Efficacy and Safety of Long-Acting Subcutaneous Lenacapavir in Heavily Treatment-Experienced People with Multi-Drug Resistant HIV-1: Week 104 Results of a Phase 2/3 Trial.

Background: Lenacapavir is a long-acting HIV-1 capsid inhibitor for treatment of HIV-1 infection. We evaluated the efficacy and safety of lenacapavir in combination with an investigator-selected optimized background regimen (OBR) after 104 weeks in adults with multidrug-resistant HIV-1.

Methods: This ongoing, international, Phase 2/3 trial at 42 sites included 72 adults living with multidrug-resistant HIV-1.

Efficacy and safety of the novel capsid inhibitor lenacapavir to treat multidrug-resistant HIV: week 52 results of a phase 2/3 trial.

Background: Lenacapavir, a first-in-class HIV-1 capsid inhibitor, is in development as a long-acting agent for treating and preventing HIV-1. We aimed to evaluate the efficacy and safety of lenacapavir with an optimised background regimen in adults living with multidrug-resistant HIV-1 up to 52 weeks.

Methods: This ongoing, international, phase 2/3 trial at 42 sites included adults living with multidrug-resistant HIV-1.

Lenacapavir administered every 26 weeks or daily in combination with oral daily antiretroviral therapy for initial treatment of HIV: a randomised, open-label, active-controlled, phase 2 trial.

Background: Antiretroviral agents with novel mechanisms and dosing intervals could expand treatment options for people with HIV. Lenacapavir, an inhibitor of capsid protein that makes use of a unique mechanism, can be administered orally or subcutaneously. We sought to explore the efficacy of lenacapavir in various combination regimens as initial and maintenance therapy for HIV.

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

Background: Lenacapavir (LEN) is a first-in-class inhibitor of human immunodeficiency virus type 1 (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 (ARV) classes and resistance to ≥2 ARV drugs per class.

Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection.

Background: Patients 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.

Methods: In 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.

Lenacapavir: a first-in-class HIV-1 capsid inhibitor.

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.

Ledipasvir/Sofosbuvir for 8, 12, or 24 Weeks in Hepatitis C Patients Undergoing Dialysis for End-Stage Renal Disease.

Introduction: We evaluated 8, 12, or 24 weeks of ledipasvir/sofosbuvir in patients with hepatitis C virus and end-stage renal disease undergoing dialysis.

Methods: Primary efficacy end point was sustained virologic response 12 weeks after treatment. Primary safety end point was treatment discontinuation because of adverse events (AEs).

Twelve weeks of ledipasvir/sofosbuvir all-oral regimen for patients with chronic hepatitis C genotype 2 infection: Integrated analysis of three clinical trials.

Aim: The combination of ledipasvir and sofosbuvir (LDV/SOF) has been approved for the treatment of various hepatitis C virus (HCV) genotypes across many countries. This article presents an integrated analysis of three prospective phase II/III trials in the Asia-Pacific region to evaluate the efficacy and safety of 12 weeks of LDV/SOF in HCV genotype 2 patients without cirrhosis or with compensated cirrhosis.

Methods: A total of 200 patients were included in the integrated analysis.

Sofosbuvir susceptibility of genotype 1 to 6 HCV from DAA-naïve subjects.

High sequence diversity of HCV may lead to variation in susceptibility to antiviral agents amongst different genotypes and subtypes of the virus. We assessed the susceptibility to sofosbuvir of chimeric replicons carrying the full length NS5B coding region from 479 HCV infected, treatment-naïve patients, including 15 subtypes in 6 genotypes. NS5B replicon vectors with subtype 1b, subtype 4a and subtype 6a backbone were modified to support testing of patient samples.

Sofosbuvir/velpatasvir for 12 weeks in hepatitis C virus-infected patients with end-stage renal disease undergoing dialysis.

Background & Aims: Although off-label use of sofosbuvir-containing regimens occurs regularly in patients with hepatitis C virus (HCV) infection undergoing dialysis for severe renal impairment or end-stage renal disease (ESRD), these regimens are not licensed for this indication, and there is an absence of dosing recommendations in this population. This study evaluated the safety and efficacy of sofosbuvir/velpatasvir in patients with HCV infection with ESRD undergoing dialysis.

Methods: In this phase II, single-arm study, 59 patients with genotype 1-6 HCV infection with ESRD undergoing hemodialysis or peritoneal dialysis received open-label sofosbuvir/velpatasvir (400 mg/100 mg) once daily for 12 weeks.

In vitro resistance profile of hepatitis C virus NS5A inhibitor velpatasvir in genotypes 1 to 6.

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.

Susceptibility of Hepatitis C Virus Genotype 1 through 6 Clinical Isolates to the Pangenotypic NS3/4A Inhibitor Voxilaprevir.

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.

Sofosbuvir/Velpatasvir/Voxilaprevir for patients with HCV who previously received a Sofosbuvir/Velpatasvir-containing regimen: Results from a retreatment study.

This study evaluated 12-week retreatment with sofosbuvir/velpatasvir/voxilaprevir in patients with chronic hepatitis C virus (HCV) infection who did not achieve sustained virologic response after previous treatment with a sofosbuvir- and velpatasvir-containing regimen. All 31 patients maintained a sustained virologic response 12 weeks after the last sofosbuvir/velpatasvir/voxilaprevir dose.

Sofosbuvir-velpatasvir for treatment of chronic hepatitis C virus infection in Asia: a single-arm, open-label, phase 3 trial.

Background: Treatment with combined sofosbuvir and velpatasvir has resulted in high sustained virological response rates in patients chronically infected with hepatitis C virus (HCV) with genotypes 1-6 in clinical trials and real-world settings, but its efficacy and safety has not been assessed in Asia, a region with diverse HCV genotypes.

Methods: In this single-arm, open-label, phase 3 trial, we recruited patients from 38 sites across China, Thailand, Vietnam, Singapore, and Malaysia, who were chronically infected with HCV genotypes 1-6, and were HCV treatment-naive or treatment-experienced, either without cirrhosis or with compensated cirrhosis. Patients self-administered a combined sofosbuvir (400 mg) and velpatasvir (100 mg) tablet once daily for 12 weeks.

Efficacy and safety of sofosbuvir-velpatasvir with or without ribavirin in HCV-infected Japanese patients with decompensated cirrhosis: an open-label phase 3 trial.

Background: In Japan, hepatitis C virus (HCV)-infected patients with decompensated cirrhosis currently have no treatment options. In this Phase 3 study, we evaluated sofosbuvir-velpatasvir with or without ribavirin for 12 weeks in patients with any HCV genotype and decompensated cirrhosis [Child-Pugh-Turcotte (CPT) class B or C] in Japan.

Methods: Patients were randomized 1:1 to receive sofosbuvir-velpatasvir with or without ribavirin for 12 weeks.

No impact of resistance-associated substitutions on the efficacy of sofosbuvir, velpatasvir, and voxilaprevir for 12 weeks in HCV DAA-experienced patients.

Background & Aims: In phase III studies, the fixed dose combination of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) administered for 12 weeks led to a sustained virologic response at 12 weeks (SVR12) in 96% of NS5A inhibitor-experienced patients, and an SVR12 rate of 98% in DAA-experienced patients who had not previously received an NS5A inhibitor. Herein, we evaluate the relationship between the presence of detectable resistance-associated substitutions (RASs) at baseline and treatment outcome, and whether RASs were selected for in cases of virologic failure.

Methods: NS3, NS5A, and NS5B deep sequencing analyses were performed at baseline for all patients and at the time of virologic failure.

Deferred treatment with sofosbuvir-velpatasvir-voxilaprevir for patients with chronic hepatitis C virus who were previously treated with an NS5A inhibitor: an open-label substudy of POLARIS-1.

Background: Direct-acting antiviral regimens containing NS5A inhibitors are highly effective treatments for chronic hepatitis C virus (HCV) infection, but are not always successful. In the POLARIS-1 phase 3 study, sofosbuvir-velpatasvir-voxilaprevir for 12 weeks was highly effective in the treatment of chronic HCV infection in patients previously treated with a direct-acting antiviral regimen containing an NS5A inhibitor. We aimed to assess the efficacy and safety of sofosbuvir-velpatasvir-voxilaprevir in patients from the deferred treatment group of POLARIS-1, who were initially assigned to masked placebo treatment.

The emergence of NS5B resistance associated substitution S282T after sofosbuvir-based treatment.

S282T in NS5B is the primary amino acid substitution associated with resistance to sofosbuvir (SOF) but has rarely been detected in patients treated with a SOF-based regimen. Here, the emergence and fitness of the S282T substitution in virologic failure patients administered SOF-based regimens across the SOF and ledipasvir (LDV)/SOF phase 2 and 3 programs was evaluated. Plasma samples collected at baseline and at virologic failure were amplified and deep sequenced (1% cutoff).

Ledipasvir-sofosbuvir for treating Japanese patients with chronic hepatitis C virus genotype 2 infection.

Background & Aims: Japanese patients with chronic hepatitis C virus (HCV) genotype 2 infection have high rates of sustained virological response (SVR) following 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir in combination with ribavirin, which was the standard of care at the time this study was undertaken. We assessed the efficacy of 12 weeks of treatment with a ribavirin-free regimen of ledipasvir-sofosbuvir.

Methods: In an open-label, Phase 3 trial we enrolled Japanese patients with chronic HCV genotype 2 infection, with or without compensated cirrhosis.

Resistance analysis in patients with genotype 1-6 HCV infection treated with sofosbuvir/velpatasvir in the phase III studies.

Background & Aims: The fixed-dose combination of sofosbuvir/velpatasvir was highly efficacious in patients infected with genotype (GT)1-6 hepatitis C virus (HCV) in the ASTRAL studies. This analysis evaluated the impact of baseline resistance-associated substitutions (RASs) on treatment outcome and emergence of RASs in patients infected with HCV GT1-6 who were treated with sofosbuvir/velpatasvir.

Methods: Non-structural protein 5A and 5B (NS5A and NS5B) deep sequencing was performed at baseline and at the time of relapse for all patients treated with sofosbuvir/velpatasvir for 12 weeks (n = 1,778) in the ASTRAL-1-3, ASTRAL-5 and POLARIS-2-3 studies.

Establishment of robust HCV genotype 4d, 5a, and 6a replicon systems.

Hepatitis C Virus (HCV) is a diverse human pathogen which displays ~15% divergence at the subtype level. To facilitate development of antivirals with pan-genotype activity, we developed the first genotype 4d subgenomic replicon, as well as new replicons for genotypes 5a, and 6a. Adaptive mutations developed in these replicons differ greatly across genotypes.

Long-term persistence of HCV NS5A resistance-associated substitutions after treatment with the HCV NS5A inhibitor, ledipasvir, without sofosbuvir.

Background: Data on persistence of NS5A resistance-associated substitutions (RASs) may have implications for resistance testing approaches and selection of initial and retreatment strategies.

Methods: Long-term persistence of NS5A RASs in HCV genotype (GT) 1 infected subjects (n=76) who did not achieve sustained virological response after receiving ledipasvir (LDV) without sofosbuvir (SOF) and were subsequently enrolled in an ongoing 3-year follow-up registry study was investigated by population or deep sequencing.

Results: Of the 76 subjects enrolled, 67 and 9 subjects had GT1a and GT1b infection, respectively.