Twice-Yearly Lenacapavir Wins Persistence But Pricing Blocks Prevention Scale

Twice-Yearly Lenacapavir Doubles PrEP Persistence Over Daily Oral F/TDF

Gilead Sciences announced positive results from the Phase 2 PURPOSE 5 trial, demonstrating significantly higher one-year persistence for twice-yearly injectable lenacapavir compared to daily oral emtricitabine/tenofovir disoproxil fumarate (F/TDF) for HIV pre-exposure prophylaxis (PrEP). The study, conducted in the UK and France, showed 85.6% persistence for lenacapavir versus 46.3% for F/TDF (p<0.0001). Notably, zero HIV acquisitions occurred among participants receiving lenacapavir during the 52-week study period, highlighting its potential to address persistence challenges and enhance real-world HIV prevention effectiveness.

• The PURPOSE 5 trial's primary endpoint revealed that twice-yearly lenacapavir achieved significantly greater one-year PrEP persistence compared to daily oral F/TDF. Specifically, 85.6% of participants on lenacapavir maintained consistent and continuous on-time use through Week 52, in contrast to 46.3% of those on F/TDF, a difference that was highly statistically significant (p<0.0001). This finding underscores the potential of long-acting options to improve adherence to HIV prevention regimens.
• A critical outcome of the study was the complete absence of HIV acquisitions among participants receiving twice-yearly lenacapavir over the 52-week period. In the F/TDF group, one HIV acquisition was reported, which was linked to inconsistent drug levels. These results strongly suggest that lenacapavir's enhanced persistence translates into robust real-world prevention effectiveness, offering a promising solution to reduce new HIV infections globally.
• PURPOSE 5 is distinguished as the first randomized study specifically designed to compare the persistence of a long-acting injectable HIV prevention option against daily oral PrEP among individuals not currently taking PrEP. The study enrolled 267 participants, including a diverse representation of cisgender men (72.3%), cisgender women (7.1%), and gender-diverse individuals (20.6%), with 37.8% being PrEP-naïve at baseline. This design provides valuable insights into the practical benefits of long-acting PrEP in a real-world setting.

Addressing the Critical Challenge of PrEP Persistence

Despite significant biomedical advances, approximately 1.3 million new infections annually continue to occur, particularly in sub-Saharan Africa. While oral PrEP opened new possibilities, adherence challenges have limited its impact, and long-acting injectable cabotegravir demonstrated superior efficacy but encountered access, cost, and delivery barriers that restricted uptake.

• Adherence-dependent effectiveness and persistence: Efficacy was correlated with levels of adherence and efficacy was strongly associated with adherence (p<0.01). Adherence was correct in 80% of users, retention in care was 57%, and discontinuations and loss to follow-up were high, mainly affecting transgender women, sex workers, and people practicing fisting. Dosing simulations indicated that high-risk women require full adherence to maintain protective levels.

• Awareness, stigma, and social-structural barriers: Lack of basic HIV and PrEP knowledge, low PrEP awareness, limited community awareness regarding PrEP availability, and misperceptions about personal risk impede uptake and continuation. Reported barriers included financial hardship, unintended pregnancy, parental rejection, inadequate peer- and [non-cohabiting] partner support, housing instability, stigma related to substance use and HIV, fear of stigma and discrimination, and concerns about privacy and confidentiality.

• Health-system access and delivery constraints: Perceived complexity in navigating health system access to PrEP impedes continuation, with tangible barriers including inconsistent access to phone service and transportation. The majority of healthcare providers being untrained in PrEP provision, high costs of PrEP medications, and need for simplified PrEP-focused healthcare access pathways for pregnant and postpartum adolescent girls and young women were reported.

• Safety, tolerability, and evidence gaps: Main adverse effects are gastrointestinal related, basically mild to moderate nausea, vomiting and diarrhea, with monitoring of liver enzymes, renal function and bone mineral density. Studies demonstrated an approximately 1-3% greater bone mineral density loss with tenofovir disoproxil fumarate compared with other agents, and unrecognised HIV at enrolment increased the risk of viral drug resistance mutations. PrEP was found to be effective in men who have sex with men, serodiscordant couples and people who inject drugs, but not in heterosexuals (RR 0.77, 95% CI 0.46 to 1.29), no RCTs reported effectiveness or safety data for other high-risk groups, such as transgender women and sex workers, and the safety and efficacy of long-acting PrEP (e.g., injectables, implants) among pregnant or breastfeeding women, specifically, remains to be confirmed.

PURPOSE 5: Lenacapavir's Efficacy and Safety in PrEP

Two randomised controlled trials with 8660 participants evaluated long-acting injectable lenacapavir for HIV pre-exposure prophylaxis compared to oral fixed-dose combination PrEP. The first trial, conducted in South Africa and Uganda, included adolescent girls and young women (16 to 25 years) and compared injectable lenacapavir with daily oral PrEP consisting of F/TAF in one comparator arm and F/TDF in the other. The second trial, conducted in the USA, Brazil, Thailand, South Africa, Peru, Argentina, and Mexico, included cisgender gay, bisexual and other men, transgender women, transgender men, and gender-nonbinary persons of any age who have condomless, receptive anal sex with partners assigned male at birth, and compared injectable lenacapavir with F/TDF. In both trials, participants in the lenacapavir group received placebo tablets that matched the oral PrEP, and participants in the oral PrEP group received placebo injections that matched lenacapavir.

Lenacapavir results in a large reduction in new HIV infections at 52 weeks compared to oral PrEP (RR 0.07, 95% CI 0.02 to 0.22; 2 studies, 8660 participants; high-certainty evidence). There were 14 fewer new HIV infections per 1000 (ranging from 15 fewer to 12 fewer), with a number needed to treat for an additional beneficial outcome (NNTB) of 70. No studies compared lenacapavir to injectable long-acting cabotegravir, placebo or no prophylaxis.

Lenacapavir results in a slight reduction in SAEs at 52 weeks compared to oral PrEP (RR 0.78, 95% CI 0.61 to 0.99; 2 studies, 8660 participants; high-certainty evidence). There were 8 fewer SAEs per 1000 (ranging from 15 fewer to 0 fewer), NNTB of 128. Lenacapavir results in little to no difference in AEs at 52 weeks compared to oral PrEP (RR 0.99, 95% CI 0.96 to 1.01; 2 studies, 8660 participants; high-certainty evidence). Lenacapavir likely increases adverse drug reactions: injection site reactions compared to oral PrEP at 52 weeks (RR 1.68, 95% CI 1.20 to 2.33; 2 studies, 8660 participants; moderate-certainty evidence). There were 295 more adverse drug reactions per 1000 (ranging from 87 more to 577 more), number needed to treat for an additional harmful outcome of 4. Lenacapavir results in little to no difference in all-cause mortality at 52 weeks compared to oral PrEP (RR 0.57, 95% CI 0.11 to 3.06; 2 studies, 8660 participants; high-certainty evidence).

Lenacapavir's Potential to Transform HIV Prevention Landscape

Long-acting injectable cabotegravir has shifted HIV pre-exposure prophylaxis from daily oral tenofovir disoproxil fumarate plus emtricitabine toward every-2-months dosing with superior efficacy in phase 3 trials. In HPTN 083 among cisgender men and transgender women who have sex with men, updated HIV incidence in the blinded phase was 0·41 per 100 person-years for long-acting injectable cabotegravir PrEP and 1·29 per 100 person-years for daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP (hazard ratio [HR] 0·31 [95% CI 0·17-0·58], p=0·0003), with HIV incidence in the first unblinded year of 0·82 per 100 person-years for long-acting PrEP and 2·27 per 100 person-years for daily oral PrEP (HR 0·35 [0·18-0·69], p=0·002). Indirect treatment comparison via daily oral tenofovir disoproxil fumarate/emtricitabine as common comparator predicted effectiveness of cabotegravir versus no PrEP of 92% in HPTN 083 and 93% in HPTN 084, and 96% (90%, 98%) in men who have sex with men and transgender women and 98% (89%, 100%) in cisgender women, while counterfactual placebo analyses in women estimated 93%-94% risk reduction with lower bounds of the confidence intervals above 72%.

Twice-yearly subcutaneous lenacapavir, a first-in-class capsid inhibitor approved as HIV PrEP based on PURPOSE 1 and PURPOSE 2, has extended the interval to every 6 months with high efficacy and sustained drug levels. The two trials reported LEN efficacy at reducing HIV infection as 100% among females and 96% among a primarily male trial population, compared with the estimated background HIV incidence over a follow-up of 52 weeks, with no significant safety concerns identified and mild (grade 1) to moderate (grade 2) injection site reactions as the most common adverse events. Across five trials involving 9,986 participants, HIV incidence was reduced to 0.00-0.10 per 100 person-years versus 0.93-2.37 in controls (incidence-rate ratio 0.00-0.11; p<0.001), and an indirect treatment comparison estimated hazard ratio of lenacapavir versus cabotegravir of 1.04 (0.19, 5.69) in men who have sex with men and transgender women and 0.00 (0.00, 3.21) in cisgender women, with predicted efficacy versus no PrEP of 96% (82%, 99%) in men and gender-diverse people and 100% (96%,100%) in cisgender women.

The monthly dapivirine vaginal ring has provided a non-systemic option for women, while HIV vaccine candidates have not demonstrated efficacy. In secondary analysis of MTN-020/ASPIRE data in HIV-uninfected, African women aged 18-45 years, women in the dapivirine ring group had an estimated incidence rate of 2.3 (95% confidence interval [CI], 1.8-3.1) HIV-1 acquisition events per 10 000 sex acts versus 3.6 (95% CI, 2.9-4.4) per 10 000 acts in the placebo group, with dapivirine release indicative of consistent ring use associated with a 63% (95% CI, 33%-80%) per-sex-act HIV-1 risk reduction. In contrast, the Mosaico phase 3 trial of Ad26.Mos4.HIV vaccine among 3,900 participants was discontinued due to insufficient efficacy in reducing HIV acquisition, and the Imbokodo/HVTN 705/HPX2008 phase 2b trial of Ad26.Mos4.HIV and clade C gp140 in women showed incidence of 3·38 (95% CI 2·54-4·41) per 100 person-years in the vaccine group and 3·94 (3·04-5·03) in the placebo group, with an estimated VE(7-24) of 14·10% (95% CI -22·00 to 39·51; p=0·40).