Resistance Analyses in Highly Treatment-Experienced People With Human Immunodeficiency Virus (HIV) Treated With the Novel Capsid HIV Inhibitor Lenacapavir

Abstract

Background Lenacapavir is a first-in-class inhibitor of HIV-1 capsid function in clinical development for the treatment of heavily treatment-experienced (HTE) people with HIV (PWH) harboring multidrug resistance (MDR) in combination with an optimized background regimen (OBR). Here we describe resistance analyses conducted in the pivotal phase 2/3 CAPELLA study. Methods CAPELLA enrolled viremic HTE PWH with resistance to ≥ 3 of 4 of the main antiretroviral classes and resistance to ≥ 2 ARV drugs per class. Baseline resistance analyses used commercial assays (HIV-1 protease, RT, integrase genotypic/phenotypic tests). Post-baseline resistance was evaluated in participants experiencing virologic failure. Results At baseline, 46% of participants had resistance to the 4 main ARV drug classes, with one third of participants having exhausted all drugs from ≥ 3 of the 4 main ARV classes. Treatment with LEN + OBR for 26 weeks led to viral suppression in 81% of participants. Post-baseline resistance mutations to lenacapavir occurred in 8 participants (6 with M66I, 1 with K70H, 1 with Q67H + K70R) who were receiving unintended functional LEN monotherapy at the time of resistance selection. Conclusions LEN added to OBR led to high efficacy in this HTE patient population with MDR but could select for resistance when used unintentionally as functional monotherapy.

Discovery and Mechanistic Investigation of Piperazinone Phenylalanine Derivatives with Terminal Indole or Benzene Ring as Novel HIV-1 Capsid Modulators

“…Extensive decoration of the PF74 skeleton by Gilead Sciences generated lenacapavir (LEN; GS-6207), which has picomolar anti-HIV-1 activity (EC 50 = 105 pM), favorable metabolic stability, and is approved by the European Community (EC) [ 27 ]. Nevertheless, limited by its complicated structure and labor-intensive synthesis, LEN displays extremely poor water solubility, resulting in mainly injectable use, and drug-resistant strains have also already appeared in clinical trials [ 28 ]. Further structural optimization of PF74 to identify novel CA modulators is needed to address these inadequacies.…”

Future of Antiretroviral Drugs and Evolution of HIV-1 Drug Resistance

“…Thus, the capsid inhibitor lenacapavir (LEN) is administered subcutaneously (sc) every six months. The recent CALIBRATE trial showed the non-inferiority of sc LEN, combined with two oral daily ARV, in ARV-naïve patients [ 1 ], and the CAPELLA trial showed a high percentage of virological response of LEN in combination with an optimized background regimen; in patients with virological failure and multidrug-resistant viruses, 86% of them achieved a plasma viral load < 200 c/mL at week 52 [ 2 ]. The NNRTI rilpivirine (RPV) and the integrase strand-transfer inhibitor (INSTI) cabotegravir (CAB) have also been developed in a long-acting form.…”

“…Indeed, protease inhibitors mutations can be accompanied by selection of mutations in the gag cleavage sites. Resistance analyses performed in the randomized controlled phase 3 trials showed the emergence of resistance mutations in case of VF in 2/157 patients in the CALIBRATE trial, including ARV-naïve patients, and in 8/72 in the CAPELLA trial including patients with MDR viruses [ 1 , 2 ]. These data suggest a low genetic barrier to resistance of LEN, and a 2nd generation of capsid inhibitors will probably be needed to improve genetic barrier to resistance.…”

Discovery, Crystallographic Studies, and Mechanistic Investigations of Novel Phenylalanine Derivatives Bearing a Quinazolin-4-one Scaffold as Potent HIV Capsid Modulators

“…Despite PF74’s unique antiviral profiles, its poor antiviral activity (EC 50 = 0.87 μM, MT-4 cells) and metabolic instability have hindered further studies . Lenacapavir (LEN, Figure ), a multi-round iterative modification of PF74 by Gilead Science, has picomolar-level anti-HIV activity (EC 50 = 105 pM, MT-4 cells) and excellent metabolic stability and is the first FDA-approved HIV-1 CA inhibitor. , However, resistant strains insensitive to LEN have emerged during clinical trials and in vitro screening, and its complex synthesis and high administration costs have limited its clinical application. , Therefore, the challenge remains to discover new structural types of HIV-1 CA modulators that can be seamlessly integrated into current cART regimens.…”