Fumitaka Suzuki

Publications (235)799.08 Total impact

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

  Norio Akuta, Fumitaka Suzuki, Yuya Seko, Yusuke Kawamura, Hitomi Sezaki, Yoshiyuki Suzuki, Tetsuya Hosaka, Masahiro Kobayashi, Tasuku Hara, Mariko Kobayashi, Satoshi Saitoh, Yasuji Arase, Kenji Ikeda, Hiromitsu Kumada
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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.
  Journal of Medical Virology 06/2013; 85(6):1028-36. · 2.82 Impact Factor
• Article: Renal dysfunction and hypophosphatemia during long-term lamivudine plus adefovir dipivoxil therapy in patients with chronic hepatitis B.

  Mio Tanaka, Fumitaka Suzuki, Yuya Seko, Tasuku Hara, Yusuke Kawamura, Hitomi Sezaki, Tetsuya Hosaka, Norio Akuta, Masahiro Kobayashi, Yoshiyuki Suzuki, Satoshi Saitoh, Yasuji Arase, Kenji Ikeda, Mariko Kobayashi, Hiromitsu Kumada
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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.
  Journal of Gastroenterology 03/2013; · 4.16 Impact Factor
• Article: Efficacy and safety in sitagliptin therapy for diabetes complicated by non-alcoholic fatty liver disease.

  Yasuji Arase, Yusuke Kawamura, Yuya Seko, Mariko Kobayashi, Fumitaka Suzuki, Yoshiyuki Suzuki, Norio Akuta, Masahiro Kobayashi, Hitomi Sezaki, Satoshi Saito, [......], Kazuhisa Amakawa, Kyoko Ogawa, Naoki Matsumoto, Akiko Iwao, Hiroshi Tsuji, Shigeko Hara, Yasumichi Mori, Minoru Okubo, Hirohito Sone, Tetsuro Kobayashi
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  ABSTRACT: AIM: The 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 48 weeks 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 48 weeks after the initiation of treatment. RESULTS: In the sitagliptin group, average HbA1c levels decreased approximately 0.7% at 48 weeks after the initiation of sitagliptin. Next, average FPG levels decreased approximately 15 mg/dL at 48 weeks 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 50 mg/day without reduction necessitated by sitagliptin-related side-effects. There were no significant changes of average AST and ALT levels during follow up of 48 weeks in both sitagliptin and control groups. CONCLUSION: Our results indicate sitagliptin is effective and safe for the treatment of T2DM complicated with NAFLD.
  Hepatology Research 03/2013; · 2.20 Impact Factor
• Article: Transcatheter arterial chemotherapy with miriplatin for hepatocellular carcinoma patients with chronic renal failure: report of three cases.

  Norihiro Imai, Kenji Ikeda, Yuya Seko, Yusuke Kawamura, Hitomi Sezaki, Tetsuya Hosaka, Norio Akuta, Masahiro Kobayashi, Satoshi Saitoh, Fumitaka Suzuki, Yoshiyuki Suzuki, Yasuji Arase, Hiromitsu Kumada
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  ABSTRACT: Miriplatin is a novel lipophilic platinum complex that was developed to treat hepatocellular carcinoma (HCC). Although HCC patients frequently have coexisting chronic renal failure, little prospective data are available regarding the clinical toxicity of chemotherapeutic agents used to treat HCC patients with chronic renal failure. In a phase II study, the plasma concentration of total platinum in patients who received miriplatin was very low, and no severe renal toxicity caused by miriplatin injection was reported. Here, we present three cases of HCC with stage 4 chronic renal failure who received transcatheter arterial chemotherapy with miriplatin. All cases were male, ages 72, 84, and 83 years, and had serum creatinine levels of 2.3, 1.6, and 1.9 mg/dL, respectively. Their estimated glomerular filtration rates were 21.9, 20.3, and 22.2 mL/min, respectively. All cases were treated for unresectable HCC with transcatheter arterial chemotherapy with miriplatin. No serious adverse events were observed, and serum creatinine levels did not elevate, even in the patient who experienced renal failure caused by cisplatin administration. These results might suggest that transcatheter arterial chemotherapy with miriplatin can be safely used in HCC patients with chronic renal failure.
  Gut and liver 03/2013; 7(2):246-51. · 0.83 Impact Factor
• Article: Antitumor efficacy of transcatheter arterial chemoembolization with warmed miriplatin in hepatocellular carcinoma.

  Yuya Seko, Kenji Ikeda, Yusuke Kawamura, Taito Fukushima, Tasuku Hara, Hitomi Sezaki, Tetsuya Hosaka, Norio Akuta, Fumitaka Suzuki, Masahiro Kobayashi, Yoshiyuki Suzuki, Satoshi Saitoh, Yasuji Arase, Hiromitsu Kumada
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  ABSTRACT: AIM: 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. METHODS: Chemotherapy efficacy was evaluated by dynamic computed tomography 1-3 months after TACE, according to the Modified Response Evaluation Criteria in Solid Tumors. A total of 203 patients with HCC who received TACE with miriplatin for the first time were included in a follow-up study to retrospectively investigate its efficacy and safety. Overall, 45 patients underwent TACE with warmed (40°C) miriplatin and 158 patients received TACE with room temperature miriplatin. RESULTS: Seventy patients (44.3%) treated with room temperature miriplatin and 32 patients (71.1%) who received warmed miriplatin experienced complete or partial responses. Multivariate analysis identified miriplatin temperature (warmed miriplatin, risk ratio (RR) = 2.26, P = 0.047), tumor number (solitary, RR = 3.48, P = 0.007), α-fetoprotein (AFP) level (<50 ng/mL, RR = 2.35, P = 0.012) and history of TACE (no history, RR = 2.22, P = 0.041) as predictors of objective response following TACE with miriplatin, and no serious complications were observed. CONCLUSION: Warm temperature, solitary tumors, low AFP level and first TACE are significant and independent predictors of objective response after TACE using miriplatin. These results suggest that warmed miriplatin can be considered as one of the standard treatments for unresectable HCC.
  Hepatology Research 12/2012; · 2.20 Impact Factor
• Article: Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection.

  Tetsuya Hosaka, Fumitaka Suzuki, Masahiro Kobayashi, Yuya Seko, Yusuke Kawamura, Hitomi Sezaki, Norio Akuta, Yoshiyuki Suzuki, Satoshi Saitoh, Yasuji Arase, Kenji Ikeda, Mariko Kobayashi, Hiromitsu Kumada
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  ABSTRACT: Chronic hepatitis B virus (HBV) infection leads to cirrhosis and hepatocellular carcinoma (HCC). Antiviral agents are thought to reduce HCC development, but agent such as lamivudine (LAM) has a high rate of drug resistance. We compared the incidence of HCC in 472 entecavir (ETV)-treated patients and 1143 non-treated HBV patients (control group). Propensity score matching eliminated the baseline differences, resulting in a sample size of 316 patients per cohort. The drug mutation resistance was 0.8% (4/472) in the ETV group. The cumulative HCC incidence rates at 5-year were 3.7% and 13.7% for the ETV, and control groups, respectively (P < 0.001). Cox proportional hazard regression analysis, adjusted for a number of known HCC risk factors, showed that patients in the ETV group were less likely to develop HCC than those in the control group (hazard ratio: 0.37; 95% CI: 0.15 to 0.91; P = 0.030). Both cohorts were applied into 3 previously reported risk scales and risk scores were generated based on age, gender, cirrhosis status, levels of ALT, HBeAg, baseline HBV DNA, albumin, and bilirubin. The greatest HCC risk reduction occurred in high-risk patients who scored higher on respective risk scales. In a group analysis, we compared treatment effect between nucleos(t)ide analogues (NAs) which included matched LAM-treated patients without rescue therapy (n = 182). We found HCC suppression effect greater in etv-treated (P < 0.001) than non-rescued LAM-treated (P = 0.019) cirrhotic patients when they were compared with the control group. Conclusion: Long-term entecavir treatment may reduce the incidence of HCC in HBV-infected patients. The treatment effect was greater in patients at higher risk of HCC. (HEPATOLOGY 2012.).
  Hepatology 12/2012; · 11.66 Impact Factor
• Article: Exploratory study on telaprevir given every 8 h at 500 mg or 750 mg with peginterferon-alpha-2b and ribavirin in hepatitis C patients.

  Fumitaka Suzuki, Yoshiyuki Suzuki, Hitomi Sezaki, Norio Akuta, Yuya Seko, Yusuke Kawamura, Tetsuya Hosaka, Masahiro Kobayashi, Satoshi Saito, Yasuji Arase, Kenji Ikeda, Rie Mineta, Sachiyo Watahiki, Mariko Kobayashi, Yoshiyuki Nakayasu, Hidetaka Tsuda, Keiji Aoki, Ichimaro Yamada, Hiromitsu Kumada
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  ABSTRACT: AIM: 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. METHODS: 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. RESULTS: Although the difference was not statistically significant other than trough concentration (C(trough) ) at week 4, the parameters of maximum concentration (C(max) ), the area under the concentration time curve (AUC(0-∞) ) and C(trough) 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. CONCLUSION: 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.
  Hepatology Research 11/2012; · 2.20 Impact Factor
• Article: Randomized controlled trial of a new procedure of radiofrequency ablation using an expandable needle for hepatocellular carcinoma.

  Miharu Hirakawa, Kenji Ikeda, Masahiro Kobayashi, Yusuke Kawamura, Tetsuya Hosaka, Hitomi Sezaki, Norio Akuta, Fumitaka Suzuki, Yoshiyuki Suzuki, Satoshi Saitoh, Yasuji Arase, Hiromitsu Kumada
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  ABSTRACT: AIM: To evaluate the efficacy of a new ablation procedure for the stepwise hook extension technique using a SuperSlim needle for radiofrequency ablation (RFA) treatment of hepatocellular carcinoma (HCC), a randomized controlled trial was performed. METHODS: Thirty patients with HCC measuring 20 mm or less were randomly treated with a conventional four stepwise expansion technique (group 1) and the new stepwise expansion technique (group 2; the electrode was closed in the shaft after the same three steps of the conventional procedure and then fully extended). All patients underwent the RFA procedure using a 10-hook expandable electrode of 17-G diameter (LeVeen SuperSlim 30 mm). We compared the ablation time, required energy and ablated lesions in the two groups. RESULTS: The long and short diameters of RFA-induced necrosis were significantly larger in group 2 (37 and 28 mm) than group 1 (30 and 26 mm, P = 0.001 and =0.045, respectively). Irregular and small needle expansion resulting in the parachute-like or irregularly shaped ablated zone was observed in more cases in group 1 than in group 2. The new technique made all tines expand uniformly and largely, which produced a near-oval ablated zone of which the long axis is perpendicular to the needle shaft. CONCLUSION: The two kinds of stepwise procedures allow the selection of a more suitable procedure according to the tumor size and shape in each RFA.
  Hepatology Research 11/2012; · 2.20 Impact Factor
• Article: Dual Oral Therapy with Daclatasvir and Asunaprevir for Patients with HCV Genotype 1b Infection and Limited Treatment Options.

  Yoshiyuki Suzuki, Kenji Ikeda, Fumitaka Suzuki, Joji Toyota, Yoshiyasu Karino, Kazuaki Chayama, Yoshiiku Kawakami, Hiroki Ishikawa, Hideaki Watanabe, Wenhua Hu, Timothy Eley, Fiona McPhee, Eric Hughes, Hiromitsu Kumada
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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; · 9.26 Impact Factor
• Article: Characterization of virologic escape in hepatitis C virus genotype 1b patients treated with the direct-acting antivirals daclatasvir and asunaprevir.

  Yoshiyasu Karino, Joji Toyota, Kenji Ikeda, Fumitaka Suzuki, Kazuaki Chayama, Yoshiiku Kawakami, Hiroki Ishikawa, Hideaki Watanabe, Dennis Hernandez, Fei Yu, Fiona McPhee, Hiromitsu Kumada
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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; · 9.26 Impact Factor
• Article: Magnetic resonance laparoscopy: A new non-invasive technique for the assessment of chronic viral liver disease.

  Suguru Ogura, Satoshi Saitoh, Yusuke Kawamura, Hitomi Sezaki, Tetsuya Hosaka, Norio Akuta, Masahiro Kobayashi, Fumitaka Suzuki, Yoshiyuki Suzuki, Yasuji Arase, Kenji Ikeda, Hiromitsu Kumada
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  ABSTRACT: AIM: Laparoscopy-guided liver biopsy is the most accurate method for assessing liver fibrosis but have several limitations. We designed a non-invasive method, called magnetic resonance laparoscopy (MRL), based on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging, to assess liver fibrosis in patients with chronic hepatitis B and C virus. METHODS: We prospectively analyzed 49 patients with normal liver and 353 patients with chronic viral hepatitis, laparoscopic liver biopsy was performed on 109 patients and 244 patients were diagnosed as having liver cirrhosis clinically. The MRL findings of the liver surface were classified into three categories: (i) smooth (essentially smooth surface of the entire liver or with limited areas of depression); (ii) partially irregular (several interconnected depressions on the surface mainly in the left lobe of the liver); and (iii) diffusely irregular (nodules present on the liver surface). Patients with diffusely irregular liver surface was diagnosed as liver cirrhosis. RESULTS: The liver surface changed with the progression of liver fibrosis from smooth, partially irregular to diffusely irregular, irrespective of viral type. The sensitivity, specificity, positive and negative predictive values for the diagnosis of cirrhosis according to the surface findings on MRL were 96%, 100%, 95% and 95%, respectively. The cirrhotic liver showed: (i) disappearance of impression of the right ribs; (ii) enlargement of the lateral segment; and (iii) atrophy of the right lobe according to Child-Pugh classification. CONCLUSION: Our data indicated that MRL is a potentially useful non-invasive examination for evaluation of liver fibrosis associated with viral hepatitis.
  Hepatology Research 11/2012; · 2.20 Impact Factor
• Article: Comparative quantitative analysis of hepatitis C mutations at amino acids 70 and 91 in the core region by the Q-Invader assay.

  Kenichi Tadokoro, Mariko Kobayashi, Fumitaka Suzuki, Chie Tanaka, Toshikazu Yamaguchi, Makoto Nagano, Toru Egashira, Hiromitsu Kumada
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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.
  Journal of virological methods 11/2012; · 2.13 Impact Factor
• Article: Clearance of hepatitis B surface antigen during long-term nucleot(s)ide analog treatment in chronic hepatitis B: results from a nine-year longitudinal study.

  Tetsuya Hosaka, Fumitaka Suzuki, Masahiro Kobayashi, Yuya Seko, Yusuke Kawamura, Hitomi Sezaki, Norio Akuta, Yoshiyuki Suzuki, Satoshi Saitoh, Yasuji Arase, Kenji Ikeda, Mariko Kobayashi, Hiromitsu Kumada
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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.
  Journal of Gastroenterology 10/2012; · 4.16 Impact Factor
• Article: Efficacy and Anticarcinogenic Activity of Ribavirin Combination Therapy for Hepatitis C Virus-Related Compensated Cirrhosis.

  Norio Akuta, Fumitaka Suzuki, Yuya Seko, Yusuke Kawamura, Hitomi Sezaki, Yoshiyuki Suzuki, Tetsuya Hosaka, Masahiro Kobayashi, Mariko Kobayashi, Satoshi Saitoh, Yasuji Arase, Kenji Ikeda, Hiromitsu Kumada
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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.
  Intervirology 10/2012; · 2.34 Impact Factor
• Article: Association of IL28B genotype and viral response of hepatitis C virus genotype 2 to interferon plus ribavirin combination therapy.

  Norio Akuta, Fumitaka Suzuki, Yuya Seko, Yusuke Kawamura, Hitomi Sezaki, Yoshiyuki Suzuki, Tetsuya Hosaka, Masahiro Kobayashi, Mariko Kobayashi, Satoshi Saitoh, Yasuji Arase, Kenji Ikeda, Hiromitsu Kumada
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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.
  Journal of Medical Virology 10/2012; 84(10):1593-9. · 2.82 Impact Factor
• Article: Effect of type 2 diabetes on risk for malignancies included hepatocellular carcinoma in chronic hepatitis C.

  Yasuji Arase, Mariko Kobayashi, Fumitaka Suzuki, Yoshiyuki Suzuki, Yusuke Kawamura, Norio Akuta, Masahiro Kobayashi, Hitomi Sezaki, Satoshi Saito, Tetsuya Hosaka, Kenji Ikeda, Hiromitsu Kumada, Tetsuro Kobayashi
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  ABSTRACT: 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 is the first onset of malignancies. Evaluation was performed by 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 histological staging was advanced, sustained virological response was not achieved, the patient was male, patients had aging, total alcohol intake of =200kg, and Type 2 Diabetes (T2DM). T2DM caused a 1.73-fold enhancement in HCC development. In patients with T2DM, HCC decreased when patients had mean HbA1c level of <7.0% during follow-up (hazard ratio:0.56; 95% CI 0.33-0.89; P = 0.015). The cumulative development rate of malignancies 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 had aging, smoking index (package per day × year) of =20, and T2DM. 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 mean HbA1c level of <7.0% reduces the development of HCC. (HEPATOLOGY 2012.).
  Hepatology 09/2012; · 11.66 Impact Factor
• Article: Amino Acid Substitutions in the Hepatitis C Virus Core Region and Lipid Metabolism Are Associated with Hepatocarcinogenesis in Nonresponders to Interferon plus Ribavirin Combination Therapy.

  Yuya Seko, Norio Akuta, Fumitaka Suzuki, Yusuke Kawamura, Hitomi Sezaki, Yoshiyuki Suzuki, Tetsuya Hosaka, Masahiro Kobayashi, Mariko Kobayashi, Satoshi Saitoh, Yasuji Arase, Kenji Ikeda, Hiromitsu Kumada
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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.
  Intervirology 08/2012; · 2.34 Impact Factor
• Article: Efficacy of reduction therapy of natural human β-interferon and ribavirin in elderly patients with chronic hepatitis C, genotype 2 and high virus load.

  Yasuji Arase, Yoshiyuki Suzuki, Fumitaka Suzuki, Norio Akuta, Hitomi Sezaki, Yusuke Kawamura, Masahiro Kobayashi, Norihiro Imai, Yuya Seko, Tetsuya Hosaka, Naoki Matsumoto, Satoshi Saito, Kenji Ikeda, Mariko Kobayashi, Hiromitsu Kumada
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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.
  Hepatology Research 08/2012; 42(8):750-6. · 2.20 Impact Factor
• Article: Long-term interferon monotherapy reduces the risk of HCV-associated hepatocellular carcinoma.

  Makiko Takeyasu, Norio Akuta, Fumitaka Suzuki, Yuya Seko, Yusuke Kawamura, Hitomi Sezaki, Yoshiyuki Suzuki, Tetsuya Hosaka, Masahiro Kobayashi, Mariko Kobayashi, Yasuji Arase, Kenji Ikeda, Hiromitsu Kumada
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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.
  Journal of Medical Virology 08/2012; 84(8):1199-207. · 2.82 Impact Factor
• Article: The complicated relationships of amino acid substitution in HCV core region and IL28Bgenotype influencing hepatocarcinogenesis.

  Norio Akuta, Fumitaka Suzuki, Yuya Seko, Yusuke Kawamura, Hitomi Sezaki, Yoshiyuki Suzuki, Tetsuya Hosaka, Masahiro Kobayashi, Tasuku Hara, Mariko Kobayashi, Satoshi Saitoh, Yasuji Arase, Kenji Ikeda, Hiromitsu Kumada
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  ABSTRACT: The impact of amino acid (aa) 70 substitution in the core region on hepatocarcinogenesis and survival for liver-related death in patients of HCV genotype 1b (HCV-1b), who had not received antiviral therapy, is unknown. The relationships among aa 70 substitution, IL28B genotype, and hepatocarcinogenesis, are not also clarified. 1,181 consecutive HCV-infected patients, who had not received antiviral therapy, were performed 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, respectively. 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, respectively. Multivariate analysis identified gender (male), age (ò60 years), albumin (<3.9 g/dl), platelet count (<15.0×10(4) /mm(3) ), aspartate aminotransferase (ò67 IU/l), and HCV subgroup (HCV-1b of Gln70(His70)) as determinants of both of hepatocarcinogensis 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 TT genotype. In conclusion, substitution of aa 70 in the core region of HCV-1b is the important predictor of hepatocarcinogenesis and survival for liver-related death in HCV patients, who had not received antiviral therapy. IL28B genotype might partly affect changes over time of dominant amino acid in core aa 70 of HCV-1b. (HEPATOLOGY 2012.).
  Hepatology 07/2012; · 11.66 Impact Factor