September 21. 2022
Lenacapavir in HIV With Multidrug ResistanceBy Lauren Richey, MD, MPH, FIDSA
Lenacapavir is an inhibitor of the HIV-1 capsid function, and it is the first drug in this class. It interferes with capsid mediated nuclear uptake of preintegration complexes and impairs viral replication at both early and late stages of the life cycle. It is unique in that it can be administered subcutaneously every 6 months or weekly orally. This recent study, published in the New England Journal of Medicine, presents the phase III Capella trial using lenacapavir.
Patients on failing antiretroviral therapy regimens, defined as documented resistance to at least two medicines in three of the major drug classes and no more than two active medications, were enrolled at 42 different sites. Thirty-six patients were enrolled in cohort 1 and 36 in cohort 2. Cohort 1 included those with stable viral load > 400 copies per milliliter and included 15 days of 1:2 randomization, placebo versus lenacapavir, each with their failing background therapy. After the 15 days, all were given lenacapavir plus an optimized backbone. Each group initially received oral lenacapavir, which transitioned to the subcutaneous dosing. Cohort 2 included patients with viral load < 400 copies per milliliter or those who joined after cohort 1 was full; cohort 2 did not include randomization and had oral lenacapavir transitioned to subcutaneous lenacapavir plus optimized backbone. The primary end point was the percentage of patients with a 0.5 log reduction in HIV viral load at day 15 in the randomized cohort 1.
Patients included had highly resistant virus; 47% had resistance to all four classes of medicine. For the primary outcome, 88% of the lenacapavir group had a 0.5 log drop in viral load versus 17% in the control group (P < .001). At 26 weeks, 81% of cohort 1 and 83% of cohort 2 had a viral load < 50 copies per milliliter. A total of 19 patients met the criteria for virologic failure and had a resistance analysis performed. Lenacapavir mutations occurred in eight patients, and despite documented mutations, four resuppressed the virus on lenacapavir. No serious adverse events of grade 3 or higher were reported. Injection site reactions were common (63%) but mild.
While longer term data are needed, this study on lenacapavir shows a promising medication for multidrug-resistant HIV with infrequent dosing and a new mechanism of action.
