Real-world efficacy and safety of 12-week sofosbuvir/velpatasvir treatment for patients with decompensated liver cirrhosis caused by hepatitis C virus infection.

AIM: This study aimed to evaluate the real-world efficacy and safety of 12-week sofosbuvir/velpatasvir (SOF/VEL) treatment for patients with decompensated liver cirrhosis caused by hepatitis C virus (HCV) infection. METHODS: A total 72 of patients with Child-Pugh (CP) class B or C were enrolled. We evaluated the sustained virologic response at 12 weeks after the end of treatment (SVR12), adverse events (AEs), and changes in the liver function. RESULTS: All participants had genotype 1 or 2 HCV infection. At baseline, the numbers of patients with CP class B and C were 59 and 13, respectively. The overall SVR12 rate was 95.8% (69/72); 94.9% (56/59) in CP class B and 100% (13/13) in CP class C. The serum albumin level, prothrombin time and ascites were significantly improved (P < 0.01); however, the serum bilirubin level and encephalopathy did not improve. Among patients who achieved SVR12, 75.0% showed an improvement in their CP score, while 5.9% showed a worsening. The presence of large portosystemic shunt (diameter ≥6 mm) and hyperbilirubinemia (≥2.0 mg/dL) were independent factors that interfered with the improvement in the CP score (P < 0.05). The most common AEs were encephalopathy (15.3%) and skin symptoms (7.9%). Two patients discontinued SOF/VEL due to AEs. CONCLUSIONS: Treatment with SOF/VEL for 12 weeks was relatively safe and effective for patients with decompensated cirrhosis. An SVR provided an improvement of the liver function in the majority of patients. However, large portosystemic shunt and hyperbilirubinemia were independent factors that interfered with the improvement in the CP score.

Clinical and virologic features of hepatitis E virus infection at a university hospital in Japan between 2000 and 2019.

The clinical and virologic features of hepatitis E virus (HEV) infection seem to vary among regions even in developed countries. However, we have little information on the diversity of HEV infection. Here, we investigated the characteristics of 26 patients in our hospital located in Tochigi prefecture, 90 km north of Tokyo, between 2000 and 2019. The reported number of patients with acute hepatitis E is increasing in Japan because measurement of IgA-class anti-HEV antibody was commercially available from 2011. In contrast, the numbers at our hospital were 1.5/y and 1.0/y in 2000 to 2011 and 2012 to 2019, respectively. This is attributed to the fact that we have been investigating HEV as a cause of unknown hepatitis before 2011. Among isolated HEV subgenotypes, including 3a, 3b, 4b, 4c, and 4d, all three patients with subgenotype 4c infection presented acute liver failure. Four HEV strains shared more than or equal to 99% identity within the 412-nucleotide partial sequence, in which the time and place of HEV infection varied, except for one intrafamilial infection. In addition, some strains were similar to HEV strains isolated far from Tochigi prefecture. In conclusion, the number of patients with acute hepatitis E was not increasing at Jichi Medical University Hospital and some strains were found to circulate in Japan.

Lusutrombopag is effective and safe in patients with chronic liver disease and severe thrombocytopenia: a multicenter retrospective study.

BACKGROUND: Chronic liver disease (CLD) is often complicated by severe thrombocytopenia (platelet count < 50,000/µL). Platelet transfusion has been a gold standard for increasing the platelet count to prevent hemorrhagic events in such patients. Lusutrombopag, a thrombopoietin receptor agonist, can increase the platelet count in such patients when invasive procedures are scheduled. Former studies on lusutrombopag included patients with a platelet count of > 50,000/µL at baseline: the proportions of patients who did not require platelet transfusion were 84-96%, which might be overestimated. METHODS: The efficacy and safety of lusutrombopag were retrospectively investigated in CLD patients with platelet count of < 50,000/µL, a criterion for platelet transfusion, in real-world settings. We examined the proportion of patients who did not require platelet transfusion in 31 CLD patients, which exceeded a minimum required sample size (21 patients) calculated by 80% power at a significance level of 5%. Lusutrombopag, 3 mg once daily, was administered 8-18 days before scheduled invasive procedures. RESULTS: Among 31 patients who received lusutrombopag, 23 patients (74.2%) patients showed a platelet count of ≥ 50,000/µL (Group A) and did not require platelet transfusion. The remaining 8 patients (25.8%) did not reached platelet ≥ 50,000/µL (Group B). The means of platelet increase were 38,000/µL and 12,000/µL in groups A and B, respectively. A low platelet count at baseline was a characteristic of patients in group B. Among 13 patients who repeatedly used lusutrombopag, lusutrombopag significantly increased the platelet count as the initial treatment. When all repeated uses of lusutrombopag were counted among these 13 patients, platelet transfusion was not required in 82.1% (23/28) of treatments. Although one patient showed portal thrombosis after lusutrombopag treatment, the thrombosis was disappeared by anticoagulant treatment for 35 days. The degree of platelet increase with lusutrombopag was larger than that in their previous platelet transfusion. CONCLUSIONS: The proportion of patients who did not require platelet transfusion was 74.2%, which is smaller than that in former studies which included CLD patients with a platelet count of > 50,000/µL. However, lusutrombopag is effective and safe for CLD patients with a platelet count of < 50,000/µL.

Ezetimibe suppresses development of liver tumors by inhibiting angiogenesis in mice fed a high-fat diet.

Nonalcoholic steatohepatitis (NASH) is a common cause of liver cirrhosis and hepatocellular carcinoma (HCC). However, effective therapeutic strategies for preventing and treating NASH-mediated liver cirrhosis and HCC are lacking. Cholesterol is closely associated with vascular endothelial growth factor (VEGF), a key factor that promotes HCC. Recent reports have demonstrated that statins could prevent HCC development. In contrast, we have little information on ezetimibe, an inhibitor of cholesterol absorption, in regards to the prevention of NASH-related liver cirrhosis and HCC. In the present study, a steatohepatitis-related HCC model, hepatocyte-specific phosphatase and tensin homolog (Pten)-deficient (PtenΔhep ) mice were fed a high-fat (HF) diet with/without ezetimibe. In the standard-diet group, ezetimibe did not reduce the development of liver tumors in PtenΔhep mice, in which the increase of serum cholesterol levels was mild. Feeding of a HF diet increased serum cholesterol levels markedly and subsequently increased serum levels of VEGF, a crucial component of angiogenesis. The HF diet increased the number of VEGF-positive cells and vascular endothelial cells in the tumors of PtenΔhep mice. Kupffer cells, macrophages in the liver, increased VEGF expression in response to fat overload. Ezetimibe treatment lowered cholesterol levels and these angiogenetic processes. As a result, ezetimibe also suppressed inflammation, liver fibrosis and tumor growth in PtenΔhep mice on the HF diet. Tumor cells were highly proliferative with HF-diet feeding, which was inhibited by ezetimibe. In conclusion, ezetimibe suppressed development of liver tumors by inhibiting angiogenesis in PtenΔhep mice with hypercholesterolemia.

Full-genome characterization of the RIVM-HAV16-090-like hepatitis A virus strains recovered from Japanese men who have sex with men, with sporadic acute hepatitis A.

AIM: The major transmission mode of hepatitis A virus (HAV) in Japan is the fecal-oral route by contaminated foods. In contrast, HAV infection is well documented as a sexually transmitted disease in Europe and North America. The present study was undertaken to determine the full-genome sequence of HAV and trace the transmission route of HAV in Japanese men who have sex with men (MSM). METHODS: In 2018, we encountered three Japanese MSM with acute hepatitis A co-infected with HIV for 4-12 years. Serum samples obtained from these patients were used for HAV full-genome analyses. RESULTS: Isolated HAV strains were segregated into subgenotype IA. The three HAV strains shared 100% identity within the 481-nucleotide partial sequence. The entire nucleotide sequence showed that the three strains were 99.97% similar to each other with only two nucleotide substitutions. At the amino acid level, the three strains differed from each other by only one or two amino acids. All three strains obtained in the present study were >99.6% identical to the 66 reported strains isolated from Taiwan and European countries during 2015-2017. In addition, these 66 strains include the RIVM-HAV16-090 (EuroPride) strain, which has been involved in HAV outbreaks among MSM worldwide. CONCLUSIONS: We determined for the first time the full-genome sequence of HAV isolated from Japanese MSM with acute hepatitis A and found that the strains were identical to those from MSM worldwide. Thus, these HAV strains were imported to Japan from foreign countries through MSM.

Utility of FibroScan-based scoring systems to narrow the risk group of nonalcoholic fatty liver disease with comorbidities.

BACKGROUND: Vibration-controlled transient elastography (VCTE) is proposed as a second step of examination to assess liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) after triaging by the fibrosis-4 (FIB-4) index. Recently, VCTE-based scoring systems, including FibroScan-AST (FAST), Agile 3+, and Agile 4, emerged to determine the status of NAFLD. However, the significance of these scoring systems remains unknown in narrowing the high-risk group of NAFLD patients with comorbidities, including hepatocellular carcinoma (HCC) and esophagogastric varices (EGV). AIM: To clarify the significance of VCTE-based scoring systems to narrow the high-risk group of NAFLD patients with comorbidities. METHODS: We performed a cross-sectional study to investigate the usefulness of VCTE-based scoring systems and other fibrosis markers to narrow the high-risk group of patients with NAFLD. FIB-4 index was used for the first triage. Risk groups of FAST, Agile 3+, and Agile 4 were stratified according to the published data. Among the 191 patients with NAFLD, there were 26 (14%) and 25 patients (13%) with HCC and EGV, respectively. RESULTS: When 1.3 was used as a cutoff value, the FIB-4 index narrowed the risk group to 120 patients, in which all patients with HCC and/or EGV were included. High risk group of Agile 3+ could subsequently narrow the risk group. The prevalence of HCC and EGV at this step were 33% (26/80) and 31% (25/80), respectively. In further narrowing of EGV, Agile 4 aggregated the patients with EGV into 43 patients, of whom 23 (53%) had EGV. FAST failed to narrow the risk group of patients with comorbidities. When 2.6 was used as a cutoff value of the FIB-4 index, three patients with HCC and two patients with EGV were missed at the first triage. CONCLUSION: Agile 3+ and Agile 4 are useful to narrow the NAFLD patient group, in which patients may have HCC and/or EGV.

Conventional Therapies Do Not Prolong the Prognosis of Hepatocellular Carcinoma Patients with Extrahepatic Metastases under Receiving of Tyrosine Kinase Inhibitors.

BACKGROUND: Conventional therapies, including chemoembolization and radiation therapy, have been expected to prolong the prognosis of hepatocellular carcinoma (HCC) patients with extrahepatic metastases, which remains poor. However, little information is available on the efficacy of conventional therapies for such patients under tyrosine kinase inhibitor (TKI) treatment. METHODS: We retrospectively investigated 127 HCC patients with extrahepatic metastases, who were divided into the non-TKI (conventional therapies) and TKI groups and further subdivided into the TKI alone and TKI plus conventional therapies groups. Conventional therapies included transcatheter arterial chemoembolization, cisplatin-based chemotherapy, radiation, surgery, and UFT, an oral chemotherapeutic agent. RESULTS: The median of the overall survival (OS) of the 127 patients with extrahepatic metastases was 7.0 months. Meanwhile, the median OS of the TKI and non-TKI groups was 12.1 and 4.1 months, respectively. Imitating TKI after diagnosing metastases promoted a favorable increase in OS. Among the TKI group, the median OS in the TKI alone group was 8.9 months. TKI plus conventional therapies promoted no improvement in OS after adjusting for the patients' background data. CONCLUSION: TKI promoted a better OS in HCC patients with extrahepatic metastases compared to conventional therapies. However, TKI plus conventional therapies promoted no improvement in the prognosis of such patients.

Successful treatment of hepatocellular carcinoma by laparoscopic radiofrequency ablation in a patient with hemophilia A.

Percutaneous radiofrequency ablation (RFA) is a good indication for hepatocellular carcinoma (HCC) in cases involving ≦ 3 tumors of ≦ 30 mm in size, many hepatologists are hesitant to perform the procedure for patients with hemorrhagic disorders. We herein report the successful treatment of HCC by laparoscopic RFA in a patient with hemophilia A. A 48-year-old man with moderate form of hemophilia A had a single HCC at segment 8. To perform laparoscopic RFA safely, recombinant factor VIII (rFVIII) was administered to maintain factor VIII activity (FVIII:C) > 80% on the operation day and > 40% for 6 days after the operation in accordance with the guidelines. A total of 23,000 units of rFVIII was used. Laparoscopic RFA was completed with an operation time of 105 min and < 10 mL of blood loss. As a result, blood transfusion was not required. At 2 years after the initial treatment, HCC recurred at segment 7. Under rFVIII supplementation, we performed a second laparoscopic RFA without any events. Although partial hepatectomy is the main procedure used to treat HCC in patients with hemophilia, we could reduce in total use of rFVIII, blood and operation time by laparoscopic RFA compared with those in partial hepatectomy.

Efficacy and safety of glecaprevir and pibrentasvir combination therapy in old-aged patients with chronic hepatitis C virus infection.

Objective: Combination therapy with glecaprevir and pibrentasvir (G/P) has been shown to provide a sustained virologic response (SVR) rate of >97% in patients with chronic hepatitis C virus (HCV) infection in the first published real-world Japanese data. However, a recently published study showed that the treatment was often discontinued in patients ≥75 years old, resulting in low SVR in intention-to-treat (ITT) analysis. Thus, our aim was to evaluate real-world data for G/P therapy in patients ≥75 years of age, the population density of which is high in "rural" regions. Patients and Methods: We conducted a multicenter study to assess the efficacy and safety of G/P therapy for chronic HCV infection, in the North Kanto area in Japan. Results: Of the 308 patients enrolled, 294 (95.5%) completed the treatment according to the protocol. In ITT and per-protocol analyses, the overall SVR12 rate was 97.1% and 99.7%, respectively. The old-aged patients group consisted of 59 participants, 56 of whom (94.9%) completed the scheduled protocol. Although old-aged patients tended to have non-SVR factors such as liver cirrhosis, history of HCC, and prior DAA therapies, the SVR12 rates in old-aged patients were 98.3% and 100% in the ITT and PP analyses, respectively. Of 308 patients enrolled, adverse events were observed in 74 patients (24.0%), with grade ≥3 events in 8 patients (2.6%). There was no significant difference in any grade and grade ≥3 adverse events between the old-aged group and the rest of the study participants. Only one patient discontinued the treatment because of adverse events. Conclusion: G/P therapy is effective and safe for old-aged patients.

Usefulness of Gd-EOB-DTPA-enhanced MRI for evaluating the potential for early development of hepatocellular carcinoma after HCV eradication by direct-acting antiviral treatment.

Objective: The development of hepatocellular carcinoma (HCC) is not uncommon in patients who achieve eradication of the hepatitis C virus through direct-acting antiviral (DAA) treatment. The aim of this study was to identify the patients at high risk for novel HCC development after a sustained virologic response (SVR) by DAA treatment. Patients and Methods: A total of 518 patients with no history of HCC treatment and who achieved SVR by DAA treatment were evaluated retrospectively. The correlations between HCC development and the patients' characteristics were evaluated. For patients who underwent gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) or dynamic contrast-enhanced computed tomography, the relationship between the imaging findings and subsequent HCC development was also assessed. Results: HCC developed newly in 22 patients, and the 1-year and 3-year cumulative HCC rates were 2.0% and 8.5%, respectively. In multivariate analysis, a FIB-4 index >4.0 and a post-treatment α-fetoprotein >4.0 ng/ml were significant risk factors for HCC. In 26 of 118 patients who underwent an MRI before DAA treatment, a non-hypervascular hypo-intense nodule was seen in the hepatobiliary phase, and in 6 of 182 patients who underwent a CT, a non-hypervascular hypo-enhanced nodule was seen in the delayed phase. The sensitivity and specificity of the MRI-positive findings for the subsequent development of HCC were 0.92 and 0.87, respectively, and those of the CT were 0.40 and 0.99, respectively. In multivariate analysis of patients who underwent an MRI, a non-hypervascular hypo-intense nodule was the only factor that was significantly related to HCC development (HR 32.4, p = 0.001). Conclusion: Gd-EOB-DTPA-enhanced MRI was found to be reliable for risk evaluation of subsequent HCC development in patients after SVR by DAA treatment. Patients with a non-hypervascular hypo-intense nodule need more careful observation for incident HCC.

Acute Liver Failure Caused by the Transmission of Hepatitis B Virus from the Spouse after 38 Years of Marriage.

A 65-year-old man presented with acute liver failure and grade IV coma caused by hepatitis B virus (HBV) infection in 2017. The patient died on day 12 from the disease onset. The HBV isolated from the patient was genotype/subgenotype B/B1 and had multiple genomic mutations. The patient's wife was hepatitis B surface antigen (HBsAg)-positive when she delivered her first daughter in 1979. The HBV isolates of the patient and the wife shared 100% similarity over the entire genome. Because the patient's HBsAg value had been negative one year earlier, we considered the source of HBV transmission to be his wife.

The successful treatment of hepatocellular carcinoma arising from congenital hepatic fibrosis using radiofrequency ablation under laparoscopy.

Congenital hepatic fibrosis (CHF), a fibropolycystic disease, is characterized by bile duct malformation, periportal fibrosis, and renal polycystic disease. Although cholangiocellular carcinoma is the primary tumor arising from fibropolycystic diseases, hepatocellular carcinoma (HCC) is extremely rare. In addition, no algorism for determining the optimum HCC treatment has yet been available in cases of fibropolycystic disease due to variations in the background liver and renal conditions. We herein report a patient with HCC arising from CHF that was successfully treated using radiofrequency ablation (RFA) under laparoscopic assistance. A 37-year-old man with CHF was admitted to our hospital for treatment of HCC in 2014. Imaging revealed HCC located in hepatic segments II and VIII with diameters of 28 and 24 mm, respectively. There had been no histories of recurrent cholangitis or renal failure after when CHF was diagnosed in 2003. In addition, esophageal varices were well controlled. We achieved sufficient ablation using a bipolar ablation system without any complications. The post-operative course was uneventful, and the patient was free from HCC for 4 years. Thus, locoregional therapy, including RFA, is acceptable for the treatment of HCC arising from CHF when the background liver and kidney are preserved.

No Regional Disparities in Sofosbuvir Plus Ribavirin Therapy for HCV Genotype 2 Infection in Tochigi Prefecture and Its Vicinity.

Objective Regional disparities were observed in the outcomes of interferon (IFN)-based therapy for chronic hepatitis C virus (HCV) infection in a Japanese nationwide study. However, whether or not these regional disparities are observed in the outcomes of direct-acting antiviral drugs, including sofosbuvir (SOF) plus ribavirin (RBV) therapy, remains unclear. Methods We conducted a multicenter study to assess the efficacy of SOF plus RBV therapy for HCV genotype 2 infection in Tochigi Prefecture and its vicinity, in which IFN-based therapy yielded a low sustained virologic response (SVR) rate. In addition, we divided Tochigi Prefecture into six regions to examine regional disparities in the SVR. Patients We enrolled patients with chronic HCV genotype 2 infection. Results Of the 583 patients enrolled, 569 (97.6%) completed the treatment, and 566 (97.1%) also complied with post-treatment follow-up for 12 weeks. The overall SVR12 rate was 96.1% by per protocol and 93.7% by intention-to-treat analyses. No marked differences were observed in the SVR12 between subjects ≥65 and <65 years of age. Although large gaps were observed in the characteristics of patients and accessibility to medical resources, there was no significant difference in the SVR12 rate among the six regions in Tochigi Prefecture. Conclusion SOF plus RBV therapy was effective for HCV genotype 2 infection in an area where IFN-based therapy had previously shown unsatisfactory results. In addition, no regional disparities in the SVR12 were observed in Tochigi Prefecture.

A successful treatment for hepatocellular carcinoma with Osler-Rendu-Weber disease using radiofrequency ablation under laparoscopy.

Hepatocellular carcinoma (HCC) can be difficult to diagnose and treat in patients with Osler-Rendu-Weber disease due to vascular malformation and regenerative nodular hyperplasia. In addition, percutaneous liver puncture should be avoided for the diagnosis and treatment as the procedure carries a high risk of bleeding. We herein report the successful treatment of HCC in a patient with Osler-Rendu-Weber disease using radiofrequency ablation (RFA) under laparoscopy. A 71-year-old man with Osler-Rendu-Weber disease was admitted to our hospital for the treatment of HCC. He also had chronic hepatitis C virus infection. The arterioportal shunts in the liver were detected by computed tomography (CT) and angiography. A tumor 20 mm in size was detected as a defected-lesion in the hepatic segment IV during the portal phase by CT. RFA under laparoscopy was performed for the curative treatment for HCC, with sufficient ablation obtained. Although the blood gushed out from the needle tract at the end of the procedure, complete hemostasis was achieved promptly using coagulation forceps. The post-operative course was favorable. Thus, laparoscopic RFA is a useful treatment modality for HCC in patients with Osler-Rendu-Weber disease, as a hemostasis device can be used with direct visualization.

A 79-year-old Woman with Acute Hepatitis B Caused by the Infection of Subgenotype D1 Hepatitis B Virus in Japan: A Case Study.

A 79-year-old Japanese woman was diagnosed with acute hepatitis B based on laboratory tests showing positivity for IgM-class antibody against hepatitis B virus (HBV) core and hepatitis B surface antigen (HBsAg) as well as elevated transaminases. A phylogenetic analysis revealed that the HBV strain obtained from the patient belonged to genotype D/subgenotype D1, similar to strains circulating in foreign countries but different from those in Japan. The clinical course was favorable. HBsAg became negative within 10 weeks after the onset. To our knowledge, this is the first report of acute hepatitis B caused by subgenotype D1 HBV in Japan.

Short-Term Results of Laparoscopic Radiofrequency Ablation Using a Multipolar System for Localized Hepatocellular Carcinoma.

BACKGROUND AND AIM: Multipolar radiofrequency ablation (RFA) is feasible for the treatment of hepatocellular carcinoma (HCC) for which a large ablative area is planned, and it imposes a light physical burden on patients. Multipolar RFA via the percutaneous approach is performed in the majority of cases, but the efficacy of multipolar RFA with a laparoscopic approach has rarely been studied. This study aimed to evaluate the efficacy and safety of multipolar laparoscopic RFA (LRA) for localized HCC over the short term. METHODS: From January 2014 to January 2016, 77 consecutive patients with 130 HCCs treated by multipolar LRA were assessed. One to three bipolar needle applicators were inserted under laparoscopic ultrasonography guidance, regardless of tumor location. We intended to achieve parallel insertions and no-touch ablation as much as possible. RESULTS: The median size of the main tumor was 22 mm (range, 10-42 mm). The median follow-up time was 13.6 months (range, 3.1-24.8 months). In all cases, a sufficient ablative area was obtained as planned, without thermal injury of adjacent organs. During the follow-up period, all patients were alive with no local tumor progression, while intrahepatic recurrence distant from the primary site occurred in 7 patients. The 2-year local tumor progression-free survival rate and overall cancer-free survival rate were 100 and 81.6%, respectively. There were no procedural major complications caused prolonging the hospitalization, and all patients were discharged without subjective symptoms 4-7 days after LRA. CONCLUSIONS: Multipolar LRA was efficacious in the treatment of localized HCCs by safely achieving a good ablative area.

A case of small hepatocellular carcinoma treated with laparoscopic multipolar radiofrequency ablation with a no-touch ablation procedure.

A 77-year-old man with hepatocellular carcinoma was admitted to our institution. Computed tomography revealed two nodules, one at the surface and one within the liver, ≤3 cm in diameter. We performed laparoscopic radiofrequency ablation using a bipolar system with a "no-touch ablation" procedure using multiple applicators for insertion, not into the tumor directly, but to the perimeter of the tumor. A sufficient ablated area was obtained regardless of tumor location. No operative complications were encountered and adequate therapeutic effect was achieved safely. Laparoscopic multipolar radiofrequency ablation is a feasible procedure for treating hepatocellular carcinoma.