Joji Toyota

Sapporo Kosei General Hospital, Sapporo, Hokkaidō, Japan

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Publications (46)191.43 Total impact

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    ABSTRACT: Daclatasvir combined with asunaprevir is the first all-oral, ribavirin-free treatment of hepatitis C virus genotype 1b infection in Japan. This study compared the efficacy and safety of daclatasvir plus asunaprevir versus telaprevir plus peginterferon/ribavirin in Japanese treatment-naive patients infected with hepatitis C virus genotype 1b. Treatment-naive patients (20-70 years; baseline viral load, ≥100,000 IU/mL) were randomly assigned (stratified by IL28B rs8099917 TT/non-TT status) to receive either daclatasvir 60 mg tablets once daily and asunaprevir 100 mg softgel capsules twice daily for 24 weeks, or telaprevir 750 mg (3 × 250 mg tablets) three times daily for 12 weeks and peginterferon/ribavirin per Japanese prescribing information for 24 weeks. A cohort of prior relapsers to peginterferon/ribavirin (20-75 years; baseline viral load, ≥100,000 IU/mL) received daclatasvir plus asunaprevir. In treatment-naive patients, sustained virologic response at posttreatment week 12 in daclatasvir plus asunaprevir recipients was non-inferior (treatment difference, +25.8% in favor of daclatasvir plus asunaprevir) and higher (89.1%, 106/119) than telaprevir plus peginterferon/ribavirin recipients (62.2%, 69/111); sustained viral response was achieved in 95.5% (n = 21/22) of relapsers. Numerically fewer patients receiving daclatasvir plus asunaprevir compared with telaprevir plus peginterferon/ribavirin experienced serious adverse events (4.2% versus 5.4%), adverse events leading to discontinuation of any drug (5.0% versus 62.2%), grade 3/4 treatment-related adverse events (14.3% versus 72.1%), rash-related events (0% versus 13.5%), or anemia (0% versus 47.7%). Marked differences were observed in the efficacy and safety profile of daclatasvir in combination with asunaprevir, compared with telaprevir plus peginterferon/ribavirin. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Gastroenterology and Hepatology 08/2015; DOI:10.1111/jgh.13073 · 3.63 Impact Factor
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    ABSTRACT: Oral daclatasvir (DCV; pangenotypic NS5A inhibitor) plus asunaprevir (ASV; NS3 protease inhibitor) is approved in Japan and Korea for treatment of chronic hepatitis C virus (HCV) genotype 1. Response to DCV + ASV is affected by DCV resistance-associated polymorphisms (RAPs) in HCV NS5A. The prevalence and influence of these RAPs on 12-week sustained virologic response (SVR12) to DCV + ASV was evaluated in Asian and non-Asian patients. Data were pooled from 5 national and international studies of patients with HCV genotype 1b (GT-1b) receiving DCV + ASV at their recommended doses. Baseline NS5A RAPs and their effect on SVR12 were assessed overall, in older (≥65 years) patients, patients with cirrhosis, and in patients stratified by baseline HCV RNA or prior treatment experience with interferon-based therapy. Baseline NS5A sequences were available from 988 patients (374 Japanese; 125 Korean/Taiwanese; 489 from non-Asian countries), 979 of whom were assessed for SVR12. Pretreatment NS5A-L31F/I/M/V and/or NS5A-Y93H polymorphisms were present in 18% of Japanese and 12-13% of non-Japanese patients; these RAPs reduced SVR12 by 54.9% overall (93.9% [787/838] SVR12 when absent, 39.0% [55/141] SVR12 when present), with comparable reductions observed in Asians and non-Asians and across all categories of treatment experience, age, and cirrhosis. RAP-associated SVR12 rates declined with increasing baseline HCV RNA (SVR12 with RAPs: 64.7% [11/17] at 5-6 log10 IU/mL, 29.8% [14/47] at 7-8 log10). Without baseline RAPs, very high SVR12 rates (92-100%) were observed in older patients and patients with cirrhosis irrespective of national origin, with similarly high rates observed among treatment-naïve and interferon-experienced patients and those with high baseline HCV RNA. Following DCV + ASV treatment, the SVR12 rates in GT-1b patients without baseline NS5A-L31F/I/M/V and/or NS5A-Y93H polymorphisms were very high (approximately 90-100%), irrespective of age, cirrhosis, prior interferon treatment, or baseline HCV RNA. Bristol-Myers Squibb.
    Advances in Therapy 07/2015; DOI:10.1007/s12325-015-0221-5 · 2.44 Impact Factor
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    ABSTRACT: Daclatasvir and asunaprevir is the first all-oral therapy approved in Japan for treating chronic hepatitis C patients with HCV genotype 1b infection. In the phase 3 clinical trial, the dual combination therapy has demonstrated high sustained virologic response (SVR) rates across subgroups based on baseline characteristics (age, gender, IL28B genotype, HCV-RNA load and cirrhotic), however, resistance-associated variant (RAV) s at D168 in NS3 region and at L31/Y93 in NS5A region affected the efficacy. This study evaluated correlation between efficacy of the daclatasvir/asunaprevir combination therapy and HCV NS3/NS5A RAVs detected by PCR-Invader assay for 129 patients enrolled in the phase 2 and 3 trials. The RAVs were determined as negative (<1%), weak positive (1-20%) and positive (20%≤) by signal strength of invader reaction. The incidence rates of D168, L31 and Y93 RAVs by PCR-Invader assay were higher than those by direct sequencing. Especially, D168 RAVs were observed at much higher rate than direct sequencing (28.3% vs 1.6%). SVR rates were 84-95% and 75-88% for D168 or Y93H RAVs negative and weak positive groups, respectively. They were comparative to those in the phase 3 trial. Moreover, SVR rates for D168 RAVs negative and weak positive patients without NS5A L31/Y93 RAVs were 97% and 100%. In Y93H positive cases with direct sequencing or PCR-Invader assay, SVR rates were decreased down to SVR 46-48%. Minor RAVs detected at low level by PCR-Invader assay have less impact on the efficacy with the daclatasvir/asunaprevir treatment.
    Kanzo 01/2015; 56(3):113-115. DOI:10.2957/kanzo.56.113
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    ABSTRACT: AimsThis study assessed the efficacy and safety of telaprevir in combination with peginterferon alfa-2b (PEG-IFN) and ribavirin (RBV), for Japanese difficult-to-treat patients with hepatitis C virus (HCV) genotype 2 who had not achieved sustained virological response (SVR) during prior treatment.Methods In total, 108 relapsed (median age, 59.0 years) and 10 non-responding (median age, 59.0 years) patients with genotype 2 HCV participated. Patients received telaprevir (750 mg, every 8 hours) for 12 weeks and PEG-IFN/RBV for 24 weeks.ResultsThe SVR rates for relapsers and non-responders were 88.0% (95/108) and 50.0% (5/10), respectively. The SVR rates did not differ significantly between patients with rs8099917 TT and non-TT. The SVR rates for relapsers and non-responders with extended rapid viral response (eRVR) were 97.6% (82/84) and 100% (5/5), respectively. On the other hand, the SVR rates for relapsers and non-responders completing the treatment protocol were 98.4% (61/62) and 100% (5/5), respectively. The overall safety profiles of telaprevir-based regimens were similar for Japanese patients with genotype 1 and 2 HCV infection who experienced treatment failure.Conclusion Telaprevir, in combination with PEG-IFN/RBV, provided a high SVR rate for genotype 2 HCV, difficult-to-treat patients who had not achieved SVR during prior IFN-based treatment. The eRVR had a strong influence on the cure rate of telaprevir-based therapy. In addition, the continuation of telaprevir-based treatment for up to 24 weeks was a significant predictor of SVR.
    Hepatology Research 09/2014; 45(7). DOI:10.1111/hepr.12416 · 2.22 Impact Factor
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    ABSTRACT: All-oral combinations of direct-acting antivirals may improve efficacy and safety outcomes for patients with hepatitis C virus (HCV) infection, particularly those who are poor candidates for current interferon/ribavirin-based regimens. In this open-label, phase 3 study, 135 interferon-ineligible/intolerant and 87 nonresponder patients with chronic HCV genotype 1b infection were enrolled at 24 centers in Japan. Patients received daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily for 24 weeks. The primary end point was sustained virologic response 24 weeks after treatment (SVR24 ). This study is registered with (NCT01497834). SVR24 was achieved by 87.4% of interferon-ineligible/intolerant patients and 80.5% of nonresponder (null and partial) patients; rates were similar in cirrhotic (90.9%) and non-cirrhotic (84.0%) patients, and in patients with IL28B CC (84.5%) or non-CC (84.8%) genotypes. Fourteen patients in each group (12.6%) discontinued dual therapy, mainly due to adverse events or lack of efficacy. Nine nonresponder patients received additional treatment with peginterferon/ribavirin per protocol-defined criteria. The rate of serious adverse events was low (5.9%) and varied among patients. The most common adverse events were nasopharyngitis, increased ALT and AST, headache, diarrhea, and pyrexia. Conclusion: Interferon-free, ribavirin-free all oral therapy with daclatasvir and asunaprevir for 24 weeks is well tolerated and can achieve a high rate of SVR in patients with HCV genotype 1b who were ineligible, intolerant, or had not responded to prior interferon-based therapy. (Hepatology 2014;).
    Hepatology 06/2014; 59(6). DOI:10.1002/hep.27113 · 11.19 Impact Factor
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    ABSTRACT: Objectives Pegylated-interferon-α (IFN-α)-based therapies for viral hepatitis C (HCV) are effective, but they are associated with several adverse events (AEs). The primary objectives of this study were to quantify the burden of IFN-α–based treatment and to measure the prevalence and burden of IFN-α–related AEs in Japan. Methods A cross-sectional survey was administered online to patients with HCV in 2013. Patients who were currently taking IFN-α–based therapy (n = 188) were compared with patients who were taking a liver protectant but not IFN-α–based therapy (n = 180) and with patients who were untreated (n = 365) on measures of health-related quality of life (using the Hepatitis Quality of Life Questionnaire, version 2), work productivity, and health care resource use, controlling for sociodemographic characteristics and health history. Among patients taking IFN-α–based therapy, the prevalence and burden of AEs was examined on the same set of health outcomes as noted above along with treatment satisfaction and adherence. Results Compared with untreated patients, patients using IFN-α reported poorer health-related quality of life (physical component summary score, 50.13 vs. 52.04; mental component summary score, 44.12 vs. 47.97), more overall work impairment (32.73 vs. 25.64), more physician visits in the past 6 months (14.51 vs. 8.36), and an increased likelihood of an emergency room visit (odds ratio = 7.25) and hospitalization (odds ratio = 4.05) (all P < 0.05). The mean number of AEs was 6.05 for patients using IFN-α. All AEs were associated with poorer health outcomes (particularly the mental component summary score), and most were also associated with lower treatment satisfaction and medication adherence. Conclusions A significant patient burden for IFN-α treatment itself and various AEs was observed. The results suggest that effective, non-IFN-α–based treatments may reduce the societal burden.
    05/2014; 3:50–58. DOI:10.1016/j.vhri.2014.01.002
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    ABSTRACT: Daclatasvir-containing regimens have the potential to address limitations of current regimens combining peginterferon alfa and ribavirin with first-generation protease inhibitors for treatment of chronic hepatitis C virus (HCV) genotype 1 infection. In this randomized, double-blind study, 27 Japanese treatment-naive patients received once-daily daclatasvir 10 mg or 60 mg or placebo, each combined with peginterferon alfa-2b/ribavirin; 18 prior null (n=9) or partial (n=9) responders received the same daclatasvir-containing regimens without a placebo arm. Daclatasvir recipients with protocol-defined response (HCV RNA <15 IU/mL at week 4, undetectable at week 12) were treated for 24 weeks; those without protocol-defined response and placebo recipients continued treatment to week 48. Sustained virologic response 24 weeks posttreatment (SVR24) was achieved by 66.7%, 90.0%, and 62.5% of treatment-naive patients in the daclatasvir 10 mg, 60 mg, and placebo groups, respectively. Prior nonresponders had more frequent virologic failure; 22.2% and 33.3% of daclatasvir 10 mg and 60 mg recipients, respectively, achieved SVR24. Adverse events were similar across groups and were typical of peginterferon alfa-2b/ribavirin. Pyrexia, headache, alopecia, decreased appetite, and malaise were the most common adverse events; two daclatasvir recipients discontinued due to adverse events. Daclatasvir 60 mg combined with peginterferon alfa-2b and ribavirin achieved a high rate of SVR24 in treatment-naive patients with HCV genotype 1 infection, with tolerability similar to that of peginterferon alfa-2b/ribavirin alone. However, regimens with greater antiviral potency are needed for prior nonresponders.
    Antiviral therapy 01/2014; 19(5). DOI:10.3851/IMP2730 · 3.14 Impact Factor
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    ABSTRACT: Daclatasvir (DCV; BMS-790052) is a picomolar inhibitor of the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) and has demonstrated efficacy in patients chronically infected with HCV. In the double-blind, randomized studies AI444021 and AI444022, 71 Japanese patients chronically infected with HCV genotype 1 (predominantly genotype 1b) received DCV (10mg or 60mg) plus peginterferon alfa (alfa)-2b or -2a and ribavirin. Virologic failure occurred in 14% (5/36) of treatment-naïve patients and 54% (19/35) of prior alfa/ribavirin nonresponders. Resistance testing was performed on baseline samples and samples with HCV RNA ≥ 1000 IU/mL at Week 1 through posttreatment Week 24. Baseline NS5A resistance-associated polymorphisms had less impact on virologic response rates than IL28B genotype. All patients with virologic failure had NS5A DCV-resistant variants at the time of failure. The predominant NS5A variants were L31V/M/I plus Y93H; this combination was detected in 100% (5/5) treatment-naïve patients and 74% (14/19) of nonresponders with failure. Emergent resistance variants in prior nonresponders (4 viral breakthroughs, 1 relapse) were more varied with novel combinations such as L31F-ΔP32 and L28M-R30Q-A92K detected. Significant loss in DCV antiviral activity was generally only seen with ≥2 resistance-associated NS5A substitutions. All DCV-resistant variants were still detected at end of study. Virologic failure in HCV genotype 1b treatment-naive Japanese patients receiving DCV plus alfa-2a/ribavirin or alfa-2b/ribavirin was associated with enrichment of NS5A resistance variants L31V/M-Y93H. In prior nonresponders, emergent variants associated with failure also included NS5A-A92K or NS5A-ΔP32. As with L31-Y93 variants, these variants persisted.
    Antiviral therapy 01/2014; 19(5). DOI:10.3851/IMP2729 · 3.14 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) establishes a chronic infection in 70-80% of infected individuals. Many researchers have examined the effect of human leukocyte antigen (HLA) on viral persistence because of its critical role in the immune response against exposure to HCV, but almost all studies have proven to be inconclusive. To identify genetic risk factors for chronic HCV infection, we analyzed 458,207 single nucleotide polymorphisms (SNPs) in 481 chronic HCV patients and 2,963 controls in a Japanese cohort. Next, we performed a replication study with an independent panel of 4,358 cases and 1,114 controls. We further confirmed the association in 1,379 cases and 25,817 controls. In the GWAS phase, we found 17 SNPs that showed suggestive association (P < 1 × 10(-5)). After the first replication study, we found one intronic SNP in the HLA-DQ locus associated with chronic HCV infection, and when we combined the two studies, the association reached the level of genome-wide significance. In the second replication study, we again confirmed the association (P combined = 3.59 × 10(-16), odds ratio [OR] = 0.79). Subsequent analysis revealed another SNP, rs1130380, with a stronger association (OR=0.72). This nucleotide substitution causes an amino acid substitution (R55P) in the HLA-DQB1 protein specific to the DQB1*03 allele, which is common worldwide. In addition, we confirmed an association with the previously reported IFNL3-IFNL4 locus and propose that the effect of DQB1*03 on HCV persistence might be affected by the IFNL4 polymorphism. Our findings suggest that a common amino acid substitution in HLA-DQB1 affects susceptibility to chronic infection with HCV in the Japanese population and may not be independent of the IFNL4 genotype.
    PLoS ONE 12/2013; 8(12):e84226. DOI:10.1371/journal.pone.0084226 · 3.23 Impact Factor
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    ABSTRACT: The aim of this study is to explore the efficacy, safety and pharmacokinetics of 750mg telaprevir (TVR) given at 8 or 12 hour intervals during triple therapy with peg-interferon-alfa-2b (PEG-IFN) and ribavirin (RBV) for patients with chronic hepatitis C virus (HCV) infection. 52 patients with high viral loads of genotype 1b who were expected to respond well to therapy (rs8099917 TT genotype or relapse to previous therapy) were randomly assigned to two groups who were given 750mg TVR at either 8 or 12 hour intervals (q8h or q12h) in combination with PEG-IFN and RBV for 12 weeks, followed by an 12 additional weeks of treatment with PEG-IFN and RBV alone. The primary end point of the study was undetectable HCV RNA at 12 weeks after the end of treatment (SVR12). SVR12 rates were 92.3% (24/26) for both q8h and q12h. The changes in mean log10 HCV RNA levels and viral response were also similar in q8h compared to q12h, whereas pharmacokinetic properties such as Cmax, AUC0-24h and Ctrough of TVR were slightly higher in q8h than in q12h (P>0.2). The frequency of TVR discontinuation due to anemia or renal damage was significantly higher in q12h than in q8h (6/26(23%) vs. 0/20, respectively; P=0.02). TVR given at 12 hour intervals should be considered for patients with lower body weight, especially patients with prior relapse and with IL28B polymorphisms at rs8099917 TT (interferon lambda 4 ss469415590 polymorphism TT/TT) genotype in patients with genotype 1b HCV infection.
    Antiviral therapy 11/2013; 19(3). DOI:10.3851/IMP2706 · 3.14 Impact Factor
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    ABSTRACT: BACKGROUND&AIM: We performed a genome-wide association study (GWAS) of hepatitis C virus (HCV)-induced liver cirrhosis (LC) to identify predictive biomarkers for the risk of LC in patients with chronic hepatitis C (CHC). METHOD: A total of 682 HCV-induced LC cases and 1,045 CHC patients of Japanese origin were genotyped by Illumina Human Hap 610-Quad bead Chip. RESULT: Eight SNPs which showed possible associations (P < 1.0 x 10(-5)) in the GWAS stage were further genotyped using 936 LC cases and 3,809 CHC patients. We found that two SNPs within the major histocompatibility complex (MHC) region on chromosome 6p21, rs910049 and rs3135363, were significantly associated with the progression from CHC to LC (P(combined) = 9.15 x 10(-11) and 1.45 x 10(-10), odds ratio (OR) = 1.46 and 1.37, respectively). We also found that HLA-DQA1∗0601 and HLA-DRB1∗0405 were associated with progression from CHC to LC (P = 4.53 x 10(-4) and 1.54 x 10(-4) with OR = 2.80 and 1.45, respectively). Multiple logistic regression analysis revealed that rs3135363, rs910049, and HLA-DQA1∗0601 were independently associated with the risk of HCV-induced LC. In addition, individuals with four or more risk alleles for these three loci have a 2.83-fold higher risk for LC than those with no risk allele, indicating the cumulative effects of these variations. CONCLUSION: Our findings elucidated the crucial roles of multiple genetic variations within the MHC region as prognostic/predictive biomarkers for CHC patients.
    Journal of Hepatology 01/2013; 58(5). DOI:10.1016/j.jhep.2012.12.024 · 10.40 Impact Factor
  • Kanzo 01/2013; 54(9):607-613. DOI:10.2957/kanzo.54.607
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    ABSTRACT: In 18 of 547 patients who had received nucleoside analogue preparations for 1 year or more, multi-drug resistance was detected, after a median follow-up of 53 months. No patient showed liver failure related to multi-drug resistance acquisition. Multi-drug resistance was associated with entecavir (ETV) therapy in 7 lamivudine (LAM) -resistant patients, combination therapy with adefovir dipivoxil (ADV) in 8 LAM-resistant patients, LAM switching to ETV in 2 patients, and initial ETV administration in 1. For treatment, combination therapy with LAM and ADV was performed. In non-responders, combination therapy with ADV and ETV was employed. In all LAM- and ADV-resistant patients, and the HBV DNA level decreased to 3.0LC/ml or less. However, a similar decrease was noted in 7 (58.3%) of 12 LAM- and ETV-resistant patients. Of the 18 patients, 1 did not respond to combination therapy with ADV and ETV. Therapy with tenofovir disoproxil fumarate (TDF) was required.
    Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology 01/2013; 110(1):44-55.
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    ABSTRACT: BACKGROUND & AIMS: Improved therapeutic options for chronic hepatitis C virus (HCV) infection are needed for patients who are poor candidates for treatment with current regimens due to anticipated intolerability or low likelihood of response. METHODS: In this open-label, phase 2a study of Japanese patients with chronic HCV genotype 1b infection, 21 null responders (<2 log(10) HCV RNA reduction after 12 weeks of peginterferon/ribavirin) and 22 patients intolerant to or medically ineligible for peginterferon/ribavirin therapy received dual oral treatment for 24 weeks with the NS5A replication complex inhibitor daclatasvir (DCV) and the NS3 protease inhibitor asunaprevir (ASV). The primary efficacy endpoint was sustained virologic response at 12 weeks posttreatment (SVR(12)). RESULTS: Thirty-six of 43 enrolled patients completed 24 weeks of therapy. Serum HCV RNA levels declined rapidly, becoming undetectable in all patients on therapy by week 8. Overall, 76.7% of patients achieved SVR(12) and SVR(24), including 90.5% of null responders and 63.6% of ineligible/intolerant patients. There were no virologic failures among null responders. Three ineligible/intolerant patients experienced viral breakthrough and four relapsed posttreatment. Diarrhea, nasopharyngitis, headache, and ALT/AST increases, generally mild, were the most common adverse events; three discontinuations before week 24 were due to adverse events that included hyperbilirubinemia and transaminase elevations (two patients). CONCLUSIONS: Dual therapy with daclatasvir and asunaprevir, without peginterferon/ribavirin, was well tolerated and achieved high SVR rates in two groups of difficult-to-treat patients with hepatitis C virus genotype 1b infection.
    Journal of Hepatology 11/2012; 58(4). DOI:10.1016/j.jhep.2012.09.037 · 10.40 Impact Factor
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    ABSTRACT: BACKGROUND AND AIMS: Daclatasvir and asunaprevir are NS5A- and NS3 protease-targeted antivirals currently under development for treatment of chronic hepatitis C virus infection. Clinical data on baseline and on-treatment correlates of drug resistance and response to these agents are currently limited. METHODS: Hepatitis C virus genotype 1b Japanese patients (prior null-responders to peginterferon-alfa/ribavirin [n=21] or peginterferon-alfa/ribavirin ineligible or intolerant [n=22]) were administered daclatasvir/asunaprevir for 24 weeks during a phase 2a open-label study. Genotypic and phenotypic analyses of NS3 and NS5A substitutions were performed at baseline, after virologic failure, and post-treatment through follow-up Week36. RESULTS: There were three viral breakthroughs and four relapsers. Baseline NS3 polymorphisms (T54S, Q80L, V170M) at amino acid positions previously associated with low-level resistance (<9-fold) to select NS3 protease inhibitors were detected in four null-responders and three ineligibles but were not associated with virologic failure. Baseline NS5A polymorphisms (L28M, L31M, Y93H) associated with daclatasvir resistance (<25-fold) were detected in five null-responders and six ineligibles. All three viral breakthroughs and 2/4 relapsers carried a baseline NS5A-Y93H polymorphism. NS3 and NS5A resistance-associated variants were detected together (NS3-D168A/V,NS5A-L31M/V-Y93H) after virologic failure. Generally, daclatasvir-resistant substitutions persisted through 48 weeks post-treatment whereas asunaprevir-resistant substitutions were no longer detectable. Overall, 5/10 patients with baseline NS5A-Y93H experienced virologic failure while 5/10 achieved a sustained virologic response. CONCLUSIONS: The potential association of a pre-existing NS5A-Y93H polymorphism with virologic failure on daclatasvir/asunaprevir combination treatment will be examined in larger studies. The persistence of treatment-emergent daclatasvir- and asunaprevir-resistant substitutions will require assessment in longer-term follow-up studies.
    Journal of Hepatology 11/2012; 58(4). DOI:10.1016/j.jhep.2012.11.012 · 10.40 Impact Factor
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    ABSTRACT: Patients with chronic hepatitis C virus (HCV) infection and previous null response to pegylated interferon (Peg-IFN) and ribavirin (RBV) have limited therapeutic options. HCV genotype 1 is the most common worldwide and the most difficult to treat; genotype 1b is the most common subtype of genotype 1 outside North America. The enhanced antiviral activity achieved by combining two direct-acting antiviral (DAA) agents may improve clinical outcomes. This open-label, phase IIa study included 10 patients with chronic HCV genotype 1b infection and previous null response (<2 log(10) reduction in HCV RNA after 12 weeks) to Peg-IFN and RBV. Patients received dual DAA treatment for 24 weeks with the nonstructural protein 5A replication complex inhibitor, daclatasvir (60 mg once-daily), and the nonstructural protein 3 protease inhibitor, asunaprevir (initially 600 mg twice-daily, then subsequently reduced to 200 mg twice-daily). The primary efficacy endpoint was the proportion of patients with sustained virologic response (SVR) at 12 weeks post-treatment (SVR(12) ). Nine patients completed 24 weeks of treatment; 1 patient discontinued treatment after 2 weeks. In the 9 patients who completed the full course of treatment, HCV RNA was undetectable at week 8 and remained undetectable through the end of treatment; all 9 patients achieved SVR(12) and SVR(24) . HCV RNA also remained undetectable post-treatment in the patient who discontinued after 2 weeks. There was no viral breakthrough. Diarrhea and headache, generally mild, were the most common adverse events; transaminase elevations were reported in 3 patients, but did not result in discontinuation. CONCLUSIONS: Dual therapy with daclatasvir and asunaprevir, without Peg-IFN and RBV, can achieve high SVR rates in difficult-to-treat patients with HCV genotype 1b infection and previous null response to Peg-IFN and RBV.
    Hepatology 03/2012; 55(3):742-8. DOI:10.1002/hep.24724 · 11.19 Impact Factor
  • Kanzo 01/2012; 53(2):69-77. DOI:10.2957/kanzo.53.69
  • Kanzo 01/2012; 53(7):425-428. DOI:10.2957/kanzo.53.425
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    ABSTRACT: To evaluate the efficacy and safety of telaprevir in combination with peginterferon-α2b (PEG-IFN) and ribavirin (RBV) in patients with chronic hepatitis C. In a multi-center randomized clinical trial in Japan, on patients infected with HCV of genotype 1, 126 patients were assigned to telaprevir for 12 weeks along with PEG-IFN and RBV for 24 weeks (Group A), while 63 to PEG-IFN and RBV for 48 weeks (Group B). HCV RNA disappeared more swiftly in patients in Group A than B, and the frequency of patients without detectable HCV RNA at week 4 (rapid virological response (RVR)) was higher in Group A than B (84.0% vs. 4.8%, p <0.0001). Grade 3 and 4 skin disorders, including Stevens-Johnson syndrome and drug rashes with eosinophilia and systemic symptoms, as well as Grade 3 anemia (<8.0 g/dl), occurred more frequently in Group A than B (skin disorders, 11.9% vs. 4.8%; anemia, 11.1% vs. 0.0%). The total RBV dose was smaller in Group A than B (47.0% vs. 77.7% of the target, p <0.0001). Despite these drawbacks, sustained virological response (SVR) was achieved more frequently in Group A than B (73.0% vs. 49.2%, p=0.0020). Although the triple therapy with telaprevir-based regimen for 24 weeks resulted in more adverse events and less total RBV dose than PEG-IFN and RBV for 48 weeks, it was able to achieve higher SVR within shorter duration by carefully monitoring adverse events and modifying the RBV dose as required.
    Journal of Hepatology 08/2011; 56(1):78-84. DOI:10.1016/j.jhep.2011.07.016 · 10.40 Impact Factor
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    ABSTRACT: Chronic viral hepatitis is the most important risk factor for progression to hepatocellular carcinoma (HCC). To identify genetic risk factors for progression to HCC in individuals with chronic hepatitis C virus (HCV), we analyzed 467,538 SNPs in 212 Japanese individuals with chronic HCV with HCC and 765 individuals with chronic HCV without HCC. We identified one intronic SNP in the DEPDC5 locus on chromosome 22 associated with HCC risk and confirmed the association using an independent case-control population (710 cases and 1,625 controls). The association was highly significant when we analyzed the stages separately as well as together (rs1012068, P(combined) = 1.27 × 10(-13), odds ratio = 1.75). The significance level of the association further increased after adjustment for gender, age and platelet count (P = 1.35 × 10(-14), odds ratio = 1.96). Our findings suggest that common variants within the DEPDC5 locus affect susceptibility to HCC in Japanese individuals with chronic HCV infection.
    Nature Genetics 07/2011; 43(8):797-800. DOI:10.1038/ng.876 · 29.65 Impact Factor

Publication Stats

1k Citations
191.43 Total Impact Points


  • 2000–2014
    • Sapporo Kosei General Hospital
      Sapporo, Hokkaidō, Japan
  • 2010
    • Kurume University
      • Division of Gastroenterology
      Куруме, Fukuoka, Japan
  • 2009
    • Kosei Chuo General Hospital
      Edo, Tōkyō, Japan