Prospective Game Changer: Lenacapavir for HIV Preexposure Prophylaxis

In 2024, approximately 1.3 million people contracted HIV.¹ Since the peak of 3.4 million new HIV infections in 1996, the incidence has dropped by 61%.¹ Preexposure prophylaxis (PrEP) has been a key component in HIV prevention. Medication for PrEP was first approved by the US Food and Drug Administration in 2012. However, prophylaxis against HIV with zidovudine has been practiced since the 1980s in health care workers following accidental HIV exposure.² Despite extensive efforts to expand antiretroviral therapy (ART) and impressive declines in new HIV infections, the goal of getting below 370,000 new infections globally by 2025 is still out of reach.¹

Populations with high HIV prevalence include persons who inject drugs (PWID), sex workers, and prisoners.² People in these groups often face stigma and discrimination, preventing access to HIV care. In addition to addressing individuals’ social determinants of health, which is critical to advancing health equity, current strategies to mitigate HIV burden among affected groups include PrEP, HIV testing, and treatment.² PrEP effectiveness depends on adherence.² The options in PrEP formulation and frequency have evolved, including single-tablet regimens and long-acting injectable (LAI) formulations. Cabotegravir (Apretude), the first LAI approved for PrEP, is administered as an intramuscular injection every 2 months. A second LAI option, lenacapavir (LEN), is administered subcutaneously every 6 months. These LAIs improve PrEP effectiveness by removing the psychological burden of daily administration and addressing stigma through fewer clinic visits, minimizing public visibility. LEN is used in combination with other antiretroviral medications for individuals with multidrug HIV resistance under the brand name Sunlenca; when administered alone, under the brand name Yeztugo, it can be used for PrEP to prevent sexually acquired HIV.^3,4

Overview

Novel classes of ART have been developed in response to growing HIV resistance. LEN is a capsid inhibitor that targets viral capsid stability.⁵ Without proper capsid assembly and disassembly, HIV-1 replication is halted.⁵ The inhibition is multistage and selective to HIV-1. LEN inhibits multiple stages of the HIV-1 replication cycle by interfering with capsid-mediated nuclear uptake of HIV-1 proviral DNA, virus assembly and release, and capsid core formation.³ Prior to all LEN injections for PrEP, patients must be screened for HIV with antigen/antibody (Ag/Ab)-specific tests.³ Confirmed negative laboratory-based HIV Ag/Ab test results are acceptable within 7 days of initiation, or rapid HIV Ag/Ab test results are acceptable on initiation day pending results of laboratory-based HIV Ag/Ab tests.⁶ LEN reduces the risk of HIV infection in adults and adolescents with a weight of at least 35 kg; it does not prevent other sexually transmitted diseases.³ LEN injections must be administered by a health care professional.³ LEN initiation includes four 300-mg tablets and two 463.5-mg/1.5-mL injection solution vials, which all should be stored at 20 to 25 °C (68-77 °F).³

On initiation day 1, patients take 2 tablets by mouth (600 mg total) and receive the subcutaneous injections (927 mg total) in office. The injections are given in the abdomen or thigh.³ Alternative sites, such as the upper arm and gluteal area, have been evaluated; results have shown similar pharmacokinetics as abdominal administration.^7,8 On day 2, patients take the 2 remaining tablets at home.³ Continuation therapy involves 2 subcutaneous injections (total of 927 mg) every 6 months.³ LEN has a range of plus/minus 2 weeks (ie, a 4-week injection window) on either side of the target continuation dose 6 months (26 weeks) after the previous injection.³ In the case of anticipated delayed injections, a weekly 300-mg oral dose can be used to bridge until the next injection for up to 6 months.³ If weekly oral bridge is utilized, it must be started 26 to 28 weeks after the last injection.³ If patients miss continuation injections, they should be clinically reassessed for HIV-negative status and appropriateness of resuming LEN. If the time since the last injection is more than 28 weeks and no oral bridge therapy was used, patients will need to be reinitiated with oral and injection therapy.³ LEN is a moderate CYP3A4 inhibitor and may increase the concentration, and consequent adverse reaction risks, of drugs metabolized by CYP3A4.³

PURPOSE Trials

PURPOSE 1 (NCT04994509) was a phase 3 double-blinded, randomized study that evaluated the efficacy and safety of twice-yearly subcutaneous LEN and once-daily oral emtricitabine/tenofovir alafenamide fumarate (FTC/TAF) as HIV-1 PrEP.⁹ It was actively controlled with a third group assigned once-daily oral FTC/tenofovir disoproxil fumarate (TDF).⁹ HIV-negative women and adolescent girls (n = 5345) in South Africa and Uganda were randomly assigned 2:2:1 to LEN 927 mg subcutaneously every 26 weeks (n = 2134), FTC/TAF 200/25 mg orally daily (n = 2136), or FTC/TDF 200/300 mg orally daily (n = 1068).⁹

The primary outcome was HIV incidence reported per 100 patient years (PY) for LEN, FTC/TAF, and FTC/TDF compared with background HIV (bHIV) incidence in the screened population (n = 8094).⁹ A total of 55 incident HIV cases were reported: 0 cases in the LEN group (0 per 100 PY; 95% CI, 0-0.91), 39 cases in the FTC/TAF group (2.02 per 100 PY; 95% CI, 1.44-2.76), and 16 cases in the FTC/TDF group (1.69 per 100 PY; 95% CI, 0.96-2.74).⁹ bHIV incidence in the screened population was 2.41 per 100 PY (95% CI, 1.82-3.19).⁹

Adherence in the LEN group, defined as on-time injection, was 90% or higher at weeks 26 and 52; this contrasts with low adherence, defined as fewer than 2 doses per week, which was seen in 84% and 93% of the population at 52 weeks in the FTC/TAF and FTC/TDF groups, respectively.⁹ High adherence, defined as 4 or more doses per week, was seen in 11% and 7% in the FTC/TAF and FTC/TDF groups, respectively.⁹ In the FTC/TAF group, there was a lower incidence of HIV when 2 or more doses were taken per week.⁹ Adherence in the oral groups was measured using dried blood spot analysis of TDF levels in 10% of randomly preselected participants.⁹ PURPOSE 2 (NCT04925752) was also a phase 3 double-blinded, randomized study. It evaluated the efficacy of LEN as PrEP, and its international population included cisgender men, transgender women, transgender men, and gender-nonbinary persons.¹⁰

This study randomly assigned participants 2:1 to LEN subcutaneously every 26 weeks (n = 2179) or FTC/TDF orally daily (n = 1086).¹⁰ The outcomes assessed in this study included HIV incidence in the LEN group compared with the FTC/TDF group and bHIV in the screened population (n = 4634). In the LEN group, there were 2 cases of HIV infection (0.10 per 100 PY; 95% CI, 0.01-0.37).¹⁰ In the FTC/TDF group, there were 9 cases (0.93 per 100 PY; 95% CI, 0.43-1.77).¹⁰ bHIV incidence was reported as 2.37 per 100 PY (95% CI, 1.65-3.42).⁹ Adherence in the LEN group, defined as on-time injection, was 90% or higher at both 26 and 52 weeks, similar to PURPOSE 1 results.¹⁰ At 52 weeks, low adherence (< 2 doses/week) for oral FTC/TDF was seen in 27% of patients vs high adherence in 62%, defined as 4 or more doses per week.¹⁰ Adherence was evaluated using the same methodology as PURPOSE 1. The incidence of HIV was significantly lower in the LEN group in both PURPOSE 1 and 2 studies. Only 2 patients in the LEN groups (n = 4313) acquired HIV compared with 64 in the oral FTC/TAF and FTC/TDF groups (n = 4290). LEN demonstrated superiority with a 100% and 89% risk reduction of incident HIV-1 infection over FTC/TDF in PURPOSE 1 and PURPOSE 2, respectively.³ The most common adverse effect reported in PURPOSE 1 and PURPOSE 2 was injection site reaction (ISR), seen in 83.2% and 68.8% in the LEN groups, respectively, with the majority of cases being mild. Injection site nodules were common in participants taking LEN. The nodules had a median diameter of 3 cm and a median duration of 300 to 350 days.³ In PURPOSE 1, 9 participants (0.4%) discontinued LEN due to adverse drug reactions, including ISR (0.2%), nausea, decrease in renal function, increase in liver enzymes, spontaneous abortion, depression, and suicide attempt. In PURPOSE 2, 32 participants (1.5%) discontinued LEN due to adverse drug reactions, including ISR (1.2%), gastrointestinal disorders, gastroenteritis, onychomycosis, and brain neoplasm. Across both studies, sexually transmitted infections, headaches, gastrointestinal disorders, urinary and respiratory infections, and dizziness were also reported.

Conclusion

LEN is an injectable PrEP that can be used to reduce the risk of sexually acquired HIV. The PURPOSE 1 and PURPOSE 2 results showed that twice-yearly LEN significantly lowered HIV incidence compared with other oral PrEP options.^9,10 Higher adherence to LEN was shown in both studies compared with oral PrEP.^9,10 ISRs were the most common adverse effect reported, though discontinuation due to ISR was not common.^9,10 Though current studies only evaluated LEN’s use for sexually acquired HIV, ongoing studies are evaluating its pharmacokinetics for PrEP use in PWID.¹¹ Currently, there are no head-to-head studies comparing the efficacy of cabotegravir vs LEN for PrEP. LEN’s novelty as a twice-yearly LAI option could address adherence and stigma barriers to PrEP use, which may be the way forward in ending the HIV epidemic.

References

1. Global HIV & AIDS statistics — fact sheet. UNAIDS. Accessed July 27, 2025. https://www.unaids.org/en/resources/fact-sheet

2. Rosas Cancio-Suárez M, Díaz-Álvarez J, Ron R, et al. From innovation to implementation: the evolution of HIV pre-exposure prophylaxis and future implications. Pathogens. 2023;12(7):924. doi:10.3390/pathogens12070924

3. Yeztugo. Prescribing information. Gilead Sciences Inc; 2025. Accessed July 27, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/220020s000lbl.pdf

4. Sunlenca. Prescribing information. Gilead Sciences Inc; 2024. Accessed July 27, 2025. https://www.gilead.com/-/media/files/pdfs/medicines/hiv/sunlenca/sunlenca_pi.pdf

5. Thenin-Houssier S, Valente ST. HIV-1 capsid inhibitors as antiretroviral agents. Curr HIV Res. 2016;14(3):270-282. doi:10.2174/1570162x14999160224103555

6. Interim guideline on the use of twice-yearly lenacapavir for HIV prevention. Clinical Guidelines Program. Updated July 2, 2025. Accessed September 1, 2025. https://www.hivguidelines.org/guideline/hiv-prep-len/

7. Lat AK, Kim A, Zhang H, et al. 1542: impact of subcutaneous administration sites on the clinical pharmacokinetics of lenacapavir, a long-acting HIV capsid inhibitor: does body site matter? Open Forum Infect Dis. 2023;10(suppl 2):ofad500.1377. doi:10.1093/ofid/ofad500.1377

8. Saunders G, Mortensen E, Shen G, Kim A. Injection site reactions with subcutaneous lenacapavir administration at alternate injection sites. National AIDS Treatment Advocacy Project. July 2024. Accessed September 5, 2025. https://www.natap.org/2024/IAS/IAS_52.htm

9. Bekker LG, Das M, Karim QA, et al; PURPOSE 1 Study Team. Twice-yearly lenacapavir or daily F/TAF for HIV prevention in cisgender women. N Engl J Med. 2024;391(13):1179-1192. doi:10.1056/NEJMoa2407001

10. Kelley CF, Acevedo-Quiñones M, Agwu AL, et al; PURPOSE 2 Study Team. Twice-yearly lenacapavir for HIV prevention in men and gender-diverse persons. N Engl J Med. 2025;392(13):1261-1276. doi:10.1056/NEJMoa2411858

11. Study of lenacapavir and emtricitabine/tenofovir disoproxil fumarate (F/TDF) for prevention of HIV in people who inject drugs (HPTN 103) (PURPOSE 4). ClinicalTrials.gov. Updated August 21, 2025. Accessed August 28, 2025. https://clinicaltrials.gov/study/NCT06101342