Machine learning for individualized prediction of hepatocellular carcinoma development after the eradication of hepatitis C virus with antivirals.

BACKGROUND AND AIMS: Accurate risk stratification for hepatocellular carcinoma (HCC) after achieving a sustained viral response (SVR) is necessary for optimal surveillance. We aimed to develop and validate a machine learning (ML) model to predict the risk of HCC after achieving an SVR in individual patients. METHODS: In this multicenter cohort study, 1742 patients with chronic hepatitis C who achieved an SVR were enrolled. Five ML models were developed including DeepSurv, gradient boosting survival analysis, random survival forest (RSF), survival support vector machine, and a conventional Cox proportional hazard model. Model performance was evaluated using Harrel' c-index and was externally validated in an independent cohort (977 patients). RESULTS: During the mean observation period of 5.4 years, 122 patients developed HCC (83 in the derivation cohort and 39 in the external validation cohort). The RSF model showed the best discrimination ability using seven parameters at the achievement of an SVR with a c-index of 0.839 in the external validation cohort and a high discriminative ability when the patients were categorized into three risk groups (P <0.001). Furthermore, this RSF model enabled the generation of an individualized predictive curve for HCC occurrence for each patient with an app available online. CONCLUSIONS: We developed and externally validated an RSF model with good predictive performance for the risk of HCC after an SVR. The application of this novel model is available on the website. This model could provide the data to consider an effective surveillance method. Further studies are needed to make recommendations for surveillance policies tailored to the medical situation in each country. IMPACT AND IMPLICATIONS: A novel prediction model for HCC occurrence in patients after hepatitis C virus eradication was developed using machine learning algorithms. This model, using seven commonly measured parameters, has been shown to have a good predictive ability for HCC development and could provide a personalized surveillance system.

Simple drainage versus drainage with minocycline infusion for symptomatic hepatic cysts.

Percutaneous treatment of symptomatic hepatic cysts includes simple drainage and drainage with sclerosing agents. We compared the efficacy of simple drainage with that of drainage with minocycline infusion for treating symptomatic hepatic cysts. We retrospectively evaluated 11 patients who underwent percutaneous drainage of symptomatic hepatic cysts. In seven cases, minocycline infusion was added at the discretion of the clinician. Cyst volume was evaluated before drainage, immediately after drainage, and after long-term follow-up. Cyst volume was calculated before treatment by multiplying the orthogonal diameters using the ellipsoid formula. Relapse was defined as the regrowth of the cyst with symptoms. Cyst volume immediately after drainage and after long-term follow-up was significantly less than that before treatment for the drainage with minocycline infusion group (p<0.05) but not for the simple drainage group. The relapse rates were 25% (1/4) for the simple drainage group and 0% for the drainage with minocycline infusion group. Drainage with minocycline infusion could be a promising option for treating symptomatic hepatic cysts, although simple drainage was not reliable.

Early-phase prothrombin time-international normalized ratio in acute liver injury indicates the timing of therapeutic intervention and predicts prognostic improvement.

AIM: We investigated whether an early-phase prothrombin time-international normalized ratio (PT-INR) is an interventional prognostic indicator for patients with acute liver injury, including acute liver failure. METHODS: This was a multicenter retrospective observational study. We included 595 patients with alanine aminotransferase levels ≥300 U/L due to acute liver injury who were admitted to Kagoshima University Hospital or other collaborative investigation organizations between January 1, 2010, and December 31, 2015. Patients with alanine aminotransferase levels ≥300 U/L and no previous liver disease were defined as having an acute liver injury. Acute liver failure was defined by PT-INR ≥1.5 with or without hepatic encephalopathy in acute liver injury patients. Data were obtained retrospectively from case reports and analyzed. RESULTS: The PT-INR on day 1 was the most accurate independent prognosis predictor in patients with acute liver injury and acute liver failure. On day 1, the transplant-free survival rates were significantly lower in patients with PT-INR ≥1.3. The transplant-free survival rates were also significantly higher in patients with acute liver injury and acute liver failure, in whom the PT-INR had recovered from ≥1.3 on day 1 to <1.3 by day 8. CONCLUSION: Early-phase changes in the PT-INR can predict the prognosis of patients with acute liver injury and acute liver failure. Furthermore, PT-INR ≥1.3 could be an interventional marker, whereas PT-INR <1.3 after 1 week could reflect prognostic improvement.

Factors that affect the development of acute hemorrhagic rectal ulcer syndrome and rebleeding.

Objectives: Acute hemorrhagic rectal ulcer syndrome (AHRUS) causes massive bleeding and often recurrent rebleeding from rectal ulcers that form immediately above the dentate line. This study aimed to determine the clinical background and risk factors contributing to rebleeding in patients with AHRUS and the most appropriate method of hemostasis treatment. Methods: This retrospective study included 93 patients diagnosed with AHRUS at Showa University Fujigaoka Hospital, Japan, between April 2009 and November 2018. Information on clinical background factors, endoscopic findings, and hemostasis was obtained from medical records. The relationship with episodes of rebleeding was analyzed by multivariate logistic regression analysis. Results: The median age was 79 years, and 84 patients (90%) had a performance status of grade 2 or higher. The patients had multiple background factors, with a median number of 5 per patient. The background factors could be classified into two major factors: those related to arteriosclerosis and those related to delayed wound healing.In the multivariate analysis, significantly more rebleeding occurred in patients with active bleeding during the initial endoscopy (odds ratio 4.88, 95% confidence interval 1.80-14.46, p = 0.003); significantly less rebleeding occurred in patients for whom hemostasis was first performed by clipping (odds ratio 0.30, 95% confidence interval 0.09-0.88, p = 0.035). Conclusions: In bedridden older individuals with poor general health, multiple combinations of arteriosclerosis-related factors and protracted wound healing factors can induce AHRUS. We strongly recommend performing hemostasis via the clipping method on suspected bleeding points, including active bleeding sites, in AHRUS.

Diagnostic criteria for acute-on-chronic liver failure and related disease conditions in Japan.

The Intractable Hepato-Biliary Disease Study Group of Japan, sponsored by the Ministry of Health, Labor and Wealth, proposed in 2018 that patients with cirrhosis and a Child-Pugh score of 5-9 should be diagnosed as having acute-on-chronic liver failure (ACLF) when a deterioration of liver function ("serum bilirubin level of 5.0 mg/dl or more" and "prothrombin time value of 40% or less of the standardized values and/or international normalization rates of 1.5 or more") caused by severe liver damage develops within 28 days after an acute insult, including alcohol abuse, bacterial infection, gastrointestinal bleeding, and the exacerbation of underlying liver diseases. Disease severity can be classified into 4 grades depending on the extent of the deterioration in organ functions, including liver, kidney, cerebral, blood coagulation, circulatory and respiratory functions. The Study Group has since performed an annual nationwide survey of patients with ACLF diagnosed according to the proposed diagnostic criteria as well as those with disease conditions related to ACLF. A total of 501 patients, including 183 patients diagnosed as having ACLF, seen between 2017 and 2019 were enrolled, and univariate and multivariate analyses revealed that the proposed diagnostic criteria were useful for identifying cirrhotic patients with an unfavorable outcome following an acute insult. Consequently, the Study Group determined that the proposed diagnostic criteria should be used in both clinical practice and clinical research as formal diagnostic criteria.

Safety, tolerability, and anti-fibrotic efficacy of the CBP/ß-catenin inhibitor PRI-724 in patients with hepatitis C and B virus-induced liver cirrhosis: An investigator-initiated, open-label, non-randomised, multicentre, phase 1/2a study.

BACKGROUND: We conducted an exploratory study to assess the safety tolerability, and anti-fibrotic effects of PRI-724, a CBP/ß-catenin inhibitor, in patients with hepatitis C virus (HCV)- and hepatitis B virus (HBV)-induced cirrhosis. METHODS: This multicentre, open-label, non-randomised, non-placebo-controlled phase 1/2a trial was conducted at three hospitals in Japan. Between July 27, 2018, and July 13, 2021, we enrolled patients with HCV- and HBV-induced cirrhosis classified as Child-Pugh (CP) class A or B. In phase 1, 15 patients received intravenous infusions of PRI-724 at escalating doses of 140, 280, and 380 mg/m2/4 h twice weekly for 12 weeks. In phase 2a, 12 patients received the recommended PRI-724 dose. The primary endpoints of phases 1 and 2a were the frequency and severity of adverse events and efficacy in treating cirrhosis based on liver biopsy. This study was registered at ClinicalTrials.gov (no. NCT03620474). FINDINGS: Three patients from phase 1 who received the recommended PRI-724 dose were evaluated to obtain efficacy and safety data in phase 2a. Serious adverse events occurred in three patients, one of which was possibly related to PRI-724. The most common adverse events were diarrhoea and nausea. PRI-724 did not decrease hepatic fibrosis with any statistical significance, either by ordinal scoring or measurement of collagen proportionate area at 12 weeks; however, we observed statistically significant improvements in liver stiffness, Model for End-stage Liver Disease score, and serum albumin level. INTERPRETATION: Intravenous administration of 280 mg/m2/4 h PRI-724 over 12 weeks was preliminarily assessed to be well tolerated; however, further evaluation of anti-fibrotic effects in patients with cirrhosis is warranted. FUNDING: AMED, Ohara Pharmaceutical.

The Japanese Society for Apheresis clinical practice guideline for therapeutic apheresis.

Most of the diseases for which apheresis therapy is indicated are intractable and rare, and each patient has a different background and treatment course prior to apheresis therapy initiation. Therefore, it is difficult to conduct large-scale randomized controlled trials to secure high-quality evidence. Under such circumstances, the American Society for Apheresis (ASFA) issued its guidelines in 2007, which were repeatedly revised until the latest edition in 2019. The ASFA guidelines are comprehensive. However, in the United States, a centrifugal separation method is mainly used for apheresis, whereas the mainstream procedure in Japan is the membrane separation method. The target diseases and their backgrounds are different from those in Japan. Due to these differences, the direct adoption of the ASFA guidelines in Japanese practice creates various problems. One of the features of apheresis in Japan is the development of treatment methods using hollow-fiber devices such as double filtration plasmapheresis (DFPP) and selective plasma exchange and adsorption-type devices such as polymyxin B-immobilized endotoxin adsorption columns. Specialists in emergency medicine, hematology, collagen diseases/rheumatology, respiratory medicine, cardiovascular medicine, gastroenterology, neurology, nephrology, and dermatology who are familiar with apheresis therapy gathered for this guideline, which covers 86 diseases. In addition, since apheresis therapy involves not only physicians but also clinical engineers, nurses, dieticians, and many other medical professionals, this guideline was prepared in the form of a worksheet so that it can be easily understood at the bedside. Moreover, to the clinical purposes, this guideline is designed to summarize apheresis therapy in Japan and to disseminate and further develop Japanese apheresis technology to the world. As diagnostic and therapeutic techniques are constantly advancing, the guidelines need to be revised every few years. In order to ensure the high quality of apheresis therapy in Japan, both the Japanese Society for Apheresis Registry and the guidelines will be inseparable.

Nationwide survey for patients with acute-on-chronic liver failure occurring between 2017 and 2019 and diagnosed according to proposed Japanese criteria.

BACKGROUND: The significance of the 2018 Japanese diagnostic criteria for acute-on-chronic liver failure (ACLF) has not yet been evaluated. METHODS: A nationwide survey was performed for patients with ACLF occurring between 2017 and 2019. Cirrhotic patients with a Child-Pugh score of 5-9 were diagnosed as having ACLF when liver failure (serum bilirubin level of ≥ 5.0 mg/dL and a prothrombin time international normalization rate [INR] of ≥ 1.5) occurred within 28 days after an acute insult. Patients who fulfilled either criterion (total serum bilirubin or INR) and/or those with indeterminate Child-Pugh scores at baseline were also enrolled. RESULTS: Among the 501 enrolled patients, 183 patients (37%) were diagnosed as having ACLF. The etiologies of the cirrhosis and acute insults were alcohol intake/abuse in 114 (62%) and 75 (41%) patients, respectively. Sixty-eight patients (37%) were also diagnosed as having severe alcoholic hepatitis. The survival rate without liver transplantation was 48% among the ACLF patients and 71% in the remaining patients (P < 0.01). A multivariate analysis revealed that the disease condition was significantly associated with mortality, with an odds ratio of 2.025 in ACLF patients relative to the remaining patients (P < 0.01), and patient age and the number of organs with functional failure were also associated with mortality among the ACLF patients. CONCLUSION: The proposed diagnostic criteria for ACLF were useful for identifying cirrhotic patients with an unfavorable outcome following acute insults. A therapeutic strategy for patients with severe alcoholic hepatitis should be established, since such patients accounted for the majority of ACLF patients.

Clinical features and mechanism of liver injury in patients with mild or moderate coronavirus disease 2019.

BACKGROUND AND AIM: We aimed to identify clinical features that suggest that coronavirus disease 2019 (COVID-19) should be a differential diagnosis in patients presenting with a chief complaint of fever and abnormal liver function. METHODS: We retrospectively studied the presence or absence of abnormal liver function in 216 patients diagnosed with mild-moderate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection between February and September 2020. RESULTS: Abnormal liver function was observed in 51 patients with mild-moderate COVID-19. The median peak aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) levels were 57.5, 75.5, and 332.5 U/L, respectively. The median number of days from symptom onset to peak AST, ALT, and LDH were 8.5, 9, and 8.5, respectively. The median peak LDH/AST ratio was 9.0. Low lymphocyte-to-white blood cell ratio and elevated LDH were found to be independent contributing factors for intensive care unit (ICU) admission on a multivariate analysis. CONCLUSIONS: AST-predominant AST/ALT/LDH elevation peaking 8-9 days after symptom onset and not accompanied by elevated alkaline phosphatase or gamma-glutamyl transferase may be a useful clinical feature for differentiating COVID-19 from other diseases. Since the median LDH/AST ratio was 9.0, it seems that the abnormal liver function caused by SARS-CoV-2 is an indirect damage to liver cells due to elevated cytokine levels caused by liver-infiltrating lymphocytes. SARS-CoV-2 infection should be considered in patients presenting with a chief complaint of fever and liver injury; those with a high lymphocyte-to-white blood cell ratio or and a high LDH/AST ratio may be admitted to the ICU.

Impact of Obesity and Heavy Alcohol Consumption on Hepatocellular Carcinoma Development after HCV Eradication with Antivirals.

BACKGROUND AND AIMS: It remains unclear whether obesity increases the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C who achieved a sustained virological response (SVR) with antiviral therapy. METHODS: In this multicenter cohort study, we enrolled patients with chronic hepatitis C who achieved SVR with interferon (IFN)-based therapy (IFN group) or direct-acting antiviral (DAA) therapy (DAA group) between January 1, 1990, and December 31, 2018. The patients underwent regular surveillance for HCC. Cumulative incidence of and the risk factors for HCC development after SVR were assessed using the Kaplan-Meier method and Cox proportional hazard regression analysis, respectively. RESULTS: Among 2,055 patients (840 in the IFN group and 1,215 in the DAA group), 75 developed HCC (41 in the IFN group and 34 in the DAA group) during the mean observation period of 4.1 years. The incidence rates of HCC at 1, 2, and 3 years were 1.2, 1.9, and 3.0%, respectively. Multivariate analysis revealed that in addition to older age, lower albumin level, lower platelet count, higher alpha-fetoprotein level, and absence of dyslipidemia, obesity (body mass index ≥25 kg/m2) and heavy alcohol consumption (≥60 g/day) were independent risk factors for HCC development, with adjusted hazard ratio (HR) of 2.53 (95% confidence interval [CI]: 1.51-4.25) and 2.56 (95% CI: 1.14-5.75), respectively. The adjusted HR was not significant between the 2 groups (DAA vs. IFN; HR 1.19, 95% CI: 0.61-2.33). CONCLUSIONS: Obesity and heavy alcohol consumption increased the risk of HCC development after SVR.

Analysis of the safety of pretransplant corticosteroid therapy in patients with acute liver failure and late-onset hepatic failure in Japan.

BACKGROUND AND AIM: In Japan, corticosteroids have been commonly used as a part of multidisciplinary therapy for patients with acute liver failure and late-onset hepatic failure. However, there is controversy regarding the development of infections and other complications. In this study, the influence of corticosteroids on patient outcomes after liver transplantation was investigated. METHODS: This study included 167 patients with acute liver failure and late-onset hepatic failure who underwent liver transplantation between 2010 and 2015. The effects of pretransplant corticosteroid therapy on patient outcomes were evaluated using a database constructed by the subcommittee for fulminant hepatitis in the Intractable Hepato-Biliary Diseases Study Group of Japan. RESULTS: The subacute type and the median total bilirubin levels were higher in those receiving corticosteroids than in those not receiving corticosteroids. Although infections tended to be higher in patients receiving corticosteroids, pretransplant corticosteroid administration did not affect the survival rates. The duration from corticosteroid initiation to liver transplantation was longer in patients who developed infections. The survival rates, however, did not differ between patients with and without infections. CONCLUSIONS: Corticosteroids were administered to patients with poor prognoses. Otherwise, the overall outcome in those administered corticosteroids was not significantly different from that in those administered without corticosteroids. Although infectious complications tended to occur, they were generally controllable and nonfatal. Pretransplant corticosteroid therapy may be permissible, with regarding for infections and performed within the minimum duration.

Pharmacokinetics and Safety of Ranirestat in Patients With Hepatic Impairment.

Ranirestat is an aldose reductase inhibitor hypothesized to improve diabetic neuropathy. An open-label, single-dose, parallel-group study was conducted to compare pharmacokinetic (PK) characteristics of an oral dose of ranirestat across subjects with normal hepatic function and patients with mild and moderate hepatic impairment because ranirestat is expected to be used by patients with diabetes mellitus, possibly including those with hepatic impairment. To evaluate the necessity for dose adjustment, PK profiles and tolerability were studied at the dose of 40 mg, the expected optimal clinical dose in patients with diabetic neuropathy and normal hepatic function. In total, 20 subjects, including 5, 10, and 5 subjects with normal hepatic function, mild hepatic impairment, and moderate hepatic impairment, respectively, completed the study. Serial PK sampling was conducted up to 504 hours, and PK parameters were calculated and compared between healthy subjects and patients with mild or moderate hepatic impairment. The geometric mean ratios of peak concentration and area under the concentration-time curve in patients with mild hepatic impairment (90%CI) were 86.7% (55.3% to 135.9%) and 84.7% (68.5% to 104.8%), respectively. The values in patients with moderate hepatic impairment were 81.3% (48.8% to 135.5%) and 91.7% (72.1% to 116.7%), respectively. These results demonstrated that plasma ranirestat exposure and the plasma protein binding of the drug were not substantially altered by normal, mild, or moderate hepatic impairment (protein binding 99.22%, 99.29%, and 99.00%, respectively). All adverse events were mild in severity. Based on these findings, no dose adjustment will be required for ranirestat in patients with mild or moderate hepatic impairment.

A prospective trial of vaccine to prevent hepatitis B virus reactivation after hematopoietic stem cell transplantation.

Hepatitis B virus (HBV) reactivation reportedly occurs frequently after hematopoietic stem cell transplantation (HSCT) in resolved HBV-infected patients. Here, 50 patients with resolved HBV infections and scheduled to undergo HSCT were enrolled; all subjects were vaccinated with three doses of hepatitis B vaccine 12 months after HSCT and the incidence of HBV reactivation was monitored. The patients' characteristics were: median age, 61 (34-72) years; male/female, 27/19; allogeneic/autologous, 40/6; bone marrow/peripheral blood stem cells/cord blood, 26/16/4. Of the 46 patients who underwent HSCT, 19 were excluded and did not make it to vaccination due to relapse of underlying disease, HBV reactivation within 12 months of HSCT, or transfer of patients. The remaining 27 were vaccinated 12 months after HSCT and monitored for 2 years. Six showed HBV reactivation, with a 2-year cumulative reactivation incidence of 22.2%; the same incidence was 27.3% only in allogeneic HSCT patients. Factors associated with HBV reactivation included the discontinuation of immunosuppressants (P = 0.0379) and baseline titers of antibody against hepatitis B surface antigen (P = 0.004). HBV reactivation with vaccination following HSCT could occur despite maintenance of serum anti-HBs at more than protective levels.

Pharmacokinetics and Safety of a Single Oral Dose of Peficitinib (ASP015K) in Japanese Subjects With Normal and Impaired Hepatic Function.

Peficitinib (ASP015K) is a novel Janus kinase inhibitor developed for the treatment of rheumatoid arthritis (RA). The impact of hepatic impairment on the peficitinib pharmacokinetic (PK) and safety profile was investigated in non-RA subjects (n = 24) in an open-label, parallel-group, multicenter comparative study in Japan. Subjects received a single, clinically relevant, oral dose of a peficitinib 150 mg tablet under fasting conditions. Plasma PK parameters were measured for peficitinib and its metabolites H1 (sulfate and methylated metabolite), H2 (sulfate metabolite), and H4 (methylated metabolite) in subjects with normal hepatic function, mild hepatic impairment, or moderate hepatic impairment. The peficitinib area under the plasma-concentration-time curve from time 0 to infinity (AUCinf ) and maximum observed concentration (Cmax ) were not markedly different in subjects with mild hepatic impairment versus normal hepatic function. In subjects with moderate hepatic impairment versus normal hepatic function, the geometric mean ratios for peficitinib AUCinf and Cmax , were 1.92 (90% CI: 1.39, 2.66) and 1.82 (90% CI: 1.24, 2.69), respectively. Five treatment-emergent adverse events (TEAEs) were experienced by 3 subjects, 1 in each group. There were no deaths, no serious TEAEs, and no TEAEs leading to withdrawal. In summary, the PK profile was unaltered in subjects with mild hepatic impairment after a single clinically relevant dose of peficitinib, but exposure almost doubled in subjects with moderate hepatic impairment. Peficitinib dose reduction may be considered in RA patients with moderate hepatic impairment.

Dotinurad: a clinical pharmacokinetic study of a novel, selective urate reabsorption inhibitor in subjects with hepatic impairment.

BACKGROUND: Dotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by inhibiting the urate transporter 1 (URAT1). We compared the pharmacokinetics (PK), pharmacodynamics (PD), and safety of dotinurad in subjects with hepatic impairment and normal hepatic function. METHODS: This was a multicenter, open-label, single dose study. A total of 24 subjects were divided into four groups: the normal hepatic function group and the mild, moderate, and severe hepatic impairment groups. The primary endpoints were changes in plasma dotinurad levels and PK parameters. RESULTS: The geometric mean ratio of the maximum plasma concentration (Cmax) [two-sided 90% confidence interval (CI)] of dotinurad in in the mild, moderate, and severe hepatic impairment groups relative to that in the normal hepatic function group was 0.840 (0.674-1.047), 0.798 (0.653-0.976), and 0.747 (0.570-0.979), respectively, showing a lower Cmax in the moderate and severe hepatic impairment groups. Following adjustment for body weight, only the moderate hepatic impairment group had a lower Cmax than the normal hepatic function group. No meaningful differences in other PK parameters were observed between the groups. Regarding the PD of dotinurad, the changes in serum uric acid levels after dosing were similar in all groups. As for safety, no noteworthy concerns were raised in relation to any group. CONCLUSION: The study revealed no clinically meaningful influence of hepatic impairment on the PK, PD, or safety of dotinurad. These findings indicate possibility that dotinurad can be used without dose adjustment in patients with hepatic impairment.

Intention-to-treat assessment of glecaprevir + pibrentasvir combination therapy for patients with chronic hepatitis C in the real world.

AIMS: We assessed the problems and efficacy of glecaprevir + pibrentasvir (GLE/PIB) therapy for patients infected with hepatitis C virus (HCV) in the real world. METHOD: A total of 423 patients infected with HCV who started treatment at eight different centers in Japan were enrolled in the study. Glecaprevir (300 mg) and pibrentasvir (120 mg) were given once daily for 8 weeks to 246 non-cirrhotic direct-acting antiviral (DAA)-naive patients with HCV genotype (GT)-1 or -2, and for 12 weeks to patients who: were DAA-naive cirrhotic (n = 55), had experienced DAA failure (n = 78), were cirrhotic and had DAA failure (n = 37), and were other GT-1/2 (n = 7). Anti-HCV efficacy was defined as a sustained virologic response 12 weeks post-treatment (SVR12). The evaluation was undertaken in an intention-to-treat (ITT) population and in patients who were assessed at SVR12 (modified ITT population). RESULTS: In the ITT population, 220 (89%) patients on the 8-week regimen and 164 (93%) patients on the 12-week regimen achieved SVR12. The 30 dropout patients were predominantly men and with GT-2. All other DAA-naive GT-1 patients achieved SVR12. The 12-week regimen resulted in 100% SVR12 in 41 GT-2 patients. Nine patients did not achieve SVR12: two DAA naive with GT-2a, two GT-3b patients, two GT-1 patients with discontinuation, and three other GT-1 patients with a history of DAA failure. Four of seven patients who discontinued treatment due to severe adverse effects were more than 75 years old. CONCLUSIONS: Glecaprevir + pibrentasvir had a remarkable anti-HCV effect in GT-1 and GT-2 patients, but not in GT-3b patients. Although this therapy was reasonably safe, it is necessary to carefully consider elderly and dropout patients.

An intensive medical care network led to successful living-donor liver transplantation in late-onset hepatic failure with disseminated Staphylococcus aureus infection.

Here, we describe a 42-year-old male patient with late-onset hepatic failure (LOHF) due to acute-onset autoimmune hepatitis. At first, his response to steroid therapy was good, but hepatitis relapsed during steroid pulse therapy. Deterioration of liver function caused LOHF, and LOHF has a poor prognosis, particularly when it is complicated by infection. Systemic infection by Staphylococcus aureus resulted in a skin rash and septic pulmonary embolism, and is an absolute contraindication for liver transplantation (LT). In this treatment network, hepatologists and a transplant surgeon cooperated to overcome severe infection and their efforts led to successful transplantation. On-line hemodiafiltration is an indispensable treatment option for acute liver failure. Infection control is crucial for LT and an intensive medical care network led to successful living-donor LT.

Proposed diagnostic criteria for acute-on-chronic liver failure in Japan.

To establish diagnostic criteria for acute-on-chronic liver failure (ACLF) in Japan, the Intractable Hepato-Biliary Disease Study Group of Japan undertook a multicenter pilot survey for patients fulfilling the Asian Pacific Association for the Study of the Liver (APASL), Association for the Study of the Liver-Chronic Liver Failure (EASL-Clif) Consortium, or Chinese Medical Association (CMA) diagnostic criteria for ACLF. The APASL criteria were suitable for screening Japanese patients with ACLF when patients whose conditions were triggered by gastrointestinal bleeding were included within the disease entity, and the EASL-Clif Consortium criteria were useful for classifying the severity of the patients' conditions. Based on these observations, the Study Group proposed the following diagnostic criteria for ACLF in Japan: patients with cirrhosis and a Child-Pugh score of 5-9 should be diagnosed as having ACLF when a deterioration of liver function (serum bilirubin level ≥5.0 mg/dL and prothrombin time value ≤40% of the standardized values and/or international normalization rate ≥1.5) caused by severe liver damage develops within 28 days after acute insults, such as alcohol abuse, bacterial infection, gastrointestinal bleeding, or the exacerbation of underlying liver diseases. The severities of the patients can be classified into four grades depending on the extent of the deterioration in organ functions, including kidney, cerebral, blood coagulation, circulatory and respiratory functions, as well as liver function. The usefulness of these novel criteria should be validated prospectively in a large-scale cohort in the future.