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We examined whether hepatitis C virus (HCV) genotype 1b core- and NS5A-region mutations are associated with response to peginterferon α-2b plus ribavirin combination therapy. A total of 103 patients with high HCV genotype 1b viral loads (≥100 KIU/mL) were treated with the combination therapy. Pretreatment mutations in the core region and interferon sensitivity determining region (ISDR) in the NS5A region were analyzed. In univariate analysis, arginine and leucine at positions 70 and 91 in the core region, defined as double wild (DW)-type, were associated with early virologic response (p = 0.002), sustained virologic response (SVR) (p = 0.004), and non-response (p = 0.005). Non-threonine at position 110 was associated with SVR (p = 0.004). Multivariate analysis showed the following pretreatment predictors of SVR: hemoglobin level ≥ 14 g/dL (odds ratio (OR) 6.2, p = 0.04); platelet count ≥ 14 × 104/mm3 (OR 5.2, p = 0.04); aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio < 0.9 (OR 6.17, p = 0.009); DW-type (OR 6.8, p = 0.02); non-threonine at position 110 (OR 14.5, p = 0.03); and ≥2 mutations in the ISDR (OR 12.3, p = 0.02). Patients with non-DW-type, non-threonine at position 110, and

Direct-acting antivirals with or without peginterferon α (PEG-IFN α) plus ribavirin are now available for the treatment of hepatitis C virus (HCV) infection. Direct-acting antivirals are potent inhibitors of HCV replication, but some of them occasionally possess serious adverse events. We experienced a 64-year-old female with chronic HCV genotype 1b infection who showed elevated alanine aminotransferase of 528 IU/l at week 9 after the commencement of treatment of simeprevir with PEG-IFN α-2a plus ribavirin. However, she achieved sustained virological response at week 24 after the end of treatment. In Japan, we also have to treat elderly patients infected with HCV and/or advanced hepatic fibrosis. Until an effective interferon-free regimen is established, direct-acting antivirals with PEG-IFN plus ribavirin may still play a role in the treatment for certain patients. To avoid serious results from adverse events, careful attention and follow-up will be needed in the treatment course of simeprevir with PEG-IFN plus ribavirin for chronic HCV infection.

We retrospectively reviewed 413 recipients with hematologic malignancies who underwent hematopoietic stem cell transplantation (HSCT) between June 1986 and March 2013. Recipients with antibody to hepatitis B core antigen (anti-HBc) and/or to hepatitis B surface antigen (anti-HBs) were regarded as experiencing previous hepatitis B virus (HBV) infection. Clinical data of these recipients were reviewed from medical records. We defined ≥1 log IU/mL increase in serum HBV DNA from nadir as HBV reactivation in hepatitis B surface antigen (HBsAg)-positive recipients, and also defined ≥1 log IU/mL increase or re-appearance of HBV DNA and/or HBsAg as HBV reactivation in HBsAg-negative recipients. In 5 HBsAg-positive recipients, 2 recipients initially not administered with nucleos(t)ide analogues (NUCs) experienced HBV reactivation, but finally all 5 were successfully controlled with NUCs. HBV reactivation was observed in 11 (2.7%) of 408 HBsAg-negative recipients; 8 of these were treated with NUCs, and fortunately none developed acute liver failure. In 5 (6.0%) of 83 anti-HBc and/or anti-HBs-positive recipients, HBV reactivation occurred. None of 157 (0%) recipients without HBsAg, anti-HBs or anti-HBc experienced HBV reactivation. In HSCT recipients, HBV reactivation is a common event in HBsAg-positive recipients, or in HBsAg-negative recipients with anti-HBc and/or anti-HBs. Further attention should be paid to HSCT recipients with previous exposure to HBV.

The use of phlebotomy is relatively common for ‘difficult-to-treat by antiviral therapies' hepatitis C virus (HCV)-infected patients and for certain patients having chronic liver diseases with an iron overload of the liver. In the present study, we retrospectively analyzed patients treated with phlebotomy and their adverse events. We observed the occurrence and recurrence of hepatocellular carcinoma, and the appearance of ascites in some patients infected with HCV as well as the reduction of serum ferritin and alanine aminotransferase levels. Severe adverse events necessitating a cessation of phlebotomy occurred independently of α-fetoprotein (≥10 ng/ml) in patients infected with HCV according to multivariate logistic regression analysis. These findings may serve as a basis for phlebotomy especially in older patients with chronic hepatitis C.

Some patients with alcohol dependence may initially present with atypical laboratory and histological features resembling autoimmune hepatitis (AIH) or drug-induced liver injury (DILI). Even with liver biopsy, it may be difficult to diagnose certain patients with alcohol dependence. However, careful follow-up of our patient and consultations with the attending psychiatrist were successful in diagnosing alcohol dependence and its liver injury. The immune mechanisms of alcoholic liver diseases, AIH and DILI may be overlapping. Certain patients are suffering from AIH with flares on a background of alcohol abuse. Certain patients with alcohol abuse may have a past history of DILI. This might be consistent with the fact that alcohol dependence initially presents with atypical laboratory features of AIH or DILI. With careful observation, the clinician should remind himself that alcohol dependence is not always required for developing liver disease, since many patients with liver disease do not meet the criteria for alcohol dependence.

It has been reported that inosine triphosphatase (ITPA) gene variants protect against ribavirin-induced anemia in patients treated for chronic hepatitis C. IL28B variants also influence the treatment response of peginterferon plus ribavirin treatment in these patients. In the present study, we examined how ITPA and IL28B genotypes have clinical impacts on treatment-induced hematotoxicities and treatment response in HCV-infected patients treated with peginterferon plus ribavirin. ITPA genotypes (rs1127354 and rs6051702) and IL28B genotype (rs8099917) were determined by TaqMan SNP assay. We compared clinical background, treatment course and treatment response in terms of these genotypes. Only IL28B rs8099917 major type could predict sustained virological response. ITPA rs1127354 major type leads to significantly greater ribavirin-induced anemia than ITPA rs1127354 minor type between days 0 and 84. We noticed that IL28B rs8099917 minor genotype was associated with higher reduction of neutrophils and platelets. ITPA rs1127354 is useful for the prediction of ribavirin-induced anemia in the early phase after the commencement of peginterferon plus ribavirin treatment and IL28B rs8099917 is useful for the prediction of sustained virological response. Use of the combination of these two genotypes could lead to safe and effective treatment of chronic hepatitis C patients.

Antimitochondrial antibody (AMA) is one of the representative features of primary biliary cirrhosis (PBC). PBC is a female-dominant disease usually presenting intrahepatic bile duct destruction, cholestasis and fibrosis with or without chronic nonsuppurative destructive cholangitis. We presented the case of a 63-year-old man with acute liver failure who had AMA, pronounced alanine aminotransferase elevation and high bilirubinemia. We administered corticosteroids and rescued this patient without liver transplantation. It is well known that some patients within the spectrum of autoimmune liver disease present with characteristics of both PBC and autoimmune hepatitis. Although corticosteroids may be associated with a significant worsening of adverse events in patients with PBC, if acute liver failure in AMA-positive cases is progressive, the administration of corticosteroids has to be considered, as well as the preparation of urgent liver transplantation.

The aim of this study was to characterize the treatment response and tolerability of sofosbuvir plus ribavirin therapies in Japanese patients infected with hepatitis C virus (HCV) genotype (GT)-2. This retrospective study analyzed 114 Japanese HCV GT-2 patients treated for 12 weeks with 400 mg of sofosbuvir plus weight-based ribavirin daily. This treatment led to higher sustained virologic response at 12-weeks post-treatment (SVR12) rates in both treatment-naïve and treatment-experienced patients. The efficacy of this treatment in compensated cirrhotics was the same as that in patients with chronic hepatitis. HCV GT-2a infection and lower estimated glomerular filtration rates (eGFR) tended to be associated with SVR12. Of 114 patients, 113 completed the combination of sofosbuvir plus ribavirin for 12 weeks. Seven patients without SVR12 did not have HCV NS5B-S282 mutations. The overall SVR12 rate was 90.4% (103 of 114). More effective therapeutic options with less adverse events are desired to achieve higher SVR rates in HCV GT-2 Japanese patients.

Determination of hepatitis C virus (HCV) genotypes plays an important role in the direct-acting agent era. Discrepancies between HCV genotyping and serotyping assays are occasionally observed. Eighteen samples with discrepant results between genotyping and serotyping methods were analyzed. HCV serotyping and genotyping were based on the HCV nonstructural 4 (NS4) region and 5′-untranslated region (5′-UTR), respectively. HCV core and NS4 regions were chosen to be sequenced and were compared with the genotyping and serotyping results. Deep sequencing was also performed for the corresponding HCV NS4 regions. Seventeen out of 18 discrepant samples could be sequenced by the Sanger method. Both HCV core and NS4 sequences were concordant with that of genotyping in the 5′-UTR in all 17 samples. In cloning analysis of the HCV NS4 region, there were several amino acid variations, but each sequence was much closer to the peptide with the same genotype. Deep sequencing revealed that minor clones with different subgenotypes existed in two of the 17 samples. Genotyping by genome amplification showed high consistency, while several false reactions were detected by serotyping. The deep sequencing method also provides accurate genotyping results and may be useful for analyzing discrepant cases. HCV genotyping should be correctly determined before antiviral treatment.

Aim. Eradication of hepatitis C virus (HCV) is still challenging even if interferon- (IFN-) free regimens with direct-acting antiviral agents (DAAs) for HCV-infected individuals are available in clinical practice. IFNL4 is a newly described protein, associated with human antiviral defenses. We investigated whether IFNL4 ss469415590 variant has an effect on the prediction of treatment response in HCV-infected patients treated with IFN-including regimens. Patients and Methods. In all, 185 patients infected with HCV genotype 1 treated with peg-IFN plus ribavirin, with or without telaprevir, were genotyped for IFNL4 ss469415590. We retrospectively investigated whether the role of IFNL4 ss469415590 variant and other factors could predict sustained virological response (SVR) in Japanese patients infected with HCV genotype 1. Results. There were 65.7%, 31.5%, and 2.8% patients in the IFNL4 ss469415590 TT/TT, TT/-G, and -G/-G groups, respectively. SVR rates were 82.1% or 49.3% in patients treated with peg-IFN plus ribavirin with or without telaprevir, respectively. IFNL4 ss469415590 variant and HCV viral loads or IFNL4 ss469415590 variant and early virological response were better predictors of SVR in patients treated with peg-IFN plus ribavirin with or without telaprevir, respectively. Conclusion. In the era of DAAs, measurement of IFNL4 ss469415590 variant could help the prediction of SVR in Japanese HCV genotype 1 infected individuals treated with IFN-including regimens.

BACKGROUND:We investigated associations between signal transducer and activator of transcription (STAT) 1 in pretreated liver tissues, interleukin (IL) 28B polymorphism and treatment response in hepatitis C virus (HCV)-infected patients treated with peginterferon and ribavirin. METHODS AND FINDINGS:We performed immunostaining analysis of STAT1 in liver tissues and determined IL28B polymorphism at rs8099917. We then compared the results with treatment outcomes in HCV genotype 1 patients with high viral load who were receiving peginterferon plus ribavirin. In univariate analysis, younger age, white blood cell counts, virological responder, early virological responder (EVR), mild activity (A1) of liver inflammation grading, and lower STAT1 nuclear-stain of hepatocytes in zone 1, zone 2 and total zones of liver were associated with sustained virological responder (SVR). Multivariate analysis showed that EVR, age and hepatic STAT1 nuclear-stain in zone 2 of liver were independent predictors of SVR. It was also revealed that IL28B and STAT1-nuclear translocation in hepatocytes are independent predictors of response to treatment with peginterferon and ribavirin in chronic hepatitis C patients. CONCLUSIONS:Concomitant assessment of lower STAT1 nuclear-stain of hepatocytes and IL28B polymorphism is useful for prediction of SVR in HCV genotype 1 patients.

The aim of the study was to analyze genotype I hepatitis A virus (HAV) 5' nontranslated region (NTR) sequences from a recent outbreak in South Korea and compare them with reported sequences from Japan. We collected a total of 54 acute hepatitis A patients' sera from HAV genotype I [27 severe disease (prothrombin time INR ≥ 1.50) and 27 mild hepatitis (prothrombin time INR

Some patients infected with hepatitis C virus (HCV) genotype 2 could be cured with treatment shorter than 24 weeks using peginterferon plus ribavirin, but there are still treatment-refractory patients. Direct-acting antivirals (DAAs) are not currently available for HCV genotype 2 patients, different from genotype 1 patients, in clinical practice. We investigated 29 HCV genotype 2-infected Japanese patients who had been previously treated and failed to clear HCV. We retreated them with peginterferon alfa-2a plus ribavirin and measured HCV RNA level to assess the efficacy and safety of this treatment in patients who had failed previous therapy. We found that retreatment of HCV genotype 2-infected Japanese patients with peginterferon alfa-2a plus ribavirin for 24-48 weeks led to 60 to 66.6% sustained virological response (SVR) in patients previously treated with (peg-)interferon monotherapy and to 69.9% SVR in relapsers previously treated with peginterferon plus ribavirin. Attention should be paid to certain patients with unique features. Selection of patients according to their previous treatment could lead to optimal therapy in HCV genotype 2 treatment-experienced patients.

Background/Aims: Spontaneous acute exacerbation of chronic hepatitis B virus (HBV) infection occasionally occurs in its natural history, sometimes leading rapidly to fatal hepatic failure. We compared the effects of lamivudine (LAM) with those of entecavir (ETV) treatments in acute exacerbation of chronic hepatitis B with 500 IU/L or higher alanine aminotransferase (ALT) levels.Methods: Thirty-four patients with acute exacerbation were consecutively treated with LAM /ETV. Their clinical improvements were compared.Results: Among LAM-treated and ETV-treated patients, none showed a reduction of Conclusions: ETV appears to be as effective as LAM in the treatment of patients with acute exacerbation of chronic hepatitis B. Clinicians should carefully start to treat these patients as soon as possible.