Nationwide Experience of Treatment with Protease Inhibitors in Chronic Hepatitis C Patients in Denmark: Identification of Viral Resistance Mutations

Abstract

Background and AimsThe first standard of care in treatment of chronic HCV genotype 1 infection involving directly acting antivirals was protease inhibitors telaprevir or boceprevir combined with pegylated-interferon and ribavirin (triple therapy). Phase III studies include highly selected patients. Thus, treatment response and development of viral resistance during triple therapy in a routine clinical setting needs to be determined. The aims of this study were to investigate treatment outcome and identify sequence variations after triple therapy in patients with chronic HCV genotype 1 infection in a routine clinical setting.Methods80 patients, who initiated and completed triple therapy in Denmark between May 2011 and November 2012, were included. Demographic data and treatment response were obtained from the Danish Database for Hepatitis B and C. Direct sequencing and clonal analysis of the RT-PCR amplified NS3 protease were performed in patients without cure following triple therapy.Results38 (47%) of the patients achieved cure, 15 (19%) discontinued treatment due to adverse events and remained infected, and 27 (34%) experienced relapse or treatment failure of whom 15 of 21 analyzed patients had well-described protease inhibitor resistance variants detected. Most frequently detected protease variants were V36M and/or R155K, and V36M, in patients with genotype 1a and 1b infection, respectively.ConclusionsThe cure rate after triple therapy in a routine clinical setting was 47%, which is substantially lower than in clinical trials. Resistance variants towards protease inhibitors were seen in 71% of patients failing therapy indicating that resistance could have an important role in treatment response.

Hepatitis C Virus Genotype 1 to 6 Protease Inhibitor Escape Variants: In Vitro Selection, Fitness, and Resistance Patterns in the Context of the Infectious Viral Life Cycle

“…Substitutions at position 18 might influence the positioning of the NS3P active site on the membrane and thus NS3P activity, or they might induce conformational changes influencing interactions with NS4A and/or NS3H. Substitutions might increase HCV fitness across genotypes, since changes at position 18 were observed in genotype (isolate) 1a (TN), 2a (J6), and 5a (SA13) boceprevir escape variants, in treatment-naïve HCV genotype 1 or 4 patients (78), and in HCV genotype 1 patients with linear-PI treatment failure (38,79,80). Further, position 98 is located between two positions coordinating the zinc ion, and changes might influence NS3P stability (9,81,82).…”

Broadening CD4+and CD8+T Cell Responses against Hepatitis C Virus by Vaccination with NS3 Overlapping Peptide Panels in Cross-Priming Liposomes

“…Persistent HCV infection can lead to chronic inflammation of the liver, cirrhosis, liver failure, and liver cancer, ultimately causing 700,000 annual HCV-related deaths (1). Despite the recent breakthrough in HCV therapy with the introduction of direct-acting antivirals (DAAs) resulting in viral clearance rates above 90%, the impact of these drugs on the global disease burden remains unknown, as high prices and development of viral resistance represent important challenges to current treatment strategies (2)(3)(4). Furthermore, successful treatment with DAAs does not prevent HCV reinfection, which is an issue of concern in highly exposed patient groups, such as intravenous drug users (5,6).…”

Mechanisms of Virologic Failure in Hepatitis C and Strategies for Treatment Failure

“…While most RAVs are quickly lost in the absence of DAAs, compensatory mutations may reinforce fitness [3]. In spite of the potent, and highly efficient, novel treatment regimens, response data outside of clinical trials suggest that treatments will fail in approximately 10% to 15% of patients [4]. HCV kinetics in antiviral treatments are typical biphasic.…”