Lenacapavir for multidrug-resistant HIV-1 infection

Background:
Despite the availability of highly effective antiretroviral therapies, some people with HIV-1 infection develop treatment resistance and experience inadequate viral load suppression. People with multidrug-resistant HIV-1 infection are at increased risk of hospitalisation and progression to advanced HIV infection (acquired immunodeficiency syndrome).¹ Lenacapavir is an injectable antiretroviral drug with a 6-month dosing frequency; it joins the limited range of therapies specifically indicated for people with HIV and multiple treatment failures and significant drug resistance.

Mechanism of action:
Lenacapavir is a first-in-class selective inhibitor of HIV-1 capsid function. It interferes with multiple stages of the HIV life cycle, including uptake of viral DNA into the host cell, virus assembly, and capsid core formation.²

Clinical trials:
Data on the efficacy and safety of lenacapavir for treatment of HIV-1 are based on a phase 3 clinical trial (CAPELLA) that included 72 patients with multidrug-resistant HIV-1 infection.³ The majority were male and the median age was 52 years. Participants had virological resistance to 2 or more drugs from at least 3 of the 4 standard classes of antiretrovirals: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and integrase strand inhibitors.

Participants were divided into 2 cohorts. In cohort 1, participants were randomised to receive directly observed treatment with either oral lenacapavir (n=24) or placebo (n=12) on days 1, 2 and 8, while continuing their other (failing) antiretroviral therapy.³ From day 15, the treatment group received 6-monthly subcutaneous lenacapavir and the placebo group commenced oral lenacapavir, followed by subcutaneous lenacapavir. Both groups also commenced optimised background therapy. In cohort 2 (n=36), all participants were treated with open-label oral lenacapavir on days 1, 2 and 8, followed by 6-monthly subcutaneous lenacapavir, with an optimised background regimen from day 1.

Cohort 1: After 2 weeks, 88% of patients in the lenacapavir group and 17% in the placebo group achieved a reduction in viral load of at least 0.5 log10 copies/mL. At 26 weeks, when both groups were on active treatment, 81% of participants had a viral load less than 50 copies/mL. There was a mean increase in CD4+ count from baseline of 75 cells/mm³.

Cohort 2: At 26 weeks, 83% of patients achieved a viral load less than 50 copies/mL. There was a mean increase in CD4+ count from baseline of 104 cells/mm³.

Adverse effects:
In the CAPELLA trial, nausea occurred in 13% of lenacapavir (oral)-treated patients compared with 0% in placebo-treated patients during the 14-day randomised period (cohort 1).³ Across both cohorts, over 26 weeks of treatment with oral and subcutaneous lenacapavir, other common adverse effects were injection-site reactions (62%), constipation (11%) and diarrhoea (11%). These events were mostly mild or moderately severe.³ According to data from the extension phase at 104 weeks, the most common adverse effects related to lenacapavir were diarrhoea (6.9%) and nausea (5.6%).⁴

Dosage and administration:
Initiation: 600 mg orally on days 1 and 2, followed by 300 mg orally on day 8, and 927 mg by subcutaneous injection on day 15.

Maintenance: 927 mg by subcutaneous injection every 6 months.

The 927 mg doses require 2 x 1.5 mL subcutaneous injections, which should be administered by a healthcare professional into separate abdominal sites.

No dose adjustment is required in mild to moderate renal or hepatic impairment. Lenacapavir has not been studied in patients with creatinine clearance below 15 mL/min or severe hepatic impairment.

Practice points:
Immune recovery following antiretroviral therapy initiation can trigger immune reconstitution inflammatory syndrome. Patients should inform their clinician if they develop symptoms of inflammation.

If lenacapavir treatment is stopped, an active antiretroviral regimen must be initiated no later than 28 weeks after the last injection.

Precautions:
As lenacapavir is a substrate of cytochrome P450 (CYP) 3A, P-glycoprotein and UGT1A1, coadministration with moderate or strong inducers/inhibitors is not recommended; interactions can be checked via the University of Liverpool HIV Drug Interactions website. Lenacapavir is also a moderate inhibitor of CYP3A and can affect the exposure of substrate drugs. Lenacapavir has a prolonged half-life of up to 12 weeks following subcutaneous injection; it can affect the pharmacokinetics of drugs taken up to 9 months after the last injection.^5,6

Use in pregnancy:
There are limited data on the safety of lenacapavir in pregnancy. It is classified as Therapeutic Goods Administration pregnancy category B1.⁵

Place in therapy:
Lenacapavir plus an optimised background antiretroviral regimen may be useful for patients with multidrug-resistant HIV-1 infection with inadequate viral suppression. Following the initiation period, its 6-monthly subcutaneous administration means it potentially decreases the pill burden for patients and is less prone to adherence issues. Lenacapavir has also been evaluated in HIV-1 patients without prior antiretroviral therapy,⁷ and is being investigated as pre-exposure prophylaxis for people at high risk of HIV-1 infection (PURPOSE 1 and 2 trials),^8,9 but it is not currently approved in Australia for these indications.

This new drug comment was finalised on 13 March 2025.

At the time this new drug comment was prepared, the Australian Public Assessment Report was available from the Therapeutic Goods Administration. The sponsor did not provide the Clinical Evaluation Report.

 

References

1. Grover D, Copas A, Green H, Edwards SG, Dunn DT, Sabin C, et al. What is the risk of mortality following diagnosis of multidrug-resistant HIV-1? J Antimicrob Chemother 2008;61:705-13.
2. Hitchcock AM, Kufel WD, Dwyer KAM, Sidman EF. Lenacapavir: A novel injectable HIV-1 capsid inhibitor. Int J Antimicrob Agents 2024;63:107009.
3. Segal-Maurer S, DeJesus E, Stellbrink HJ, Castagna A, Richmond GJ, Sinclair GI, et al. Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection. N Engl J Med 2022;386:1793-803.
4. Ogbuagu O, Molina JM, Chetchotisakd P, Ramgopal MN, Sanchez W, Brunetta J, et al. Efficacy and Safety of Long-Acting Subcutaneous Lenacapavir in Heavily Treatment-Experienced People with Multi-Drug Resistant HIV-1: Week 104 Results of a Phase 2/3 Trial. Clin Infect Dis 2024.
5. Therapeutic Goods Administration. Australian Product Information – Sunlenca (lenacapavir (as sodium) injection, tablets). Department of Health and Aged Care; 2023. [cited 2025 Mar 6]
6. Therapeutic Goods Administration. Australian Public Assessment Report for Sunlenca. Department of Health and Aged Care; 2024. [cited 2025 Mar 6]
7. Gupta SK, Berhe M, Crofoot G, Benson P, Ramgopal M, Sims J, et al. Lenacapavir administered every 26 weeks or daily in combination with oral daily antiretroviral therapy for initial treatment of HIV: a randomised, open-label, active-controlled, phase 2 trial. Lancet HIV 2023;10:e15-e23.
8. ClinicalTrials.gov. Study of lenacapavir for HIV pre-exposure prophylaxis in people who are at risk for HIV infection (PURPOSE 2). Identifier NCT04925752. National Library of Medicine (US); 2024. [cited 2025 Jan 31]
9. ClinicalTrials.gov. Pre-Exposure Prophylaxis Study of Lenacapavir and Emtricitabine/Tenofovir Alafenamide in Adolescent Girls and Young Women at Risk of HIV Infection (PURPOSE 1). Identifier NCT04994509. National Library of Medicine (US); 2025. [cited 2025 Mar 11]

 

The new drug comments in Australian Prescriber are prepared by the editors and reviewed by the Editorial Advisory Committee. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. Before new drugs are prescribed, it is important that more detailed information is obtained from the approved product information, a medicines information centre or some other appropriate source.

Report all suspected adverse reactions to new drugs to enable continued monitoring of their benefit–harm balance.