Treatment of hepatitis C with direct-acting antiviral agents: Japanese experience

( Fumitaka Suzuki ),( Hiromitsu Kumada ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.1

In Japan, an estimated 100-150 million people are persistently infected with hepatitis C virus (HCV). The present standard-of-care (SOC) therapy for patients infected with HCV of genotype 1b, the most prevalent genotype in Japan, is peginterferon (PEG-IFN) combined with ribavirin (RBV) for 48 weeks. However, sustained virological response (SVR), judged by the loss of detectable HCV RNA from serum 24 weeks after the completion of therapy, can be achieved in only 42?52% of the patients. To cope with this grim situation, a number of direct acting antivirals (DAAs) have been designed and developed, represented by NS3/4A protease inhibitors and NS5B polymerase or NS5A inhibitors. Among them, telaprevir (TVR) has shown promising results, when combined with PEG-IFN and RBV, in the phase 2 and 3 clinical trials, by improving SVR to ~70% in patients infected with HCV-1. Moreover, the triple therapy with TVR, PEG-IFN, and RBV for 12 weeks, followed by PEG-IFN and RBV for an additional 12 weeks (T12PR24) were reimbursed since November 2011 in Japan. In Japanese clinical studies (phase III, T12PR24), the SVR rates of naive, relapse and non-responder were 73% (92/126), 88% (96/109) and 35% (11/32). We investigate the predictive factors of SVR to a 12-week or 24-week regimen of triple therapy in 81 Japanese patients infected with HCV genotype 1. SVR was achieved by 45% and 67% in the 12- and 24 week regimens, respectively. Multivariate analysis identified rs8099917 near the IL28B gene (genotype TT) and substitution at aa 70 (Arg70) as significant determinants of SVR. Prediction of response to therapy based on a combination of these factors had high sensitivity, specificity, and positive and negative predictive values. The efficacy of triple therapy was high in the patients with genotype TT, who accomplished SVR (85%), irrespective of substitution of core aa 70. In the patients having genotype non-TT, those of Arg70 gained high SVR (57%), and SVR (17%) was the worst in patients who possessed both genotype non-TT and Gln70 (His70). Important adverse events were anemia and shin disorder (mainly rash, drug eruptions, and erythema). Next, dual oral therapy with the NS5A inhibitor (daclatasvir) and NS3 protease inhibitor (asunaprevir) in HCV genotype 1b-infected null responders or patients ineligible or intolerant to peginterferon/ribavirin were done (phase II) in Japan. This study (AI447-017) enrolled two populations infected with HCV genotype 1, including null responders and patients intolerant or medically ineligible to PEG-IFN and RBV. The overall SVR rate was 77%. A higher SVR rate was observed in the null responders (91%) compared to the ineligible and intolerant patients (64%). The overall response to therapy was not influenced by IL28B genotype. Potential association between virologic failure and pre-existing NS5A polymorphisms and low plasma concentrations of asunaprevir and daclatasvir requires further study.

Treatment of hepatitis C with direct-acting antiviral agents: Japanese experience

( Fumitaka Suzuki ),( Hiromitsu Kumada ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.-

In Japan, an estimated 100-150 million people are persistently infected with hepatitis C virus (HCV). The present standard-of-care (SOC) therapy for patients infected with HCV of genotype 1b, the most prevalent genotype in Japan, is peginterferon (PEG-IFN) combined with ribavirin (RBV) for 48 weeks. However, sustained virological response (SVR), judged by the loss of detectable HCV RNA from serum 24 weeks after the completion of therapy, can be achieved in only 42-52% of the patients. To cope with this grim situation, a number of direct acting antivirals (DAAs) have been designed and developed, represented by NS3/4A protease inhibitors and NS5B polymerase or NS5A inhibitors. Among them, telaprevir (TVR) has shown promising results, when combined with PEG-IFN and RBV, in the phase 2 and 3 clinical trials, by improving SVR to ~70% in patients infected with HCV-1. Moreover, the triple therapy with TVR, PEG-IFN, and RBV for 12 weeks, followed by PEG-IFN and RBV for an additional 12 weeks (T12PR24) were reimbursed since November 2011 in Japan. In Japanese clinical studies (phase III, T12PR24), the SVR rates of naive, relapse and non-responder were 73% (92/126), 88% (96/109) and 35% (11/32). We investigate the predictive factors of SVR to a 12-week or 24-week regimen of triple therapy in 81 Japanese patients infected with HCV genotype 1. SVR was achieved by 45% and 67% in the 12- and 24-week regimens, respectively. Multivariate analysis identified rs8099917 near the IL28B gene (genotype TT) and substitution at aa 70 (Arg70) as significant determinants of SVR. Prediction of response to therapy based on a combination of these factors had high sensitivity, specificity, and positive and negative predictive values. The efficacy of triple therapy was high in the patients with genotype TT, who accomplished SVR (85%), irrespective of substitution of core aa 70. In the patients having genotype non-TT, those of Arg70 gained high SVR (57%), and SVR (17%) was the worst in patients who possessed both genotype non-TT and Gln70 (His70). Important adverse events were anemia and shin disorder (mainly rash, drug eruptions, and erythema). Next, dual oral therapy with the NS5A inhibitor (daclatasvir) and NS3 protease inhibitor (asunaprevir) in HCV genotype 1b-infected null responders or patients ineligible or intolerant to peginterferon/ribavirin were done (phase II) in Japan. This study (AI447-017) enrolled two populations infected with HCV genotype 1, including null responders and patients intolerant or medically ineligible to PEG-IFN and RBV. The overall SVR rate was 77%. A higher SVR rate was observed in the null responders (91%) compared to the ineligible and intolerant patients (64%). The overall response to therapy was not influenced by IL28B genotype. Potential association between virologic failure and pre-existing NS5A polymorphisms and low plasma concentrations of asunaprevir and daclatasvir requires further study.

Post Marketing Surveillance of Daclatasvir/Asunaprevir in Japanese Patients with Chronic Hepatitis C: An Interim Report

( Fumitaka Suzuki ),( Naoya Hatanaka ),( Etsuya Bando ),( Akira Komoto ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Daclatasvir (DCV) combined with asunaprevir (ASV) was the first all-oral treatment to be approved in Japan for chronic hepatitis C virus (HCV) serogroup 1 infection in patients with/without compensated cirrhosis. We report interim findings of a post-marketing survey of DCV+ASV in Japanese patients treated in the routine clinical setting. Methods: The survey aimed to register a total of 3000 HCV-infected patients, including 1000 patients with compensated cirrhosis, between September 2014 and August 2015. All patients received oral DCV 60mg once daily + ASV 100 mg twice daily for 24 weeks. This report includes safety data collected up to 3 July 2016. Results: Of the 3089 patients registered, 2165 (70.0%) patients (female, n=1233 [57.0%]; mean age, 69.1 years [range: 21-92]; compensated cirrhosis, n=862 [39.8%]) are included in the safety set; 1874 (86.6%) patients have completed the treatment period. The main reasons for discontinuation in the safety set were adverse events (n=146 [6.7%]) and lack of efficacy (n=86 [4.0%]). A total of 538 patients (24.85%) in the safety set experienced a total of 811 adverse drug reactions (ADRs). Events corresponding to the composite ADR term ‘hepatic function disorder’ occurred in 315 patients (14.55%). Common ADRs were: hepatic function abnormal (n=133 [6.14%]), increased eosinophil count (n=67 [3.09%]), increased alanine aminotransferase (n=63 [2.91%]), increased aspartate aminotransferase (n=61 [2.82%]), liver disorder (n=58 [2.68%]) and pyrexia (n=53 [2.45%]); rates of ADRs in patients with/without compensated cirrhosis were generally comparable (Table). Serious ADRs which occurred in two or more patients were liver disorder (n=5 [0.23%]), pyrexia (n=4 [0.18%]); hepatic function abnormal (n=3 [0.14%]) hepatic hepatic encephalopathy (n=2 [0.09%]) and jaundice (n=2 [0.09%]); all serious ADRs have/are resolved/resolving and all patients have/are recovered/recovering. No deaths have been reported. Conclusions: DCV + ASV was generally well tolerated in this interim analysis of real-world data.

SOUND POWER LEVELS AND RUNNING PATTERNS OF ACCELERATING CARS BASED ON A NEW MEASURING METHOD

Hiroshi Suzuki,Hironori Watanabe,Fumitaka Saito,Yoiti Suzuki,Shunichi Kono 한국소음진동공학회 2003 한국소음진동공학회 국제학술대회논문집 Vol.2003 No.8

Feasibility Study of Isotope Ratio Analysis of Individual Uranium-Plutonium Mixed Oxide Particles with SIMS and ICP-MS

( Fumitaka Esaka ),( Masaaki Magara ),( Daisuke Suzuki ),( Yutaka Miyamoto ),( Chi-gyu Lee ),( Takaumi Kimura ) 한국질량분석학회 2011 Mass spectrometry letters Vol.2 No.4

Isotope ratio analysis of nuclear materials in individual particles is of great importance for nuclear safeguards. Although secondary ion mass spectrometry (SIMS) and thermal ionization mass spectrometry (TIMS) are utilized for the analysis of individual uranium particles, few studies were conducted for the analysis of individual uranium-plutonium mixed oxide particles. In this study, we applied SIMS and inductively coupled plasma mass spectrometry (ICP-MS) to the isotope ratio analysis of individual U-Pu mixed oxide particles. In the analysis of individual U-Pu particles prepared from mixed solution of uranium and plutonium standard reference materials, accurate 235U/238U, 240Pu/239Pu and 242Pu/239Pu isotope ratios were obtained with both methods. However, accurate analysis of 241Pu/239Pu isotope ratio was impossible, due to the interference of the 241Am peak to the 241Pu peak. In addition, it was indicated that the interference of the 238UH peak to the 239Pu peak has a possibility to prevent accurate analysis of plutonium isotope ratios. These problems would be avoided by a combination of ICP-MS and chemical separation of uranium, plutonium and americium in individual U-Pu particles.

SOUND POWER LEVELS OF MUSICAL INSTRUMENTS AND THE ESTIMATION OF THE INFLUENCE ON PLAYERS’ HEARING ABILITY

Fumitaka Saito,Makiko Kasuya,Toshio Harima,Yoiti Suzuki 한국소음진동공학회 2003 한국소음진동공학회 국제학술대회논문집 Vol.2003 No.8

Feasibility Study of Isotope Ratio Analysis of Individual Uranium-Plutonium Mixed Oxide Particles with SIMS and ICP-MS

Esaka, Fumitaka,Magara, Masaaki,Suzuki, Daisuke,Miyamoto, Yutaka,Lee, Chi-Gyu,Kimura, Takaumi Korean Society for Mass Spectrometry 2011 Mass spectrometry letters Vol.2 No.4

Isotope ratio analysis of nuclear materials in individual particles is of great importance for nuclear safeguards. Although secondary ion mass spectrometry (SIMS) and thermal ionization mass spectrometry (TIMS) are utilized for the analysis of individual uranium particles, few studies were conducted for the analysis of individual uranium-plutonium mixed oxide particles. In this study, we applied SIMS and inductively coupled plasma mass spectrometry (ICP-MS) to the isotope ratio analysis of individual U-Pu mixed oxide particles. In the analysis of individual U-Pu particles prepared from mixed solution of uranium and plutonium standard reference materials, accurate $^{235}U/^{238}U$, $^{240}Pu/^{239}Pu$ and $^{242}Pu/^{239}Pu$ isotope ratios were obtained with both methods. However, accurate analysis of $^{241}Pu/^{239}Pu$ isotope ratio was impossible, due to the interference of the $^{241}Am$ peak to the $^{241}Pu$ peak. In addition, it was indicated that the interference of the $^{238}UH$ peak to the $^{239}Pu$ peak has a possibility to prevent accurate analysis of plutonium isotope ratios. These problems would be avoided by a combination of ICP-MS and chemical separation of uranium, plutonium and americium in individual U-Pu particles.

Flux Coating Innovation of Inorganic Crystal Layers for Next-Generation Energy and Environmental Applications

Katsuya Teshima,Fumitaka Hayashi,Tetsuya Yamada,Sayaka Suzuki,Tomohito Sudare,Nobuyuki Zettsu 한국표면공학회 2017 한국표면공학회 학술발표회 초록집 Vol.2017 No.11

The impact of systematic retroperitoneal lymphadenectomy on long-term oncologic outcome of women with advanced ovarian clear-cell carcinoma

Hiroaki Kajiyama,Shiro Suzuki,Nobuhisa Yoshikawa,Satoshi Tamauchi,Kiyosumi Shibata,Fumitaka Kikkawa 대한부인종양학회 2020 Journal of Gynecologic Oncology Vol.31 No.4

Objective: The impact of systematic retroperitoneal lymphadenectomy (SRL) remainscontroversial in patients with advanced ovarian clear-cell carcinoma (CCC) who areoptimally debulked. Methods: Between 1986 and 2017, a total of 3,227 women with epithelial ovarian carcinomawere analyzed in a multi-institutional study. Among them, 166 optimally debulked womenwith stage IIB–IV CCC were collected (residual tumor of <1 cm). All patients were divided into2 groups: 1) Group I (n=112): underwent standard radical surgery with SRL, 2) Group II (n=54):underwent non-staging limited surgery. The pathological slides were assessed based on centralpathological review. Oncologic outcomes were compared between the two groups using apropensity score (PS)-matching technique to adjust for various clinicopathologic factors. Results: The median follow-up duration of all surviving women was 52.8 (1.6–184.2) months. Overall, 88 patients (53.0%) experienced recurrence and 68 patients (41.0%) died of thedisease. In the original cohort, the 5-year overall survival (OS) rates of groups I and II were57.9 and 64.9%, respectively (log-rank p=0.415). In the PS-adjusted cohort, the 5-year OSrates were 64.9 and 58.8% in women in groups I and II, respectively (p=0.453). Furthermore,in the PS-matched cohort after adjustment for multiple clinicopathologic factors, there wasno significant difference in OS between the 2 groups (group I vs. group II; hazard ratio=1.170;95% confidence interval=0.633–2.187; p=0.615). Conclusions: This study suggests that the performance of SRL including radical surgery maynot lead to a significant improvement in the oncologic outcome of advanced CCC patientswith optimal cytoreduction.

Prognostic factors and effects of fertility-sparing surgery in women of reproductive age with ovarian clear-cell carcinoma: a propensity score analysis

Masato Yoshihara,Hiroaki Kajiyama,Satoshi Tamauchi,Shiro Suzuki,Kunihiko Takahashi,Shigeyuki Matsui,Fumitaka Kikkawa 대한부인종양학회 2019 Journal of Gynecologic Oncology Vol.30 No.6

Objective: The aim of this study was to investigate the clinical characteristics of youngpatients with stage I clear-cell carcinoma (CCC) and evaluate the prognostic factors andeffects of fertility-sparing surgery (FSS) using propensity score (PS) adjustment. Methods: We conducted a regional multi-institutional study between 1986 and 2017. Among4,277 patients with ovarian tumor, clinical and pathological data of 103 fertile women withstage I unilateral CCC were collected. We evaluated survival and reproductive outcomesin these patients. Additionally, to analyze the effects of FSS, baseline imbalance betweenpatients with and those without FSS was adjusted with an inverse probability of treatmentweighting using PSs involving independent clinical variables. Results: The mean patient age was 39.4 years, and the median follow-up period for survivingpatients was 55.6 months. In multivariate analysis, stage IC2/IC3 (vs. IA/IC1) was the onlyindependent prognostic factor for recurrence-free survival (RFS) and overall survival (OS). FSS was not associated with poorer prognosis when compared to the prognosis with nonpreservingsurgery with regard to both RFS and OS. No statistical difference in survivaloutcomes between FSS and other approaches was confirmed after PS adjustment. Amongpatients who underwent FSS, four deliveries with healthy neonates were noted without anygestational complications. Conclusion: FSS can be considered in stage I CCC, specifically in stage IA and IC1 patientswho strongly desire to have children in the future. Further clinical research is needed toclarify the optimal application of FSS for CCC.