Despite the availability of once-daily oral emtricitabine–tenofovir disoproxil fumarate (F/TDF) as a highly effective pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) prevention, significant unmet needs remain.^1,2 Many individuals, particularly adolescent girls and young women, face barriers to adherence due to daily dosing requirements, stigma and concerns regarding side effects.¹ To address these challenges, the phase 3 PURPOSE-1 trial investigated new PrEP options, including the twice-yearly injectable HIV-1 capsid inhibitor lenacapavir in women.¹ Lenacapavir showed remarkable results, demonstrating a 100% reduction in HIV incidence compared to background rates along with a favorable safety profile.¹

Lenacapavir, a novel, first-in-class HIV-1 capsid inhibitor, has high potency and a long half-life, allowing it to be administered subcutaneously twice yearly.¹ The other HIV PrEP medication investigated in the trial was the co-formulation of emtricitabine with tenofovir alafenamide (TAF) (F/TAF).¹ TAF is an HIV reverse transcriptase inhibitor with increased plasma stability and faster uptake by peripheral-blood mononuclear cells than TDF, though the F/TAF co-formulation is also administered once daily.¹

In the phase 3, double-blind, randomized active-controlled PURPOSE 1 trial, the safety and efficacy of lenacapavir, as well as of F/TAF, were evaluated for HIV prevention in adolescent girls and young women.¹ The study recruited participants across 25 sites in South Africa and 3 sites in Uganda between August 2021 and August 2023.¹ Cisgender women aged 16-25 years who were sexually active with male partners, not using PrEP, and had unknown HIV status and no HIV testing within the previous 3 months were eligible for randomization.¹ Among the screened population who had a central HIV test performed (n=8,094), 504 (6.2%) were diagnosed with an HIV infection, of which 92 (18.3%) were classified as recently infected and referred for local HIV care.¹ A total of 5,338 HIV-negative participants were randomized 2:2:1 to receive subcutaneous lenacapavir (927mg, in two 1.5mL injections every 26 weeks), daily oral F/TAF (200mg emtricitabine and 25mg TAF), or daily oral F/TDF (active control; 200mg emtricitabine and 300mg TDF).¹ Participants in the lenacapavir group received placebo tablets, while those in the F/TAF and F/TDF groups received placebo injections.¹

The primary efficacy endpoint was incident HIV infection, while safety endpoints were adverse events and clinical laboratory abnormalities.¹ As effective PrEP options already exist, having a placebo group was considered unethical.¹ Hence, background HIV incidence in the screened population (n=8,094) was used as the primary comparator, while F/TDF was used as the secondary comparator.¹ In total, 55 incident HIV infections were observed, with 0 infections among the 2,134 women in the lenacapavir group (0 per 100 person-years; 95% CI: 0.00-0.19), 39 among the 2,136 in the F/TAF group (2.02 per 100 person-years; 95% CI: 1.44-2.76), and 16 among 1,068 women in the F/TDF group (1.69 per 100 person-years; 95% CI: 0.96-2.74).¹ Compared to the background HIV incidence of 2.41 per 100 person-years (95% CI: 1.82-3.19), lenacapavir reduced HIV incidence by 100% (incidence rate ratio=0.00; 95% CI: 0.00-0.04; p<0.001), as well as by 100% compared to F/TDF (incidence rate ratio=0.00; 95% CI: 0.00-0.10; p<0.001).¹ There were no significant differences in HIV incidence with F/TAF compared to background HIV incidence (incidence rate ratio=0.84; 95% CI: 0.55-1.28; p=0.21), nor to F/TDF (incidence rate ratio=1.20; 95% CI: 0.67-2.14).¹

While injections were administered on time for 91.5% and 92.8% of participants at week 26 and 52 respectively across all groups, adherence to F/TAF and F/TDF were low as assessed by tenofovir diphosphate levels in red cells in dried-blood-spot samples from a randomly pre-selected 10% sample of participants.¹ No new safety concerns were identified, and while injection-site reactions were more common in the lenacapavir group (68.8%) than among those who received the placebo injection (34.9%), nearly all reactions were of grade 1 or 2 in severity and higher-grade reactions were rare.¹

Of note, on June 18, 2024, the randomized, blinded phase of the trial was stopped by an external independent monitoring committee as the pre-specified efficacy criteria had been met.¹ The captioned interim analysis became the primary efficacy and safety analysis of the trial.¹ Starting from July 8, 2024, participants were offered the option to receive lenacapavir in an open-label manner.¹

In summary, this PURPOSE 1 trial found that twice-yearly subcutaneous lenacapavir was highly effective at preventing HIV infection in cisgender women, with no participants acquiring HIV.¹ Lenacapavir's HIV incidence rate was significantly lower than the background rate and the rate with daily oral PrEP.¹ In contrast, adherence was low for the daily oral PrEP regimens, and their incidence rates did not differ significantly from background.¹ These results suggest twice-yearly lenacapavir may be an important new option to expand effective HIV prevention for this population, overcoming adherence challenges with daily oral PrEP.¹