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Previous infection with hepatitis B virus (HBV), which is assessed by HBV core antibody (HBcAb) or surface antibody (HBsAb) titres, has reportedly been associated with an increased risk of developing hepatocellular carcinoma (HCC). We investigated the influence of previous HBV infection on the incidence of HCC in patients with hepatitis C virus (HCV) infection who achieved eradication of HCV, that is sustained virologic response (SVR). Both HBcAb and HBsAb were measured in a total of 1214 patients with HCV infection who had not been coinfected with HBV, as determined by both negative HBs antigen and HBV DNA, and in whom SVR was confirmed. Patients were followed up for a median of 5.7 years, and the incidence of post-SVR HCC was compared based on HBcAb and/or HBsAb. In both univariate and multivariate analyses, the incidence of post-SVR HCC did not differ based on the presence of HBcAb or HBsAb. In conclusion, previous HBV infection has no impact on the incidence of HCC in patients with HCV after SVR., (© 2023 John Wiley & Sons Ltd.)

The risk factors for hepatocellular carcinoma (HCC) development in patients whose duration of sustained virological response (SVR) is over 10 years are not fully understood. We compared the incidence of HCC development within and beyond 10 years after SVR. A total of 1384 patients who achieved SVR (714, interferon-based therapy; 670, direct-acting antiviral therapy) were enrolled. Factors associated with HCC development were analysed within and beyond 10 years after SVR by Cox proportional hazards models. The annual incidence rates of HCC development were 0.568% within 10 years after SVR and 0.190% beyond 10 years, and there was a significant difference in the incidence of HCC development between the 2 periods (p = 0.0242, log-rank test). Male gender (adjusted hazard ratio [aHR] 2.930; 95% confidence interval [CI] 1.508-5.693, p = 0.0015), fibrosis-4 (FIB-4) score > 3.25 (aHR 4.364; 95%CI 2.206-8.633, p < 0.0001) and alpha-fetoprotein ≥5.0 ng/ml (aHR 2.381; 95%CI 1.325-4.280, p = 0.0037) were independently associated with HCC development within 10 years after SVR. Male gender (aHR 4.702; 95%CI 1.366-16.190, p = 0.0141), presence of diabetes mellitus (aHR 2.933; 95%CI 1.240-6.935, p = 0.0143) and gamma-glutamyl transpeptidase (GGT) ≥ 56 U/l (aHR 4.157; 95%CI 1.400-12.350, p = 0.0103) were independently associated with HCC development beyond 10 years after SVR. The incidence of HCC development beyond 10 years after SVR was very low, and the associated factors were mainly extrahepatic, including DM and elevated GGT. Annual routine check-ups with abdominal ultrasound may be sufficient for such patients. (242 words)., (© 2022 John Wiley & Sons Ltd.)

The impact of antiviral therapy on clinical outcomes in patients with hepatitis C virus (HCV) infection and mild liver fibrosis (FIB-4 score <1.45) is not well understood. We aimed to clarify the impact of viral eradication on hepatocarcinogenesis and mortality in patients with mild fibrosis.The subjects were 657 patients who achieved sustained virologic response (SVR) (Clearance group) and 586 patients who did not receive antiviral therapy or did not achieve SVR (No clearance group). We applied inverse probability weighting because the groups had different baseline characteristics. Multivariate proportional hazards models were used to analyse factors associated with hepatocarcinogenesis and mortality using a time-dependent covariate. In addition, we compared the mortality rate of the Clearance group stratified by age to the mortality rate of the general population.Clearance of HCV RNA was significantly associated with hepatocarcinogenesis and all-cause, liver-related and non-liver-related mortality (adjusted hazard ratios [95% confidence interval], 0.2653 [0.1147-0.6136, p = 0.0019], 0.3416 [0.2157-0.5409, p < 0.0001], 0.2474 [0.0802-0.8917, p = 0.0381] and 0.4118 [0.2449-0.6925, p = 0.0008], respectively). The Clearance group had significantly higher mortality than the general population matched by age, sex and follow-up duration (p < 0.0001). However, there were no significant differences between patients who achieved SVR before age 50 and the general population matched by age, sex and follow-up duration (p = 0.1570). HCV eradication in patients with mild fibrosis reduces liver-related and non-liver-related mortality. If HCV is eradicated before age 50, prognosis is likely be similar to that of the age-matched and sex-matched general population. (249 words)., (© 2021 John Wiley & Sons Ltd.)

The development of nuleos(t)ide analogues (NAs) has dramatically changed the natural history of chronic hepatitis B virus (HBV) infection. In this study, we compared patients with HBV-related decompensated cirrhosis with and without NA therapy in terms of hepatocarcinogenesis and all-cause, liver-related, and non-liver-related mortality. This study enrolled 160 patients with decompensated cirrhosis, 78 of whom were treated with NA therapy (NA group) and 82 of whom were not (non-NA group). Propensity score matching and inverse probability weighting were performed to adjust the baseline characteristics in the NA and non-NA groups. Liver-related and non-liver-related mortality were analysed using the competing risks IPW cumulative incidence functions estimator. The Cox proportional hazards model and the Fine and Gray proportional hazards model were used to analyse factors associated with hepatocarcinogenesis and all-cause, liver-related, and non-liver-related mortality. HBV DNA ≥20,000 IU/ml (adjusted hazard ratio [aHR], 8.440) and dyslipidemia (aHR, 0.178) were independently associated with hepatocarcinogenesis. HBV DNA ≥20,000 IU/ml (aHR, 4.360) and non-NA group (aHR, 4.802) were independently associated with all-cause mortality. Diabetes mellitus (aHR, 4.925), FIB-4 score >3.6 (aHR, 4.151), non-NA group (aHR, 9.180), presence of dyslipidemia (aHR, 0.182) and male gender (aHR, 3.045) were independently associated with liver-related mortality. HBV DNA ≥20,000 IU/ml (aHR, 3.216) and high age (aHR, 2.692) were independently associated with non-liver-related mortality. Although the cumulative incidence rate of hepatocarcinogenesis and non-liver-related mortality was not reduced by NA therapy, viral suppression reduced liver-related mortality in patients with DC., (© 2020 John Wiley & Sons Ltd.)

To investigate the long-term prognosis of liver disease in patients with hepatitis C virus (HCV) eradication after antiviral therapy versus those with persistent HCV infection. Four hundred and eighty patients (5259 person-years [PYs]) who received interferon-based therapy and achieved sustained virologic response and 848 patients (3853 PYs) with persistent HCV infection were included. In the analysis of 1-year liver disease state transition probability matrices using Markov chain models, progression to cirrhosis from the chronic hepatitis state was observed (0.00%-0.63%) in patients with HCV eradication. Among patients with chronic hepatitis or cirrhosis and HCV eradication, hepatocellular carcinoma (HCC) development was observed in males aged ≥ 50 years (0.97%-1.96%) and females aged ≥ 60 years (0.26%-5.00%). Additionally, in patients with cirrhosis and HCV eradication, improvement to chronic hepatitis was also observed (4.94%-10.64%). Conversely, in patients with chronic hepatitis and persistent HCV infection, progression to cirrhosis was observed in males aged ≥ 30 years and female aged ≥ 40 years (0.44%-1.99%). In males aged ≥ 40 years and female aged ≥ 50 years with cirrhosis, the transition probability for HCC was relatively high (4.17%-14.02%). Under the assumption of either chronic hepatitis or cirrhosis at age 40 or 60 years as the starting condition for simulation over the next 30 or 40 years, respectively, the probability of HCC was higher in patients with persistent HCV infection than those with HCV eradication. In conclusion, HCV eradication can reduce the risk of developing cirrhosis or HCC in patients with chronic HCV infection., (© 2020 John Wiley & Sons Ltd.)

Whilst the benefit of direct-acting antiviral agents (DAAs) in achieving sustained virological response (SVR) is now well-accepted, their impact on liver function, particularly in relation to achievement of SVR, has not been well documented. We studied 2394 patients with chronic HCV infection, 1276 receiving DAAs and 1118 interferon-based therapy. Liver function was assessed by the albumin-bilirubin (ALBI) score or grade. Overall survival according to SVR status and baseline ALBI grade was examined. We also studied time to first decompensation according to ALBI grade, as well as longitudinal changes in ALBI score over time according to SVR. Among the patients receiving DAAs, 89% achieved SVR (Japan = 99%, UK = 78%). Amongst the decompensated patients in the UK cohort, three distinct risk groups according to ALBI grade at baseline were observed. The UK patients receiving DAAs, who had predominantly decompensated disease, showed clear evidence of improvement of liver function detectable within 2 years of the start of treatment, especially in those achieving SVR. These early changes in liver function were very similar to those observed in the first 2-3 years after interferon-based therapy. DAAs improve liver function especially in those with decompensated disease who achieve SVR. Experience with interferon-based therapy suggests that failure to achieve SVR is associated with long-term decline in liver function and, in contrast, patients who do achieve SVR can expect long-term disease improvement and subsequent stabilization of liver function. Our initial analysis suggests that those receiving DAAs are likely, in the long term, to follow a similar course., (© 2020 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Based on high efficacy and safety demonstrated in clinical trials, treatment with glecaprevir/pibrentasvir (G/P) for 8 weeks is recommended for hepatitis C virus (HCV)-infected patients who are direct-acting antiviral (DAA) naïve, genotype 1 or 2, and noncirrhotic. The aim of this study was to validate real-world experience with 8-week G/P treatment in Japan. We conducted a prospective observational cohort study in 554 patients who underwent 8-week treatment from among 1,022 patients who initiated G/P therapy. The majority (54.5%) were male, with a median age of 66 years, and HCV genotype distribution was genotype 1, 43.8%; genotype 2, 55.3%; and mixed subtype, 0.9%. Overall, the sustained virologic response rate at 12 weeks (SVR12) was 92.8% (530/571) in the intention-to-treat population and 99.3% (526/530) in the per-protocol population. The SVR12 rates by subgroups were as follows: subtype 1a, 100% (6/6); 1b, 100% (189/189); 2a, 99.3% (150/151); 2b, 99.0% (103/104); and mixed subtype, 50% (2/4). Among four patients with virologic failure following 8-week treatment with G/P, none had baseline polymorphisms or treatment-emergent amino acid substitutions in NS3. However, 2 of 4 patients with virologic failure had treatment-emergent amino acid substitutions in NS5A. Adverse events (AEs) were reported in 21.5% of patients and 1.2% of patients discontinued due to drug-related AEs. In conclusion, G/P treatment for 8 weeks was safe and effective for DAA-naïve noncirrhotic genotype 1 or 2 patients in a real-world clinical setting in Japan., (© 2019 John Wiley & Sons Ltd.)

The optimal term of follow-up for patients who achieve sustained virological responses (SVR) is an important topic because of the widespread use of direct-acting antivirals (DAA), which achieve a high SVR rate. Investigations of long-term follow-up among patients with SVR after interferon (IFN) therapy have reported that approximately 80%-100% of patients maintained SVR. However, the long-term durability of SVR to DAA treatment is unknown. The aim of this study was to evaluate the incidence of late relapse in patients who achieved SVR with daclatasvir (DCV) and asunaprevir (ASV). Four hundred and thirteen patients infected with hepatitis C virus (HCV) genotype 1b who completed ASV and DCV treatment and achieved SVR were selected. Patients who were persistently negative for serum HCV RNA at 24 weeks after withdrawal of DCV and ASV were considered to have SVR24. Mean follow-up period was 21.5 months (range, 4.8-30.3 months) after SVR24. Four patients redeveloped HCV RNA in serum at 6, 12, 12 and 26 months, respectively, after achieving SVR24. Results of molecular analysis by phylogenetic tree of HCV nonstructural protein 3 and 5A regions from late relapse indicated that the same strain was present at pretreatment and late relapse. In conclusion, late relapse by the original HCV strain was confirmed by direct sequencing in 4 of 413 patients with SVR to ASV and DCV. Although a few patients may develop late relapse, SVR achieved with all oral DAA therapy is as durable as that with IFN therapy., (© 2018 John Wiley & Sons Ltd.)