Hadas Dvory-Sobol

Background: Lenacapavir is a twice-yearly HIV-1 capsid inhibitor approved, in combination with other antiretrovirals, for the treatment of heavily treatment-experienced people with multidrug-resistant HIV, based on the Phase 2/3 CAPELLA study. Here, we report week 156 efficacy and safety results. Methods: In CAPELLA (NCT04150068), participants received 2-week oral lenacapavir lead-in doses, followed by subcutaneous lenacapavir every 6 months, combined with an investigator-selected optimized background regimen. Endpoints included virologic outcomes, CD4 cell count trends, adverse events, and treatment-emergent resistance. Results: CAPELLA enrolled 72 participants: 25% female; 38% Black; median age, 52 years; CD4 cell count <200 cells/μL, 64% (<50 cells/μL, 22%). At week 156, 61% (43/70) had HIV RNA <50 copies/mL by FDA Snapshot Algorithm, 16% (11/70) had ≥50 copies/mL, and 23% (16/70) had missing data; by missing = excluded analysis, 85% (44/52) had HIV RNA <50 copies/mL. Mean CD4 cell count increase from baseline to week 156 was 164 cells/μL (95% CI: 116–211). Through week 156, 14/72 participants developed emergent LEN resistance. Injection site reactions were mostly Grade 1/2, and frequency declined over time. Through week 156, two participants discontinued lenacapavir due to Grade 1 injection site nodules. Conclusions: Lenacapavir plus an optimized background antiretroviral regimen maintained a high rate of virologic suppression at week 156 with continued increases in CD4 counts. Lenacapavir was well tolerated with a favorable safety profile and very low rates of lenacapavir discontinuation. These data demonstrate longer-term efficacy and safety of lenacapavir for heavily treatment-experienced people with multidrug-resistant HIV.

Purpose of review: This review summarizes available data for lenacapavir, an investigational first-in-class agent that disrupts functioning of HIV capsid protein across multiple steps in the viral life cycle. Recent findings: Lenacapavir demonstrated picomolar potency in vitro with no cross resistance to existing antiretroviral classes and potent antiviral activity in persons with HIV-1. In persons with HIV-1, there was no preexisting resistance to lenacapavir regardless of treatment history. Lenacapavir can be administered orally either daily or weekly and subcutaneously up to every 6 months. In heavily treatment-experienced persons with multidrug-resistant HIV-1 and in treatment-naive persons with HIV-1, lenacapavir in combination with other antiretroviral agents led to high rates of virologic suppression and was well tolerated. Summary: Ongoing studies are evaluating long-acting dosing of lenacapavir for treating HIV-1 in combination with other antiretrovirals and preventing HIV-1 as a single agent.

Velpatasvir is a pan‐genotypic hepatitis C virus (HCV) NS5A inhibitor, which is used with sofosbuvir for treatment of infection with HCV genotypes 1‐6. In vitro resistance studies were performed to characterize NS5A changes that might confer reduced velpatasvir susceptibility in vivo. Resistance selection studies using HCV replicon cells for subtypes 1a, 1b, 2a, 2b, 3a, 4a, 5a and 6a identified NS5A resistance‐associated substitutions (RASs) at nine positions, most often 28M/S/T, 31F/I/M/P/V and 93D/H/N/S. In subtype 1a, RASs were selected at positions 31 and/or 93, while in subtype 1b, replicons with two or more RASs at positions 31, 54 or 93 were selected. Y93H was selected in subtypes 1a, 1b, 2a, 3a and 4a. In subtype 5a or 6a, L31P or P32L/Q was selected, respectively. Velpatasvir susceptibility of 358 replicons from genotypes 1 to 6 containing one or more NS5A RASs was also evaluated. The majority (63%) of subtypes 1a and 1b single RAS‐containing replicons retained susceptibility to velpatasvir (50). High levels of resistance to velpatasvir were observed for six single mutants in subtype 1a, including M28G, A92K, Y93H/N/R/W and for one mutant, A92K, in subtype 1b. Most single mutants in subtypes 2a, 2b, 3a, 4a and 5a displayed low levels of reduced velpatasvir susceptibility. High‐level resistance was observed for C92T and Y93H/N in subtype 2b, Y93H/S in 3a, and L31V and P32A/L/Q/R in 6a, and several double mutants in these subtypes. Overall, velpatasvir maintained activity against most common RASs that are known to confer resistance to first‐generation NS5A inhibitors.

Voxilaprevir is a direct-acting antiviral agent (DAA) that targets the NS3/4A protease of hepatitis C virus (HCV). High sequence diversity of HCV and inadequate drug exposure during unsuccessful treatment may lead to the accumulation of variants with reduced susceptibility to DAAs including NS3/4A protease inhibitors such as voxilaprevir. The voxilaprevir susceptibility of clinical and laboratory strains of HCV was assessed. The NS3 protease regions of viruses belonging to 6 genotypes and 29 subtypes from 345 DAA-naïve or -experienced (including protease inhibitor) patients, and 344 genotype 1 to 6 replicons bearing engineered NS3 resistance-associated substitutions (RASs) were tested in transient transfection assays. Median voxilaprevir EC₅₀ against NS3 from protease inhibitor-naïve patient samples ranged from 0.38 nM for genotype 1, to 5.8 nM for genotype 3. Voxilaprevir susceptibilities of HCV replicons with NS3 RASs were dependent on subtype background and the type and number of substitutions introduced. The majority of RASs known to confer resistance to other protease inhibitors had little to no impact on voxilaprevir susceptibility, except A156L, T or V in genotype 1 to 4 which conferred >100-fold reductions but exhibited low replication capacity in most genotypes. These data support the use of voxilaprevir in combination with other DAAs in DAA-naïve and DAA-experienced patients infected with any subtype of HCV.