Tasuku Hara

Complicated relationships of amino acid substitution in hepatitis C virus core region and IL28B genotype influencing hepatocarcinogenesis

The impact of amino acid (aa) 70 substitution in the core region on hepatocarcinogenesis and survival for liver‐related death in patients of hepatitis C virus (HCV) genotype 1b (HCV‐1b), who had not received antiviral therapy, is unknown. The relationships among aa 70 substitution, IL28B genotype, and hepatocarcinogenesis are also not clear. A total of 1,181 consecutive HCV‐infected patients, who had not received antiviral therapy, were included in a follow‐up study to determine predictive factors of hepatocarcinogenesis and survival for liver‐related death. The cumulative hepatocarcinogenesis rates in HCV‐1b of Gln70(His70) (glutamine (histidine) at aa 70) were significantly higher than those in HCV‐1b of Arg70 (arginine at aa 70) and HCV‐2a/2b. The cumulative survival rates for liver‐related death in HCV‐1b of Gln70(His70) were significantly lower than those in HCV‐1b of Arg70 and HCV‐2a/2b. Multivariate analysis identified gender (male), age (≥60 years), albumin (<3.9 g/dL), platelet count (<15.0 × 104/mm3), aspartate aminotransferase (≥67 IU/L), and HCV subgroup (HCV‐1b of Gln70(His70)) as determinants of both hepatocarcinogenesis and survival rates for liver‐related death. In HCV‐1b patients, the cumulative change rates from Arg70 to Gln70(His70) by direct sequencing were significantly higher than those from Gln70(His70) to Arg70. In patients of Arg70 at the initial visit, the cumulative change rates from Arg70 to Gln70(His70) in IL28B rs8099917 non‐TT genotype were significantly higher than those in the TT genotype. Conclusion: Substitution of aa 70 in the core region of HCV‐1b is an important predictor of hepatocarcinogenesis and survival for liver‐related death in HCV patients who had not received antiviral therapy. The IL28B genotype might partly affect changes over time of dominant amino acid in core aa 70 of HCV‐1b. (HEPATOLOGY 2012;56:2134–2141)

Emergence of telaprevir-resistant variants detected by ultra-deep sequencing after triple therapy in patients infected with HCV genotype 1

Using ultra‐deep sequencing technology, the present was designed to investigate whether the emergence of telaprevir‐resistant variants (amino acid substitutions of aa36, aa54, aa155, aa156, and aa170 positions in HCV NS3 region) after commencement of triple therapy of telaprevir/peginterferon (PEG‐IFN)/ribavirin could be predicted at baseline in previous non‐responders to dual therapy. Fourteen patients infected with HCV genotype 1 who did not respond to previous PEG‐IFN/ribavirin, received a 24‐week regimen of triple therapy, and were evaluated for appearance of telaprevir‐resistant variants (amino acid substitutions of more than 0.2% among the total coverage) by ultra‐deep sequencing. The sustained virological response rate was 28.6% (4 of 14 patients), which was significantly higher in patients with Arg70 (substitution at core aa70) and partial response (type of previous response to PEG‐IFN/ribavirin) than in other patients. Telaprevir‐resistant variants at baseline were detected in 7.1% (1 of 14 patients) by direct sequencing and in 21.4% (3 of 14 patients) by ultra‐deep sequencing. The appearance of telaprevir‐resistant variants was examined by ultra‐deep sequencing in 10 who did not show sustained virological responders. De novo variants emerged at re‐elevation of viral load, regardless of variant frequencies at baseline (one patient with very high frequency variants [T54S: 99.9%], two patients with very low frequency variants [V36A: 0.2%; and V170A: 0.4%], and seven patients of undetectable variants). It is concluded that it is difficult to predict at baseline the emergence of telaprevir‐resistant variants after commencement of triple therapy in prior non‐responders of HCV genotype 1, even with the use of ultra‐deep sequencing. J. Med. Virol. 85: 1028–1036, 2013.

Lower levels of insulin‐like growth factor‐1 standard deviation score are associated with histological severity of non‐alcoholic fatty liver disease

Growth hormone (GH) deficiency may be associated with histological progression of non‐alcoholic fatty liver disease (NAFLD) which includes non‐alcoholic fatty liver (NAFL) and non‐alcoholic steatohepatitis (NASH). Insulin‐like growth factor 1 (IGF‐1) is mainly produced by hepatocytes and its secretion is stimulated by GH. Our aim was to determine whether more histologically advanced NAFLD is associated with low circulating levels of IGF‐1 in Japanese patients.

Lower circulating levels of dehydroepiandrosterone, independent of insulin resistance, is an important determinant of severity of non-alcoholic steatohepatitis in Japanese patients

Aim:  The biological basis of variability in histological progression of non‐alcoholic fatty liver disease (NAFLD) remains unknown. Dehydroepiandrosterone (DHEA), the most abundant steroid hormone, has been shown to influence sensitivity to reactive oxygen species, insulin sensitivity and expression of peroxisome proliferator‐activated receptor‐α. Our aim was to determine whether more histologically advanced NAFLD is associated with low circulating levels of DHEA in Japanese patients.

Potential of a no‐touch pincer ablation procedure for small hepatocellular carcinoma that uses a multipolar radiofrequency ablation system: An experimental animal study

Treatment of hepatocellular carcinoma located on the liver surface is frequently difficult because direct puncture of the tumor must be avoided during needle insertion. The aim of this study was to investigate the utility of a no‐touch pincer ablation procedure that uses a multipolar radiofrequency ablation (RFA) system for a tumor located on the liver surface.

Antitumor efficacy of transcatheter arterial chemoembolization with warmed miriplatin in hepatocellular carcinoma

Patients with unresectable hepatocellular carcinoma (HCC) often undergo transcatheter arterial chemoembolization (TACE). Miriplatin is a lipophilic cisplatin derivative used in TACE that is effective in HCC. However, the difference in antitumor efficacy between warmed versus room temperature miriplatin is unclear.

Effectiveness and safety of reduced-dose telaprevir-based triple therapy in chronic hepatitis C patients.

To compare the early virological effectiveness, sustained virological response and safety of telaprevir 1500 mg/day with telaprevir 2250 mg/day, when combined in triple therapy with pegylated interferon and ribavirin in Japanese patients with high viral loads of genotype 1 hepatitis C virus.

Serum alanine aminotransferase predicts the histological course of non‐alcoholic steatohepatitis in Japanese patients

Some cases with non‐alcoholic fatty liver disease (NAFLD), particularly non‐alcoholic steatohepatitis (NASH), can ultimately progress to liver cirrhosis. However, studies to clarify factors predictive of histological change in patients with NASH remain scarce. Our aim is to determine predictors of histological progression in Japanese patients with biopsy‐proven NASH.

Effect of sodium glucose cotransporter 2 inhibitor on liver function tests in Japanese patients with non-alcoholic fatty liver disease and type 2 diabetes mellitus.

No pharmacological therapies have been established for non‐alcoholic fatty liver disease (NAFLD). Sodium glucose cotransporter 2 inhibitor (SGLT2I) was developed for the treatment of adults with type 2 diabetes mellitus (T2DM). The aim of this retrospective study is to evaluate the efficacy of SGLT2I in NAFLD patients with T2DM.Aims No pharmacological therapies have been established for nonalcoholic fatty liver disease (NAFLD). Sodium glucose co-transporter 2 inhibitor (SGLT2I) developed for the treatment of adults with type 2 diabetes (T2DM). The aim of this retrospective study is to evaluate the efficacy of SGLT2I in NAFLD patients with T2DM Methods Twenty-four biopsy-proven NAFLD patients with T2DM who received SGLT2I for 24 weeks were retrospectively enrolled as the SGLT2I group. Another 21 NAFLD patients with T2DM treated with dipeptidyl peptidase-4 inhibiter (DPP4I, sitagliptin) for 24 weeks were selected as the DPP4I group. Clinical data were evaluated at baseline and at 4, 12, 24 weeks. Seventeen patients in SGLT2I group were evaluated body composition (Inbody 720) before and after therapy. Results Not only body weight and HbA1c but also transaminase activities were significantly decreased in the SGLT2I group. Reductions in transaminase activities were similar between SGLT2I and DPP4I groups. In the SGLT2I group, body mass index　and fasting plasma glucose also decreased after the treatment. Conclusion SGLT2I can be a novel promising agent for the treatment for NAFLD patients with T2DM. Prospective randomized controlled trial are warranted to confirm this efficacy of SGLT2I on NAFLD with T2DM.

Correlation between hepatitis B virus surface antigen level and alpha‐fetoprotein in patients free of hepatocellular carcinoma or severe hepatitis

Alfa‐fetoprotein (AFP) is used as a marker of early hepatocarcinogenesis. However, the impact of hepatitis B virus surface antigen (HBsAg) on this relationship in patients with HBV infection is not clear. The present study evaluated the relation between HBsAg and AFP levels at the initial visit in 1,610 untreated HBV patients, free of hepatocellular carcinoma (HCC) or severe hepatitis. The cumulative rate of HCC was significantly lower in patients with a low AFP level (≤10 µg/L; below the upper limit of normal) than in those with a high AFP level (≥11 µg/L) at the initial visit. In patients with HBsAg levels more than 500 IU/ml, HBsAg levels correlated significantly and negatively with AFP levels, and significantly with platelet count. Multivariate analysis of data of patients with HBsAg more than 500 IU/ml identified HBsAg (<7,000 IU/ml), albumin (<3.9 g/dl), platelet count (<20.0 × 104/mm3), gamma‐glutamyl transpeptidase (≥50 IU/L), aspartate aminotransferase (≥34 IU/L), HBeAg (positive), and HBV core‐related antigen (≥3.0 log U/ml) as determinants of a high AFP. Especially, in patients with HBsAg more than 500 IU/ml and low transaminase levels (below the upper limit of normal), HBsAg was identified as significant determinant of a high AFP. On the other hand, in patients with HBsAg less than 500 IU/ml, multivariate analysis identified albumin, gamma‐glutamyl transpeptidase, and HBV core‐related antigen as determinants of a high AFP. The results indicated that HBsAg level seems to affect, at least in part, the AFP levels, and that it can be used as a surrogate marker of early hepatocarcinogenesis. J. Med. Virol. 86:131–138, 2014.