CDC strongly recommends twice-yearly lenacapavir as an HIV prevention option

CDC published a clinical recommendation on 18 September for injectable lenacapavir as HIV preexposure prophylaxis: subcutaneous injection every six months is strongly recommended as a PrEP option for people weighing at least 77 lbs (35 kg) who would benefit from PrEP [s1].

The recommendation follows the FDA's approval of injectable lenacapavir for PrEP in June 2025 [s1], and updates a guideline landscape that had not moved since 2021. CDC's PrEP guidelines published that year include two oral tenofovir-based regimens and cabotegravir, which was at the time the only FDA-approved injectable PrEP regimen [s1].

The problem the drug is meant to solve

The framing in the MMWR report is worth quoting for what it concedes. Approximately 39,000 people received an HIV diagnosis in the United States in 2023 [s1]. PrEP is highly effective at preventing HIV infection — and yet, CDC writes, acceptance of, adherence to, and persistence taking the available oral and injectable regimens have been suboptimal [s1].

That is a delivery problem rather than a pharmacology problem. Daily oral PrEP requires a daily decision; two-monthly cabotegravir requires six clinic visits a year. Lenacapavir requires two. CDC states the case in exactly those terms: lenacapavir has the potential to improve PrEP adherence and thus enhance HIV prevention in the United States [s1].

The evidence, and how CDC graded it

The CDC PrEP Guidelines Work Group assessed the efficacy and safety evidence using the GRADE approach — Grading of Recommendations, Assessment, Development and Evaluation [s1]. Its conclusion was a high certainty of evidence, which is what supports a strong rather than conditional recommendation [s1].

The evidence base is two randomised trials, PURPOSE 1 and PURPOSE 2 [s1]. Over 52 weeks of follow-up, the trials reported lenacapavir efficacy at reducing HIV infection as 100% among females and 96% among a primarily male trial population, compared with estimated background HIV incidence — that is, against no PrEP use [s1].

The underlying trials give those percentages their shape. PURPOSE 1 enrolled adolescent girls and young women in South Africa and Uganda, randomising 2:2:1 to subcutaneous lenacapavir every 26 weeks, daily oral emtricitabine-tenofovir alafenamide, or daily oral emtricitabine-tenofovir disoproxil fumarate as active control [s2]. Among 5,338 participants initially HIV-negative, there were zero infections among the 2,134 assigned to lenacapavir, against 39 among 2,136 on F/TAF and 16 among 1,068 on F/TDF; background incidence in the screened population of 8,094 was 2.41 per 100 person-years [s2].

PURPOSE 2 randomised cisgender men, transgender women, transgender men and gender-nonbinary people 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 the screened population of 4,634 [s3].

What the comparator choice means

Both trials measured efficacy primarily against background incidence in the screened population rather than against an active comparator — a design used because a placebo arm would be unethical where effective PrEP exists, but one that inflates the apparent effect relative to a head-to-head comparison. PURPOSE 2 also ran the direct comparison: lenacapavir versus F/TDF gave an incidence rate ratio of 0.11 (95% CI, 0.02 to 0.51; P = 0.002) [s3]. That is a real advantage over daily oral PrEP, but it is a smaller number than 96%, and it is the more honest one to carry when comparing regimens rather than comparing a regimen to nothing.

The "100% efficacy in females" figure is likewise a consequence of zero events in 2,134 participants [s2], not a claim that the drug cannot fail.

Safety

No significant safety concerns were identified in the trials [s1]. The most common adverse events were injection site reactions, mild (grade 1) to moderate (grade 2) [s1].

What to watch

The recommendation is a clinical one; it does not by itself determine payer coverage, pricing, or whether clinics have the cold chain and appointment infrastructure for a twice-yearly injectable. The 52-week trial follow-up [s1] also means durability and resistance patterns beyond a year are still accumulating. Whether a two-visits-a-year regimen actually improves persistence in routine US care — the entire premise of the recommendation — is an empirical question that only real-world data will answer.

This article is informational and is not medical advice. Decisions about HIV prevention regimens are made with a clinician.

Sources

• [s1] "Clinical Recommendation for the Use of Injectable Lenacapavir as HIV Preexposure Prophylaxis — United States, 2025," MMWR Morbidity and Mortality Weekly Report, 18 September 2025. https://doi.org/10.15585/mmwr.mm7435a1
• [s2] "Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women," New England Journal of Medicine, 24 July 2024. https://doi.org/10.1056/NEJMoa2407001
• [s3] "Twice-Yearly Lenacapavir for HIV Prevention in Men and Gender-Diverse Persons," New England Journal of Medicine, 27 November 2024. https://doi.org/10.1056/NEJMoa2411858