New Long-Acting Options for Heavily Treatment–Experienced People With HIV-1

Key Takeaways

• Lenacapavir is a novel HIV-1 capsid inhibitor that demonstrated efficacy and safety in combination with an optimized background regimen in the CAPELLA trial.
• Drug‒drug interactions, including with other antiretroviral therapies, are possible and should be prevented.

Many healthcare professionals have become proficient in managing and treating HIV since the emergence of more durable and simple treatment options. However, treatment remains limited and challenging for people with HIV (PWH) who are heavily treatment experienced and multidrug resistant. Although they represent <1% of PWH, these individuals are at increased risk for morbidity and mortality. Ibalizumab and fostemsavir have been approved by both the European Medicines Agency and the FDA in combination with other agents for heavily treatment‒experienced adults with multidrug-resistant HIV-1 infection. The newest agent for these patients, lenacapavir, is a novel long-acting (LA) antiretroviral therapy (ART).

LA ARTs for Heavily Treatment Experienced Patients
LA ibalizumab is a monoclonal antibody that acts as an entry inhibitor and is given by infusion, while LA lenacapavir is a capsid inhibitor initiated orally with doses on Days 1, 2, and 8, followed by an SC injection on Day 15 and every 6 months thereafter. Lenacapavir has longer dosing intervals than its LA predecessors, with LA ibalizumab administered every 2 weeks. Lenacapavir is appropriate for use in PWH without virologic suppression, which is particularly important for patients with multidrug-resistant HIV-1.

Efficacy
The CAPELLA study enrolled 72 patients with multidrug-resistant HIV-1 in 2 cohorts. In cohort 1, patients were randomized to receive oral lenacapavir or placebo in addition to their failing therapy for 2 weeks. During the maintenance period, patients in the lenacapavir group received SC lenacapavir every 6 months. In cohort 2, all patients received the same lenacapavir regimen as in cohort 1, but it was open label. A decrease in HIV-1 RNA >0.5 log₁₀ copies/mL (primary endpoint) was observed in 88% (21/24) of patients receiving lenacapavir and 17% (2/12) of patients receiving placebo. At Week 26, viral suppression to <50 copies/mL was observed in 81% (29/36) of patients receiving lenacapavir vs 83% (30/36) of patients receiving placebo.

Resistance
Although lenacapavir was evaluated in PWH with extensive drug resistance, these patients are at highest risk of nonadherence and subsequent treatment failure. Of the 72 patients evaluated in the CAPELLA trial, 21 underwent resistance testing by Week 52 (cohort 1, n = 11; cohort 2, n = 10). Four patients in cohort 1 and 5 patients in cohort 2 developed lenacapavir-associated capsid substitutions. All 9 patients continued to receive lenacapavir but remain at high risk for emergent resistance due to poor adherence to the optimized background regimen (n = 5) or not having fully active drugs in their optimized background regimen (n = 4).

Drug–Drug Interactions
Just as important as medication adherence is the potential for drug interactions to cause treatment failure. Drug‒drug interactions may reduce lenacapavir concentrations, leading to the development of mutations, and an increased concentration of the drug may increase the risk of adverse events and ultimately medication discontinuation or nonadherence. Although there is no cross-resistance between capsid inhibitors such as lenacapavir and other ARTs with different mechanisms of action, there is still a potential for drug‒drug interactions. Lenacapavir is a substrate of CYP3A, P-gp, and UGT1A1, so other drugs that strongly or moderately induce these enzymes may significantly decrease plasma concentrations of lenacapavir. For this reason, the use of efavirenz, etravirine, nevirapine, or boosted tipranavir is not recommended in patients receiving lenacapavir.

Conclusions
Ultimately, fostemsavir, ibalizumab, and lenacapavir are reserved for PWH experiencing virologic failure with multiclass ART resistance. Like fostemsavir and ibalizumab, lenacapavir is not a complete ART regimen and must be taken with other ARTs. The goal in treatment selection for heavily treatment‒experienced patients should be to create an ART regimen with at least 2 fully active agents. Because lenacapavir is from a new drug class to which a patient’s virus likely has not been exposed, it is a promising component of ART if adherence can be ensured.

Your Thoughts?
If you practice in the European Union or United Kingdom, how are you currently implementing lenacapavir into your clinical practice?