Clinical Recommendation for the Use of Injectable Lenacapavir as HIV Preexposure Prophylaxis ¡ª United States, 2025

Abstract

In 2023, approximately 39,000 persons received a diagnosis of HIV in the United States. Although HIV preexposure prophylaxis (PrEP) is highly effective in preventing HIV infection, acceptance of, adherence to, and persistence taking the available oral and injectable PrEP regimens have been suboptimal. CDC PrEP guidelines published in 2021 include two oral tenofovir-based regimens and cabotegravir, the only injectable PrEP regimen approved by the Food and Drug Administration (FDA) at that time. In June 2025, FDA approved injectable lenacapavir (LEN), administered every 6 months, as HIV PrEP based on results from two randomized controlled trials (PURPOSE 1 and PURPOSE 2). The CDC PrEP Guidelines Work Group assessed evidence for the efficacy and safety of LEN PrEP using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. 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 (or no use of PrEP) over a follow-up of 52 weeks. No significant safety concerns were identified in the trials. The most common adverse events were mild (grade 1) to moderate (grade 2) injection site reactions. Based on a high certainty of evidence for the efficacy and safety of LEN as assessed by the GRADE analysis, subcutaneous injection of LEN every 6 months is strongly recommended as a PrEP option in persons weighing ≥77 lbs (≥35 kg) who would benefit from PrEP. LEN has the potential to improve PrEP adherence and thus enhance HIV prevention in the United States.

Introduction

In 2023, approximately 39,000 persons received a diagnosis of HIV in the United States (1). HIV preexposure prophylaxis (PrEP) is highly effective at preventing HIV infection (2,3); however, implementation has been challenged by low acceptance of, adherence to, and persistence taking currently available PrEP options in the United States: 1) daily oral tenofovir-based regimens and 2) injectable cabotegravir administered every 2 months (4–8). Multiple national assessments have found that approximately one half of oral daily PrEP users discontinue it within 6–12 months of beginning prophylaxis (4–6). On June 18, 2025, the Food and Drug Administration (FDA) approved injectable lenacapavir (LEN) for PrEP, an HIV-1 capsid inhibitor administered every 6 months (9).

This report presents the CDC 2024–2025 PrEP Guidelines Work Group’s assessment of evidence from two randomized controlled trials (10,11) of the efficacy and safety of injectable LEN, administered every 6 months subcutaneously, for HIV PrEP, and provides a clinical recommendation for its use. The recommendation in this policy note updates the 2021 CDC PrEP Clinical Practice Guideline (12) by including LEN as an option for PrEP.

Methods

Guideline Development Process

This recommendation was drafted according to CDC’s guideline development standards (13). The work group developed the LEN PrEP recommendations as an update to the 2021 CDC PrEP Clinical Practice Guideline (12) using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach (14). The CDC 2024–2025 PrEP Guidelines Work Group comprised members from CDC’s Division of HIV Prevention who convened and met regularly during May 2024–January 2025. Members were selected for their experience (including clinical practice or research), expertise in PrEP-related topics, or experience in CDC guideline development. The work group generated a research question, conducted a systematic literature review, and synthesized evidence to guide work group discussions (14–16).

The focused research question for evidence synthesis was, “Should injectable LEN be included as an option for persons who would benefit from HIV PrEP?” The population, intervention, comparison, and outcomes (PICO) framework was used, and the components were as follows: adults and adolescents weighing ≥77 lbs (≥35 kg) (weight criterion per LEN FDA label indication) who would benefit from PrEP for HIV (the population); LEN PrEP (the intervention); no or daily oral tenofovir disoproxil fumarate-emtricitabine (TDF/FTC) PrEP (the comparison groups); and PrEP efficacy (HIV incidence rate ratio) compared with no PrEP use or daily oral TDF/FTC use, adverse events (excluding injection site reactions), injection site reactions, and grade 3–5 adverse events (severe, life-threatening, or fatal adverse events) (the outcomes). LEN compared with injectable cabotegravir PrEP was not evaluated in the absence of randomized evidence comparing the two. All outcomes were deemed critical by the CDC 2024–2025 PrEP Guidelines Work Group to develop the LEN PrEP recommendations. The work group also considered acceptability, feasibility, resource use, and harms and benefits while developing the recommendations. This activity was reviewed by CDC, deemed not research, and conducted consistent with applicable federal law and CDC policy.*

Systematic Literature Review

The work group conducted a systematic literature search using Medline, Embase, Cochrane, CINAHL, Scopus, and databases to identify published, randomized controlled trials for the population and intervention from database inception through February 21, 2025. Two reviewers independently screened 62 titles and abstracts, excluding 60 records because they were 1) in a non-English language, 2) conference abstracts, 3) trial protocol listings, 4) HIV treatment studies, 5) pharmacokinetic trials, or 6) animal and molecular studies. Two full-text reports were reviewed and included for evidence synthesis; the GRADE assessments were presented to the work group in February 2025 (Table 1) (Table 2). Recommendations were made by work group consensus (at least two thirds of votes). Work group members, none of whom reported conflicts of interest, reviewed the draft guidelines. The work group then created an external peer review plan, and the reviewers’ comments were incorporated into the final document.

Rationale and Evidence

Clinical Efficacy Trials for LEN as HIV PrEP

The evidence base comprised two phase-3 multisite, double-blinded, randomized controlled clinical efficacy trials, PURPOSE 1 and PURPOSE 2, which were conducted during June 2021–September 2024 (10,11). The PURPOSE 1 trial enrolled females aged 16–25 years in South Africa and Uganda.^† This trial compared HIV incidence among those who received injectable LEN every 6 months (using an initial 2 days of oral loading doses) with the estimated background HIV incidence in the screened population (no PrEP use; primary endpoint) and HIV incidence among participants who received daily oral TDF/FTC (secondary endpoint) (10). The PURPOSE 1 trial also assessed the efficacy of daily oral tenofovir alafenamide-emtricitabine (TAF/FTC), a medication that has not been approved by FDA as PrEP for women, compared with no PrEP use and daily oral TDF/FTC use, and assessed safety outcomes for LEN compared with both tenofovir-based options (10).

The PURPOSE 2 trial primarily enrolled males (see Table 1 in the trial report [11]) aged 16–80 years in 92 trial sites in Argentina, Brazil, Mexico, Peru, South Africa, Thailand, and the United States. After screening the eligible trial population for HIV infection to establish background incidence, participants who tested negative were randomized to receive injectable LEN every 6 months or daily oral TDF/FTC (11). The trial’s primary efficacy analysis compared HIV infection incidence in the LEN group with background HIV incidence in the screened population. The secondary efficacy analysis compared HIV infection incidence in the LEN group with the TDF/FTC group.

In both trials, study inclusion was based on the presence of sexual risk factors for HIV infection, and the randomized design was used for the secondary endpoint (daily oral PrEP use comparator), whereas the background incidence design was used for the primary endpoint (no PrEP use comparator) (Table 1) (10,11). In both trials, follow-up visits occurred at 4, 8, and 13 weeks, as well as every 13 weeks thereafter. Testing at follow-up visits included blood-based rapid antigen and antibody (antigen/antibody) tests and central laboratory antigen/antibody tests. HIV RNA testing was available for participants who acquired HIV infection during the trial (10,11).

A preplanned interim analysis was conducted when 50% of the target population had been enrolled for ≥52 weeks. After the interim analysis, independent data monitoring committees terminated the blinded phase of both trials based on the prespecified efficacy criteria^§ (10,11).

PURPOSE 1 Clinical Efficacy Trial

The PURPOSE 1 trial included a total of 8,094 females who were screened and included in calculating the background HIV incidence; 5,338 females were enrolled in the modified intention-to-treat (mITT) analysis in a 2:1:1 design (2,134: LEN plus an oral placebo; 2,136: TAF/FTC plus an injection placebo; and 1,068: TDF/FTC plus an injection placebo) (10). No new HIV infections occurred among females receiving injectable LEN over 52 weeks of follow-up. Within this group, LEN was 100% efficacious compared with no use of PrEP (incidence rate ratio [IRR] = 0; 95% CI = 0–0.04) and with TDF/FTC (IRR = 0; 95% CI = 0–0.10) (10). In the postprimary analysis, two participants with incident HIV infection were identified in the LEN group. One of the incident infections occurred in a participant after discontinuation of LEN during a period in which drug concentrations decreased below the target levels necessary for protection against HIV. No HIV-1 capsid inhibitor mutations were detected (9). The second participant in the LEN group with an incident HIV infection had a low HIV viral load, and genotyping to detect LEN resistance-associated mutations was not possible (9).

PURPOSE 2 Clinical Efficacy Trial

The PURPOSE 2 trial included a total of 4,634 participants (see Table 1 in the trial report for details on demographics [11]) who were screened and included in calculating the background HIV incidence; 3,265 participants were enrolled in the mITT analysis in a 2:1 design (2,179 LEN plus an oral placebo and 1,086 TDF/FTC plus an injection placebo) (11). In this study, LEN was 96% efficacious in preventing HIV infection compared with no PrEP use (IRR = 0.04; 95% CI = 0.01–0.18) and 89% efficacious compared with TDF/FTC (IRR = 0.11; 95% CI = 0.02–0.51) (11). Two HIV infections occurred in participants receiving LEN; in both cases, drug concentrations were within ranges expected to be protective, and the HIV-1 capsid mutation N74D was detected. One of the participants with an incident HIV infection had a viral load of 14,000 HIV copies/mL; HIV diagnostic assays were notable for negative rapid test results and positive laboratory-based antigen/antibody test results at diagnosis. The other participant had a viral load of 934,000 HIV copies/mL; both the rapid and the laboratory-based antigen/antibody test results were positive at diagnosis (11). In the postprimary analysis, one additional incident HIV infection was identified in the LEN group, and Q67H/K70R mutations in the capsid gene were detected (9).

Safety and Adverse Events

Rates of any adverse events of any grade (excluding injection site reactions) and of grade 3 (severe), 4 (life-threatening), or 5 (fatal) adverse events were similar in all study groups in both trials (10,11). Deaths that occurred were determined to be unrelated to the study drug. Adverse events of grades 3–5 were more prevalent in the TDF/FTC group. Injection site reactions were the most commonly reported adverse event in all study groups in both trials. They occurred more often in the LEN group (PURPOSE 1 = 68.8%; PURPOSE 2 = 83.2%), were mainly grade 1 (mild) or grade 2 (moderate), and predominantly included pain, subcutaneous nodules, and induration. Symptom intensity and frequency decreased with subsequent injections. LEN discontinuations related to injection site reactions were infrequent (PURPOSE 1 = 0.2%; PURPOSE 2 = 1.2%) (10,11). In the postprimary analysis, nodules persisted for a median of 350 days (IQR = 182–470 days) in the PURPOSE 1 trial and 297 days (IQR = 176–423 days) in the PURPOSE 2 trial (9). The median diameter of the largest nodule per participant was 1.2 inches (3.0 cm) (IQR = 0.8–1.6 inches [2–4 cm]) (11).

Among 510 pregnancies that occurred among 487 women in PURPOSE 1, pregnancy-associated adverse events and pregnancy outcomes were comparable in the 184 participants receiving LEN and those receiving tenofovir-based PrEP, both consistent with background rates; no adverse events were reported among breastfed infants exposed to LEN (10). No HIV infections occurred among pregnant women who received LEN; five infections occurred in the tenofovir-based PrEP groups (10).

The overall certainty of evidence for the five outcomes assessed was high based on GRADE. LEN is highly efficacious (Table 1) and safe (Table 2) as PrEP. The most commonly reported adverse event was an injection site reaction, which led to few discontinuations.

Clinical Recommendation for Use of Lenacapavir for HIV Prevention

Lenacapavir, administered as subcutaneous injections every 6 months, is recommended as an HIV PrEP option in persons weighing ≥77 lbs (≥35 kg) who would benefit from PrEP. This is a strong recommendation, based on high certainty of evidence.

Clinical Guidance for Use of Lenacapavir for HIV Prevention

Identification of Persons Eligible to Receive LEN

Clinicians should consider PrEP in persons whose behaviors and epidemiologic context place them at risk for HIV acquisition (12). These populations include but are not limited to those with identified high HIV incidence in the United States (including persons with diagnosed sexually transmitted infections, men who have sex with men, persons whose sexual partners have HIV infection without viral suppression, persons who engage in transactional sex, persons who are incarcerated, and persons who share needles). PrEP should be offered in addition to other evidence-based HIV prevention strategies and within a comprehensive primary care strategy (12).

Clinicians should educate all eligible persons about current available PrEP options, discuss product choice, provide follow-up and medication adherence support, reassess ongoing risk, and align PrEP care goals accordingly (12). LEN might offer a good option for persons who prefer not to take a daily oral pill. The National Clinician Consultation Center PrEPLine (855-448-7737) and the can provide guidance for prescribing PrEP medications.

Assessing eligibility for LEN consists of 1) assessing HIV acquisition risk, 2) excluding those with acute HIV infection, and 3) identifying significant drug interactions or contraindications (Box) () (9,17,18). Based on the limited available safety and efficacy data, LEN PrEP may be used in pregnant women or continued in women who become pregnant while receiving injections, considering the woman’s risk for HIV without PrEP, after provider-client shared decision-making.

Recommended Laboratory Testing

To rule out recent HIV infection, laboratory blood-based HIV antigen/antibody testing is recommended on the day of the initial LEN injection and with follow-up injections; however, LEN may also be administered if testing occurred within the preceding 7 days (Box). At initiation of LEN PrEP, a confirmatory HIV RNA test should be obtained in addition to the antigen/antibody test, if available; however, the results of the RNA assay should not delay injection (9). If HIV RNA testing is not available, a repeat laboratory-based antigen/antibody test should be scheduled in 4 weeks to exclude an undetected baseline infection (12). For those who receive positive HIV test results, confirmatory and other testing should be performed and treatment initiated; for treatment of HIV infections that were acquired after receiving LEN, integrase strand-transfer inhibitor-based therapy should be considered ().

If clinicians administer follow-up LEN injections based on a negative rapid HIV antigen/antibody test result, a confirmatory laboratory-based antigen/antibody test should also be obtained. Oral HIV antibody tests should not be used because of their low sensitivity in detecting recent HIV infection (12). If initiating LEN as a switch from tenofovir-based or cabotegravir PrEP without any interruption, only a laboratory-based HIV antigen/antibody test is needed before the injection. Tenofovir is an antiviral that can be used to treat chronic hepatitis B infection. Therefore, clinicians switching persons from tenofovir-based PrEP to LEN PrEP should determine whether the client has HBV infection or is immune to HBV. For persons with HBV infection, an alternative HBV treatment regimen should be provided if tenofovir is discontinued. HBV vaccination should be administered if a person is not immune to HBV (19,20).

LEN Initiation and Injection Site Reactions

LEN is initiated with two 300-mg oral tablets (total 600 mg) each on days 1 and 2 (loading doses), along with two 1.5-mL subcutaneous injections (total 927 mg in 3 mL) administered in immediate sequence at least 4 inches apart on day 1 (9). Injection sites include the abdomen and anterior thigh (9). LEN forms a drug depot that might result in a subcutaneous nodule. Nodules are the most frequently reported injection site reaction. Nodules can be several centimeters in size and can last for several months to more than a year (9,11). Other injection site reactions include pain and induration. Incorrect injection technique, such as inserting the needle at an angle of ≤45° (resulting in intradermal rather than subcutaneous injection), is thought to contribute to injection site reactions (11). The manufacturer recommends an injection angle of 90°. Application of ice packs and use of topical and oral analgesics before and after injection might alleviate some signs and symptoms related to injection site reactions.

Conclusion and Future Research

LEN is a highly effective and safe PrEP option administered every 6 months, which provides the potential to improve PrEP adherence and thus enhance HIV prevention in the United States. Additional research is needed to understand LEN’s effectiveness in persons who inject drugs, its ability to inhibit early viral replication if a person receiving PrEP becomes infected, the potential for emergence of resistance, safety and efficacy over longer follow-up periods, acceptability, and optimal strategies for implementation in clinical and community settings (21,22).