Reappraisal of the importance of mutations in the NS5A-PKR-binding domain of hepatitis C-1b virus in the era of optimally individualized therapy

Abstract

Past studies have reported that mutations in the protein kinase R-binding domain (PKRBD) sequences of hepatitis C virus (HCV) NS5A proteins are correlated with response to fixed-duration interferon (IFN)-based therapy in patients infected with HCV-1b. In this study, we investigated whether the substitutions in PKRBD, including the IFN sensitivity-determining region (ISDR) and 26 additional downstream amino acids from ISDR, will have effects upon patients infected with chronic HCV-1b in the era of individualized therapy with peginterferon and ribavirin. Thirty-seven patients were treated with optimally tailored therapy guided by baseline viral load combined with rapid and early virological responses while 23 patients were treated without guidance and/or assigned suboptimal treatment duration. The amino acid sequences of the PKRBD were determined by PCR and sequencing. The overall sustained virological response (SVR) rate of patients who received optimally individualized therapy was 78.4%, which was better than the SVR rate of patients who received suboptimal therapy (47.8%, P = 0.015). Multivariate analysis showed that optimally individualized therapy (P = 0.019) and 80/80/80 adherence (P = 0.006) were independent favourable predictors of SVR in the entire cohort. Further sub-analysis of the predictive factors of SVR in patients treated with optimally individualized therapy showed that mutations in the 26-amino acid downstream from the ISDR (P = 0.024) were the only independent predictor of SVR. We concluded that mutations in 26-amino acid downstream portion from the ISDR remained a prognosticator of SVR in the era of optimally tailored therapy.

Correlation between mutations in the core and NS5A genes of hepatitis C virus genotypes 1a, 1b, 3a, 3b, 6f and the response to pegylated interferon and ribavirin combination therapy

“…According to Enomoto’s studies [8,9], a high number of aa mutations in the ISDR of HCV‐1b correlated with the response to IFN monotherapy. Most recently, additional studies conducted in Japan [23] and Taiwan [24] have provided more data to support this notion. However, contradictory data have been reported from European and United States investigators [25–27].…”

The impact of hepatitis C virus outside the liver: Evidence from Asia

“…Numerous studies have demonstrated the link between different forms of non‐adherence (missing doses, early discontinuation of a regimen, interruptions during a regimen etc.) and lower SVR rates in both Western and Asian CHC patients treated with IFN+RBV‐containing regimens …”

Treatment adherence and virological response rates in hepatitis C virus infected persons treated with sofosbuvir‐based regimens: results from ERCHIVES

“…With older interferon based treatment regimens, adherence to treatment was strongly linked to treatment success in HCV infected persons. The 80/80/80 rule, indicating >80% of the cumulative dose of pegylated interferon (PEG) alfa and >80% of the cumulative dose of ribavirin (RBV) taken for >80% of the duration of a prescribed course, was associated with higher SVR in those treated with older PEG plus RBV regimens as well as those treated with these plus either boceprevir or telaprevir . Non‐completion of a full course of prescribed treatment, whether because of non‐adherence, treatment futility or other reasons, is also associated with significantly lower SVR in HCV infected persons .…”