In 2023, approximately 39,000 people in the United States were diagnosed with human immunodeficiency virus (HIV). Despite the high efficacy of HIV preexposure prophylaxis (PrEP), barriers to implementation remain, including acceptance, adherence, and persistence with the existing options, such as daily oral tenofovir-based regimens and injectable cabotegravir administered every two months. Approximately 50% of individuals who initiate daily oral PrEP discontinue use within 6 to 12 months. On June 18, 2025, the FDA approved injection lenacapavir (LEN), an HIV-1 capsid inhibitor, for 6-monthly subcutaneous injection into the body to prevent HIV infection. This CDC policy note updates the previous 2021 PrEP Clinical Practice Guideline to incorporate LEN.Â
The CDC PrEP Guidelines Work Group (2024-2025) applied the GRADE framework to evaluate whether LEN should be a recommended intervention to prevent HIV in adults and adolescents weighing at least 77 lbs (35 kg) and above. Two Phase 3 randomized controlled trials were used to gather evidence: PURPOSE 1 and PURPOSE 2. A total of 62 records were found in the systematic literature searches, and these two trials with full text were included.
PURPOSE 1 enrolled 8,094 females aged 16-25 years in South Africa and Uganda. Of 5,338 in the modified intention-to-treat (mITT) population, 2,134 received LEN. Over 52 weeks, no new HIV infections occurred in the LEN group, demonstrating 100% efficacy compared with no PrEP use (incidence rate ratio [IRR] = 0; 95% confidence interval [CI] = 0-0.04) and with tenofovir disoproxil fumarate-emtricitabine (TDF/FTC, IRR = 0; 95% CI = 0-0.10). Two HIV cases were later identified post-primary, both were linked to low or unmeasured drug concentrations, with no LEN resistance mutations detected.Â
The groups were similar in terms of adverse event rates. There were more severe (grade 3-5) events that occurred more often with TDF/FTC. The most frequent was the injection site reaction, with 68.8% in PURPOSE 1 and 83.2% in PURPOSE 2, most being mild to moderate. Reported reactions included pain, nodules, and induration with discontinuation rates of only 0.2% in PURPOSE 1 and 1.2% in PURPOSE 2. Nodules sometimes persisted for several months, with durations of 350 days (IQR: 182-470) in PURPOSE 1 and 297 days (IQR: 176-423) in PURPOSE 2, and diameters reaching up to 1.2 inches (3.0 cm). In PURPOSE-1, 510 pregnancies occurred, with adverse outcomes that were similar between the LEN and tenofovir-based PrEP groups, and no HIV infections were reported among women receiving LEN.Â
CDC strongly supports the use of LEN as PrEP in individuals at risk of HIV exposure, and this includes those with a body mass of 77 lbs or 35 kg and above. Eligible populations include male heterosexual sex with men, lack of viral suppression in partners with HIV, STIs, transactional sex, prison, or injection drug use. LEN may also be used during pregnancy when jointly decided upon by the patient and their provider.Â
Before starting, laboratory testing should encompass HIV antigen/antibody testing and, ideally, HIV RNA testing. The second and later LEN doses must be confirmed. HBV status must be evaluated before discontinuing tenofovir-based PrEP. LEN initiation requires an oral loading dose (600 mg for 2 days) followed by two subcutaneous injections (total 927mg). The injection technique is crucial for minimizing the formation of nodules.
Lenacapavir offers an effective and safe PrEP option administered every 6 months. It has a long-acting profile that can enhance adherence and prevent HIV infections in the U.S. Future studies are needed to determine its LEN’s efficacy among people who inject drugs, its long-term safety profile, and strategies for integration into diverse healthcare settings.
Reference: 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 Morb Mortal Wkly Rep. 2025;74:541–549. doi:10.15585/mmwr.mm7435a1Â
