Lenacapavir: Twice-Yearly HIV Prevention Injection Shows Zero Infections in Trials

What Is Lenacapavir and How Does It Prevent HIV?

Lenacapavir (brand name Sunlenca) is a novel antiretroviral agent that targets the HIV-1 capsid protein, a cone-shaped structure composed of approximately 1,500 copies of the p24 protein that encases the viral genetic material. Unlike other antiretroviral classes that target single steps in viral replication, lenacapavir is a multistage inhibitor: it interferes with capsid-mediated nuclear import of the viral pre-integration complex, blocks HIV DNA integration into the host genome, disrupts virus assembly, and impairs capsid core formation during viral maturation. This unique multi-step mechanism provides a high barrier to resistance development.

The drug's remarkable pharmacokinetic profile enables twice-yearly dosing. After subcutaneous injection, lenacapavir forms a drug depot at the injection site that slowly releases active drug into the bloodstream over six months, maintaining protective plasma concentrations throughout the dosing interval. The sustained release eliminates the need for daily adherence to oral medications, which has been the primary barrier to effective HIV prevention. Studies have shown that PrEP effectiveness in real-world settings drops significantly when adherence falls below 4-7 doses per week of daily oral tenofovir-based regimens.

Lenacapavir was first approved by the FDA in August 2022 for treatment of heavily treatment-experienced adults with multidrug-resistant HIV infection, in combination with other antiretrovirals. Its development as a standalone PrEP agent represented a bold expansion of its use case. The drug is administered by a healthcare provider as two 1.5 mL subcutaneous injections at initiation, at one month, and then every six months thereafter, making it a practical option for integration into routine healthcare visits.

What Did the PURPOSE Clinical Trials Show?

The PURPOSE 1 trial, a randomized, double-blind Phase 3 study, enrolled approximately 5,300 cisgender women aged 16-25 in South Africa and Uganda, two countries with high HIV incidence. Participants were randomized to receive either twice-yearly subcutaneous lenacapavir, daily oral Descovy (emtricitabine/tenofovir alafenamide), or daily oral Truvada (emtricitabine/tenofovir disoproxil fumarate). The results were unprecedented: zero HIV infections occurred among the approximately 2,134 women receiving lenacapavir over the study period, compared to an HIV incidence of 2.02 per 100 person-years in the Descovy group and 1.69 per 100 person-years in the Truvada group.

The PURPOSE 2 trial enrolled approximately 3,200 cisgender men who have sex with men, transgender women, transgender men, and gender non-binary individuals in the Americas, Asia-Pacific, Europe, and Africa. This trial similarly demonstrated superior efficacy for lenacapavir compared to daily oral Truvada. The results confirmed that lenacapavir's protective effect extends across diverse populations, sexual practices, and geographic settings. Together, the PURPOSE 1 and 2 trials provided the comprehensive efficacy and safety data needed to support regulatory submissions for the PrEP indication.

The trial results were particularly significant because they demonstrated real-world performance advantages beyond the drug's intrinsic antiviral potency. The twice-yearly injection eliminates adherence-related efficacy gaps that plague daily oral PrEP regimens. In PURPOSE 1, background HIV incidence in the Truvada arm was lower than expected based on regional epidemiological data, suggesting that even the oral PrEP groups benefited from the clinical trial infrastructure. That lenacapavir still achieved zero infections against this backdrop underscored the transformative potential of long-acting injectable prevention.

What Are the Access and Pricing Challenges for Lenacapavir PrEP?

The pricing of lenacapavir for HIV prevention has become one of the most contentious issues in global health. In the United States, Gilead priced Sunlenca for treatment at approximately $42,250 per year (equivalent to roughly $21,125 per twice-yearly injection). While PrEP-specific pricing had not been finalized as of early 2026, advocates and public health experts argue that the price must be dramatically lower to achieve meaningful impact on the HIV epidemic, particularly in sub-Saharan Africa where approximately 65% of new HIV infections occur. Generic daily oral PrEP costs as little as $4 per month in low-income countries through programs like PEPFAR and the Global Fund.

Gilead announced in 2024 that it would grant voluntary licensing agreements to generic manufacturers through the Medicines Patent Pool (MPP) to produce lenacapavir for PrEP in 120 low- and middle-income countries. This arrangement could bring the cost down to approximately $40 per year per patient, according to generic manufacturing analyses by the Clinton Health Access Initiative. However, critics have noted that several middle-income countries with significant HIV burdens, including Brazil and China, were excluded from the initial licensing agreements. Manufacturing the drug at scale also requires specialized capabilities for producing the long-acting injectable formulation.

UNAIDS and the WHO have called lenacapavir a potential game-changer for HIV prevention but emphasized that equitable global access is essential. An estimated 1.3 million new HIV infections occurred worldwide in 2023, and scaling up effective prevention tools including PrEP is critical to achieving the UNAIDS target of fewer than 200,000 new infections annually by 2030. The combination of lenacapavir's exceptional efficacy and the logistical advantage of twice-yearly dosing could dramatically increase PrEP uptake in populations that have been difficult to reach with daily oral regimens, but only if pricing and distribution barriers are overcome.

How Could Lenacapavir Change the Global HIV Response?

Daily oral PrEP has been available since 2012 and is highly effective when taken consistently, but global uptake has been disappointing relative to need. Of the approximately 10 million people estimated to benefit from PrEP worldwide, only about 3.5 million were using it in 2023 according to UNAIDS. Among adolescent girls and young women in sub-Saharan Africa, who account for a disproportionate share of new infections, PrEP adherence has been particularly challenging due to stigma, partner dynamics, privacy concerns, and the difficulty of maintaining daily medication routines. Clinical trials of daily oral PrEP in African women showed lower real-world effectiveness than in other populations, primarily due to adherence challenges.

Lenacapavir's twice-yearly dosing could overcome many of these barriers. A biannual injection administered by a healthcare provider during a routine visit removes the daily burden of self-administered medication, eliminates the need to store and carry pills that may reveal PrEP use to partners or family members, and decouples prevention from the moment of sexual activity. Modeling studies suggest that if lenacapavir PrEP could be made available at scale in countries with the highest HIV incidence, it could avert hundreds of thousands of new infections over the next decade, potentially accelerating progress toward epidemic control.

The regulatory pathway for lenacapavir PrEP is advancing rapidly. Gilead submitted applications to the FDA and EMA for the PrEP indication based on PURPOSE trial data, with FDA priority review anticipated. The WHO is expected to issue guidelines on lenacapavir PrEP following regulatory approvals, which would enable national programs and international funders like PEPFAR and the Global Fund to begin procurement. If generic manufacturing agreements are fully implemented, lenacapavir could become the most impactful biomedical HIV prevention tool since the original approval of oral PrEP, provided that health systems can build the infrastructure needed to deliver twice-yearly injections to populations in need.