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.

We showed previously that amino acid (aa) substitutions in hepatitis C virus core region (HCV-CR) are negative predictors of virologic response to pegylated interferon (IFN) plus ribavirin therapy. HCV-CR induces hepatocellular carcinoma in transgenic mice, but the clinical impact is still unclear. To evaluate the impact of aa substitutions in HCV-CR on hepatocarcinogenesis, we performed a follow-up study on 313 noncirrhotic consecutive naïve patients infected with HCV genotype 1b who received IFN monotherapy. The median follow-up was 14.7 years. A sustained virologic response (SVR) after the first IFN was achieved by 65 patients (20.8%) (group A). Of 248 patients (79.2%) of non-SVR after first IFN, 112 (35.8%) did not receive additional IFN (group B), and the remaining 136 (43.5%) received multicourse IFN monotherapy (group C). As a whole, cumulative hepatocarcinogenesis rates in double wild-type (arginine at aa 70/leucine at aa 91) of HCV-CR were significantly lower than those in nondouble wild-type. Multivariate analyses identified 3 parameters (fibrosis stage 3, nondouble wild-type of HCV-CR, and group B) that tended to or significantly influenced hepatocarcinogenesis independently. With regard to hepatocarcinogenesis rates in group C according to HCV-CR and the mean alanine aminotransferase (ALT) during IFN-free period, significantly higher rates were noted in patients of nondouble wild-type with ALT levels of more than 1.5 times the upper limit of normal (25.7%) compared with the others (2.4%). Conclusion: Amino acid substitutions in the HCV-CR are the important predictor of hepatocarcinogenesis. In multicourse IFN therapy to nondouble wild-type, we emphasize the importance of reducing the risk of hepatocarcinogenesis by mean ALT during an IFN-free period below 1.5 times the upper limit of normal.

A prospective study based on serial liver biopsies was performed to investigate the efficacy of sodium‐glucose cotransporter 2 inhibitor for nonalcoholic fatty liver disease complicated with type 2 diabetes mellitus. Conclusion: Treatment for 24 weeks resulted in improvement in histopathologic features in all 5 patients. (Hepatology Communications 2017;1:46–52)

Summary: Background: Chronic hepatitis B virus (HBV) infection is an aetiologic factor for hepatocellular carcinoma (HCC). Baseline HBV DNA is a known independent predictor of HCC, and the serum hepatitis B core‐related antigen (HBcrAg) level corresponds to intrahepatic covalently closed circular DNA.Aim: To investigate whether the baseline and on‐treatment serum HBcrAg levels can predict HCC incidence in patients with chronic hepatitis B following nucleos(t)ide analogue (NA) therapy.Methods: This retrospective cohort study included 1268 patients treated with NAs for >1 year. In all patients, serum HBcrAg and hepatitis B surface antigen levels were measured at baseline and 1 year.Results: During a median follow‐up of 8.9 years, 113 patients (8.9%) developed HCC (10.3/1000 person‐years). These patients were stratified by baseline hepatitis B e‐antigen (HBeAg) status into HBeAg+ and HBeAg‐ cohorts. High on‐treatment HBcrAg levels at 1 year were found to associate significantly with HCC (HBeAg+ cohort: P = 0.017; HBeAg‐ cohort: P = 4.30 × 10⁻⁵; cut‐off values: 4.9 log U/mL and 4.4 log U/mL, respectively). In a multivariate Cox regression analysis, patients with persistently high on‐treatment HBcrAg levels had a higher risk of HCC than those with low HBcrAg levels (HBeAg+: hazard ratio [HR], 6.15, 95% confidence interval [CI]: 1.89‐20.0, P = 0.003; HBeAg‐ cohort: HR, 2.54, 95% CI: 1.40‐4.60; P = 0.002). A sub‐analysis of patients without alcoholism yielded similar findings.Conclusions: Patients with persistently high on‐treatment HBcrAg levels were more likely to develop HCC despite sustained viral suppression via long‐term NA treatment.