WHO issues guidance on twice-yearly lenacapavir for HIV prevention

The World Health Organization has released guidelines on the use of long-acting injectable lenacapavir for HIV prevention, together with recommendations on the HIV testing strategies needed to deliver it [s1]. The document runs to 47 pages and is accompanied by eight web annexes covering safety and efficacy evidence, values and preferences, testing, modelling, drug resistance and outcomes in pregnancy [s1].

The headline is the drug. The more consequential recommendation may be the testing one.

What the guidance says

WHO's stated recommendations are to offer lenacapavir as an additional prevention choice within combination HIV prevention, and to use simplified HIV testing approaches — particularly rapid diagnostic tests — to facilitate access to and continuity of pre-exposure prophylaxis services [s1].

The guidance was developed using WHO guideline methodology and the GRADE approach, synthesising clinical trial evidence, modelling studies and implementation considerations [s1]. It examines safety, acceptability, feasibility, cost-effectiveness, equity and human rights, and it names research gaps [s1]. It is aimed at policy-makers, programme managers and health service providers [s1].

WHO frames the underlying problem as one of uptake rather than efficacy: existing PrEP modalities carry barriers including adherence to daily oral regimens and frequent clinic visits [s1]. A drug given twice a year addresses both.

The trial evidence behind it

Two phase 3 trials establish lenacapavir's efficacy as PrEP.

PURPOSE 1 enrolled adolescent girls and young women in South Africa and Uganda, randomising 5,338 initially HIV-negative participants 2:2:1 to subcutaneous lenacapavir every 26 weeks, daily oral emtricitabine-tenofovir alafenamide, or daily oral emtricitabine-tenofovir disoproxil fumarate as active control, with matching placebos [s2]. There were no infections among the 2,134 participants in the lenacapavir group — an incidence of 0 per 100 person-years (95% CI 0.00 to 0.19) — against 39 infections among 2,136 on F/TAF (2.02 per 100 person-years) and 16 among 1,068 on F/TDF (1.69 per 100 person-years) [s2]. Background incidence in the 8,094 screened participants was 2.41 per 100 person-years [s2]. Adherence to both oral regimens was low [s2].

PURPOSE 2 enrolled cisgender men, transgender women, transgender men and gender-nonbinary people, randomising 2:1 to lenacapavir every 26 weeks or daily oral F/TDF [s3]. Among 3,265 participants in the modified intention-to-treat analysis, two infections occurred in the lenacapavir group (0.10 per 100 person-years) and nine in the F/TDF group (0.93 per 100 person-years), against a background incidence of 2.37 per 100 person-years in 4,634 screened participants [s3].

Injection-site reactions were the main tolerability signal. In PURPOSE 1 they affected 68.8% of the lenacapavir group versus 34.9% of those receiving placebo injections, with four participants (0.2%) discontinuing because of them [s2]. In PURPOSE 2, 26 of 2,183 participants (1.2%) in the lenacapavir group discontinued for injection-site reactions, against 3 of 1,088 (0.3%) on F/TDF [s3].

Both trials were funded by Gilead Sciences [s2][s3].

Why the testing recommendation is the harder one

That WHO treated testing as a question requiring its own recommendation, and its own systematic review, is itself informative. One of the guideline's web annexes is devoted specifically to whether HIV testing services using rapid diagnostic tests and self-tests should be used for initiation or continuation of injectable long-acting PrEP [s1]. A separate annex addresses lenacapavir-associated drug resistance and its implications for scaling up long-acting PrEP [s1].

The direction WHO chose is toward simplification. Its recommendation is to use simplified HIV testing approaches, particularly rapid diagnostic tests, expressly to facilitate access to and continuity of PrEP services [s1] — a justification framed in terms of access rather than diagnostic performance. Requiring more complex assays before every injection would place the intervention beyond the reach of delivery points without laboratory infrastructure, which is precisely the access barrier WHO identifies as the reason long-acting PrEP is needed in the first place [s1].

That the resistance question and the testing question sit in adjacent annexes of the same guideline [s1] reflects how tightly they are linked in practice.

What the guidance does not settle

Efficacy in trials is not coverage in programmes. WHO's own framing is that the guidance aims to support countries in strengthening prevention strategies and improving access [s1] — support, not delivery. Nothing in a normative document determines price, supply volume, regulatory approval in individual countries, or whether health systems can absorb a twice-yearly injection schedule.

The guideline also names research gaps and includes an annex on outcomes of lenacapavir administration during pregnancy [s1], which is the standard signal that data in pregnancy remain thinner than data in the general trial populations.

Two further limits are worth stating. Neither PURPOSE trial had a no-prophylaxis arm; both compared against background incidence in screened populations and against oral PrEP [s2][s3]. And both were conducted under trial conditions, with trial-level follow-up and injection logistics that routine services will have to reproduce.

What to watch

Whether national programmes adopt the rapid-test pathway, or default to more conservative testing requirements that slow rollout. And whether the drug-resistance monitoring the guidance calls for is actually resourced — because it is the mechanism by which the testing trade-off would be detected if it turns out to be the wrong one.

Sources

• [s1] Guidelines on lenacapavir for HIV prevention and testing strategies for long-acting injectable pre-exposure prophylaxis — World Health Organization, issued 11 July 2025. https://iris.who.int/handle/10665/381892
• [s2] Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women (PURPOSE 1) — New England Journal of Medicine, Crossref record created 24 July 2024. https://doi.org/10.1056/NEJMoa2407001
• [s3] Twice-Yearly Lenacapavir for HIV Prevention in Men and Gender-Diverse Persons (PURPOSE 2) — New England Journal of Medicine, Crossref record created 27 November 2024. https://doi.org/10.1056/NEJMoa2411858