Prediction of Efficient Virological Response to Pegylated Interferon/Ribavirin Combination Therapy by NS5A Sequences of Hepatitis C Virus and Anti‐NS5A Antibodies in Pre‐Treatment Sera

Abstract

A considerable number of patients infected with Hepatitis C virus subtype 1b (HCV‐1b) do not respond to pegylated interferon/ribavirin combination therapy. In this study we explored a useful factor(s) to predict treatment outcome. A total of 47 HCV‐1b‐infected patients were treated with pegylated interferon/ribavirin for 48 weeks. Sera of the patients were examined for the entire NS5A sequence of the HCV genome, HCV RNA titers and anti‐NS5A antibodies. According to their responses, the patients were divided into two groups, early viral responders who cleared the virus by week 16 (EVR[16w]) and those who did not (Non‐EVR[16w]). The mean number of mutations in the V3 region (aa 2356 to 2379) or that in the V3 region plus its N‐terminally flanking region, which we refer to as interferon/ribavirin resistance‐determining region (IRRDR; aa 2334 to 2379), of NS5A obtained from the pretreatment sera was significantly larger for EVR(16w) compared with Non‐EVR(16w). Moreover, HCV‐1b isolates with ≥5 mutations in V3 or those with ≥6 mutations in IRRDR were almost exclusively found in EVR(16w). Also, the presence of detectable levels of anti‐NS5A antibodies in the pretreatment sera was closely associated with EVR(16w). In conclusion, a high degree of sequence variation in V3 (≥5) or IRRDR (≥6) and the presence of detectable levels of anti‐NS5A antibodies in the pretreatment sera would be useful factors to predict EVR(16w). On the other hand, a less diverse sequence in V3 (≤4) or IRRDR (≤5) together with the absence of detectable anti‐NS5A antibodies could be a predictive factor for Non‐EVR(16w).

Factors associated with the response to interferon-based antiviral therapies for chronic hepatitis C

“…Akuta et al [15] reported that mutations of amino acids in the core protein region (core 70 and 91) were significantly associated with a non-response to combination therapy. Subsequently, a specific region other than the ISDR (NS5A 2334-2379) was found to be related to the treatment response to IFN-α plus RBV therapy, and was reported as the Interferon/Ribavirin Resistance-Determining Region (IRRDR) [16,17] . Overall, the most important viral factors associated with the response to IFN-α treatment for HCV were determined to be the amino acid sequences in the core region and NS5A region, such as mutations of core 70, core 91, ISDR and IRRDR.…”

“…70 and 91) Mutations of amino acids were associated with a poor response to IFN-α plus RBV treatment [15] IRRDR Mutations of the IRRDR (NS5A 2334-2379) were associated with a favorable response to the IFN-α plus RBV treatment [16,17] Drug resistant mutation associated with the response to IFN treatment for HCV infection. In addition, viral mutations resistant to DAAs have become problematic in recent triple therapies.…”

Predicting response to hepatitis C therapy

“…Markers may be based on viral factors, such as viral sequence variation (3); host factors, such as gene expression profiles (4) or polymorphisms in specific host genes (5); or combinations thereof (6,7). Interestingly, very different types of biomarkers can give similar results, indicative of the intimate interactions between the manifold host and viral players in virus replication and disease progression.…”

A Case of Chronic Hepatitis C with Nephrotic Diabetic Nephropathy who Achieved Sustained Viral Remission by Double-Filtration Plasmapheresis and Interferon Combination Therapy

“…Presently, therefore, prediction of the effectiveness of treatment of chronic hepatitis C before its initiation is considered extremely important, and many predictive factors of the effect of treatment have been reported. Among them, gene mutations and polymorphisms in the virus and host have been suggested to be factors that markedly affect the sensitivity to INF (12)(13)(14)(15)(16)(17)(18). Particularly, it has been considered difficult to achieve SVR in a patient showing the progres- Figure 2.…”