Lenacapavir demonstrates effectiveness for resistant HIV
In HIV, progression of illness or treatment failure is often characterized by increased HIV viral load and decreased CD4+ T-cell count. When illness progression or treatment failure occurs on ART, it is often a result of drug-resistant HIV.
The prevalence of people living with HIV is increasing, in part due to the advancements of ART. However, there is also an increasing incidence of resistant HIV. It is estimated that for viral levels to remain undetectable and to reduce the incidence of resistance, a person must remain about 95% adherent to their prescribed ART. Additionally, in patients with newly diagnosed HIV, it is expected that about 18% of people have at least one drug-resistant mutation. This is in part due to the ability to transfer mutations from person to person.
Since 2018, three medications have been approved by the FDA for use in heavily treatment-experienced or treatment-resistant HIV: ibalizumab, fostemsavir and lenacapavir.
Recommendations for heavily treatment-experienced people
Ibalizumab, fostemsavir and lenacapavir are recommended for people with HIV who are heavily treatment-experienced with multidrug-resistant (MDR) HIV-1 and unable to achieve or maintain viral suppression on their current ART.
Ibalizumab should be added to an optimized background regimen that includes at least one fully active medication. Fostemsavir or lenacapavir should be added to an optimized background regimen that includes at least one active medication, or if not possible, multiple partially-active medications.
Safety and efficacy of lenacapavir
Lenacapavir, is a capsid inhibitor, the first of its kind. It has been approved by the FDA since 2022 and by the European Medicines Agency and Health Canada for the treatment of MDR HIV infections. The FDA is also reviewing twice-yearly lenacapavir for PrEP, which could transform HIV prevention, experts have said.
One of the most informative studies looking at the efficacy of lenacapavir as treatment is CAPELLA, a phase 3 trial with the objective of evaluating the safety and efficacy of lenacapavir in treating MDR HIV in heavily treatment experienced patients.
CAPELLA evaluated two cohorts: one assigned patients in a 2:1 ratio to receive either lenacapavir or placebo in addition to their existing failing regimen. On day 15, the lenacapavir group received subcutaneous dosing every 6 months and the placebo group started oral lenacapavir therapy. The second cohort was an open-label lenacapavir group that eventually transitioned to subcutaneous dosing, in addition to optimized background therapy.
The primary endpoint was the percent of patients with a 0.5 log10 reduction in HIV viral load on day 15, with secondary endpoints that included percent of patients with a viral load of less than 50 copies/mL and percent of patients with a viral load of less than 200 copies/mL 26 weeks after initiation of the intervention.
The study found that 88% of the lenacapavir and 17% of the placebo group experienced a 0.5 log10 reduction at day 15 (P < 0.001). For secondary endpoints, a significant portion of participants in both cohorts had viral loads less than 50 copies/mL and 200 copies/mL at week 26, respectively. Eight patients developed lenacapavir-related resistance.
The study concluded that in patients with multidrug-resistant HIV-1 infection, those who received lenacapavir had a greater reduction from baseline in viral load than those who received placebo.
An additional trial, CALIBRATE, looked at the safety and efficacy of lenacapavir in treatment-naive patients. The phase 2 randomized, open-label active-controlled study had a primary objective of exploring the efficacy of lenacapavir in various combination regimens as initial and maintenance therapy for HIV. Participants were ART naive with an HIV-1 RNA viral load and CD4+ T-cell count of at least 200 copies/mL and at least 200 cells/µL, respectively. The primary outcome was the proportion of patients who achieved an undetectable viral load, defined as less than 50 copies/mL by week 54.
The study had four groups, including two that received subcutaneous lenacapavir every 26 weeks plus oral emtricitabine/tenofovir alafenamide (FTC/TAF) daily. After 28 weeks, FTC/TAF was changed to oral TAF alone in group one, and oral bictegravir in group two. Group three received daily oral lenacapavir plus oral FTC/TAF. Group four received bictegravir, FTC and TAF without any form of lenacapavir.
The study found no statistically significant difference between treatment groups for the proportion of patients to achieve an undetectable viral load by week 54. The researchers did find that viral suppression was rapid, with 94% of patients receiving any form of lenacapavir achieving viral suppression by week 28.
Looking more specifically at safety data, the researchers found that the primary adverse reaction was injection site reactions, which were characterized by swelling, pain, erythema, nodules, indurations, pruritus, extravasation and mass. Most symptoms resolved within 5 days; however, nodules and indurations had a median time to resolution of about 148 days. The next most common adverse reactions were nausea and headache. In general, studies indicated that lenacapavir was overall well tolerated.
Lenacapavir has shown to be both safe and efficacious in patients with MDR HIV-1. With the increasing incidence of drug-resistant HIV, lenacapavir has demonstrated it can be an option in patients who are heavily treatment-experienced with multi-drug resistance.
References:
- CDC. Clinical care of HIV. https://www.cdc.gov/hivnexus/hcp/clinical-care/index.html. Updated Feb. 10, 2025. Accessed March 31, 2025.
- Cluck DB, et al. Pharmacotherapy. 2024;doi:10.1002/phar.2913.
- Dzinamarira T, et al. Medicina (Kaunas). 2023;doi:10.3390/medicina59061041.
- Gupta SK, et al. Lancet HIV. 2023;doi:10.1016/S2352-3018(22)00291-0.
- Prather C, et al. Am J Health Syst Pharm. 2023;doi:10.1093/ajhp/zxad223.
- Segal-Maurer S, et al. New Engl J Med. 2022;doi:10.1056/nejmoa2115542.
- VanderVeen L, et al. Open Forum Infect Dis. 2021;doi:10.1093/ofid/ofab466.073.
For more information:
Sarah Goldsmith, PharmD, is a PGY1 pharmacy practice resident at Denver Health Medical Center.
Kati Shihadeh, PharmD, BCIDP, is a clinical pharmacy specialist in infectious diseases at Denver Health Medical Center. Shihadeh can be reached at katherine.shihadeh@dhha.org.
Collapse
Expert Submission
Read more about