Yoshihiko Tachi

Impact of amino acid substitutions in the hepatitis C virus genotype 1b core region on liver steatosis and hepatic oxidative stress in patients with chronic hepatitis C

Background: Liver steatosis and hepatic oxidative stress are the histopathological features of chronic hepatitis C. Hepatitis C virus (HCV) genotype 1 core protein induces hepatic steatosis and reactive oxygen species production in transgenic mice. The amino acid substitutions in the HCV core region appear to be related to hepatocarcinogenesis.

Progressive fibrosis significantly correlates with hepatocellular carcinoma in patients with a sustained virological response

Hepatocellular carcinoma develops even in some patients who achieve a sustained virological response following treatment for hepatitis C virus infection. This study investigated the relationship between changes in fibrosis, as assessed by sequential biopsies, and development of hepatocellular carcinoma in patients who achieved a sustained virological response for hepatitis C virus.

Prevalence of hepatitis C virus genotype 1a in Japan and correlation of mutations in the NS5A region and single-nucleotide polymorphism of interleukin-28B with the response to combination therapy with pegylated-interferon-alpha 2b and ribavirin†

Hepatitis C virus (HCV) genotype 1a is rare in Japanese patients and the clinical characteristics of this genotype remain unclear. The interferon (IFN) sensitivity‐determining region (ISDR) and single‐nucleotide polymorphisms (SNPs) of interleukin‐28B (IL28B) among patients with HCV genotype 1b are associated with IFN response, but associations among patients with genotype 1a are largely unknown. This study investigated the clinical characteristics of genotype 1a and examined whether genomic heterogeneity of the ISDR and SNPs of IL28B among patients with HCV genotype 1a affects response to combination therapy with pegylated‐IFN‐α2b and ribavirin. Subjects comprised 977 patients infected with HCV genotype 1, including 574 men and 412 women (mean age, 55.2 ± 10.6 years). HCV was genotyped by direct sequencing of the 5′‐untranslated region and/or core regions and confirmed by direct sequencing of the NS5A region. HCV genotypes 1a (n = 32) and 1b (n = 945) were detected. Twenty‐three (71.9%) of the 32 patients with genotype 1a were patients with hemophilia who had received imported clotting factors. Prevalence of genotype 1a after excluding patients with hemophilia was thus 0.9%. Of the 23 patients with genotype 1a who completed IFN therapy, 11 (47.8%) were defined as achieving sustained virological response. Factors related to sustained virological response by univariate analysis were IL28B and ISDR. In conclusion, HCV genotype 1a is rare in Japan. The presence of IL28B genotype TT, and more than two mutations, in the ISDR are associated with a good response to IFN therapy in patients with HCV genotype 1a. J. Med. Virol. 84:438–444, 2012.

Efficacy and tolerability of an IFN-free regimen with DCV/ASV for elderly patients infected with HCV genotype 1B

BACKGROUND & AIMS Anti-hepatitis C virus (HCV) therapy by interferon (IFN)-free regimen with oral direct-acting antiviral drugs are tolerable in aged patients, with fewer adverse effects than IFN-based therapies. We investigated the efficacy and tolerability of an IFN-free anti-HCV therapy in extremely aged patients, as well as the survival benefit of sustained virologic response (SVR). METHODS Following IFN-free therapy with daclatasvir and asunaprevir, tolerability and SVR rate were compared between 115 HCV genotype 1-infected patients aged 80years or older, 151 patients in their 70s (⩾70 and <80years), and 115 patients under the age of 70. One-year mortality and morbidity in patients aged ⩾80years were compared between SVR patients and propensity score-matched patients with persistent HCV infection. RESULTS The SVR rate was 96.5% in patients ⩾80years, comparable to that in patients aged ⩾70 and <80years (95.4%) and patients aged <70years (93.9%). There were no differences in treatment discontinuation rate (2.6%, 1.3%, and 0.9%, respectively). One-year mortality was significantly lower in SVR patients (2.7%) than in patients with persistent HCV infection (15.3%, p=0.0016). Whereas 1-year mortality due to liver-related diseases was 8.1% in patients with persistent HCV infection who were aged ⩾80years, no SVR patients died from liver diseases within 1-year after the end of therapy. CONCLUSIONS IFN-free therapy for HCV infection was associated with high tolerability and antiviral efficacy, even in patients aged ⩾80years. In addition, there seemed to be a survival benefit from the eradication of HCV in this population. LAY SUMMARY IFN-free therapy with oral direct-acting antiviral drugs (daclatasvir and asunaprevir) for HCV infection showed similar tolerability and antiviral efficacy in patients aged ⩾80years as in younger patients (patients aged ⩾70 and <80years and patients aged <70years), with an SVR rate over 90% and no severe adverse effects. There was a survival benefit from the eradication of HCV even in patients aged ⩾80years.

Characteristics and Prognosis of Hepatocellular Carcinoma Detected in Patients with Chronic Hepatitis C after the Eradication of Hepatitis C Virus: a Multicenter Study from Japan

We investigated the characteristics and prognosis of patients with hepatocellular carcinoma (HCC) diagnosed after sustained virological response (SVR) to antiviral therapy for chronic hepatitis C virus (HCV) infection, namely, the eradication of HCV, according to surveillance status after SVR.

Liver stiffness measurement using acoustic radiation force impulse elastography in hepatitis C virus‐infected patients with a sustained virological response

Acoustic radiation force impulse (ARFI) elastography is a non‐invasive method for measuring liver stiffness. However, there are no reports evaluating the value of ARFI elastography for liver fibrosis in chronic hepatitis C patients with a sustained virological response (SVR).

Predictive Ability of Laboratory Indices for Liver Fibrosis in Patients with Chronic Hepatitis C after the Eradication of Hepatitis C Virus.

Liver fibrosis remains an important risk factor for hepatocarcinogenesis in patients with chronic hepatitis C even after the eradication of hepatitis C virus (HCV). However, it is difficult to estimate liver fibrosis based on liver biopsy after the eradication of HCV. We investigated the ability of laboratory indices to predict liver fibrosis in patients with sustained virologic response (SVR) to antiviral therapy. Three laboratory liver fibrosis indices (aspartate aminotransferase-platelet ratio index (APRI), FIB-4 index, and Forns index) were calculated based on data at the time of initial pretreatment liver biopsy and at second liver biopsy performed approximately 5 years after SVR in 115 patients who underwent serial liver biopsies. The indices at the time of initial biopsy were compared to histological degree of liver fibrosis in initial biopsy, and laboratory indices at the time of second liver biopsy were compared to the degree of fibrosis in second biopsy. In both comparisons, there were significant increases in all 3 indices with the increase of liver fibrosis grade as assessed in liver biopsy specimens. All 3 indices at the time of second biopsy were able to predict moderate to advanced (METAVIR score F2-4) and advanced (F3-4) fibrosis on liver biopsy, with the area under the receiver-operating characteristics curve >0.8 and the accuracy >70%. All 3 laboratory indices of fibrosis accurately reflected liver fibrosis in patients with SVR for 5 years despite the normalization of serum liver transaminase activity and the lack of liver inflammation.

Liver stiffness reduction correlates with histological characteristics of Hepatitis C patients with sustained virological response

We investigated the correlation between histological characteristics and changes in liver stiffness (LS) in patients with sustained virological response (SVR) using acoustic radiation force impulse (ARFI) elastography.

A comparison of direct sequencing and Invader assay for Y93H mutation and response to interferon-free therapy in hepatitis C virus genotype 1b

Virologic failure of interferon‐free therapy has been associated with Y93H mutation in the non‐structure 5A region in hepatitis C virus (HCV) genotype 1b, and screening is recommended. A simple assay based on Q‐Invader technology was developed for Y93H mutant screening to reduce cost and effort. The present study sought to compare two methods of detection of Y93H mutation and to evaluate the effect of Y93H mutation on response to interferon‐free therapy.

Liver fibrosis indices for identifying patients at low risk of developing hepatocellular carcinoma after eradication of HCV.

BACKGROUND Hepatocellular carcinoma (HCC) in patients with chronic hepatitis C can develop after sustained virological response (SVR) to antiviral therapy for HCV, that is, the eradication of HCV, and effective surveillance systems for HCC should be established for this population. We retrospectively evaluated the utility of three laboratory liver fibrosis indices (aspartate aminotransferase-platelet ratio index [APRI], FIB-4 index and Forns index) for identifying patients at low risk of HCC development after SVR, for whom the termination of surveillance for HCC can be considered. METHODS APRI, FIB-4 index and Forns index scores were calculated based on laboratory data prior to anti-HCV therapy and at 24 weeks after the end of anti-HCV therapy (SVR24) in 522 patients with SVR who continued surveillance for HCC after SVR. The associations between HCC development and laboratory indices at both points were analysed. RESULTS Twenty-one patients developed HCC after SVR during 2.3-24.4 years follow-up. Whereas HCC developed even in patients with low APRI or FIB-4 index scores, no patients with low Forns index scores developed HCC after SVR. These results were confirmed in a separate cohort of 309 patients who achieved SVR (HCC developed in 17 patients during 1.7-21.6 years follow-up). CONCLUSIONS Forns index, especially assessed prior to anti-HCV therapy, was a useful laboratory liver fibrosis index for identifying patients at low likelihood of HCC after SVR. This index may be used as one of indicators to consider the termination of surveillance for HCC after the eradication of HCV.