Akio Miyasaka

Epidemiological and clinical study of sporadic acute hepatitis E caused by indigenous strains of hepatitis E virus in Japan compared with acute hepatitis A.

BackgroundWe compared acute hepatitis E (AH-E) and acute hepatitis A (AH-A) to investigate the epidemiology, clinical features, and prognosis of AH-E caused by an indigenous hepatitis E virus (HEV) in Japan.MethodsWe enrolled 58 patients diagnosed with AH-A or AH-E (32 men and 26 women; age, 20–72 years) from December 1997 to October 2002. Phylogenetic analysis of the partial 412-nucleotide sequence of open reading frame (ORF) 2 was performed in patients with AH-E.ResultsRegarding the geographic distribution of the HEV genotype, genotype III was principally distributed in Honshu Island, and genotype IV in Hokkaido Island (P = 0.0034). The phylogenetic analysis of the ORF2 region revealed that there were significant geographic differences in the distribution of the HEV strains in Japan, with some strains being widespread and some, localized. In comparison with AH-A patients, those with AH-E were older (56.1 ± 10.6 vs 45.9 ± 10.8 years; P = 0.0017). The proportion of males among patients with AH-E was significantly higher (P = 0.0001). Pyrexia was often observed in AH-A, and malaise in AH-E. Laboratory data indicate that AH-E induces a weak immunological reaction, whereas jaundice appears earlier in AH-E than in AH-A. One patient with AH-E died of acute hepatic failure, but none of those with AH-A died during the study period.ConclusionsOur results suggest that there are geographical differences between HEV strains in Japan, and that AH-E is more common in males and older patients than AH-A. Laboratory data indicate a weak immunological reaction and early appearance of jaundice in AH-E.

Visualizing the hepatic vascular architecture using superb microvascular imaging in patients with hepatitis C virus: A novel technique.

AIM To identify the hepatic vascular architecture of patients with hepatitis C virus (HCV) using superb microvascular imaging (SMI) and investigate the use of SMI in the evaluation of liver fibrosis. METHODS SMI was performed in 100 HCV patients. SMI images were classified into five types according to the vascular pattern, and these patterns were compared with the fibrosis stage. Moreover, the images were analyzed to examine vascularity by integrating the number of SMI signals in the region of interest ROI [number of vascular trees (VT)]. The number of VT, fibrosis stage, serum parameters of liver function, and CD34 expression were investigated. RESULTS There was a significant difference between SMI distribution pattern and fibrosis stage (P < 0.001). The mean VT values in each of the fibrosis stages were as follows: 26.69 ± 7.08 in F0, 27.72 ± 9.32 in F1, 36.74 ± 9.23 in F2, 37.36 ± 5.32 in F3, and 58.14 ± 14.08 in F4. The VT showed excellent diagnostic ability for F4 [area under the receiver operator characteristic (AUROC): 0.911]. The VT was significantly correlated with the CD34 labeling index (r = 0.617, P < 0.0001). CONCLUSION SMI permitted the detailed delineation of the vascular architecture in chronic liver disease. SMI appears to be a reliable tool for noninvasively detecting significant fibrosis or cirrhosis in HCV patients.

Identification of amino acids in antigen-binding site of class II HLA proteins independently associated with hepatitis B vaccine response

BACKGROUND & AIMS Genetic factors in class II human leukocyte antigen (HLA) have been reported to be associated with inter-individual variation in hepatitis B virus (HBV) vaccine response. However, the mechanism underlying the associations remains elusive. In particular, the broad linkage disequilibrium in HLA region complicates the localization of the independent effects of genetic variants. Thus, the present study aimed to identify the most probable causal variations in class II HLA loci involved in the immune response to HBV vaccine. METHODS We performed a case-control study to assess whether HLA-DRB1, -DQB1, and -DPB1 4-digit alleles were associated with the response to primary HBV vaccination in 574 healthy Japanese students. To identify causative variants, we next assessed independently associated amino acid variants in these loci using conditional logistic regression analysis. Furthermore, to clarify the functional effects of these variants on HLA proteins, we performed computational structural studies. RESULTS HLA-DRB1∗01:01, HLA-DRB1∗08:03, HLA-DQB1∗05:01, and HLA-DPB1∗04:02 were significantly associated with sufficient response, whereas HLA-DPB1∗05:01 was associated with poor response. We then identified amino acids independently associated with sufficient response, namely, leucine at position 26 of HLA-DRβ1 and glycine-glycine-proline-methionine at positions 84-87 of HLA-DPβ1. These amino acids were located in antigen-binding pocket 4 of HLA-DR and pocket 1 of HLA-DP, respectively, which are important structures for selective binding of antigenic peptides. In addition, the detected variations in HLA-DP protein were responsible for the differences in the electrostatic potentials of the pocket, which can explain in part the sufficient/poor vaccine responses. CONCLUSION HLA-DRβ1 position 26 and HLA-DPβ1 positions 84-87 are independently associated with anti-HBs production against HBV vaccine. Our results suggest that HBsAg presentation through these HLA pocket structures plays an important role in the inter-individual variability of HBV vaccination.

Serum markers for mitochondrial dysfunction and cell death are possible predictive indicators for drug-induced liver injury by direct acting antivirals

We prospectively screened patients treated with direct‐acting antivirals (DAA) in order to detect and analyze serum markers that are present prior to the development of drug‐induced liver injury (DILI).

Icteric acute hepatitis E with no response of immunoglobulin M class anti‐hepatitis E virus antibody

A 68‐year‐old Japanese man developed icteric acute hepatitis during periodic care after undergoing gastrectomy due to early gastric cancer. The routine serological markers for hepatitis A, B and C viruses were all negative. Although the liver enzymes spontaneously recovered without any specific therapy, cholestasis was relatively prolonged and successfully treated with prednisolone. Determination of serum hepatitis E virus (HEV) RNA revealed the transient infection of HEV, and both immunoglobulin (Ig)A and IgG class anti‐HEV antibodies were detected after the disease onset, whereas those were negative when measured 3 weeks prior to the onset. In addition, the titer of serum IgA class antibody was associated with the clinical signs of hepatitis. In contrast, no IgM class antibody was detected throughout the course. This case suggests that screening only with IgM class antibody is not sufficient to detect acute HEV infection.

Clinical and molecular analyses of sporadic acute hepatitis A and E and the specific viral genotypes isolated in Iwate and three neighboring prefectures in the northern part of Honshu, Japan, between 2004 and 2013

To examine the prevalence and characteristics of hepatitis A virus (HAV) and hepatitis E virus (HEV) infections in the northern part of Honshu, Japan, during the last decade.

Accuracy of 2D shear wave elastography in the diagnosis of liver fibrosis in patients with chronic hepatitis C

This prospective study was conducted to assess the diagnostic accuracy of two‐dimensional shear wave elastography (2D SWE) in the diagnosis of liver fibrosis in patients with chronic liver disease and hepatitis C virus (HCV) compared with the serum liver fibrosis biomarkers using the results of liver biopsy as the reference standard.

The Real-world Efficacy and Safety of Ombitasvir/Paritaprevir/Ritonavir for Hepatitis C Genotype 1

Objective There are few reports on the outcomes of 12-week paritaprevir, ombitasvir, and ritonavir (PTV/OBV/r) treatment in real-world clinical settings. We aimed to evaluate the efficacy and safety of 12-week treatment with ritonavir-boosted paritaprevir and ombitasvir in patients with hepatitis C virus (HCV) genotype 1 infection in a real-world setting. Methods Fifty-eight patients with chronic hepatitis or compensated hepatic cirrhosis and genotype-1 HCV infection were treated with PTV/OBV/r and followed for 24 weeks after the completion of treatment in 10 centers in northern Tohoku. The efficacy and safety of this 12-week treatment regimen was analyzed. Results Among the 58 treated patients, 18 (31%) had compensated liver cirrhosis, while 11 (19%) patients had experienced treatment failure with another treatment regimen. NS5A resistance-associated variants (RAVs) were detected at baseline in 3 patients (5.2%), including Y93H in two patients and L31M in two patients. One patient had NS5A RAVs at both positions 93 and 31. The overall sustained virological response (SVR) 24 rate was 96.6%. Three patients with NS5A RAVs also achieved an SVR24. The SVR24 rate was not significantly affected by age, sex, prior treatment, prior history of HCC, or liver stiffness. The mean alanine aminotransferase (ALT) levels decreased significantly during this treatment. Adverse events occurred in 15 patients (26%), 26% of which were grade 1 or 2. No severe adverse events occurred. Conclusion In this real-world study, 12-week PTV/OBV/r treatment was effective and safe for treating patients with HCV-1 infection who had chronic hepatitis or compensated hepatic cirrhosis.

Fatal acute hepatic failure in a family infected with the hepatitis A virus subgenotype IB: A case report.

Rationale: Hepatitis A viral infection is a well-known cause of subclinical or acute self-limited hepatitis. Few cases of hepatitis A virus (HAV)–associated acute liver failure (ALF) have been reported in low HAV endemic countries annually. Patients concerns: To investigate the possible factors that affected the severity of HAV infection, a family cluster infected with the HAV subgenotype IB strain, which is not common in Japan, was described. Diagnoses: This family consisted of five members who all were infected with HAV. Interventions: Four of the five patients hospitalized except for an asymptomatic patient. Outcomes: Two of the five patients, men in their 50s and 60s, developed ALF, and one patient died. Various host factors, including sex (male), age, and a high bilirubin level, may affect the outcomes. Based on viral factors, HAV RNA was higher in the fatal case compared with others, and it decreased within a short period of time. The similarity of the nucleotide sequences was 99.9% among the HAV isolates based on an entire genomic sequence. Deletions and/or insertions on the HAV protein-coding sequences that caused a frameshift were found in surviving cases but not in the fatal case. Lessons: The rapid clearance of increased HAV and the absence of defective HAV might be closely associated with the onset of liver failure.

Viral decline over 48h and HCV amino acid mutations are related to efficacy of PEG-IFN/ribavirin.

BACKGROUND/AIMS The relationship between mutations and HCV dynamics has not been fully studied in terms of the efficacy of PEG-IFN/Rib combination treatment. Here we aimed to systematically examine HCV dynamics during PEG-IFN/Rib treatment and evaluate the association between amino acid (aa) substitutions in HCV and efficacy of PEG-IFN/Rib treatment. METHODOLOGY Patients (n=36) having HCV genotype 1b infection and high viral loads with PEG-IFN/Rib for 48 weeks were treated. HCV RNA levels were quantified every 24h from 0-144h after initial injection of PEGIFN and every month thereafter. The aa substitutions in HCV core region (CoreR) and interferon sensitivity determining region (ISDR) were determined at baseline. On the basis of treatment response, we divided patients into 3 groups: sustained virological response (SVR: n=18), transient response (TR: n=9) and no response (NR: n=9). RESULTS Patients with double wild type (DW) in CoreR had higher SVR rate as compared to patients with non-double wild type (NDW) in CoreR (58% vs. 33%). Patients with =2 aa substitutions in ISDR had significantly higher SVR rate compared with patients with =1 aa substitution in ISDR (71% vs. 36%). Further, 68% patients who exhibited =2-log decline in HCV-RNA levels within the initial 48h of treatment achieved SVR, and only 18% patients who reached <2 log declines did not achieve SVR. Patients who reached =2 log declines in HCV-RNA levels within the initial 48h of treatment with DW in CoreR or =2 aa substitutions in ISDR could achieve SVR and those with NDW in CoreR or =1 aa substitution in ISDR could not achieve SVR. CONCLUSIONS The combination of the apparent =2-log decline in HCV RNA level within the initial 48h and aa substitutions in CoreR and ISDR may be useful predictors of PEG-IFN/Rib treatment.