Retreatment of patients who failed glecaprevir/pibrentasvir treatment for hepatitis C virus infection

Abstract

Curative treatment of patients who previously failed hepatitis C virus (HCV) therapies is critical to achieving HCV elimination. Glecaprevir/pibrentasvir (G/P) demonstrated high rates of sustained virologic response at post-treatment week 12 (SVR12) in patients with HCV infection; however, retreatment of patients who failed G/P has yet to be evaluated. MAGELLAN-3 is an ongoing, open-label, phase IIIb trial evaluating the efficacy and safety of G/P plus sofosbuvir (SOF) plus ribavirin (RBV) as a retreatment regimen for patients who had virologic failure with G/P in an AbbVie study. Patients with HCV genotype (GT) 1, 2, 4, 5 or 6 infection, without cirrhosis, and naïve to NS3/4A protease and NS5A inhibitors prior to virologic failure with G/P received 12 weeks of treatment; patients with GT3, and/or compensated cirrhosis, and/or experience with NS3/4A protease and NS5A inhibitors prior to virologic failure with G/P received 16 weeks of treatment. The primary efficacy endpoint was the SVR12 rate. Safety, tolerability, and presence of resistance-associated substitutions (RASs) were assessed. To date, 23 patients enrolled: 30% (7/23), 9% (2/23), and 61% (14/23) of patients had GT1, 2, and 3 infections, respectively; 30% (7/23) of patients had compensated cirrhosis, and 91% (21/23) had baseline RASs in NS5A. The SVR12 rate was 96% (22/23); 1 patient with GT1a infection and compensated cirrhosis had virologic failure. One unrelated serious adverse event (AE) of symptomatic cholelithiasis occurred. There were no treatment discontinuations. Retreatment of G/P virologic failures with G/P plus SOF plus RBV for 12 or 16 weeks was well-tolerated and highly efficacious, regardless of HCV genotype or baseline RASs.

Treatment-failure to direct antiviral HCV regimens in real world: frequency, patient characteristics and rescue therapy – data from the German hepatitis C registry (DHC-R)

“…Previous experience with IFN-containing therapy was significantly more often detectable in patients with virologic failure than in SVR patients (46.3 % versus 39.0 %, respectively). Biochemical, virologic, and histological characteristics and treatment history observed in patients with relapse to DAA-based therapies were similar in previous publications [13,23,24]. In our cohort of patients treated between November 2014 and 2018, only 50.5 % of 188 relapse patients (n = 95) received a second course of DAA combination therapy.…”

Pooled Resistance Analysis in Patients with Hepatitis C Virus Genotype 1 to 6 Infection Treated with Glecaprevir-Pibrentasvir in Phase 2 and 3 Clinical Trials

“…Seventeen of the 22 patients receiving glecaprevir/pibrentasvir who experienced virologic failure in the registrational phase 2 and 3 studies (1 GT1a, 2 GT2a, 13 GT3a, and 1 GT3b infections) were enrolled in the MAGELLAN-3 retreatment study, where the patients received glecaprevir/pibrentasvir plus sofosbuvir plus RBV for 12 or 16 weeks; all achieved SVR12 ( 37 ). The glecaprevir/pibrentasvir regimen has been approved in some countries for the treatment of protease inhibitor-experienced patients without prior experience with an NS5A inhibitor (12-week treatment duration) or of NS5A inhibitor-experienced patients without prior experience with a protease inhibitor (16-week treatment duration) ( 38 ).…”

Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors

“…therapies with direct-acting antivirals (DAAs) against essential viral proteins NS3/4A, NS5A, and NS5B have significantly improved treatment options and outcomes (2)(3)(4)(5) with cure rates of ϳ95% for treatment-naive patients (6)(7)(8)(9)(10)(11)(12). However, even the most recent DAA combinations, still in 2019, fail to cure some patients (4,5,13,14). Especially for DAA-experienced patients, baseline polymorphisms among diverse genotypes and preexisting resistance-associated substitutions (RASs) negatively impact treatment outcomes (3-5, 14, 15).…”