Tatsuo Kanda

Hepatitis A virus (HAV) infection is a major cause of acute viral hepatitis worldwide. However, no effective antiviral therapy is currently available. HAV manipulates host secretory pathways, including the endosomal sorting complex required for transport (ESCRT)-dependent pathways, to facilitate viral propagation. Nevertheless, whether HAV also utilizes alternative secretory pathways remains unclear. Here, we provide evidence suggesting that an ESCRT-independent pathway may contribute to extracellular HAV RNA levels in Huh7 cells infected with HAV genotype IB (HM175-18f) and genotype IIIA (HA11-1299). Treatment with the ESCRT-independent pathway inhibitor GW4869 significantly reduced extracellular HAV RNA levels. GW4869 did not significantly affect HAV subgenomic RNA replication. These results suggest that the neutral sphingomyelinase 2 (nSMase2)-dependent ESCRT-independent pathway may contribute to extracellular HAV RNA levels rather than intracellular HAV RNA replication. Consistent with these findings, knockdown of sphingomyelin phosphodiesterase 3, which encodes SMase2, also significantly reduced extracellular HAV RNA levels. These findings suggest that an nSMase2-dependent ESCRT-independent extracellular vesicle pathway may contribute to extracellular HAV RNA levels.

Hepatitis A virus (HAV) infection remains a global public health concern in both developing and developed countries. In the present study, we identified anti-HAV drugs, using AutoDock Vina Modeling software, and evaluated the compounds in vitro. Following cytotoxicity for Huh7 cells, 5 out of 10 compounds were selected. We evaluated effective HAV 3C protease inhibitors with activity against both HAV genotype IB HM175/18f and HAV genotype IIIA HA11-1299-infected human hepatoma cells. Among the five compounds, we identified only one (KCN-A-12), which had an inhibitory effect on both HAV genotype IB HM175/18f and HAV genotype IIIA HA11-1299 replication in human hepatoma Huh7 cells. KCN-A-12 has more effective inhibitory effects on the replication of HAV genotype IB HM175/18f than that of HAV genotype IIIA HA11-1299. This difference may be attributable to the fact that our discovery system depends on crystal structures from HAV 3C protease based on the HAV genotype IB HM175 strain. In conclusion, we observed that KCN-A-12 was able to inhibit HAV replication. In silico screening for HAV 3C protease inhibitors may be useful for further discovery of anti-HAV drugs.

Aim: To examine concordance between the Japanese acute‐on‐chronic liver failure (ACLF) classification and the organ failure (OF)‐based European association for the study of the liver‐chronic liver failure (EASL‐CLIF) framework, and to clarify the medium‐term prognostic implications of discordance in alcohol‐related cirrhosis. Methods: Adults with alcohol‐related cirrhosis were studied in a single‐center consecutive cohort. Japanese‐defined ACLF episodes were classified as confirmed (bilirubin plus coagulation criteria) or extended (either criterion alone), then cross‐classified by EASL‐CLIF grade. First ACLF episodes were analyzed for 1‐year mortality using Kaplan–Meier, Cox, and receiver operating characteristic (ROC) analyses. Results: Among 158 patients, 26 developed Japanese‐defined ACLF (30 episodes). Discordance was substantial: 66.7% of extended and 22.2% of confirmed episodes were EASL‐CLIF grade 0, not meeting EASL‐CLIF criteria. In the first‐episode cohort ( n = 26), 1‐year survival was 77.8% for confirmed and 69.5% for extended ACLF (log‐rank p = 0.692). Among Japanese‐defined ACLF episodes classified as EASL‐CLIF grade 0, the estimated 90‐day mortality was 0%, whereas the estimated 1‐year mortality was 21.4%. In exploratory ROC analyses, the model for end‐stage liver disease (MELD) showed the numerically highest area under the ROC curve for 1‐year mortality (AUC 0.797, 95% confidence interval [CI] 0.627–0.967); however, pairwise AUC differences were not significant. Conclusions: Japanese‐defined ACLF, particularly extended ACLF, often corresponds to EASL‐CLIF grade 0, yet discordant patients showed non‐negligible 1‐year mortality. These findings suggest that acute hepatic deterioration without overt OF may represent a clinically relevant early‐risk phase in alcohol‐related cirrhosis. Hepatic‐ and OF‐based frameworks should therefore be interpreted as complementary.

Antiviral therapy and the risk of extrahepatic malignancies in chronic hepatitis C: insights from recent evidence

Hepatitis A virus (HAV) infection can occasionally cause acute severe hepatitis. Patients with this disease sometimes need to undergo liver transplantation with immunosuppressants. Although rare, breakthrough HAV infections, despite vaccination, appear to be more common among immunocompromised populations. The effect of immunosuppressants on HAV replication is unclear. In this study, we examined the effects of immunosuppressants on HAV HA11-1299 genotype IIIA replication in human hepatocytes, finding that azathioprine inhibited HAV replication with a half-maximal inhibitory concentration of 0.967 μmol/L. We further examined the effect of azathioprine on the replication of HAV HM175 18f genotype IB using replication-competent or replication-incompetent subgenomic replicon in HuhT7 cells. Azathioprine had significant inhibitory effects on the HAV replication-competent subgenomic replicon compared to the replication-incompetent subgenomic replicon. The effect of azathioprine on the activity of the HAV HM175 18f genotype IB-internal ribosomal entry site (IRES) was investigated in COS7-HAV-IRES cells using a reporter assay. Azathioprine at 1 μmol/L had a significant inhibitory effect on HAV IRES activity but at 0.5 μmol/L had no inhibitory effect. Azathioprine appears to inhibit HAV replication as well as HAV translation. In conclusion, we found that azathioprine inhibits HAV replication in human hepatocytes, meaning that it may be useful for patients with a HAV infection who need to use immunosuppressants.

Editorial Commentary STRIDE sustained an overall survival benefit with safety profiles in unresectable hepatocellular carcinoma at 5-year follow-up Tatsuo Kanda, Reina Sasaki-Tanaka, Hiroteru Kamimura, Kazunao Hayashi, Kenya Kamimura, Shuji Terai

In April 2023, the Japan Society of Hepatology published its official guidelines on liver rehabilitation for chronic liver disease. In this article, we summarize the current evidence on the role of liver rehabilitation in slowing the progression of chronic liver disease, particularly metabolic dysfunction‐associated steatotic liver disease (MASLD), liver cirrhosis, and hepatocellular carcinoma (HCC). Specifically, we outline the following: (1) the definition of liver rehabilitation and its target population; (2) exercise therapy in liver rehabilitation according to disease state; (3) considerations for patients with complications; (4) nutritional therapy in liver rehabilitation; and (5) potential economic benefits. Liver rehabilitation represents a novel therapeutic approach for patients with chronic liver disease, and this guidance aims to promote high‐quality clinical research and strengthen the evidence base for its application.