Association of Amino Acid Substitution Pattern in Core Protein of Hepatitis C Virus Genotype 1b High Viral Load and Non-Virological Response to Interferon-Ribavirin Combination Therapy

Abstract

Objective: Patients with high titer (≧100 kIU/ml) of hepatitis C virus (HCV) genotype 1b do not achieve highly sustained virological response rates to combination therapy with interferon plus ribavirin. Non-virological responders (NVRs, namely ultimate resistant cases) who do not achieve HCV-RNA negativity during treatment are also encountered. We investigated the pretreatment virological features of NVRs. Methods: We evaluated 50 consecutive Japanese adults with high titer of HCV genotype 1b who received combination therapy for 48 weeks. We investigated the pretreatment substitution patterns in amino acids 1–191 of the core region and amino acids 2209–2248 of NS5A, and early viral kinetics. Results: Overall, a non-virological response was noted in 12 (24%) patients. Multivariate analysis identified serum albumin <3.9 g/dl, substitutions of amino acid 70 in the core region, and substitutions of amino acid 91 as independent and significant factors associated with a non-virological response. Especially, substitutions of arginine (R) by glutamine (Q) at amino acid 70, and/or leucine (L) by methionine (M) at amino acid 91 were significantly more common in NVRs. The falls in HCV-RNA levels during treatment in patients with specific substitutions in the core region were significantly less than in those without such substitutions. Conclusions: Our results suggest that serum albumin and amino acid substitution patterns in the core region in patients with high titers of HCV genotype 1b may have an effect on combination therapy in NVRs. Further large-scale studies are required to examine the role of amino acid substitutions specific to a non-virological response to combination therapy.

Efficacy and Safety of Combination Therapy of Natural Human Interferon Beta and Ribavirin in Chronic Hepatitis C patients

“…The result shows that patients with mutant type of core aa 70 have the possibility of getting SVR. Several authors have reported that virus clearance in combination therapy of peginterferon-alpha and ribavirin is associated with HCV mutations in the core region and IL-28B (21)(22)(23)(24)(25)(26). The present study confirmed that IL-28B was related with SVR for HCV patients with genotype 1b and high virus load.…”

“…HCV-genotype was examined by polymerized chain reaction assay, using a mixture of primers for the six subtypes known to exist in Japan, as reported previously (20). The core protein of HCV-1b was determined by the previous report (21). Next, the genetic variations near the IL28B gene (rs8099917), reported as the pretreatment predictors of treatment efficacy and clinical outcome, were investigated (22)(23)(24)(25)(26).…”

Predictive factors of virological non‐response to interferon–ribavirin combination therapy for patients infected with hepatitis C virus of genotype1b and high viral load

“…Especially, substitutions of arginine (R) by glutamine (Q) at aa 70, and/or leucine (L) by methionine (M) at aa 91 were significantly more common in virological nonresponders. Decline of HCV-RNA levels during treatment in patients with specific substitutions in the core region was significantly less than in those without such substitutions [Akuta et al, 2005b].…”

“…Virological non-responders who could not or could achieve a log decline of more than 2 from baseline of HCV RNA based on quantitative PCR analyses during the initial 24 weeks of combination therapy, were defined as absolute virological non-responders or relative virological non-responders, respectively. Applying multivariate analysis, previous studies identified substitutions of aa 70 in the core region and substitutions of aa 91 as independent and significant pretreatment factors associated with virological nonresponse to combination therapy in patients with high viral load of genotype 1b [Akuta et al, 2005b]. Therefore, based on the larger numbers of patients, a case-control study was conducted to compare the substitution patterns in aa 70 and/or aa 91 of the core region, between virological non-responders and virological responders who were matched for age, sex, genotype, and viral load, in the present study.…”

“…Using multivariate analysis, Akuta et al [2005b] identified hypoalbuminemia, pretreatment substitutions of amino acid (aa) 70 in the core region and pretreatment substitutions of aa 91 as independent and significant pretreatment factors associated with virological non-response, based on 48-week combination therapy of IFN plus ribavirin [Akuta et al, 2005b]. Especially, substitutions of arginine (R) by glutamine (Q) at aa 70, and/or leucine (L) by methionine (M) at aa 91 were significantly more common in virological nonresponders.…”