per year in the United States. To address access in lower-income settings, Gilead has signed royalty-free voluntary licensing agreements with six generic manufacturers covering 120 low- and middle-income countries. Independent researchers have estimated that generic production could cost as little as $25–40 per person per year. Advocacy groups including UNAIDS and the Global Fund have called for aggressive pricing to enable universal access. The WHO has supported expedited regulatory pathways for lenacapavir PrEP to facilitate procurement through multilateral mechanisms.

What Are the Side Effects and Practical Aspects of Lenacapavir PrEP?

The safety profile of lenacapavir in the PURPOSE trials was favorable across all populations studied. The most frequently reported adverse event was injection-site reactions (ISRs), occurring in approximately 69% of participants in PURPOSE 1 and 63% in PURPOSE 2 after at least one injection. The majority were mild (Grade 1): subcutaneous nodules were the most common, followed by induration, pain, and erythema. ISRs decreased in frequency and severity with subsequent injections. The rate of discontinuation due to ISRs was very low — 0.2% in PURPOSE 1 and approximately 1.2% in PURPOSE 2. The nodules are related to the drug's formulation as a sustained-release subcutaneous depot and typically resolve over several weeks.

Beyond ISRs, adverse event rates were comparable between lenacapavir and oral PrEP groups. No clinically significant changes in renal function were observed — a notable advantage over tenofovir disoproxil-based oral PrEP, which carries established risks of proximal renal tubular dysfunction and decreased bone mineral density with long-term use. Serious adverse events were not increased in the lenacapavir groups compared to comparators.

Participant preference strongly favored twice-yearly injection over daily oral pills in structured assessments conducted during the trials. Treatment adherence — defined as attending the scheduled injection visit within the protocol-specified window — was high across the PURPOSE program, substantially exceeding typical adherence rates observed with daily oral PrEP in open-label studies. This real-world adherence advantage is the key driver of lenacapavir's superior population-level effectiveness and the reason infectious disease experts consider it a potential turning point in the HIV pandemic response. The FDA approved lenacapavir for PrEP under the brand name Yeztugo in June 2025.