Two Shots a Year: CDC's 2025 Recommendation for Lenacapavir HIV PrEP

HIV preexposure prophylaxis (PrEP) is highly effective. Its weak point is people: national assessments find that about half of daily oral PrEP users stop within 6–12 months of starting. In 2023, roughly 39,000 people in the United States were diagnosed with HIV.

Lenacapavir (LEN) attacks that weak point. It is an HIV-1 capsid inhibitor given as an injection under the skin once every six months, and the FDA approved it for PrEP on June 18, 2025. In a 2025 policy note, CDC's PrEP guidelines work group gave it a strong recommendation, based on high certainty of evidence, as a PrEP option for anyone weighing at least 77 lbs (35 kg) who would benefit from PrEP. It joins the options in the 2021 CDC PrEP Clinical Practice Guideline: two daily oral tenofovir-based regimens and cabotegravir, an injection every two months.

CDC.

How the recommendation was reached

The CDC 2024–2025 PrEP Guidelines Work Group, from CDC's Division of HIV Prevention, met from May 2024 to January 2025 and graded the evidence with the GRADE approach. Its question: should injectable LEN be an option for people who would benefit from HIV PrEP? A systematic search of six databases through February 21, 2025, screened 62 records and kept 2 — the phase 3 trials PURPOSE 1 and PURPOSE 2, double-blinded and run from June 2021 to September 2024. LEN was not compared with cabotegravir, because no randomized trial has compared the two.

The two trials

Each trial measured HIV among people on LEN against two yardsticks: the background infection rate among everyone screened (no PrEP), and a randomized group taking daily oral TDF/FTC (tenofovir disoproxil fumarate–emtricitabine). Participants were tested at 4, 8 and 13 weeks and every 13 weeks after. Both trials were stopped early when an interim analysis — run once half the target population had been enrolled for 52 weeks — showed LEN was superior.

PURPOSE 1 also tested daily TAF/FTC, which the FDA has not approved as PrEP for women; its 5,338-person analysis ran 2:1:1 (2,134 LEN, 2,136 TAF/FTC, 1,068 TDF/FTC).

The few infections on LEN. In PURPOSE 2's two cases, drug levels were in the protective range and the capsid mutation N74D was found; viral loads were 14,000 and 934,000 copies/mL, and in the first case a rapid test was negative while the laboratory antigen/antibody test was positive. Later analyses found two more infections in PURPOSE 1 — one after the person had stopped LEN and drug levels had fallen below target (no capsid mutations), one with a viral load too low to genotype — and one more in PURPOSE 2, with Q67H/K70R mutations.

Safety

Rates of adverse events other than injection-site reactions were similar across groups, as were severe, life-threatening and fatal events; no death was related to the study drug, and grade 3–5 events were more common on TDF/FTC.

The reactions were mostly mild or moderate — pain, nodules under the skin and hardening — and eased with later injections. Only 0.2% (PURPOSE 1) and 1.2% (PURPOSE 2) stopped LEN because of them. Nodules lasted a median of 350 days (IQR 182–470) and 297 days (IQR 176–423); the largest per person had a median diameter of 1.2 inches (3.0 cm).

Among 510 pregnancies in 487 women in PURPOSE 1, outcomes for the 184 on LEN were comparable to those on tenofovir PrEP and to background rates. No breastfed infant exposed to LEN had an adverse event, and no pregnant woman on LEN acquired HIV (five did in the tenofovir groups).

Using it in practice

Who. People whose behavior and circumstances put them at risk, including but not limited to people with diagnosed sexually transmitted infections, men who have sex with men, people whose partners have HIV without viral suppression, people who engage in transactional sex, people who are incarcerated and people who share needles — offered alongside other prevention and primary care. LEN may suit people who would rather not take a daily pill.

Testing. A laboratory blood-based HIV antigen/antibody test on the day of each injection, or within the previous 7 days, plus an HIV RNA test at the start if available (it should not delay the injection; without it, repeat the antigen/antibody test in 4 weeks). Oral HIV tests should not be used. Someone switching straight from tenofovir or cabotegravir PrEP needs only the laboratory antigen/antibody test — but because tenofovir also treats hepatitis B, switchers need their HBV status checked, treatment if infected and vaccination if not immune. An infection acquired on LEN should be treated with an integrase strand-transfer inhibitor-based regimen.

Injections go into the abdomen (at least 2 inches from the navel) or front of the thigh, at a 90° angle; an angle of 45° or less puts the drug into the skin and is thought to worsen reactions. Ice packs and pain relievers may help. Strong and moderate CYP3A inducers require extra LEN, and LEN raises levels of some other drugs for up to 9 months after the last injection.

Timing. With both oral loading days, protective levels are reached about 2 hours after the day-2 dose; without them, an estimated 21–28 days. After stopping, levels decline for 18 months, starting 6 months after the last injection, but give no protection after 6 months. If an injection will be 14 or more days late, a 300-mg tablet every 7 days for under 6 months can bridge the gap; otherwise LEN is restarted from the beginning, or another PrEP offered.

LEN may be used in pregnancy after shared decision-making. Clinicians can get prescribing help from the PrEPLine (855-448-7737) and report pregnancies to the Antiretroviral Pregnancy Registry (800-258-4263).

What is still unknown

How well LEN works for people who inject drugs, whether it blunts early viral replication in someone who becomes infected, how often resistance emerges, safety over longer follow-up, and how best to deliver it in clinics and communities.

Sources

Based on Patel RR, Hoover KW, Lale A, Cabrales J, Byrd KM, Kourtis AP, "Clinical Recommendation for the Use of Injectable Lenacapavir as HIV Preexposure Prophylaxis — United States, 2025," MMWR Morbidity and Mortality Weekly Report 2025;74(35), Centers for Disease Control and Prevention, drawing on the PURPOSE 1 (Bekker et al., N Engl J Med 2024) and PURPOSE 2 (Kelley et al., N Engl J Med 2025) trials and the FDA prescribing information; a work of the United States government in the public domain.