Significant advances in HIV infection using long-acting injectables for both prevention and treatment have been made over the last several years. Currently, the only long-acting injectable agent available for HIV pre-exposure prophylaxis (PrEP) is cabotegravir (Apretude, ViiV Healthcare), which requires people to come in every 4 or 8 weeks.1 The frequency of visits may be a barrier to some people interested in PrEP but are unable to take an oral regimen due to adherence concerns or other medical reasons.
Potential options for those people interested in long-acting injectables for PrEP may be expanding in the near future, as recent data demonstrate that lenacapavir (Gilead), administered as a subcutaneous injection every 6 months, prevented acquisition of HIV in all participants receiving it.
Lenacapavir (Sunlenca) is indicated for treatment, not PrEP. In this article, we review the recent literature demonstrating the effectiveness of lenacapavir for PrEP.2
In July 2024, Bekker and colleagues published the PURPOSE 1 study, a phase 3, multicenter, randomized, double-blind, active-controlled trial evaluating subcutaneous lenacapavir compared with background incidence, emtricitabine and tenofovir alafenamide (F/TAF; Descovy, Gilead), and emtricitabine and tenofovir disoproxil fumarate (F/TDF) for HIV PrEP.3
The study included women ages 16 to 25 years in South Africa and Uganda who were sexually active with male partners, were not using PrEP, and had unknown HIV status and no HIV testing within the previous 3 months. HIV testing was conducted using a fourth-generation point-of-care (POC) or central laboratory antibody–antigen test. If positive, the test result was automatically confirmed by an antibody assay to differentiate between HIV-1 and HIV-2. All participants received a quantitative HIV-1 RNA viral load test.
Study Design
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Participants who were found to be HIV-negative were randomly assigned in a 2:2:1 fashion to receive lenacapavir, dosed as an oral loading dose (two 300-mg tablets on days 1 and 2), followed by 927 mg administered subcutaneously every 26 weeks (±7-day window), daily oral F/TAF (emtricitabine 200 mg and TAF 25 mg), or daily oral F/TDF (emtricitabine 200 mg and TDF 300 mg). Participants in the lenacapavir group received placebo tablets, and those in the F/TAF or F/TDF groups received placebo oral loading doses and injections. Follow-up visits were conducted at weeks 4, 8, and 13, and every 13 weeks thereafter to perform safety laboratory, pregnancy, and HIV testing; provide medication adherence, HIV prevention, and reproductive health counseling; and evaluate intimate partner violence with appropriate referrals for support and counseling. At baseline and every 26 weeks thereafter, participants were screened for Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, and syphilis. Women who became pregnant could choose to continue the trial drug and remain in the study after completion of an updated informed consent process.3
Adherence to lenacapavir therapy was defined as an on-time injection (within 28 weeks after the last injection). Participants who presented later than 28 weeks after the previous injection underwent HIV-1 viral load and rapid POC and central laboratory antibody–antigen testing. If they were determined to be PrEP candidates, the patients received reloading with oral lenacapavir or placebo.
The primary efficacy end point was incident HIV infection. Efficacy analyses were evaluated using a modified intention-to-treat approach, which excluded participants who were found to have HIV infection on the date of randomization. Adverse events were documented in participants who received at least 1 dose of trial drug or placebo.
Results
A total of 5,345 participants were randomized and received at least 1 dose of a trial drug or placebo, with 7 women found to have HIV infection at the time of randomization. Treatment and comparator groups were distributed as follows: 2,134 in the lenacapavir group, 2,136 in the F/TAF group, and 1,068 in the F/TDF group. Overall, baseline characteristics were similar among the 3 groups. Median age of included participants was 21 years (IQR, 16-26 years), with 2.4% of participants younger than 18 years. While most participants (80.5%) had received previous HIV testing, a small percentage of women previously used PrEP (6.3%). Sexually transmitted infections were diagnosed at notable rates at baseline: 25.5% with C trachomatis, 8.7% with N gonorrhoeae, 7.5% with T vaginalis, and 2.8% with syphilis. Lenacapavir injections were administered on time in 92.8% of participants at week 52. In contrast, participants receiving F/TAF or T/TDF demonstrated poor adherence, with 89% and 100% of patients taking fewer than 3 doses per week at week 52.3
The identified background HIV incidence was 2.41 per 100 person-years (95% CI, 1.82-3.19 per 100 person-years). A total of 55 incident HIV infections were identified over the study period: none in the lenacapavir group (95% CI, 0.00-0.19 per 100 person-years), 39 in the F/TAF group (2.02 per 100 person-years; 95% CI, 1.44-2.76), and 16 in the F/TDF group (1.69 per 100 person-years; 95% CI, 0.96-2.74). Receiving lenacapavir for PrEP reduced HIV incidence by 100% compared with background HIV incidence (incidence rate ratio, 0.00; 95% CI, 0.00-0.04; P<0.001) and by 100% compared with F/TDF (incidence rate ratio, 0.00; 95% CI, 0.00-0.10; P<0.001). There was no difference in HIV incidence between F/TAF and background HIV incidence (incidence rate ratio, 0.84; 95% CI, 0.55-1.29; P=0.21) or those taking T/TAF or T/TDF (incidence rate ratio, 1.20; 95% CI, 0.67-2.14). Participants in the F/TAF group who took 2 doses or more per week were significantly less likely to acquire HIV infection than those who took less than 2 doses per week (odds ratio, 0.11; 95% CI, 0.01-0.49).
The most frequently reported adverse effect was injection site reactions, specifically subcutaneous nodules, injection site pain, and swelling. Injection site reactions occurred in 68.8% of participants who received lenacapavir and 34.9% of patients who received placebo injections. Other common adverse effects were headache, urinary tract infection, and genitourinary tract Chlamydia infection, which were reported at similar rates across all groups. Nausea and vomiting occurred more frequently in patients receiving F/TAF or F/TDF than lenacapavir.
On June 18, 2024, the interim efficacy analysis met prespecified criteria for stopping the trial early. Participants were offered the option to receive lenacapavir in an open-label fashion on July 8, 2024.
Discussion and Conclusion
The PURPOSE 1 study demonstrated the superiority of subcutaneous lenacapavir administered every 26 weeks over daily oral F/TDF for HIV PrEP in young cisgender women. This success was driven predominantly by poor adherence to the oral regimen.4 Lenacapavir is an efficacious and convenient option for HIV PrEP in a population that historically has been omitted from HIV PrEP trials. Application for FDA approval for this indication is pending the results of the PURPOSE 2 study, which is evaluating lenacapavir for PrEP in cisgender men who have sex with men, transgender men, transgender women, and gender non-binary individuals who have sex with partners assigned male.
Expansion of long-acting injectable agents for PrEP, especially with every-6-month frequency, will open up the opportunity for PrEP to additional people and help to support achievement of the goals set forth in the federal Ending the HIV Epidemic initiative.
References
- FDA approves first injectable treatment for HIV Pre-Exposure Prevention. December 20, 2021. Accessed September 12, 2024. https://bit.ly/3ZEBqtZ
- IDSE News Staff. FDA Approves Sunlenca for Adults With Resistant HIV. 2022 Dec. 22. Infectious Disease Special Edition. https://bit.ly/4eeCl8O-IDSE
- Bekker LG, Das M, Abdool Karim Q, et al. Twice-yearly lenacapavir or daily F/TAF for HIV prevention in cisgender women. N Engl J Med. 2024 Jul 24. doi:10.1056/NEJMoa2407001
- Gilead’s twice yearly lenacapavir demonstrated 100% efficacy and superiority to daily Truvada for HIV prevention. Gilead; 2024 Jun 20 [cited 2024 Aug 31]. Accessed September 12, 2024. https://bit.ly/3XzZxax-IDSE
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New Data Show Lenacapavir’s Efficacy for PrEP
