• Sorana Segal-Maurer, Edwin DeJesus, Hans-Jurgen Stellbrink, Antonella Castagna, Gary J Richmond, Gary I Sinclair, Krittaecho Siripassorn, Peter J Ruane, Mezgebe Berhe, Hui Wang, Nicolas A Margot, Hadas Dvory-Sobol, Robert H Hyland, Diana M Brainard, Martin S Rhee, Jared M Baeten, Jean-Michel Molina, and CAPELLA Study Investigators.
• From NewYork-Presbyterian Queens, Flushing, NY (S.S.-M.); Orlando Immunology Center, Orlando (E.D.), and Fort Lauderdale (G.J.R.) - both in Florida; Infektionsmedizinisches Centrum Hamburg, Hamburg, Germany (H.-J.S.); Vita-Salute University, San Raffaele Scientific Institute, Milan (A.C.); Prism Health North Texas (G.I.S.) and North Texas Infectious Diseases Consultants (M.B.) - both in Dallas; Bamrasnaradura Infectious Diseases Institute, Nonthaburi, Thailand (K.S.); Ruane Clinical Research Group, Los Angeles (P.J.R.), and Gilead Sciences, Foster City (H.W., N.A.M., H.D.-S., R.H.H., D.M.B., M.S.R., J.M.B.) - both in California; the University of Paris and the Department of Infectious Diseases, St. Louis-Lariboisière Hospitals, Assistance Publique-Hôpitaux de Paris, Paris (J.-M.M.); and AlloVir, Cambridge, MA (D.M.B.).
• N. Engl. J. Med. 2022 May 12; 386 (19): 1793-1803.

BackgroundPatients with multidrug-resistant human immunodeficiency virus type 1 (HIV-1) infection have limited treatment options. Lenacapavir is a first-in-class capsid inhibitor that showed substantial antiviral activity in a phase 1b study.MethodsIn this phase 3 trial, we enrolled patients with multidrug-resistant HIV-1 infection in two cohorts, according to the change in the plasma HIV-1 RNA level between the screening and cohort-selection visits. In cohort 1, patients were first randomly assigned in a 2:1 ratio to receive oral lenacapavir or placebo in addition to their failing therapy for 14 days; during the maintenance period, starting on day 15, patients in the lenacapavir group received subcutaneous lenacapavir once every 6 months, and those in the placebo group received oral lenacapavir, followed by subcutaneous lenacapavir; both groups also received optimized background therapy. In cohort 2, all the patients received open-label oral lenacapavir with optimized background therapy on days 1 through 14; subcutaneous lenacapavir was then administered once every 6 months starting on day 15. The primary end point was the percentage of patients in cohort 1 who had a decrease of at least 0.5 log10 copies per milliliter in the viral load by day 15; a key secondary end point was a viral load of less than 50 copies per milliliter at week 26.ResultsA total of 72 patients were enrolled, with 36 in each cohort. In cohort 1, a decrease of at least 0.5 log10 copies per milliliter in the viral load by day 15 was observed in 21 of 24 patients (88%) in the lenacapavir group and in 2 of 12 patients (17%) in the placebo group (absolute difference, 71 percentage points; 95% confidence interval, 35 to 90). At week 26, a viral load of less than 50 copies per milliliter was reported in 81% of the patients in cohort 1 and in 83% in cohort 2, with a least-squares mean increase in the CD4+ count of 75 and 104 cells per cubic millimeter, respectively. No serious adverse events related to lenacapavir were identified. In both cohorts, lenacapavir-related capsid substitutions that were associated with decreased susceptibility developed in 8 patients during the maintenance period (6 with M66I substitutions).ConclusionsIn 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. (Funded by Gilead Sciences; CAPELLA ClinicalTrials.gov number, NCT04150068.).Copyright © 2022 Massachusetts Medical Society.

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