Mariko Kobayashi

Toranomon Hospital, Edo, Tōkyō, Japan

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Publications (226)655.97 Total impact

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    ABSTRACT: Background: Rate of hepatitis B surface antigen (HBsAg) seroclearance was determined in 2,112 Japanese patients with chronic hepatitis B who were followed up for at least 15 years. Methods: Patients had a median age of 37 years and included 1,431 (67.8 %) men. Median values were AST/ALT, 43/62 IU/L; platelet counts, 182 × 10(3)/mm(3); HBsAg, 3,400 IU/mL; and hepatitis B virus (HBV) DNA, 6.2 log copies/mL. Factors influencing HBsAg seroclearance were evaluated by the Cox proportional model and annual rate of HBsAg seroclearance by the Kaplan-Meier life table method. Results: The overall annual rate of HBsAg seroclearance was 1.75 % in 2,112 patients; it was 1.65 % in 1,130 untreated and 2.05 % in 982 treated patients (p = 0.289). In untreated patients, seroclearance was influenced by age, no HBV infections in third-degree or closer relatives, and HBsAg levels in univariate analysis. Seroclearance was influenced by a median age ≥50 years [relative risk (RR) 1.61 (p = 0.018)] and HBsAg ≤2,000 IU/mL [RR 1.77 (p = 0.014)] in multivariate analysis. In treated patients, age, male gender, no HBV infections in third-degree or closer relatives, interferon therapy, chronic hepatitis, high AST and γ-GTP levels, low platelet counts, hepatitis B e antigen (HBeAg)-negative status, low HBsAg levels and the wild-type precore sequence significantly influenced HBsAg seroclearance. In multivariate analysis, no family history [RR 2.22 (p = 0.006)], interferon treatment [RR 3.15 (p < 0.001)], and HBeAg-negative status [RR 3.75 (p < 0.001)] significantly influenced HBsAg seroclearance. Conclusions: In this retrospective cohort study, the annual rate of HBsAg seroclearance was 1.65 % in untreated patients and 2.05 % in treated patients.
    No preview · Article · Jun 2013 · Journal of Gastroenterology
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    ABSTRACT: It is often difficult to predict the response to telaprevir/peginterferon (PEG-IFN)/ribavirin therapy and appearance of telaprevir-resistant variants. The present study determined the predictive factors of sustained virological response (SVR) to 12- or 24-week triple therapy (T12PR12 or T12PR24) in 194 Japanese patients infected with hepatitis C virus (HCV) genotype 1b. The study also evaluated whether ultra-deep sequencing technology can predict the emergence of resistant variants at baseline. Analysis of data of the entire group indicated that SVR was achieved by 78% of the patients. Multivariate analysis identified IL28B rs8099917 (genotype TT), substitution of aa70 (Arg70), response to prior treatment (naive or relapse), PEG-IFN dose (≥1.3 μg/kg), and treatment regimen (T12PR24) as significant determinants of SVR. Among patients of the T12PR24 group, 92% with genotype TT achieved SVR, irrespective of substitution of aa70. In patients with genotype non-TT, SVR was 76% for those of Arg70; while only 14% of patients with genotype non-TT, Gln70(His70) and non-response to ribavirin combination therapy achieved SVR. Ultra-deep sequencing was conducted in 17 patients who did not achieve SVR to determine the emergence of resistant variants during therapy. De novo resistant variants were detected in 16 of 17 patients (94%), regardless of variants frequencies at baseline. In conclusion, the results indicated that the response to triple therapy could be predicted by the combination of host, viral, and treatment factors, and that it is difficult to predict at baseline the emergence of telaprevir-resistant variants during triple therapy, even with the use of ultra-deep sequencing.
    Preview · Article · Jun 2013 · Journal of clinical microbiology
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    ABSTRACT: 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. © 2013 Wiley Periodicals, Inc.
    No preview · Article · Jun 2013 · Journal of Medical Virology
  • Yasuji Arase · Mariko Kobayashi · Hiromitsu Kumada

    No preview · Article · May 2013 · Hepatology
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    ABSTRACT: Background: Renal dysfunction and Fanconi's syndrome associated with hypophosphatemia caused by long-term administration of low-dose adefovir dipivoxil (ADV) has been reported in recent years. The aim of this retrospective study was to determine the incidence and factors associated with renal dysfunction and hypophosphatemia in patients with hepatitis B infection on long-term treatment with ADV and lamivudine (LAM). Methods: The study subjects were 292 patients treated with 10 mg/day ADV and 100 mg/day LAM for more than 6 months. We evaluated estimated glomerular filtration rate (eGFR), serum creatinine and serum phosphate level at the start of ADV and every 6 months. Result: During a median treatment duration of 64 months, 28 (9.6 %) patients developed renal impairment (defined as eGFR < 50 ml/min/1.73 m(2)), and 73 (27.1 %) developed hypophosphatemia, including 14 with persistent hypophosphatemia. The cumulative incidences of renal impairment at 1, 3, and 5 years were 1.4, 7.5, 10.5 %, respectively, and those of hypophosphatemia were 6.8, 20.6, 26.7 %, respectively. Multivariate analysis identified old age, liver cirrhosis and hypertension as determinants of renal impairment, and male sex, HCC, low baseline serum phosphate as determinants of hypophosphatemia. Three of the 14 patients with persistent hypophosphatemia developed Fanconi's syndrome; their serum creatinine level remained normal, but eGFR was lower than at baseline. Conclusion: Long-term treatment of hepatitis B with low-dose (10 mg/day) ADV and LAM can potentially cause renal impairment and hypophosphatemia. We advocate regular monitoring of serum phosphate and evaluation of eGFR, in addition to serum creatinine, in such patients.
    No preview · Article · Mar 2013 · Journal of Gastroenterology
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    ABSTRACT: AimThe aim of this case-control study was to assess the efficacy and safety of dipeptidyl peptidase-4 inhibitor (sitagliptin) for type 2 diabetes mellitus (T2DM) with non-alcoholic fatty liver disease (NAFLD). Methods Twenty NAFLD patients with T2DM treated by sitagliptin were retrospectively enrolled as the sitagliptin group. These patients were given sitagliptin between January 2010 and July 2011. Another 20 NAFLD patients with T2DM treated only with diet and exercise for 48weeks were selected as the control group. Serum levels of fasting plasma glucose (FPG), hemoglobin A1C (HbA1c), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured before and 12, 24, 36 and 48weeks after the initiation of treatment. ResultsIn the sitagliptin group, average HbA1c levels decreased approximately 0.7% at 48weeks after the initiation of sitagliptin. Next, average FPG levels decreased approximately 15mg/dL at 48weeks after the initiation of sitagliptin. The serum levels of HbA1c and FPG in the sitagliptin group decreased with statistical significance compared to those in the control group (P<0.05). All the patients could take sitagliptin of 50mg/day without reduction necessitated by sitagliptin-related side-effects. There were no significant changes of average AST and ALT levels during follow up of 48weeks in both sitagliptin and control groups. Conclusion Our results indicate sitagliptin is effective and safe for the treatment of T2DM complicated with NAFLD.
    No preview · Article · Mar 2013 · Hepatology Research
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    ABSTRACT: Unlabelled: The aim of this retrospective cohort study was to assess the cumulative development incidence and predictive factors for malignancies after the termination of interferon (IFN) therapy in Japanese patients for hepatitis C virus (HCV). A total of 4,302 HCV-positive patients treated with IFN were enrolled. The mean observation period was 8.1 years. The primary outcome was the first onset of malignancies. Evaluation was performed using the Kaplan-Meier method and Cox proportional hazard analysis. A total of 606 patients developed malignancies: 393 developed hepatocellular carcinoma (HCC) and 213 developed malignancies other than HCC. The cumulative development rate of HCC was 4.3% at 5 years, 10.5% at 10 years, and 19.7% at 15 years. HCC occurred significantly (P<0.05) when the following characteristics were present: advanced histological staging, sustained virological response not achieved, male sex, advanced age of ≥50 years, total alcohol intake of ≥200 kg, and presence of type 2 diabetes (T2DM). T2DM caused a 1.73-fold enhancement in HCC development. In patients with T2DM, HCC decreased when patients had a mean hemoglobin A1c (HbA1c) level of <7.0% during follow-up (hazard ratio, 0.56; 95% confidence interval, 0.33-0.89; P=0.015). The cumulative development rate of malignancy other than HCC was 2.4% at 5 years, 5.1% at 10 years, and 9.8% at 15 years. Malignancies other than HCC occurred significantly when patients were of advanced age of ≤50 years, smoking index (package per day×year) was ≥20, and T2DM was present. T2DM caused a 1.70-fold enhancement in the development of malignancies other than HCC. Conclusion: T2DM causes an approximately 1.7-fold enhancement in the development of HCC and malignancies other than HCC in HCV-positive patients treated with IFN. In T2DM patients, maintaining a mean HbA1c level of <7.0% reduces the development of HCC.
    No preview · Article · Mar 2013 · Hepatology
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    ABSTRACT: Unlabelled: 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 × 10(4) /mm(3) ), 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.
    Preview · Article · Dec 2012 · Hepatology
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    ABSTRACT: The aims of this study are to assess the antiviral effects, safety and telaprevir (TVR) pharmacokinetics in two cohorts given TVR every 8 h (q8h) at doses of 500 mg and 750 mg with peginterferon-α-2b and ribavirin in chronic hepatitis C patients. Twenty chronic hepatitis C (HCV) patients with genotype 1b in high viral loads were randomly assigned to two TVR-based regimens of 750 mg q8h (group A) and 500 mg q8h (group B) in combination with peginterferon-α-2b and ribavirin for 12 weeks. Although the difference was not statistically significant other than trough concentration (Ctrough) at week 4, the parameters of maximum concentration (Cmax), the area under the concentration time curve (AUC0–∞) and Ctrough tended to be higher in group A than those in group B. The antiviral effects were similar in the two groups (sustained virological response rates [SVR], 40% in group A, 50% in group B). The discontinuation rates by anemia were 30% in group A and 20% in group B. Serum creatinine concentrations were lower in group B than those in group A. Although the exposure to TVR tended to be lower in 500 mg q8h than that in 750 mg q8h, the SVR rates in both groups were similar. The result suggests that the 500 mg q8h dose may be one option for treatment. In addition, the present findings indicate that the development of adverse events which increase with a TVR-based regimen, specifically anemia and creatinine, could be avoided by dose adjustment of TVR.
    No preview · Article · Nov 2012 · Hepatology Research
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    ABSTRACT: Hepatitis C virus (HCV) is a major worldwide public health problem, and mutations at amino acids 70 and 91 in the genotype 1b core region predict the effectiveness of combination therapy with peginterferon and ribavirin. An assay based on the Q-Invader technology was developed to determine the relative ratios of the mutant to wild-type virus with high sensitivity. The assay detected a minor type plasmid that constituted only 1% of a mixture of plasmids containing wild-type and mutant sequences. The calculated ratios agreed with those of the template DNA. A total of 123 serum samples of HCV in Japan were examined with the Q-Invader assay. The Q-Invader assay detected all of the mutations that were detected by direct sequencing and even some mutants that direct sequencing could not. PCR with mutant specific primers confirmed those mutations found by the Q-Invader assay and not by direct sequencing. The Q-Invader assay, thus, is a useful tool for detecting mutations at positions 70 and 91 in the HCV-1b core region.
    No preview · Article · Nov 2012 · Journal of virological methods
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    ABSTRACT: Background: Clearance of hepatitis B surface antigen (HBsAg) is considered the ultimate goal in chronic hepatitis B treatment. One treatment option is long-term nucleot(s)ide analog (NA) therapy. We followed a group of long-term NA therapy patients to evaluate the efficacy of this treatment in promoting clearance and longitudinal declines of HBsAg. Method: The study included 791 NA therapy patients who received lamivudine as their first drug. At the baseline, 442 patients were hepatitis B e antigen (HBeAg)+ and 349 were HBeAg-. All analyses were performed after separating the HBeAg+ and HBeAg- cohorts. Cox proportional hazards models were used to determine which factors were associated with HBsAg clearance. Results: HBsAg clearance was observed in 18 (4.1 %) of the HBeAg+ patients and 20 (5.7 %) of the HBeAg- patients at baseline, giving seroclearance rates of 6.4 and 6.9 %, respectively, over the nine-year study period. HBsAg clearance was influenced by several independent factors that varied according to HBeAg cohort. For HBeAg+ patients, these included previous interferon therapy, infection with hepatitis B virus (HBV) genotype A, a ≥0.5 log IU/mL decline in HBsAg level within six months, and clearance of HBeAg at six months. For HBeAg- patients, these included infection with HBV genotype A, decline in HBsAg at six months, and a baseline HBsAg level of <730 IU/mL. Conclusion: This study suggests that both direct antiviral potential and host immune response are needed to achieve HBsAg clearance by NA therapy. Viral genotype strongly influenced HBsAg clearance during NA therapy.
    No preview · Article · Oct 2012 · Journal of Gastroenterology
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    ABSTRACT: Objective: Anticarcinogenic activity of ribavirin combination therapy for hepatitis C virus (HCV)-related compensated cirrhosis is still unclear. Methods: In study 1, in 157 consecutive patients with HCV-related compensated cirrhosis, treatment efficacy with interferon plus ribavirin therapy was evaluated for 48 weeks of HCV genotype 1b (HCV-1b) or 24 weeks of HCV-2a/2b. In study 2, in 185 consecutive patients with HCV-related compensated cirrhosis, who showed no sustained virological response following the first course of interferon monotherapy, hepatocarcinogenesis rates were evaluated according to the additional treatment, and they were classified into three groups: no treatment, interferon monotherapy, and ribavirin combination therapy. Results: In study 1, in HCV-1b, rates of sustained virological response and sustained biochemical response were 21 and 56%, respectively. In HCV-2a/2b, rates of sustained virological response and sustained biochemical response were 70 and 78%, respectively. In HCV-1b, sustained biochemical response rates were significantly higher than those of sustained virological response. In study 2, the hepatocarcinogenesis rates in ribavirin combination therapy were significantly lower than those in interferon monotherapy and no treatment, respectively. Conclusion: Ribavirin combination therapy for HCV-related compensated cirrhosis reduces the risk of hepatocarcinogenesis in comparison with interferon monotherapy, and higher rates of sustained biochemical response might be associated with lower hepatocarcinogenesis rates.
    No preview · Article · Oct 2012 · Intervirology
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    ABSTRACT: The impacts of IL28B genotype to treatment response of hepatitis C virus (HCV) genotype 2 are still not clear. A total of 381 consecutive Japanese patients infected with HCV genotype 2, who could complete combination therapy with interferon (IFN) plus ribavirin for 24 weeks, were evaluated to investigate pretreatment predictors. Patients, who could not achieve sustained virological response at the first course of 24-week IFN plus ribavirin, were recruited into the study protocol of total 48-week IFN plus ribavirin. In 24-week regimen, rates of sustained virological response and rapid virological response were 82% and 50%, respectively. There were no significant differences in rates of sustained virological response and rapid virological response, according to IL28B genotype. Multivariate analysis identified younger age, higher level of albumin, absence of past history of IFN, and lower level of viremia as significant determinants of sustained virological response. As significant or marginal significant determinants of non-sustained virological response regardless of rapid virological response, multivariate analysis identified IL28B rs8099917 genotype TG + GG and lower level of albumin. In 48-week regimen to 10 patients of non-sustained virological response at the first course of 24-week regimen, sustained virological response rates were 70%. All of six patients, with IL28B TT and relapse at the first course of 24-week regimen, could achieve sustained virological response, but two patients with IL28B TG could not achieve sustained virological response. In conclusion, the present results suggest that IL28B genotype might partly affect viral response of HCV genotype 2 to combination therapy.
    No preview · Article · Oct 2012 · Journal of Medical Virology
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    ABSTRACT: Cyclooxygenase (COX)-2 is involved in inflammation, anti-apoptosis and carcinogenesis. The -1195GG genotype of single nucleotide polymorphism (SNP) in COX-2 promoter was associated with low platelet counts in patients with chronic hepatitis C. Polymorphism of patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene (rs738409 C>G) have been reported to be associated with cirrhosis, and the major genotype of SNPs near interleukin (IL)28B are related to viral clearance. The present study was designed to assess the contribution of these SNPs to disease progression in patients with chronic hepatitis C. The study enrolled 220 Japanese patients with chronic hepatitis C. Three SNPs, -1195 COX-2, PNPLA3 and IL28B (rs8099917), were genotyped in order to analyze their association with hepatic fibrosis and inflammation. The -1195GG genotype in COX-2 was associated with advanced fibrosis and higher levels of inflammation in the liver tissues. The major genotype of IL28B was also associated with advanced fibrosis, but the polymorphism of PNPLA3 was neither associated with fibrosis nor inflammation. Multivariate analysis showed that -1195GG in COX-2 is an independent factor associated with advanced fibrosis, while the major genotype of IL28B and HCV genotype 2 were other independent factors. In conclusion, the -1195GG genotype in COX-2 is a genetic marker for liver disease progression, while the PNPLA3 genotypes are not associated with disease progression in Japanese patients with chronic hepatitis C.
    No preview · Article · Sep 2012 · Journal of Viral Hepatitis
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    ABSTRACT: Background: Substitution of amino acid 70 and/or 91 in the core region of hepatitis C virus (HCV) genotype 1b (HCV-1b) is an important predictor of hepatocellular carcinoma (HCC), but its impact on HCC in nonresponders to interferon (IFN) and ribavirin (RIB) combination therapy is not clear. Methods: A total of 292 patients with HCV-1b-related chronic liver disease who did not achieve a sustained virological response to 24-48 weeks of IFN+RIB combination therapy were included in a follow-up study to investigate the risk factors for HCC. Results: Sixteen patients developed HCC during the follow-up. The cumulative HCC rates were 5.0, 13.1 and 16.9% at the end of 3, 5 and 7 years, respectively. Multivariate analysis identified substitution of core amino acid 70 (Gln70/His70; hazard ratio 4.64, p = 0.018) and low serum levels of high-density lipoprotein cholesterol (<50 mg/dl; hazard ratio 9.35, p = 0.041) as determinants of HCC. Gender, stage of fibrosis and interleukin-28B showed no such relationship. Conclusions: Amino acid substitution in the core region of HCV-1b and low serum levels of high-density lipoprotein cholesterol are significant and independent predictors of HCC in nonresponders to IFN+RIB combination therapy. These results emphasize the importance of viral and lipid metabolic factors in the development of HCC after combination therapy.
    No preview · Article · Aug 2012 · Intervirology
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    ABSTRACT: The aims of this study were to evaluate the efficacy of long-term interferon (IFN) monotherapy on hepatocellular carcinoma (HCC) in patients who showed no virological response to the first course of IFN therapy, define predictive factors for HCC in patients on long-term IFN monotherapy, and evaluate the clinical impact of amino acid (aa) substitutions in the hepatitis C virus (HCV)-1b core region on HCC rate. This retrospective study included 494 consecutive treatment-naive patients infected with HCV-1b who failed to achieve sustained virological response after ≥24-week IFN monotherapy. Of 494 patients, 113 (22.9%) received another course of ≥48-week IFN monotherapy (additional-IFN group), while the remaining 381 (77.1%) received no such therapy (no-additional-IFN group), and 10 years have elapsed since the end of the first IFN monotherapy. The cumulative HCC rate was significantly higher in the no-additional-IFN group than additional-IFN group, and in those with aa substitutions in the core region of Gln70(His 70) and Met 91 than those with Arg 70 and/or Leu 91. Multivariate analysis identified stage of liver fibrosis, liver enzymes, age, treatment group, aa substitution in the core region, low-density lipoprotein cholesterol (LDL-cholesterol), and gender as determinants of HCC, and that additional IFN treatment significantly lowered the cumulative rate of HCC, even in patients with cirrhosis. In conclusion, long-term IFN monotherapy reduces the risk of HCC, even in patients with cirrhosis. Substitution of aa at position 70 and/or 91 in the core region and lipid metabolism are important predictors of HCC in long-term IFN monotherapy.
    No preview · Article · Aug 2012 · Journal of Medical Virology
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    ABSTRACT: Aim: To evaluate the efficacy of natural human interferon (IFN)-β and ribavirin in elderly patients infected with hepatitis C virus (HCV) genotype 2 and high virus load. Methods: Inclusion criteria were age of 65 years or older, HCV genotype 2 and serum HCV RNA level of 5.0 logIU/mL or more. A total of 33 were enrolled in this retrospective cohort study. IFN-β was administrated i.v. at a dose of 6 million units daily for 4 weeks initially, followed by three times a week for 20 weeks. Ribavirin was given daily for 24 weeks at the dose described based on bodyweight. Fifteen patients were given a standard dose of ribavirin (standard group). Eighteen patients were given a reduction dose of ribavirin that decreased by one tablet per day compared to the standard group (reduction group). Results: Of the 33 study patients, no patient stopped the treatment due to treatment-related adverse events. The dose of IFN-β was reduced in three patients: Two patients belonged to the standard group and one patient belonged to the reduction group. The dose of ribavirin was reduced in 11 patients during combination therapy: nine patients belonged to the standard group and two patients belonged to the reduction group. The sustained virological response (SVR) was 72.2% (13/18) in the reduction group and 80.0% (12/15) in the standard group. There was no significant difference in SVR rate between the reduction and standard groups (P = 0.699). Conclusion: The reduction therapy of IFN-β and ribavirin in elderly chronic hepatitis C patients with genotype 2 and high virus load is one selection of treatment.
    No preview · Article · Aug 2012 · Hepatology Research
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    ABSTRACT: Patients who do not achieve sustained virological response to telaprevir/peginterferon (PEG-IFN)/ribavirin need to be identified. Predictive factors of virological response to the triple therapy in non-responders to previous PEG-IFN/ribavirin therapy are not clear. The aims of this study were to determine the predictive factors of virological response to a 24-week regimen of triple therapy in 15 non-responders to previous PEG-IFN/ribavirin therapy among 61 Japanese adults infected with HCV genotype 1. Overall, sustained virological response and end-of-treatment response were achieved by 27% and 60%, respectively. Telaprevir-resistant variants (by direct sequencing) appeared during or after treatment in 82% of patients who did not show sustained virological response, but disappeared at the end of study, except for one patient with resistant variant at baseline. Substitution at aa 70 (Arg70) and type of previous response to PEG-IFN/ribavirin (partial response) were identified as significant determinants of sustained virological response. In addition, alpha-fetoprotein level (<10 µg/L) and type of previous response (partial response) were identified as significant determinants of end-of-treatment response. Prediction of response to therapy based on the combination of these factors had high sensitivity, specificity, positive, and negative predictive values. In conclusion, this study identified amino acid substitution of the core region, alpha-fetoprotein level, and type of previous response as predictors of virological response to telaprevir/PEG-IFN/ribavirin in patients infected with HCV genotype 1b who had not responded to previous PEG-IFN/ribavirin therapy.
    No preview · Article · Jul 2012 · Journal of Medical Virology
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    ABSTRACT: Hepatitis C virus (HCV) of genotype 1b is the most prevalent worldwide, and the least responsive to interferon-based treatments. A combination therapy with two direct-acting antivirals has shown promising results in patients with HCV-1b, but the prevalence of drug-resistant variants before treatment is not known in the Japanese population. To detect HCV variants resistant to NS3 protease inhibitors or the NS5A inhibitor (BMS-790052) in hepatitis patients infected with HCV-1b. Drug-resistant mutations were determined in the 362 hepatitis patients infected with HCV-1b who had not received direct-acting antivirals before. Amino-acid substitutions resistant to NS3 inhibitors (V36A, T54S, Q80H and D168E) were detected in 15 of the 307 (4.9%) patients, who had been examined, and T54S (3.3%) predominated over V36A (0.3%), Q80R (0.7%) and D168E (0.7%) in them. Amino-acid substitutions resistant to BMS-790052 (L31M and/or Y93H) were detected in 33 of the 294 (11.2%) patients, and Y93H (8.2%) predominated over L31M (2.7%). One of the 239 (0.4%) patients, who had been examined for amino-acid substitutions in both NS3 and NS5A regions, possessed HCV-1b variants resistant to NS3 inhibitors (T54S) and BMS-790052 (L31M). Mutations conferring resistance to NS3 inhibitors or BMS-790052 were frequent in our treatment-naive study population, but double mutants with possible resistance to both drugs were rare. Since single mutations did not result in treatment failure in a previous pilot trial combining BMS-790052 and an NS3 inhibitor, larger trials of this drug regimen appear warranted in the Japanese population.
    No preview · Article · Jun 2012 · Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology
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    ABSTRACT: We determined the antiviral potency and viral resistance rate after 4 years of continuous entecavir treatment in patients with chronic hepatitis B (CHB) infection. The cumulative rates of undetectable hepatitis B virus DNA (HBV DNA;<2.6 log(10) copies/ml), hepatitis B e antigen (HBeAg) seronegativity, seroconversion, alanine aminotransferase (ALT) normalization, and entecavir signature mutations were calculated in 474 nucleos(t)ide-naïve CHB patients (HBeAg-positive: 47%) on continuous entecavir treatment for 4 years. Median age was 47 years and follow-up period was 2.4 years, with 403, 281, 165, and 73 patients followed-up for at least 1, 2, 3, and 4 years, respectively. Incremental increases were observed in the rates of undetectable HBV DNA, HBeAg seroclearance and seroconversion, and ALT normalization, reaching 96%, 42%, 38% and 93%, respectively, by the fourth year. In all, 100% and 93% of patients negative and positive for HBeAg, respectively, had undetectable HBV DNA at year 4. Of 165 patients, HBV DNA was detectable in nine patients after 3 years. Multivariate analysis identified HBV DNA level (≤7.6 log(10) copies/ml, OR=15.8; 95% CI=43.1-79.9, P=0.001) as an independent predictor of undetectable HBV DNA at year 3. Five patients experienced virological breakthrough including two (0.4%) who developed entecavir-resistance mutations. Continuous treatment of nucleos(t)ide-naïve CHB patients with entecavir over 4 years was associated with 96% chance of undetectable HBV DNA and only 0.4% chance of emerging entecavir-resistant mutations.
    No preview · Article · May 2012 · Journal of Hepatology