Lenacapavir Injection and Tablets (Yeztugo)
July 30, 2025 4 minutes read
By William Elliott, MD, FACP, and James Chan, PharmD, PhD
The U.S. Food and Drug Administration has approved lenacapavir, a potent, first-in-class, capsid inhibitor, for reducing the risk of sexually acquired human immunodeficiency virus type 1 (HIV-1). It is the first pre-exposure prophylaxis (PrEP) to be administered twice a year.
Lenacapavir was initially approved in 2022, as Sunleca, for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug resistant HIV-1. Lenacapavir received a priority review and was granted Breakthrough Therapy designation for this new indication.1
Lenacapavir is distributed by Gilead Sciences, Inc., as Yeztugo. It is the fourth PrEP marketed after emtricitabine-tenofovir disoproxil fumarate (F/TDF) (Truvada), emtricitabine-tenofovir alafenamide (F/TAF) (Descovy), and cabotegravir (Apretude).
Indications
Lenacapavir is indicated for PrEP to reduce the risk of sexually acquired HIV-1 in adults and adolescents weighing at least 35 kg who are at risk for HIV-1 acquisition and have a negative HIV-1 test prior to the initiation of treatment.2
Dosage
The recommended dosage is 927 mg (2 x 1.5 mL) given by subcutaneous (SQ) injection by a healthcare provider on day 1 along with 600 mg (two 300-mg tablets) orally. On day 2, 600 mg is taken orally, followed by 927-mg SQ injection every six months from the date of last injection, ± 2 weeks.2
A supplemental dose of lenacapavir is recommended for co-administration of strong and moderate CYP3A inducers.2 The tablets may be taken without regard to food. Individuals should be screened for HIV-1 prior to each injection. Lenacapavir is available as 300-mg tablets and 309 mg/mL (1.5 mL) single-dose vials.
Potential Advantages
Lenacapravir has an elimination half-life of eight to 12 weeks, permitting dosing every six months. Lenacapaivr every six months is more effective than F/TDF or F/TAF daily in preventing HIV infection.3,4 It is dosed less frequently than cabotegravir (Apretude), which is dosed every two months.
Potential Disadvantages
Like other PrEP regimens, lenacapavir has a box warning for the risk of drug resistance. The most frequently reported adverse reaction was injection site nodules reported in 63% of study participants.2 This is because of the formation of a drug depot upon injection and elicitation of granulomatous foreign body reaction.3
The median duration of nodules associated with the first injection was 297 to 350 days, with an observed median maximum diameter of 3 cm. Lenacapavir is a moderate CYP3A inhibitor and, because of its long elimination half-life, may increase exposure to substrates of this cytochrome enzyme (e.g., increase adverse reactions) initiated within nine months after the last SQ dose.2
Comments
Lenacapavir interferes with the normal function of the HIV capsid, a protein shell surrounding the virus’s core. The efficacy of lenacapavir was evaluated in two randomized, double-blind, active-controlled trials (PURPOSE 1 and PURPOSE 2).2-4
PURPOSE 1 enrolled cisgender adolescent girls and young women (ages 16-25 years) in South Africa and Uganda.2,3 They were assigned to lenacapavir (n = 2,134), F/TDF (n = 1,068), or F/TAF (n = 2,136). The efficacy endpoint was the rate of incident HIV-1 infection per 100 person-years. Follow-up occurred at weeks 4, 8, and 13 and every 13 weeks thereafter. Lenacapavir prophylaxis resulted in zero HIV infections per 100 person-years, F/TDF resulted in 1.69 infections per 100 person-years, and F/TAF resulted in 2.02 infections per 100 person-years. Lenacapvir reduced HIV-1 incidence by 100%. Medication adherence played a key role in HIV incidence, since most participants with incident HIV infection had low or no detection of TDF or TAF in red cells.3
In the F/TAF group, those with medium or high adherence were 89% less likely to acquire HIV infection than those with low adherence.3 PURPOSE 2 enrolled gender-diverse (transgender women, transgender men, and gender nonbinary people).2,4 The median age was 29 years (range, 17-74 years), and 63% were Hispanic/Latino. They were randomized to lenacapavir (n = 2,195) or F/TDF (n = 1,097). Lenacapavir resulted in 0.1 infections per 100 person-years, and F/TDF resulted in 0.93 infections per 100 person-years — an 89% reduction in risk.
Clinical Implications
There currently are four different PrEP regimens approved with different mechanisms of action. Emtricitabine and tenofovir are reverse transcriptase inhibitors, carbotegravir an HIV integrase inhibitor, and lenacapavir a capsid inhibitor.
The therapeutic objective of PrEP is to provide sufficient drug levels in the body to prevent viral replication when the individual is exposed to HIV. All regimens are effective with appropriate adherence. However, adherence generally is inversely associated with the complexity of the treatment regimen. F/TAF and F/TDF require daily dosing, carbotegravir extended-release injection is administered every two months after initial dosing, and lenacapavir is administered every six months after initial dosing. The latter potentially optimizes adherence if patients follow up to visits every six months for their injection.
In a study of the effect of adherence in men who have sex with men, protective TDF concentrations were achieved with four or more doses per week with a risk reduction of 96%, 99% for seven doses per week, and 76% for two doses per week.5 The cost for lenacapravir is $16,460 for the loading dose (injection plus tablets) and $14,109 per subsequent injections. For comparison, generic F/TDF is available at $30 per month.
William T. Elliott, MD, FACP, is Assistant Clinical Professor of Medicine, University of California, San Francisco.
James Chan, PharmD, PhD, is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
References
- Gilead. Yeztugo (Lenacapavir) is now the first and only FDA-approved HIV prevention option offering 6 months of protection. Published June 18, 2025. https://www.gilead.com/news/news-details/2025/yeztugo-lenacapavir-is-now-the-first-and-only-fda-approved-hiv-prevention-option-offering-6-months-of-protection
- U.S. Food and Drug Administration. Yeztugo Prescribing Information. Revised June 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/220020s000lbl.pdf
- Bekker L-G, Das M, Karim QA, et al. Twice-yearly lenacapavir or daily F/TAF for HIV prevention in cisgender women. N Engl J Med. 2025;391(13):1179-1192.
- Kelley CF, Acevedo-Quiñones M, Agwu AL, et al. Twice-yearly lenacapavir for HIV prevention in men and gender-diverse persons. N Engl J Med. 2025;392(13):1261-1276.
- Anderson PL, Glidden DV, Liu A, et al. Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. Sci Transl Med. 2012;4(151):151ra125.
The U.S. Food and Drug Administration has approved lenacapavir, a potent, first-in-class, capsid inhibitor, for reducing the risk of sexually acquired human immunodeficiency virus type 1.
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