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The identification of patients with advanced fibrosis who do not need any further hepatocellular carcinoma (HCC) surveillance after the eradication of hepatitis C is pivotal. In this study, we developed a simple serum-based risk model that could identify patients with low-risk HCC. This was a nationwide multicenter study involving 16 Hospitals in Japan. Patients with advanced fibrosis (1,325 in a derivation cohort and 508 in a validation cohort) who achieved sustained virological responses at 24 weeks after treatment (SVR24) were enrolled. The HCC risk model at any point after SVR24 and its change were evaluated, and subsequent HCC development was analyzed. Based on the multivariable analysis, patients fulfilling all of the factors (GAF4 criteria: gamma-glutamyl transferase

BackgroundIt is unclear whether the fibrosis 4 index (FIB-4), a marker of liver fibrosis, at baseline and change in FIB-4 after sustained virological response (SVR) is associated with incident hepatocellular carcinoma (HCC) risk. In this study, we examined the association of incident HCC risk with baseline FIB-4 and sustained high FIB-4 (>3.25) at any time point after SVR.MethodsA total of 3823 patients who received direct-acting antiviral treatment and achieved SVR were enrolled. The FIB-4 was measured 24 weeks after the end of direct-acting antiviral treatment and achievement of SVR (SVR24), and 1, 2, and 3 years after SVR24, after which subsequent HCC development was investigated.ResultsIn patients with an FIB-4 >3.25 at SVR24 and 1, 2, and 3 years after SVR24, subsequent HCC development was significantly higher than in those with an FIB-4 ≤3.25 at each point. The rates of HCC development 1, 2, 3, and 4 years after SVR24 were significantly higher in patients with sustained FIB-4 >3.25 than in those whose FIB-4 decreased to ≤3.25 (5.4%, 9.2%, 11.7%, and 16.0%, respectively, vs 2.2%, 3.1%, 3.7%, and 4.4%; P 3.25 at SVR24 and 1, 2, and 3 years later were 3.38 (2.4-4.8), 2.95 (1.9-4.7), 2.62 (1.3-5.1), and 3.37 (1.4-9.8), respectively.ConclusionsThe FIB-4 could be used to assess HCC development risk at any time after SVR, and changes in FIB-4 were associated with changes in the HCC development risk. Repeated assessments of FIB-4 could serve as a prognostic indicator of a high-risk HCC cohort that may require more intensive HCC surveillance strategy.

Background and Aims: The impact of hepatitis C virus (HCV) eradication via direct‐acting antiviral (DAA) therapy on overall mortality, particularly non‐liver‐related mortality, is understudied. Methods: We recruited 4180 patients with chronic HCV infection who achieved sustained virological response (SVR) (HCV eradication) through DAA therapy (n = 2501, SVR group) or who did not receive antiviral therapy (n = 1679, non‐SVR group); 1236 from each group were chosen using propensity score matching. Causes of death and all‐cause mortality, including non‐liver‐related diseases, were investigated. Results: Of the 4180 patients, 592 died during the follow‐up period. In the SVR group, the mortality rates from liver‐related and non‐liver‐related diseases were 16.5% and 83.5%, respectively. Compared to the non‐SVR group, mortality rates from liver‐related and non‐liver‐related diseases were 50.1% and 49.9%, respectively (p <.001). In non‐cirrhotic patients, multivariable analysis revealed that SVR was an independent factor associated with both liver‐related (hazard ratio [HR],.251; 95% confidence interval [CI],.092–.686) and non‐liver‐related (HR,.641; 95% CI,.415–.990) mortalities. In cirrhotic patients, multivariable analysis revealed that SVR remained an independent factor significantly associated with liver‐related mortality (HR,.151; 95% CI,.081–.279). In propensity score‐matched patients, the eradication of HCV (SVR group) decreased both liver‐related (p <.001) and non‐liver‐related mortality (p =.008) rates compared to persistent HCV infection (non‐SVR group). Conclusions: The elimination of HCV via DAA therapy reduced not only liver‐related mortality but also non‐liver‐related mortality in patients with chronic HCV. [ABSTRACT FROM AUTHOR]

Aim: Nucleos(t)ide analogs do not completely prevent hepatocellular carcinoma (HCC) in chronic hepatitis B virus infection. This study aimed to evaluate the dynamics of a non‐invasive liver fibrosis marker, the Fibrosis‐4 (FIB‐4) index, for predicting HCC development. Methods: Among a total of 882 chronically hepatitis B virus infection‐infected patients who were treated with nucleos(t)ide analogs, 472 patients without HCC history whose FIB‐4 at baseline and 1 year of treatment was obtained were evaluated for the incidence of HCC. Results: The median FIB‐4 was 2.00 at baseline and was significantly reduced to 1.58 at 1 year (P < 0.001), but the reduction was small at 2 years or later. When a receiver operating characteristic analysis of FIB‐4 was performed to predict HCC within 5 years, the area under the curve of FIB‐4 at 1 year was higher than that at baseline (0.676 vs. 0.599). The HCC incidence was significantly higher in patients with FIB‐4 ≥1.58 than in those with FIB‐4 <1.58 (14.8% vs. 3.6% at 10 years, P < 0.001). Additionally, an abnormal alanine aminotransferase (≥31 U/L) at 1 year was an independent risk for HCC. When a fibrosis and alanine aminotransferase‐1 (FAL‐1) score was evaluated as an applicable number of FIB‐4 ≥1.58, and alanine aminotransferase ≥31 as 0, 1, and 2, the HCC risk in patients with score 2 was significantly higher than in those with score 1 or score 0 (24.1% vs. 9.8% vs. 0.7% at 10 years, P < 0.001). Conclusions: FIB‐4 ≥1.58 and alanine aminotransferase ≥31 at 1 year of nucleos(t)ide analog was an independent risk factor for HCC development, and a score using these factors stratified the risk of HCC. [ABSTRACT FROM AUTHOR]

This study aimed to elucidate whether interferon (IFN)-free direct-acting antiviral (DAA) therapy for hepatitis C after curative treatment of hepatocellular carcinoma (HCC) promotes HCC recurrence in a real-world large-scale cohort.This multicenter study was conducted by the Japanese Red Cross Hospital Liver Study Group. This retrospective study analyzed 516 patients who underwent antiviral treatment for hepatitis C with either IFN (n = 148) or IFN-free DAA (n = 368) after curative HCC treatment; 78 IFN-treated patients and 347 IFN-free DAA-treated patients achieved sustained virological response (SVR). The recurrence rate of HCC was compared between the antiviral therapies. Logistic analysis and Cox proportional hazards analysis identified factors associated with early recurrence of HCC within 24 weeks of antiviral therapy and recurrence throughout the observation period, respectively.AFP at the completion of antiviral therapy, clinical stage of HCC, and non-SVR were independent factors associated with early recurrence of HCC. Among patients who had achieved SVR, the clinical stage of HCC and the level of AFP at completion of antiviral therapy were independent factors associated with early recurrence of HCC. For recurrence throughout the observation period in SVR patients, AFP at completion of antiviral therapy, duration between last HCC treatment to antiviral therapy, and the number of treatments were independent factors. There was no significant difference in the rate of early recurrence of HCC or recurrence throughout the observation period between IFN and IFN-free DAA treated patients.There were no differences in the early recurrence rate of HCC between patients who underwent IFN and those who underwent IFN-free DAA as antiviral therapies.

Aim: We investigated pretreatment neutrophil‐to‐lymphocyte ratio (NLR) for predicting survival outcomes of atezolizumab plus bevacizumab therapy for hepatocellular carcinoma (HCC) and determined the predictive ability of combined liver reserve–NLR. Methods: This retrospective, multicenter study enrolled 242 patients receiving atezolizumab plus bevacizumab for unresectable HCC. Pretreatment NLR <2.56 was designated as the "low group" and NLR ≥2.56 as the "high group" (120 and 122 patients, respectively). Propensity score‐matched analysis was undertaken between the low and high groups. Results: In this cohort, the objective response and disease control rates were 20% and 72.5%, respectively, in the low group and 19.6% and 72.9%, respectively, in the high group. After matching, median progression‐free survival (PFS) time was 283 and 167 days in the low and high groups, respectively (p = 0.022). Neutrophil‐to‐lymphocyte ratio ≥2.56 (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.05–2.28; p = 0.028), modified albumin–bilirubin index (mALBI) grade 2b or 3 (HR 1.55; 95% CI, 1.05–2.29; p = 0.025), and protein induced by vitamin K absence or antagonist‐II ≥ 400 (HR 2.03; 95% CI, 1.36–3.02; p = 0.001) were significantly associated with PFS in univariate analysis using the Cox proportional hazards model. In cases involving mALBI grade 1 or 2a (n = 131), the median PFS time was not reached in the low group, whereas it was 210 days in the high group (p = 0.037). Conclusions: Pretreatment NLR is a simple tool for routine measurement in clinical practice. It can predict PFS in patients with unresectable HCC treated with atezolizumab plus bevacizumab, especially mALBI grade 1 or 2a. [ABSTRACT FROM AUTHOR]

Nucleos(t)ide analogs (NAs) cannot completely suppress the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study aimed to identify the risk factors for HCC development in naïve CHB patients treated with current NA. Patients receiving NA (n = 905) were recruited retrospectively from the 17 hospitals of the Japanese Red Cross Liver Study Group. All treatment‐naïve patients had been receiving current NA continuously for more than 1 year until the end of the follow‐up. We analyzed the accuracy of predictive risk score using the area under receiver operating characteristic curve. The albumin–bilirubin (ALBI) score was significantly improved by NA therapy (−0.171 ± 0.396; p < 0.001 at Week 48). A total of 72 (8.0%) patients developed HCC over a median follow‐up of 6.2 (1.03–15.7) years. An independent predictive factor of HCC development was older age, cirrhosis, lower platelet counts at baseline and ALBI score, and alpha‐fetoprotein (AFP) at 1 year after NA therapy according to multivariate analysis. The accuracy was assessed using the PAGE‐B, mPAGE‐B, aMAP, APA‐B, and REAL‐B scores that included these factors. Discrimination was generally acceptable for these models. aMAP and REAL‐B demonstrated high discrimination with 0.866/0.862 and 0.833/0.859 for 3‐ and 5‐year prediction from the status of 1 year after NA therapy, respectively. Baseline age and platelet count, as well as ALBI and AFP one year after NA, were useful for stratifying carcinogenesis risk. The aMAP and REAL‐B scores were validated with high accuracy in Japanese CHB patients. [ABSTRACT FROM AUTHOR]

Patients with a chronic hepatitis B virus (HBV) infection who are treated with nucleos(t)ide analogues (NAs) are still at risk for hepatocellular carcinoma (HCC), and it has been clinically questioned whether patients with a high risk of HCC can be identified efficiently. We aimed to clarify the risk factors associated with the development of HCC during NA therapies. A total of 611 chronically HBV-infected patients without a history of HCC, who were treated with NAs for more than 6 months (median 72 months), from 2000 to 2021, were included from 16 hospitals in the Tohoku district in Japan. Incidences of HCC occurrence were analyzed with clinical factors, including on-treatment responses. Alanine aminotransferase (ALT) normalization, based on the criteria of three guidelines, was analyzed with other parameters, including the age–male–ALBI–platelets (aMAP) risk score. During the observation period, 48 patients developed HCC, and the cumulative HCC incidence was 10.6% at 10 years. Non-achievement of ALT normalization at 1 year of therapy was mostly associated with HCC development when ALT ≤ 30 U/L was used as the cut-off (cumulative incidence, 19.9% vs. 5.3% at 10 years, p < 0.001). The effectiveness of the aMAP risk score at the start of treatment was validated in this cohort. A combination of an aMAP risk score ≥ 50 and non-achievement of ALT normalization could stratify the risk of HCC significantly, and notably, there was no HCC development in 103 patients without these 2 factors. In conclusion, non-achievement of ALT normalization (≤30 U/L) at 1 year might be useful in predicting HCC during NA therapies and, in combination with the aMAP risk score, could stratify the risk more precisely. [ABSTRACT FROM AUTHOR]

Background and Aim: The pathogenic process underlying the development of hepatocellular carcinoma (HCC) is not yet clear in patients with hepatitis C virus (HCV) who have received direct‐acting antiviral (DAA) therapy and achieved sustained virological response (SVR). This study validated a composite predictive model for HCC in these patients. Methods: This study included 3058 patients in whom HCV was eradicated with DAA therapy. After DAAs recommendation for surveillance (ADRES) score, which is based on sex, FIB‐4 index, and α‐fetoprotein, was used as a composite predictive model for HCC development. Results: The 1‐, 3‐, and 5‐year cumulative incidence rates of HCC were 0.9, 4.5, and 15.2%, respectively. Multivariate analysis with Cox proportional hazards models showed that male sex (hazard ratio [HR], 2.646; 95% confidence interval [CI], 1.790–3.911), FIB‐4 index >3.25 (HR, 2.891; 95% CI, 1.947–4.293), and α‐fetoprotein >5 ng/mL (HR, 2.835; 95% CI, 1.914–4.200) are independently associated with HCC development. The incidence of HCC differed significantly by ADRES score (P < 0.001). Cox proportional hazards models showed that compared to the ADRES score 0 group, the HR for HCC development was 2.947 (95% CI, 1.367–6.354) in the ADRES score 1 group, 9.171 (95% CI, 4.339–19.380) in the ADRES score 2 group, and 20.630 (95% CI, 8.641–49.230) in the ADRES score 3 group. ADRES score had superior predictive power for HCC development compared with the FIB‐4 index and α‐fetoprotein according to time‐dependent receiver operating characteristic analysis. Conclusion: The ADRES score is useful for predicting HCC development after SVR. [ABSTRACT FROM AUTHOR]

Background: In clinical trials, a pangenotype direct‐acting antiviral (DAA) regimen consisting of glecaprevir (GLE) and pibrentasvir (PIB) exhibited high virologic efficacy and tolerability in patients with hepatitis C virus (HCV) infection. This study sought to confirm these findings in real‐world settings, focusing on patients with cirrhosis, history of DAA failure, or HCV genotype 3 who were treated with a 12‐week regimen in a large multicenter study from Japan. Methods: In a nationwide multicenter prospective cohort study, we analyzed background characteristics, tolerability, and treatment outcome of patients who underwent a 12‐week GLE/PIB regimen. Results: Of 1190 patients, 509 (42.8%) underwent the 12‐week regimen, and the remaining patients underwent an 8‐week regimen. The rate of sustained virologic response (SVR) of patients treated with the 12‐week regimen was 99.0%, comparable with that of patients treated with the 8‐week regimen. The adverse events were observed in 29.1% of patients. The main adverse event was pruritus, which was observed in 14.7%. Ten patients (2.0%) discontinued therapy during treatment period. Conclusion: The 12‐week GLE/PIB regimen was well‐tolerated with high virologic efficacy in patients with cirrhosis, experience of DAA, or HCV genotype 3; tolerability and SVR rate were comparable with those of DAA‐naïve, non‐cirrhotic, non‐genotype 3 patients who underwent 8‐week regimen. [ABSTRACT FROM AUTHOR]

Background: Direct-acting anti-virals (DAAs) have markedly improved the effectiveness of anti-viral therapy for chronic hepatitis C (CHC) patients. In a phase III trial in Japan, treatment with the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir (G/P) resulted in a small number of patients with refractory factors. We aimed to evaluate the effectiveness and safety of G/P, especially among patients with these refractory factors, and the influence of these factors on treatment. Methods: In a prospective, multicenter study involving 33 medical institutions, 1439 patients were treated with G/P, and their efficacy, safety, and most frequent adverse effects (AEs) were analyzed. Results: Overall SVR12 rates were 99.1% (1397/1410) in the per-protocol-analysis, and genotype sustained virologic response SVR12 rates were: genotype 1, 99.4% (707/711); genotype 2, 99.4% (670/674); genotype 3, 80.0% (16/20). DAA-naïve patients (p = 0.008) with HCV genotype except 3 (genotype 1 vs. 3, p = 2.68 × 10–5; genotype 2 vs. 3, p = 3.28 × 10–5) had significantly higher SVR12 rates. No significant difference was observed between CKD stage 1–3 (99.1% [1209/1220]) and chronic kidney disease (CKD) stage 4–5 (98.9% [188/190]) patients, or between cirrhotic (99.0% [398/402]) and non-cirrhotic (99.1% [999/1008]) patients. Multiple logistic regression analysis revealed that genotype 3 [OR 33.404, 95% CI (7.512–148.550), p value (p = 4.06 × 10–5)] and past experience of IFN-free DAAs [OR 3.977, 95% CI (1.153–13.725), p value (p = 0.029)] were both significantly independent predictors of non-SVR12. AEs were reported in 28.2% of patients, and 1.6% discontinued treatment owing to drug-related AEs. AEs were significantly higher in CKD stage 4–5 (41.6% [79/190]) than CKD stage 1–3 (26.1% [319/1220]) patients (p = 2.00 × 10–5). AEs were also significantly higher in cirrhotic (38.6% [155/402]) than in non-cirrhotic (24.1% [243/1008]) (p = 2.91 × 10–18) patients. Conclusions: G/P regimen is highly effective and safe to treat CHC patients even with refractory factors such as CKD and advanced liver fibrosis. However, patients with past experience of IFN-free DAA treatment and genotype 3, CKD stage 4 or 5, and advanced liver fibrosis should be more closely observed. [ABSTRACT FROM AUTHOR]