Sequence variation in hepatitis C virus nonstructural protein 5A predicts clinical outcome of pegylated interferon/ribavirin combination therapy†

Abstract

A substantial proportion of hepatitis C virus (HCV)-1b-infected patients still do not respond to interferon-based therapy. This study aims to explore a predictive marker for the ultimate virological response of HCV-1b-infected patients treated with pegylated interferon/ribavirin (PEG-IFN/RBV) combination therapy. Nonstructural protein 5A (NS5A) sequences of HCV in the pretreated sera of 45 patients infected with HCV-1b were analyzed. The mean number of mutations in the variable region 3 (V3) plus its upstream flanking region of NS5A (amino acid 2334-2379), referred to as IFN/RBV resistance-determining region (IRRDR), was significantly higher for HCV isolates obtained from patients who later achieved sustained virological response (SVR) by PEG-IFN/RBV than for those in patients undergoing non-SVR. The receiver operating characteristic curve analysis estimated six mutations in IRRDR as the optimal threshold for SVR prediction. Indeed, 16 (76%) of 21 SVR, but only 2 (8%) of 24 non-SVR, had HCV with six or more mutations in IRRDR (IRRDR > 6) (P < 0.0001). All of 18 patients infected with HCV of IRRDR of 6 or greater examined showed a significant (>1 log) reduction or disappearance of serum HCV core antigen titers within 24 hours after initial dose of PEG-IFN/RBV, whereas 10 (37%) of 27 patients with HCV of IRRDR of 5 or less did (P < 0.0001). The positive predictive value of IRRDR of 6 or greater for SVR was 89% (16/18; P ‫؍‬ 0.0007), with its negative predictive value for non-SVR being 81% (22/27; P ‫؍‬ 0.0008). Conclusion: A high degree (>6) of sequence variation in IRRDR would be a useful marker for predicting SVR, whereas a less diverse (<5) IRRDR sequence predicts non-SVR. (HEPATOLOGY 2008;48:38-47.) H epatitis C virus (HCV) infection is the major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma in industrialized countries. However, HCV infection is curable, and its complications can be prevented by antiviral therapy. 1,2 Currently, the most effective treatment of chronic HCV infection is based on a combination of pegylated interferon (PEG-IFN) and ribavirin (RBV). 3 Even with this treatment regimen, however, sustained virological response (SVR) rates for those infected with the most resistant genotypes, HCV-1a and HCV-1b, still hover at approximately 50%. 3,4 Considering the high cost and the significant side effects associated with this combination therapy, it is worthy to identify patients most likely to benefit from therapy. 5 Predictors of IFN-based therapy can be classified into two categories, pretreatment and on-treatment factors. Pretreatment factors comprise host factors, such as age, sex, obesity, ethanol consumption, hepatic iron overload, fibrosis, immune responses, and coinfection with other viruses, and viral factors, which mainly include viral genotypes and viral load. On-treatment factors are mainly related to the viral kinetics within

Response of Hepatitis C Virus to Long-Term Passage in the Presence of Alpha Interferon: Multiple Mutations and a Common Phenotype

“…1). The "low" lineage was further passaged in the presence of IFN-␣, with the concentration increased by 1 IU/ml after passages 45,55,60,65,70,80,85,90, and 95, reaching a final IFN-␣ concentration of 10 IU/ml (Fig. 1A).…”

Identification of Genotype 2 HCV in Serotype-1 Hepatitis C Patients Unresponsive to Daclatasvir plus Asunaprevir Treatment

“…HCV serotype (Tanaka et al 1994) and genotype (Okamoto et al 1996;Ohno et al 1997) were determined as described previously. The NS5A RAVs were tested with a commercial-based DS method targeting genotype 1b HCV (El-Shamy et al 2008;Suzuki et al 2012;Kudoh et al 2015) or a commercial-based PCR-invader method (Tadokoro et al 2014).…”

Viral Factors Associated with Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection

“…The extended ISDR, including PKRBD (2209-2274) and V3 (2356-2379), has therefore been tested. In 2007, IFN RBV resistancedetermining region (IRRDR) (2334-2376) was identified as a factor involved in response to PEG-IFN plus RBV therapy for HCV G1b [41]. A high degree (≥ 6) of sequence variation in IRRDR was thought to be a useful marker for predicting SVR, whereas a less diverse (≤ 5) IRRDR sequence predicted non-SVR.…”

“…Substitution of aa 2356 in HCV G1b and 2368 in HCV G1a were noted as markers of prognosis in IFN-based therapy on meta-analysis [44]. In contrast, aa substitution at particular positions within IRRDR was reported not to affect the outcome of PEG-IFN plus RBV therapy [41]. Therefore, the significance of IRRDR is uncertain.…”