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Saegusa Y, Imaoka Y, Ohira M, Kobayashi T, Honmyo N, Hamaoka M, Onoe T, Takei D, Oishi K, Abe T, Nakayama T, Akabane M, Sasaki K, Ohdan H. Cluster analysis of hepatocellular carcinoma prognosis using preoperative alpha-fetoprotein and des-gamma-carboxy prothrombin levels: a multi-institutional study. J Gastrointest Surg 2025; 29:101980. [PMID: 39884550 DOI: 10.1016/j.gassur.2025.101980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 01/23/2025] [Accepted: 01/25/2025] [Indexed: 02/01/2025]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) remains the leading cause of cancer-related mortality worldwide and is characterized by high recurrence rates after curative resection. The tumor markers des-gamma-carboxy prothrombin (DCP) and alpha-fetoprotein (AFP) are crucial for HCC diagnosis and prognosis. However, their roles in the modern era of HCC epidemiology require reevaluation. METHODS This multi-institutional retrospective study analyzed 1515 patients who underwent hepatectomy for primary HCC. Patients were classified into 4 clusters using k-means analysis based on preoperative DCP and AFP levels. Clinicopathologic characteristics, overall survival (OS), and recurrence rate (RR) were evaluated using Cox proportional hazards models and area under the receiver operating characteristic curve (AUROC) comparisons. RESULTS Cluster 3 (concurrent elevations of DCP and AFP) had the poorest 5-year OS (52.8%) and the highest RR (79.3%), whereas cluster 4 (low levels of both markers) had the most favorable outcomes, with a 5-year OS rate of 71.5% and an RR of 55.7%. Cluster 1 (elevated DCP alone) was associated with larger tumors (median of 45 mm) and more frequent vascular invasion (43%) than cluster 2 (elevated AFP alone, median tumor size of 24 mm, and vascular invasion of 36%). DCP was a stronger predictor of 5-year OS in patients with preserved liver function (AUROC, 0.63), whereas AFP was more effective in stratifying RR in patients with impaired liver function (AUROC, 0.57). Non-B, non-C hepatitis (NBNC)-related HCC exhibited a distinct biomarker profile, with an elevated DCP level correlating with a higher 5-year RR (67%) than other etiologies. CONCLUSION Our study introduces tumor marker clustering as a novel analytical approach, providing a nuanced understanding of AFP and DCP's combined utility in predicting prognosis and recurrence. Our findings highlight the independent and complementary roles of these biomarkers, particularly in NBNC-related HCC and in cases with impaired liver function. AFP and DCP remain crucial tools for recurrence risk assessment, guiding personalized management strategies, such as surveillance, neoadjuvant therapies, and tailored postoperative interventions.
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Affiliation(s)
- Yoshitaka Saegusa
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuki Imaoka
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Division of Abdominal Transplant, Stanford University, Stanford, CA, United States
| | - Masahiro Ohira
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan.
| | - Tsuyoshi Kobayashi
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Naruhiko Honmyo
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Department of Surgery, Hiroshima City North Medical Center Asa Citizens Hospital, Hiroshima, Japan
| | - Michinori Hamaoka
- Department of Gastroenterological, Breast and Transplant Surgery, Hiroshima Prefectural Hospital, Hiroshima, Japan
| | - Takashi Onoe
- Department of Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure City, Japan
| | - Daisuke Takei
- Department of Surgery, Onomichi General Hospital, Onomichi City, Japan
| | - Koichi Oishi
- Department of Surgery, Chugoku Rosai Hospital, Kure City, Japan
| | - Tomoyuki Abe
- Department of Surgery, National Hospital Organization, Higashihiroshima Medical Center, Higashihiroshima, Japan
| | - Toshihiro Nakayama
- Division of Abdominal Transplant, Stanford University, Stanford, CA, United States
| | - Miho Akabane
- Division of Abdominal Transplant, Stanford University, Stanford, CA, United States
| | - Kazunari Sasaki
- Division of Abdominal Transplant, Stanford University, Stanford, CA, United States
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Chuang CH, Cheng TL, Chen WC, Huang YJ, Wang HE, Lo YC, Hsieh YC, Lin WW, Hsieh YJ, Ke CC, Huang KC, Lee JC, Huang MY. Micro-PET imaging of hepatitis C virus NS3/4A protease activity using a protease-activatable retention probe. Front Microbiol 2022; 13:896588. [PMID: 36406412 PMCID: PMC9672079 DOI: 10.3389/fmicb.2022.896588] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 09/27/2022] [Indexed: 11/03/2023] Open
Abstract
Hepatitis C virus (HCV) NS3/4A protease is an attractive target for direct-acting antiviral agents. Real-time tracking of the NS3/4A protease distribution and activity is useful for clinical diagnosis and disease management. However, no approach has been developed that can systemically detect NS3/4A protease activity or distribution. We designed a protease-activatable retention probe for tracking HCV NS3/4A protease activity via positron emission topography (PET) imaging. A cell-penetrating probe was designed that consisted of a cell-penetrating Tat peptide, HCV NS3/4A protease substrate, and a hydrophilic domain. The probe was labeled by fluorescein isothiocyanate (FITC) and 124I in the hydrophilic domain to form a TAT-ΔNS3/4A-124I-FITC probe. Upon cleavage at NS3/4A substrate, the non-penetrating hydrophilic domain is released and accumulated in the cytoplasm allowing PET or optical imaging. The TAT-ΔNS3/4A-FITC probe selectively accumulated in NS3/4A-expressing HCC36 (NS3/4A-HCC36) cells/tumors and HCV-infected HCC36 cells. PET imaging showed that the TAT-ΔNS3/4A-124I-FITC probe selectively accumulated in the NS3/4A-HCC36 xenograft tumors and liver-implanted NS3/4A-HCC36 tumors, but not in the control HCC36 tumors. The TAT-ΔNS3/4A-124I-FITC probe can be used to represent NS3/4 protease activity and distribution via a clinical PET imaging system allowing. This strategy may be extended to detect any cellular protease activity for optimization the protease-based therapies.
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Affiliation(s)
- Chih-Hung Chuang
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- College of Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tian-Lu Cheng
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- College of Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Biomedical and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wei-Chun Chen
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Yi-Jung Huang
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- College of Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hsin-Ell Wang
- Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei City, Taiwan
| | - Yen-Chen Lo
- Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei City, Taiwan
| | - Yuan-Chin Hsieh
- School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan
| | - Wen-Wei Lin
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Laboratory Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ya-Ju Hsieh
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chien-Chih Ke
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Kang-Chieh Huang
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jin-Ching Lee
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Yii Huang
- College of Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Radiation Oncology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
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Kaya M, Nakamura K, Sugiyama K, Kinae A, Yamaguchi H, Ukita H, Odagiri K, Ujiie C, Kato J, Kageyama F, Nagura M, Matsushita K, Sugiue K, Ishida H, Endo S, Suzuki T. Retrospective multicentre study on the effectiveness of first-line direct-acting antivirals against hepatitis C virus genotype-1. J Clin Pharm Ther 2022; 47:940-947. [PMID: 35229326 PMCID: PMC9543670 DOI: 10.1111/jcpt.13624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 02/02/2022] [Accepted: 02/09/2022] [Indexed: 11/29/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE In Japan, ledipasvir/sofosbuvir, elbasvir/grazoprevir and glecaprevir/pibrentasvir are recommended as first-line treatments for patients with untreated hepatitis C virus genotype 1. Although they have demonstrated a high efficacy in clinical trials, there are no direct comparative studies. Clarification of their effectiveness and safety in real-world clinical practice is required. Therefore, we conducted a retrospective multicentre study on the effectiveness of these direct-acting antivirals in real-world clinical practice. METHODS We retrospectively evaluated the clinical data of untreated patients with persistent HCV genotype 1 infection who started first-line treatment with ledipasvir/sofosbuvir, elbasvir/grazoprevir or glecaprevir/pibrentasvir between September 2015 and January 2019 at 11 medical institutions in Japan. The primary efficacy endpoint was a sustained virologic response after 12 weeks of treatment. The secondary endpoints included sustained virologic response after 24 weeks of treatment and end of treatment response. The safety endpoint was treatment completion rate. RESULTS AND DISCUSSION During the study, 420 patients (median age, 70 years; 181 males) received ledipasvir/sofosbuvir, 48 (median age 72, years; 29 males) received elbasvir/grazoprevir and 63 (median age 66, years; 35 males) received glecaprevir/pibrentasvir. For ledipasvir/sofosbuvir, elbasvir/grazoprevir and glecaprevir/pibrentasvir, the sustained virologic response after 12 weeks of treatment was 98.6%, 97.9% and 100%; the sustained virologic response after 24 weeks of treatment was 99.0%, 97.7% and 100%; the end of treatment response was 99.8%, 97.9% and 98.4%; and the treatment completion rate was 98.3%, 91.7% and 100% respectively. WHAT IS NEW AND CONCLUSION In real-world clinical practice, hepatitis C virus treatment with ledipasvir/sofosbuvir, elbasvir/grazoprevir and glecaprevir/pibrentasvir was effective with safety.
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Affiliation(s)
- Michihiro Kaya
- Department of PharmacyShizuoka General HospitalShizuoka CityShizuokaJapan
| | - Kazuyo Nakamura
- Department of PharmacyShizuoka General HospitalShizuoka CityShizuokaJapan
| | - Kyohei Sugiyama
- Department of PharmacyShizuoka General HospitalShizuoka CityShizuokaJapan
| | - Ayumi Kinae
- Department of PharmacyShizuoka General HospitalShizuoka CityShizuokaJapan
| | - Hiromi Yamaguchi
- Department of PharmacyShizuoka City Shimizu HospitalShizuoka CityShizuokaJapan
| | - Hirotoshi Ukita
- Clinical Study Management OfficeIwata City HospitalIwata CityShizuokaJapan
| | - Keiichi Odagiri
- Center for Clinical ResearchHamamatsu University School of MedicineHamamatsu CityShizuokaJapan
| | - Chika Ujiie
- Department of PharmacySeirei Mikatahara General HospitalHamamatsu CityShizuokaJapan
| | - Jun Kato
- Department of PharmacyYaizu City HospitalYaizu CityShizuokaJapan
| | - Fujito Kageyama
- Department of Gastroenterology and HepatologyHamamatsu Medical CenterHamamatsu CityShizuokaJapan
| | - Mariko Nagura
- Clinical Research CenterChutoen General Medical CenterKakegawa CityShizuokaJapan
| | - Kumi Matsushita
- Department of PharmacyKikugawa General HospitalKikugawa CityShizuokaJapan
| | - Kaori Sugiue
- Department of PharmacyJapan Japanese Red Cross Shizuoka HospitalShizuoka CityShizuokaJapan
| | - Hiroki Ishida
- Department of PharmacyJA Shizuoka Kohseiren Enshu HospitalHamamatsu CityShizuokaJapan
| | - Shinya Endo
- Department of GastroenterologyShizuoka General HospitalShizuoka CityShizuokaJapan
| | - Takaya Suzuki
- Department of PharmacyShizuoka General HospitalShizuoka CityShizuokaJapan
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Tahata Y, Sakamori R, Takehara T. Treatment progress and expansion in Japan: From interferon to direct-acting antiviral. Glob Health Med 2021; 3:321-334. [PMID: 34782876 DOI: 10.35772/ghm.2021.01083] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/24/2021] [Accepted: 09/10/2021] [Indexed: 12/17/2022]
Abstract
Hepatitis C virus (HCV) was first discovered in 1989, and patients infected with HCV were initially treated with interferon (IFN) monotherapy. In the 2000s, pegylated IFN combined with ribavirin was the mainstay of therapy for infected patients, but the sustained virologic response (SVR) rate was less than 50% for patients with HCV genotype 1. To further improve the therapeutic effect, direct-acting antiviral (DAA) was developed, and combination therapy with DAA and IFN has been available since 2011. In addition, IFN-free DAA therapy became available in 2014, and SVR was achieved in more than 95% of patients with chronic hepatitis and compensated cirrhosis. Thus, in just 30 years since the discovery of HCV, we aim to eliminate HCV in almost all patients. However, there are remaining issues to be addressed. Many of the patients who achieved SVR with DAA therapy had advanced liver fibrosis, and it is necessary to verify to what extent DAA therapy improves their prognosis in terms of liver function, hepatocellular carcinoma occurrence, and mortality. Resistance-associated substitutions can cause failure of DAA therapy, and the search for an effective therapy for high-level resistant viruses such as P32 deletion is particularly important. DAA therapy was approved for use in patients with decompensated cirrhosis in Japan in 2019, which is an unmet need so far. It is also important to verify the efficacy and safety in real-world settings. The World Health Organization aims to eliminate HCV by 2030, and Japan must tackle its remaining issues to achieve this goal.
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Affiliation(s)
- Yuki Tahata
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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Arai J, Ito T, Shimozuma Y, Uchikoshi M, Nakajima Y, Sakaki M, Uozumi S, Kajiwara A, Sugiura I, Otoyama Y, Nozawa H, Kurihara T, Eguchi J, Nomura N, Sakuma D, Sato M, Deguchi Y, Yoshida H. Decreased expression of interferon-stimulated genes in B cells of patients with chronic hepatitis C during interferon-free therapy potentially suggests the eradication of hepatitis C virus in the B cells: A cohort study. Health Sci Rep 2020; 3:e176. [PMID: 32685701 PMCID: PMC7362757 DOI: 10.1002/hsr2.176] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 05/14/2020] [Accepted: 06/03/2020] [Indexed: 01/03/2023] Open
Abstract
AIMS Hepatitis C virus (HCV) infection is monitored by the host innate immunity that includes the endogenous interferon (IFN), which up-regulates IFN-stimulated genes (ISGs). HCV is both hepatotropic and lymphotropic, but HCV replication in lymphoid cells is a controversial issue. Here, we analyzed the mRNA levels of the ISGs in B cells of HCV-infected patients during antiviral therapy and investigated the effects of viral eradication. METHODS One hundred and eighty-one patients with chronic hepatitis C and 26 healthy volunteers were enrolled in this study. Levels of HCV RNA and mRNA of ISGs in B cells isolated from the patients were monitored before, during, and after antiviral therapy. RESULTS HCV RNA was detected in B cells of 133/175 (76.0%) patients who achieved sustained virologic response (SVR) before therapy was started. The positive ratio of HCV RNA in B cells was higher in patients with genotype 1 and the non-major genotype of interleukin 28B. HCV RNA in B cells of most patients disappeared 1 week after antiviral therapy was started. The baseline expression of ISG mRNA was significantly higher in the patients than in the healthy volunteers. Levels of ISG mRNA were increased and remained high throughout the IFN-based therapy. In contrast, levels of ISG mRNA in patients who achieved SVR were significantly decreased 1 week after the IFN-free therapy was started and remained low during the therapy. CONCLUSIONS These results suggested that IFN-free therapy potentially eradicated HCV in the B cells, leading to the down-regulation of endogenous ISGs. The level of ISG mRNA could be used as a marker for viral eradication in B cells.
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Affiliation(s)
- Jun Arai
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
| | - Takayoshi Ito
- Digestive Disease CenterShowa University Koto Toyosu HospitalTokyoJapan
| | - Yuu Shimozuma
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
| | - Manabu Uchikoshi
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
| | - Yoko Nakajima
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
| | - Masashi Sakaki
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
| | - Shojiro Uozumi
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
| | - Atsushi Kajiwara
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
| | - Ikuya Sugiura
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
| | - Yumi Otoyama
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
| | - Hisako Nozawa
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
| | | | - Junichi Eguchi
- Digestive Disease CenterShowa University Koto Toyosu HospitalTokyoJapan
| | - Norihiro Nomura
- Digestive Disease CenterShowa University Koto Toyosu HospitalTokyoJapan
| | - Dai Sakuma
- Digestive Disease CenterShowa University Koto Toyosu HospitalTokyoJapan
| | - Masashi Sato
- Digestive Disease CenterShowa University Koto Toyosu HospitalTokyoJapan
| | - Yoshio Deguchi
- Digestive Disease CenterShowa University Koto Toyosu HospitalTokyoJapan
| | - Hitoshi Yoshida
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
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Takehara T, Chayama K, Kurosaki M, Yatsuhashi H, Tanaka Y, Hiramatsu N, Sakamoto N, Asahina Y, Nozaki A, Nakano T, Hagiwara Y, Shimizu H, Yoshida H, Huang Y, Biermer M, Vijgen L, Hayashi N. JNJ-4178 (adafosbuvir, odalasvir, and simeprevir) in Japanese patients with chronic hepatitis C virus genotype 1 or 2 infection with or without compensated cirrhosis: the Phase IIa OMEGA-3 study. J Gastroenterol 2020; 55:640-652. [PMID: 32065330 PMCID: PMC7242285 DOI: 10.1007/s00535-020-01672-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 01/18/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND The efficacy, safety, and pharmacokinetics of the combination of three direct-acting antiviral (DAA) agents (adafosbuvir [also known as AL-335], odalasvir, and simeprevir) were investigated in DAA treatment-naïve Japanese patients with genotype (GT)1 or GT2 chronic hepatitis C virus (HCV) infection, with or without compensated cirrhosis. METHODS In this Phase IIa, open-label, multicenter study-OMEGA-3 (NCT02993250)-patients received JNJ-4178 (adafosbuvir 800 mg once daily [QD], odalasvir 25 mg QD, and simeprevir 75 mg QD) for 8 (non-cirrhotic patients; Cohort 1) or 12 (cirrhotic patients; Cohort 2) weeks. Patients were followed-up to 24 weeks following the end of treatment (EOT). The primary endpoint was safety, including adverse events (AEs). RESULTS Overall, 33 patients were enrolled into Cohort 1 (N = 22) or 2 (N = 11) and received combined treatment with JNJ-4178. During the treatment and follow-up phases, a higher percentage of patients in Cohort 2 (81.8%) experienced AEs compared with Cohort 1 (68.2%), but the incidence of treatment-related AEs was similar. Most AEs were mild-to-moderate in severity and no patients discontinued due to an AE. There was one serious AE (cataract) in a patient in Cohort 2, which was not considered related to treatment. All patients achieved sustained virologic response 12 weeks after EOT (SVR12). No incidences of viral relapse were observed during follow-up. CONCLUSIONS In HCV GT1- and GT2-infected Japanese patients, treatment with JNJ-4178 was well tolerated and resulted in 100% of patients achieving SVR12.
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Affiliation(s)
- Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, 467-8601, Japan
| | - Naoki Hiramatsu
- Osaka Rosai Hospital, 1179-3 Kita, Sakai, Osaka, 591-8025, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, North 15 West 7 Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Yasuhiro Asahina
- Department of Liver Disease Control, Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Akito Nozaki
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, 232-0024, Japan
| | - Toshikazu Nakano
- Janssen Pharmaceutical K.K, 5-2, Nishi-kanda 3-chome, Chiyoda-ku, Tokyo, 101-0065, Japan
| | - Yosuke Hagiwara
- Janssen Pharmaceutical K.K, 5-2, Nishi-kanda 3-chome, Chiyoda-ku, Tokyo, 101-0065, Japan
| | - Hiroko Shimizu
- Clinical Pharmacology, Quantitative Sciences Division, R&D, Janssen Pharmaceutical K.K., 5-2, Nishi-kanda 3-chome, Chiyoda-ku, Tokyo, 101-0065, Japan
| | - Hiroki Yoshida
- Clinical Biostatistics Group 1 Biostatistics Department, 5-2, Nishi-kanda 3-chome, Chiyoda-ku, Tokyo, 101-0065, Japan
| | - Yuhan Huang
- Statistics and Decision Sciences, Janssen (China) Research and Development, LLC., 6F, Building A, Xinyan Mansion, No. 65 Guiqing Road, Xuhui District, Shanghai, People's Republic of China
| | - Michael Biermer
- Janssen Research and Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340, Beerse, Belgium
| | - Leen Vijgen
- Janssen Research and Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340, Beerse, Belgium
| | - Norio Hayashi
- Kansai Rosai Hospital, Inabasou 3-1-69, Amagasaki-shi, Hyogo, 660-8511, Japan
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7
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Nagai K, Ide K, Kawasaki Y, Tanaka-Mizuno S, Seto K, Iwane S, Eguchi Y, Kawakami K. Estimating the cost-effectiveness of screening for hepatitis C virus infection in Japan. Hepatol Res 2020; 50:542-556. [PMID: 31899841 DOI: 10.1111/hepr.13478] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 11/28/2019] [Accepted: 12/04/2019] [Indexed: 01/15/2023]
Abstract
AIM The management of hepatitis C virus (HCV) has changed with the advent of interferon (IFN)-free treatment and the declining prevalence of HCV infection, which may impact the cost-effectiveness of the screening. We aimed to compare the cost-effectiveness and clinical outcomes of three screening strategies in the Japanese general population: no screening, screening plus IFN-based therapy, and screening plus IFN-free therapy. METHODS We developed a decision analytic Markov model for screening intervention and natural history of HCV. Model parameters were derived from published literature. A lifetime horizon and the healthcare payer perspective were taken. Subanalyses included high screening scenario with improved rates of screening and attending referral, in addition to heterogeneity analysis by age subgroup. RESULTS In the base case, the incremental cost-effectiveness ratio in the Japanese general population aged 40-89 years was ¥1 124 482 and ¥1 085 183 per quality-adjusted life year gained for screening plus IFN-free therapy compared with no screening and screening plus IFN-based therapy, respectively. Screening plus IFN-free therapy remained cost-effective below ¥5 000 000 per quality-adjusted life year gained in sensitivity analyses. Incremental cost-effectiveness ratios were lower in the younger population. Nearly 0.2% of HCV-related deaths were avoided by 1.5% of the general population screened followed by IFN-free therapy relative to no screening; the impact was greater with improved rates of screening and attending referral. CONCLUSIONS Screening and subsequent IFN-free therapy for HCV appears to be cost-effective. Early diagnosis and treatment would produce a favorable incremental cost-effectiveness ratio. Improved rates of screening and attending referral would result in further reduction of disease progression.
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Affiliation(s)
- Kota Nagai
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan.,Eisai Co., Ltd., Tokyo, Japan
| | - Kazuki Ide
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan.,Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan
| | - Yohei Kawasaki
- Biostatistics Section, Clinical Research Center, Chiba University Hospital, Chiba, Japan
| | | | - Kahori Seto
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan
| | - Shinji Iwane
- Liver Center, Saga University Hospital, Saga, Japan
| | | | - Koji Kawakami
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan.,Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan
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8
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Tamori A, Inoue K, Kagawa T, Takaguchi K, Nouso K, Iwasaki Y, Minami M, Hai H, Enomoto M, Kawada N. Intention-to-treat assessment of glecaprevir + pibrentasvir combination therapy for patients with chronic hepatitis C in the real world. Hepatol Res 2019; 49:1365-1373. [PMID: 31323165 DOI: 10.1111/hepr.13410] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2019] [Revised: 06/20/2019] [Accepted: 07/11/2019] [Indexed: 02/08/2023]
Abstract
AIMS We assessed the problems and efficacy of glecaprevir + pibrentasvir (GLE/PIB) therapy for patients infected with hepatitis C virus (HCV) in the real world. METHOD A total of 423 patients infected with HCV who started treatment at eight different centers in Japan were enrolled in the study. Glecaprevir (300 mg) and pibrentasvir (120 mg) were given once daily for 8 weeks to 246 non-cirrhotic direct-acting antiviral (DAA)-naive patients with HCV genotype (GT)-1 or -2, and for 12 weeks to patients who: were DAA-naive cirrhotic (n = 55), had experienced DAA failure (n = 78), were cirrhotic and had DAA failure (n = 37), and were other GT-1/2 (n = 7). Anti-HCV efficacy was defined as a sustained virologic response 12 weeks post-treatment (SVR12). The evaluation was undertaken in an intention-to-treat (ITT) population and in patients who were assessed at SVR12 (modified ITT population). RESULTS In the ITT population, 220 (89%) patients on the 8-week regimen and 164 (93%) patients on the 12-week regimen achieved SVR12. The 30 dropout patients were predominantly men and with GT-2. All other DAA-naive GT-1 patients achieved SVR12. The 12-week regimen resulted in 100% SVR12 in 41 GT-2 patients. Nine patients did not achieve SVR12: two DAA naive with GT-2a, two GT-3b patients, two GT-1 patients with discontinuation, and three other GT-1 patients with a history of DAA failure. Four of seven patients who discontinued treatment due to severe adverse effects were more than 75 years old. CONCLUSIONS Glecaprevir + pibrentasvir had a remarkable anti-HCV effect in GT-1 and GT-2 patients, but not in GT-3b patients. Although this therapy was reasonably safe, it is necessary to carefully consider elderly and dropout patients.
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Affiliation(s)
- Akihiro Tamori
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kazuaki Inoue
- Department of Gastroenterology, Showa University, Yokohama, Japan
| | - Tatehiro Kagawa
- Department of Gastroenterology, Tokai University, Isehara, Japan
| | - Koichi Takaguchi
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Kazuhiro Nouso
- Department of Gastroenterology, Okayama City General Medical Center, Okayama, Japan
| | - Yoshiaki Iwasaki
- Department of Gastroenterology, Okayama University, Okayama, Japan
| | | | - Hoang Hai
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masaru Enomoto
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
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9
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Zhu X, Wang M, Liu M, Yu X, Huang P. Efficacy and safety of direct-acting antivirals for treatment-naive patients with genotype 1 hepatitis C virus infection. Per Med 2019; 16:421-429. [PMID: 31591934 DOI: 10.2217/pme-2018-0121] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This systematic review was performed on the basis of Preferred Reporting Items for Systematic Reviews and Meta-analyses and Cochrane recommendations to compare sustained virological response (SVR12) and the serious adverse events in patients treated by directing-acting antivirals. We conducted a literature search in PubMed/Medline, EBSCO, Embase and the Cochrane Library until 2018. A consistency model was used to get the relative effect of odds ratio among regimens and the possibility for the efficacy and safety of 13 regimen, and we divided these regimens into DUAL or TRIO regimens to conduct integrated data analysis. The results demonstrated that dual or triple directing-acting antiviral-combined regimens had higher SVR12 rates, Daclatasvir plus Asunaprevir may be a good choice for genotype 1 patients, and regimens without Ribavirin and interferon are safer.
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Affiliation(s)
- Xiaobo Zhu
- Department of Pharmacy, People's Hospital of Danyang, Danyang 212300, China
| | - Mingqi Wang
- Department of Epidemiology, Xu Zhou Medical University, Xuzhou 221000, China
| | - Mei Liu
- Department of Epidemiology, Nanjing Medical University, Nanjing 211166, China
| | - Xinghao Yu
- Department of Epidemiology, Xu Zhou Medical University, Xuzhou 221000, China
| | - Peng Huang
- Department of Epidemiology, Nanjing Medical University, Nanjing 211166, China.,Key Laboratory of Infectious Diseases, Nanjing Medical University, Nanjing 211166, China
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10
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Takeda H, Yamashita T, Ueda Y, Sekine A. Exploring the hepatitis C virus genome using single molecule real-time sequencing. World J Gastroenterol 2019; 25:4661-4672. [PMID: 31528092 PMCID: PMC6718035 DOI: 10.3748/wjg.v25.i32.4661] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 07/04/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Single molecular real-time (SMRT) sequencing, also called third-generation sequencing, is a novel sequencing technique capable of generating extremely long contiguous sequence reads. While conventional short-read sequencing cannot evaluate the linkage of nucleotide substitutions distant from one another, SMRT sequencing can directly demonstrate linkage of nucleotide changes over a span of more than 20 kbp, and thus can be applied to directly examine the haplotypes of viruses or bacteria whose genome structures are changing in real time. In addition, an error correction method (circular consensus sequencing) has been established and repeated sequencing of a single-molecule DNA template can result in extremely high accuracy. The advantages of long read sequencing enable accurate determination of the haplotypes of individual viral clones. SMRT sequencing has been applied in various studies of viral genomes including determination of the full-length contiguous genome sequence of hepatitis C virus (HCV), targeted deep sequencing of the HCV NS5A gene, and assessment of heterogeneity among viral populations. Recently, the emergence of multi-drug resistant HCV viruses has become a significant clinical issue and has been also demonstrated using SMRT sequencing. In this review, we introduce the novel third-generation PacBio RSII/Sequel systems, compare them with conventional next-generation sequencers, and summarize previous studies in which SMRT sequencing technology has been applied for HCV genome analysis. We also refer to another long-read sequencing platform, nanopore sequencing technology, and discuss the advantages, limitations and future perspectives in using these third-generation sequencers for HCV genome analysis.
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Affiliation(s)
- Haruhiko Takeda
- Department of Omics-based Medicine, Center for Preventive Medical Science, Chiba University, Chiba 260-0856, Japan
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Taiki Yamashita
- Department of Omics-based Medicine, Center for Preventive Medical Science, Chiba University, Chiba 260-0856, Japan
| | - Yoshihide Ueda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Akihiro Sekine
- Department of Omics-based Medicine, Center for Preventive Medical Science, Chiba University, Chiba 260-0856, Japan
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11
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Raja R, Baral S, Dixit NM. Interferon at the cellular, individual, and population level in hepatitis C virus infection: Its role in the interferon-free treatment era. Immunol Rev 2019; 285:55-71. [PMID: 30129199 DOI: 10.1111/imr.12689] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The advent of powerful direct-acting antiviral agents (DAAs) has revolutionized the treatment of hepatitis C. DAAs cure nearly all patients with short duration, oral treatments. Significant efforts are now underway to optimize DAA-based treatments. We discuss the potential role of interferon in this optimization. Clinical studies present compelling evidence that DAAs perform better in treatment-naive individuals than in individuals who previously failed treatment with interferon, a surprising correlation because interferon and DAAs are thought to act independently. Recent mathematical models explore a mechanistic hypothesis underlying this correlation. The hypothesis invokes the action of interferon at the cellular, individual, and population levels. Strong interferon responses prevent the productive infection of cells, reduce viral replication, and impede the development of resistance to DAAs in infected individuals and improve cure rates elicited by DAAs in treated populations. The models develop descriptions of these processes, integrate them into a comprehensive framework, and capture clinical data quantitatively, providing a successful test of the hypothesis. Individuals with strong endogenous interferon responses thus present a promising subpopulation for reducing DAA treatment durations. This review discusses the conceptual advances made by the models, highlights the new insights they unravel, and examines their applicability to optimize DAA-based treatments.
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Affiliation(s)
- Rubesh Raja
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, India
| | - Subhasish Baral
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, India
| | - Narendra M Dixit
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, India.,Centre for Biosystems Science and Engineering, Indian Institute of Science, Bangalore, India
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12
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Pecoraro V, Banzi R, Cariani E, Chester J, Villa E, D'Amico R, Bertele' V, Trenti T. New Direct-Acting Antivirals for the Treatment of Patients With Hepatitis C Virus Infection: A Systematic Review of Randomized Controlled Trials. J Clin Exp Hepatol 2019; 9:522-538. [PMID: 31516269 PMCID: PMC6728536 DOI: 10.1016/j.jceh.2018.07.004] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 07/07/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND New direct-acting antiviral agents (DAAs) approved for the treatment of patients infected by Hepatitis C virus (HCV) are well tolerated and increase sustained virological response (SVR) rate. We summarize current evidence on the efficacy and safety from comparative randomized controlled trials (RCTs) of DAAs. METHODS We systematically searched MEDLINE, Embase, Scopus, CENTRAL, and Lilacs as well as a list of reference literature. We included RCTs comparing DAAs with placebo or active control and reporting response rates and adverse events according to antiviral regimens. Risk ratios (RRs) were pooled as appropriate. We assessed the risk of bias of included studies and graded the quality of evidence according to the GRADE method. RESULTS We included 28 RCTs, enrolling more than 7000 patients. The quality of evidence was generally low. Twelve-week treatment with DAAs in naïve patients significantly increased SVR12 and SVR24 compared with placebo (RR 1.4, 95% CI 1.3-1.6; RR 1.5, 95% CI 1.4-1.6, respectively). This means that for every 1000 patients, 240 or 260 more patients experienced SVR12 or SVR24 if treated with any DAAs. We could not find RCTs assessing progression of liver disease or development of hepatocellular carcinoma. DAAs were not associated with higher incidence of serious adverse events or discontinuation due to adverse events. CONCLUSIONS This systematic review confirms that new DAAs are more effective in inducing SVR than placebo. Outside clinical trials, in real word, HCV cure with DAA regimens occurs in less than 90% of patients, so further comparative evaluations are needed to establish their long-term effects.
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Key Words
- AE, adverse event
- CI, confidence interval
- DAA, direct-acting antiviral agent
- HCC, hepatocellular carcinoma
- HCV, Hepatitis C virus
- NNPIs, nonnucleoside polymerase inhibitors
- NPIs, nucleoside polymerase inhibitors
- PEG-IFN, pegylated interferon
- PrIs, protease inhibitors
- RAVs, resistance-associated variants
- RBV, Ribavirin
- RCT, randomized controlled trial
- RR, risk ratio
- SAEs, serious adverse events
- SE, standard error
- SVR, sustained virological response
- hepatitis C
- liver
- meta-analysis
- outcome research
- systematic review
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Affiliation(s)
- Valentina Pecoraro
- Unit of Laboratory Medicine, Ospedale Civile Sant'Agostino Estense, Modena, Italy,Center for Drug Regulatory Policies, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy,Address for correspondence. Pecoraro Valentina, Unit of Laboratory Medicine, Ospedale Civile Sant'Agostino Estense, Modena, Italy.
| | - Rita Banzi
- Center for Drug Regulatory Policies, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Elisabetta Cariani
- Unit of Laboratory Medicine, Ospedale Civile Sant'Agostino Estense, Modena, Italy
| | - Johanna Chester
- Department of Surgery, Medical, Dentistry and Morphological Sciences, University of Modena e Reggio Emilia, Italy
| | - Erica Villa
- Department of Gastroenterology – AOU Modena, Modena, Italy
| | - Roberto D'Amico
- Cochrane Italy – University of Modena and Reggio Emilia, Italy
| | - Vittorio Bertele'
- Center for Drug Regulatory Policies, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Tommaso Trenti
- Unit of Laboratory Medicine, Ospedale Civile Sant'Agostino Estense, Modena, Italy
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13
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Taki S, Tamai H, Ida Y, Shingaki N, Kawashima A, Shimizu R, Moribata K, Maekita T, Iguchi M, Kato J, Nakao T, Kitano M. The Real-World Safety and Efficacy of Daclatasvir and Asunaprevir for Elderly Patients. Gut Liver 2018; 12:86-93. [PMID: 28798288 PMCID: PMC5753689 DOI: 10.5009/gnl17048] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 03/22/2017] [Accepted: 03/22/2017] [Indexed: 01/10/2023] Open
Abstract
Background/Aims Although daclatasvir with asunaprevir was approved in Japan for interferon ineligible or intolerant patients, patients aged ≥75 years were excluded in the phase III trial. The present study aimed to evaluate the safety and efficacy of this therapy for elderly patients aged ≥75 years and to clarify whether an extremely high sustained virological response (SVR) rate can be achieved, even in a real-world setting when patients with resistance-associated substitutions (RASs) to nonstructural protein 5A (NS5A) inhibitors or prior simeprevir failure are excluded. Methods Daclatasvir (60 mg) and asunaprevir (100 mg) were orally administered daily for 24 weeks. Patients without pre-existing NS5A RASs and simeprevir failure were enrolled in this study. Results Overall, 110 patients were treated. The median age was 73 years old. The SVR rates of total patients, those aged ≥75 years, and those aged <75 years were 97% (107/110), 98% (46/47), and 97% (61/63), respectively. The treatment of two patients (2%) was discontinued because of adverse events. Conclusions Daclatasvir with asunaprevir was a safe treatment, even in patients aged ≥75 years. When patients without pre-existing NS5A RASs and prior simeprevir failure were selected, an extremely high SVR rate could be achieved irrespective of age.
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Affiliation(s)
- Shinya Taki
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Hideyuki Tamai
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Yoshiyuki Ida
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Naoki Shingaki
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Akira Kawashima
- Department of Internal Medicine, Naga Municipal Hospital, Wakayama, Japan
| | - Ryo Shimizu
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Kosaku Moribata
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Takao Maekita
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Mikitaka Iguchi
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Jun Kato
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Taisei Nakao
- Department of Internal Medicine, Naga Municipal Hospital, Wakayama, Japan
| | - Masayuki Kitano
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
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14
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Chida T, Kawata K, Ohta K, Matsunaga E, Ito J, Shimoyama S, Yamazaki S, Noritake H, Suzuki T, Suda T, Kobayashi Y. Rapid Changes in Serum Lipid Profiles during Combination Therapy with Daclatasvir and Asunaprevir in Patients Infected with Hepatitis C Virus Genotype 1b. Gut Liver 2018; 12:201-207. [PMID: 29212314 PMCID: PMC5832345 DOI: 10.5009/gnl17179] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 06/28/2017] [Accepted: 06/28/2017] [Indexed: 12/13/2022] Open
Abstract
Background/Aims Changes in lipid profiles in patients infected with hepatitis C virus (HCV) during direct-acting antiviral therapy have been reported in recent years. However, the clinical aspects of disturbed lipid metabolism in chronic HCV infection have not been fully elucidated. Methods Dynamic changes in serum total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol and apolipoprotein levels in patients infected with HCV genotype 1b were examined during combination therapy with daclatasvir (DCV) and asunaprevir (ASV). Results Total, LDL−, and HDL-cholesterol levels increased rapidly and persistently after week 4. Apolipoprotein (apo) A-I, apo B, apo C-II, and apo C-III levels were significantly higher at week 4 than at week 0. In contrast, apo A-II and apo E levels were significantly lower. The differences in LDL− and HDL-cholesterol levels were positively correlated with those of apo B and apo A-I, respectively. Interestingly, in patients with non-sustained virological response, these cholesterol levels decreased rapidly after viral breakthrough or viral relapse. Furthermore, similar changes were observed for apo A-I, apo B and apo C-III levels. Conclusions Clearance of HCV using combination therapy with DCV and ASV results in rapid changes in serum lipid profiles, suggesting an influence of HCV infection on disturbed lipid metabolism.
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Affiliation(s)
- Takeshi Chida
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan.,Department of Virology and Parasitology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kazuhito Kawata
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kazuyoshi Ohta
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan.,Department of Virology and Parasitology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Erika Matsunaga
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Jun Ito
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Shin Shimoyama
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Satoru Yamazaki
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hidenao Noritake
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Tetsuro Suzuki
- Department of Virology and Parasitology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takafumi Suda
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yoshimasa Kobayashi
- Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
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15
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Fujii H, Kimura H, Kurosaki M, Hasebe C, Akahane T, Yagisawa H, Kato K, Yoshida H, Itakura J, Sakita S, Satou T, Okada K, Kusakabe A, Kojima Y, Kondo M, Morita A, Nasu A, Tamada T, Okushin H, Kobashi H, Tsuji K, Joko K, Ogawa C, Uchida Y, Mitsuda A, Sohda T, Ide Y, Izumi N. Efficacy of daclatasvir plus asunaprevir in patients with hepatitis C virus infection undergoing and not undergoing hemodialysis. Hepatol Res 2018; 48:746-756. [PMID: 29480939 DOI: 10.1111/hepr.13070] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 02/01/2018] [Accepted: 02/17/2018] [Indexed: 02/08/2023]
Abstract
AIM To evaluate the virologic responses and clinical course of daclatasvir plus asunaprevir treatment in non-hemodialysis (non-HD) and hemodialysis (HD) patients infected with genotype 1 hepatitis C virus (HCV). METHODS A total of 1113 non-HD patients and 67 HD patients were assessed. To evaluate pretreatment factors contributing to sustained virological response at 12 weeks (SVR12), univariate and multivariate analyses were carried out. To adjust for differences in patient background, propensity score matching was undertaken. RESULTS The overall SVR12 rates were 91.6% in non-HD patients and 95.5% in HD patients. Compared with non-HD patients, HD patients were younger, were more likely to be male, were less likely to have received interferon-based pretreatment, had a lower viral load, and had lower levels of alanine transaminase, hemoglobin, and α-fetoprotein. Multivariate analysis revealed that viral load, α-fetoprotein, L31 substitution negative, and Y93 substitution negative were independent predictive factors for SVR12 in non-HD patients. The proportion of patients with undetectable HCV-RNA during the initial 4 weeks was significantly higher in HD patients than in non-HD patients. The SVR12 rate was clearly higher in HD patients than in non-HD patients, although the difference was not statistically significant. After propensity score matching to adjust for viral load, α-fetoprotein, L31 substitution, and Y93 substitution, these trends disappeared. CONCLUSIONS For treatment of HCV genotype 1 infection, daclatasvir plus asunaprevir is useful not only in non-HD patients but also in HD patients. Viral load, α-fetoprotein levels, L31 substitution, and Y93 substitution influence treatment course and outcome.
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Affiliation(s)
- Hideki Fujii
- Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan
| | - Hiroyuki Kimura
- Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Japan
| | - Chitomi Hasebe
- Department of Gastroenterology, Asahikawa Red Cross Hospital, Asahikawa, Japan
| | - Takehiro Akahane
- Department of Gastroenterology, Japanese Red Cross Ishinomaki Hospital, Ishinomaki, Japan
| | - Hitoshi Yagisawa
- Department of Gastroenterology, Japanese Red Cross Akita Hospital, Akita, Japan
| | - Keizo Kato
- Department of Gastroenterology, Narita Red Cross Hospital, Narita, Japan
| | - Hideo Yoshida
- Department of Gastroenterology, Japanese Red Cross Medical Center, Tokyo, Japan
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Japan
| | - Shinya Sakita
- Department of Gastroenterology, Yokohama City Minato Red Cross Hospital, Yokohama, Japan
| | - Takashi Satou
- Department of Gastroenterology, Nasu Red Cross Hospital, Otawara, Tochigi, Japan
| | - Kazuhiko Okada
- Department of Gastroenterology, Toyama Red Cross Hospital, Toyama, Japan
| | - Atsunori Kusakabe
- Department of Gastroenterology, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Yuji Kojima
- Department of Gastroenterology and Hepatology, Japanese Red Cross Ise Hospital, Ise, Japan
| | - Masahiko Kondo
- Department of Gastroenterology, Otsu Red Cross Hospital, Siga, Japan
| | - Atsuhiro Morita
- Department of Gastroenterology, Kyoto Second Red Cross Hospital Gastroenterology, Kyoto, Japan
| | - Akihiro Nasu
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Takashi Tamada
- Department of Gastroenterology and Hepatology, Takatsuki Red Cross Hospital, Osaka, Japan
| | - Hiroaki Okushin
- Department of Hepatology, Japanese Red Cross Society Himeji Hospital, Himeji, Japan
| | - Haruhiko Kobashi
- Department of Hepatology, Japanese Red Cross Okayama Hospital, Okayama, Japan
| | - Keiji Tsuji
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Kouji Joko
- Center for Liver-Biliary-Pancreatic Diseases, Matsuyama Red Cross Hospital, Ehime
| | - Chikara Ogawa
- Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital, Takamatsu, Japan
| | - Yasushi Uchida
- Department of Gastroenterology, Matsue Red Cross Hospital, Matsue, Japan
| | - Akeri Mitsuda
- Department of Gastroenterology, Japanese Red Cross Tottori Hospital, Tottori, Japan
| | - Tetsuro Sohda
- Hepatology Division, Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan
| | - Yasushi Ide
- Department of Gastroenterology, Japanese Red Cross Karatsu Hospital, Karatsu, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Japan
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16
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Tamborini Permunian E, Gervaso L, Gerdes V, Moja L, Guasti L, Squizzato A. Direct-acting antiviral drugs for chronic hepatitis C and risk of major vascular events: a systematic review. Intern Emerg Med 2018; 13:775-790. [PMID: 29611106 DOI: 10.1007/s11739-018-1828-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Accepted: 03/08/2018] [Indexed: 12/23/2022]
Abstract
Direct-acting antiviral drugs (DAAs) were recently approved for treating hepatitis C virus-related chronic hepatitis. As advanced chronic liver disease may predispose patients to thrombotic events, it is still uncertain whether DAAs may influence the actual risk of major arterial and venous thrombotic events. We performed a systematic review to assess the incidence of major vascular events in patients receiving DAAs for HCV chronic hepatitis during phase-III randomized controlled trials (RCTs). Two reviewers identified studies through Pubmed database until October 2015. Reporting and incidence of any vascular events were compared with reporting and incidence of major bleeding, anemia (a prespecified safety outcome) and headache (a common non-prespecified safety outcome). 33 RCTs, encompassing 14,764 patients, were included. Only 13 (39%) and 4 (12%) RCTs provide data on any arterial or venous events, respectively. Occurrence of anemia and headache is reported in all studies. Crude unweighted rate of major arterial events is 0.16% (95% CI 0.10-0.24) of the total included population and 0.47% in those 13 RCTs reporting data. Crude unweighted rate of major venous events is 0.03% of the total included population (95% CI 0.01-0.08) and 0.22% in those four RCTs reporting data. Crude unweighted rate of major bleeding is 0.07% (95% CI 0.03-0.1). Incidence of thrombotic events in HCV patients receiving DAAs may be low, but an incorrect estimation cannot be excluded.
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Affiliation(s)
- Eleonora Tamborini Permunian
- Department of Medicine and Surgery, Research Centre on Thromboembolic Disorders and Antithrombotic Therapies, University of Insubria, Varese, Italy
| | - Lorenzo Gervaso
- Oncology Unit, IRCCS Fondazione Salvatore Maugeri, University of Pavia, Pavia, Italy
| | - Victor Gerdes
- Department of Internal Medicine, MC Slotervaart, Amsterdam, The Netherlands
| | - Lorenzo Moja
- Unit of Clinical Epidemiology, I.R.C.C.S. Orthopedic Institute Galeazzi, Milan, Italy
| | - Luigina Guasti
- Department of Medicine and Surgery, Research Centre on Thromboembolic Disorders and Antithrombotic Therapies, University of Insubria, Varese, Italy.
- U.O. Medicina Interna 1, ASST Settelaghi, Viale Borri, 57, 21100, Varese, Italy.
| | - Alessandro Squizzato
- Department of Medicine and Surgery, Research Centre on Thromboembolic Disorders and Antithrombotic Therapies, University of Insubria, Varese, Italy
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Ran M, Huang J, Liang H, Jiang J, Liang B, Ning C, Zang N, Liao W, Liu H, Qin F, Yang Q, Ho W, Ye L, Chen H. Alcohol attenuates anti-HCV function of IFN-λ1 through up-regulation of PLASy expression in human hepatic cells. J Med Virol 2018; 90:1112-1120. [PMID: 29446489 DOI: 10.1002/jmv.25053] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 02/12/2018] [Indexed: 12/23/2022]
Abstract
Alcohol could compromise the anti-hepatitis C virus (HCV) function of interferon-alpha (IFN-α). However, little information is available about the effect of alcohol on interferon-lambda (IFN-λ, type III IFN), a novel candidate for development of therapy for HCV infection. Huh7 cells were infected with HCV JFH-1 virus, then treated with alcohol, and/or IFN-λ1. RT-PCR and Western blot were used to detect the levels of HCV and key cellular factors. Overexpression or silencing expression was performed to verify the role of key factors in alcohol-attenuated anti-HCV function of IFN-λ1. Alcohol treatment compromised anti-HCV effect of IFN-λ1 in HCV JFH-1-infected Huh7 cells, evidenced by the significantly increased levels of HCV RNA, and HCV core protein in alcohol-/IFN-λ1-treated cells compared to cells with IFN-λ1 treatment alone. Investigation of the mechanisms responsible for the alcohol action revealed that alcohol enhanced the expression of protein inhibitor of activated STAT (PIASy). Overexpression of PIASy compromised anti-HCV ability of IFN-λ1, whereas silencing expression of PIASy partly restored the alcohol-attenuated anti-HCV effect of IFN-λ1. More importantly, overexpression of PIASy significantly down-regulated the level of IFN-λ1-indcued phosphorylation of STAT1 (p-STAT1), an important adaptor in IFN-λ pathway, as well as reduced the expression of IFN-λ1-induced IFN-stimulated genes 56 (ISG56), and myxovirus resistance 1 (Mx1), two antiviral effectors in in IFN-λ pathway. These findings indicate that alcohol, through inducing the expression of negative regulator in IFN-λ pathway, inhibits IFN-λ-mediated anti-HCV action in human hepatic cells, which may lead to the poor efficacy of IFN-λ-based therapy against HCV infection.
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Affiliation(s)
- Meihua Ran
- Geriatrics Digestion Department of Internal Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Jiegang Huang
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Hao Liang
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
- Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Junjun Jiang
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Bingyu Liang
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Chuanyi Ning
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
- Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Ning Zang
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
- Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Weibo Liao
- Geriatrics Digestion Department of Internal Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Huifang Liu
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
- Guangxi Collaborative Innovation Center for Biomedicine, Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Fengxiang Qin
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Quanlue Yang
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Wenzhe Ho
- Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania
| | - Li Ye
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Hui Chen
- Geriatrics Digestion Department of Internal Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Universities Key Laboratory of Prevention and Control of Highly Prevalent Disease, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
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18
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Kozuka R, Hai H, Motoyama H, Hagihara A, Fujii H, Uchida-Kobayashi S, Morikawa H, Enomoto M, Murakami Y, Kawada N, Tamori A. The presence of multiple NS5A RASs is associated with the outcome of sofosbuvir and ledipasvir therapy in NS5A inhibitor-naïve patients with chronic HCV genotype 1b infection in a real-world cohort. J Viral Hepat 2018; 25:535-542. [PMID: 29274188 DOI: 10.1111/jvh.12850] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2017] [Accepted: 11/22/2017] [Indexed: 02/06/2023]
Abstract
It is unclear whether multiple nonstructural (NS) 5A resistance-associated substitutions (RASs) correlate with the outcome of sofosbuvir (SOF) and ledipasvir (LDV) therapy. We investigated the effects of multiple NS5A RASs in NS5A inhibitor-naïve patients with chronic hepatitis C virus genotype 1b infection treated with SOF/LDV. In 313 patients treated with SOF/LDV, we assessed the effects of multiple NS5A RASs on the sustained virological response (SVR). RASs at L28, R30, L31, Q54, P58, Q62, A92, and Y93 in the NS5A region were examined by direct sequencing. The prevalence of RASs was as follows: 2.6% at L28, 8.7% at R30, 6.1% at L31, 48.7% at Q54, 9.9% at P58, 9.9% at Q62, 5.1% at A92, 13.8% at Y93, and 19.2% at L31 or Y93. A total of 133 patients had no RASs. SVR was achieved in 98.7% of the patients. SVR rates significantly differed between patients with and without the L31 or Y93 RAS (93.0% [53/57] vs 100% [250/250], P = .0011). In addition, among patients with the L31 or Y93 RAS, 29.8%, 45.6% and 24.6% had one, two and three or more NS5A RASs, respectively. The SVR rate was significantly lower in patients with the L31 or Y93 RAS with more than three NS5A RASs compared to those with fewer than three NS5A RASs (71.4% [10/14] vs 100% [43/43], P = .0025). Although the prevalence of multiple NS5A RASs at baseline was low in NS5A inhibitor-naïve patients, the presence of multiple NS5A RASs was associated with the effectiveness of SOF/LDV therapy.
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Affiliation(s)
- R Kozuka
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - H Hai
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - H Motoyama
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - A Hagihara
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - H Fujii
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - S Uchida-Kobayashi
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - H Morikawa
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - M Enomoto
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Y Murakami
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - N Kawada
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - A Tamori
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
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Tamai H, Ida Y, Kawashima A, Shingaki N, Shimizu R, Moribata K, Nasu T, Maekita T, Iguchi M, Kato J, Nakao T, Kitano M. Simeprevir-Based Triple Therapy with Reduced Doses of Pegylated Interferon α-2a Plus Ribavirin for Interferon Ineligible Patients with Genotype 1b Hepatitis C Virus. Gut Liver 2018; 11:551-558. [PMID: 28506030 PMCID: PMC5491091 DOI: 10.5009/gnl16525] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 12/10/2016] [Accepted: 12/23/2016] [Indexed: 12/28/2022] Open
Abstract
Background/Aims The present study aimed to evaluate the safety and efficacy of simeprevir-based triple therapy with reduced doses of pegylated interferon (PEG-IFN) and ribavirin for interferon (IFN) ineligible patients, such as elderly and/or cirrhotic patients, and to elucidate the factors contributing to a sustained virologic response (SVR). Methods One hundred IFN ineligible patients infected with genotype 1b hepatitis C virus (HCV) were treated. Simeprevir (100 mg) was given orally together with reduced doses of PEG-IFN-α 2a (90 μg), and ribavirin (200 mg less than the recommended dose). Results The patients’ median age was 70 years, and 70 patients were cirrhotic. Three patients (3%) discontinued treatment due to adverse events. The SVR rate was 64%. Factors that significantly contributed to the SVR included the γ-glutamyl transferase and α-fetoprotein levels, interleukin-28B (IL28B) polymorphism status, and the level and reduction of HCV RNA at weeks 2 and 4. The multivariate analysis showed that the IL28B polymorphism status was the only independent factor that predicted the SVR, with a positive predictive value of 77%. Conclusions Simeprevir-based triple therapy with reduced doses of PEG-IFN and ribavirin was safe and effective for IFN ineligible patients infected with genotype 1b HCV. IL28B polymorphism status was a useful predictor of the SVR.
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Affiliation(s)
- Hideyuki Tamai
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Yoshiyuki Ida
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Akira Kawashima
- Department of Internal Medicine, Naga Municipal Hospital, Wakayama, Japan
| | - Naoki Shingaki
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Ryo Shimizu
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Kosaku Moribata
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Tetsushi Nasu
- Department of Internal Medicine, Naga Municipal Hospital, Wakayama, Japan
| | - Takao Maekita
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Mikitaka Iguchi
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Jun Kato
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Taisei Nakao
- Department of Internal Medicine, Naga Municipal Hospital, Wakayama, Japan
| | - Masayuki Kitano
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
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20
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Rattanavipapong W, Anothaisintawee T, Teerawattananon Y. Revisiting policy on chronic HCV treatment under the Thai Universal Health Coverage: An economic evaluation and budget impact analysis. PLoS One 2018; 13:e0193112. [PMID: 29466415 PMCID: PMC5821370 DOI: 10.1371/journal.pone.0193112] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 02/05/2018] [Indexed: 12/15/2022] Open
Abstract
Thailand is encountering challenges to introduce the high-cost sofosbuvir for chronic hepatitis C treatment as part of the Universal Health Care's benefit package. This study was conducted in respond to policy demand from the Thai government to assess the value for money and budget impact of introducing sofosbuvir-based regimens in the tax-based health insurance scheme. The Markov model was constructed to assess costs and benefits of the four treatment options that include: (i) current practice-peginterferon alfa (PEG) and ribavirin (RBV) for 24 weeks in genotype 3 and 48 weeks for other genotypes; (ii) Sofosbuvir plus peginterferon alfa and ribavirin (SOF+PEG-RBV) for 12 weeks; (iii) Sofosbuvir and daclatasvir (SOF+DCV) for 12 weeks; (iv) Sofosbuvir and ledipasvir (SOF+LDV) for 12 weeks for non-3 genotypes and SOF+PEG-RBV for 12 weeks for genotype 3 infection. Given that policy options (ii) and (iii) are for pan-genotypic infection, the cost of genotype testing was applied only for policy options (i) and (iv). Results reveal that all sofosbuvir-based regimens had greater quality adjusted life years (QALY) gains compared with the current treatment, therefore associated with lower lifetime costs and more favourable health outcomes. Additionally, among the three regimens of sofosbuvir, SOF+PEG-RBV for genotype 3 and SOF+LDV for non-3 genotype are the most cost-effective treatment option with the threshold of 160,000 THB per QALY gained. The results of this study had been used in policy discussion which resulted in the recent inclusion of SOF+PEG-RBV for genotype 3 and SOF+LDV for non-3 genotype in the Thailand's benefit package.
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Affiliation(s)
- Waranya Rattanavipapong
- Health Intervention and Technology Assessment Program (HITAP), Department of Health, Ministry of Public Health, Nonthaburi, Thailand
| | - Thunyarat Anothaisintawee
- Health Intervention and Technology Assessment Program (HITAP), Department of Health, Ministry of Public Health, Nonthaburi, Thailand
- Department of Family Medicine, Faculty of Medicine, Ramathibodi Hospital, Bangkok, Thailand
| | - Yot Teerawattananon
- Health Intervention and Technology Assessment Program (HITAP), Department of Health, Ministry of Public Health, Nonthaburi, Thailand
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21
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Hayashi K, Ishigami M, Yasuda S, Ishizu Y, Kuzuya T, Honda T, Ishikawa T, Hirooka Y, Goto H. Occurrence of late relapse of hepatitis C virus confirmed by molecular analysis after sustained virologic response to interferon-ribavirin-based therapy. Hepatol Res 2018. [PMID: 28643404 DOI: 10.1111/hepr.12929] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM The optimal duration of follow-up for patients who achieve sustained virologic responses (SVR) has become an important issue. Reports on long-term follow-up of SVR have indicated that 99% of patients maintained SVR. However, the limitations of a majority of studies include small patient numbers, short study periods, and lack of molecular analysis of hepatitis C virus (HCV) genome. The present study sought to evaluate the late relapse rate in long-term follow-up of patients who achieved SVR, with molecular analysis of HCV. METHODS A total of 224 patients with chronic hepatitis C who were treated by interferon and ribavirin-based therapy and achieved SVR were enrolled. All patients were recommended for follow-up every 6 or 12 months. RESULTS The mean follow-up period was 6.0 years (range, 1.0-13.6 years). Cumulative 5- and 10-year follow-up rates of the patients after SVR were 87.8% and 78.8%, respectively. Cumulative 5- and 10-year follow-up rates of serum HCV RNA after SVR were 85.5% and 52.6%, respectively. Two patients had detectable serum HCV RNA at 20 and 30 months, respectively, after SVR. Phylogenetic analyses of core, non-structural protein 3, and 5A regions of HCV strains from late relapse patients confirmed the same strain was present at baseline and late relapse. CONCLUSIONS Two of 224 patients developed late relapse of HCV by the original strain, which was confirmed by direct sequencing analysis. Although few patients may develop late relapse, SVR achieved with interferon and ribavirin-based therapy is durable for prolonged periods.
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Affiliation(s)
- Kazuhiko Hayashi
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Teiji Kuzuya
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tetsuya Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshiki Hirooka
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hidemi Goto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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22
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Suda G, Ito J, Nagasaka A, Yamamoto Y, Furuya K, Okamoto M, Terashita K, Kobayashi T, Tsunematsu I, Yoshida J, Meguro T, Ohara M, Kawagishi N, Kimura M, Umemura M, Izumi T, Tsukuda Y, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N. Add-on effects of fluvastatin in simeprevir/pegylated-interferon/ribavirin combination therapy for patients with genotype 1 hepatitis C virus infection: A randomized controlled study. Hepatol Res 2018; 48:E146-E154. [PMID: 28722780 DOI: 10.1111/hepr.12938] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 07/11/2017] [Accepted: 07/12/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND The Japan Society of Hepatology guidelines indicate that hepatitis C virus (HCV) protease inhibitor combination therapy with simeprevir (SMV), pegylated-interferon (Peg-IFN), and ribavirin (RBV) is a therapeutic option for patients who fail to respond to a direct direct-acting antiviral-containing regimen. However, treatment outcomes have room for improvement. Fluvastatin (FLV) add-on treatment in Peg-IFN and RBV combination therapy for HCV-infected patients significantly improved the sustained virologic response (SVR), but the add-on effect of FLV on SMV combination therapy is not well understood. METHODS This was a prospective, randomized, multicenter study in which a total of 61 HCV genotype 1b-infected patients were recruited and 60 eligible patients were randomly allocated to two groups that received 12 weeks of SMV/Peg-IFN/RBV followed by 12 weeks of Peg-IFN/RBV with or without 24 weeks of FLV. The SVR rate and adverse events were compared between the two groups. RESULTS Thirty-one patients were allocated to the FLV add-on group and 29 patients were allocated to the control group. Baseline clinical factors, including median age, baseline platelet count, alanine aminotransferase level, HCV RNA titer, Fibrosis-4 index, and rate of IL28B minor genotype, were all similar between the two groups. The rapid virologic response, end-of-treatment response rates, SVR rates at 24 weeks after treatment, and safety profiles were also similar between the two groups. CONCLUSIONS This prospective, randomized, multicenter study indicated that FLV had no add-on effect when given with SMV/Peg-IFN/RBV combination therapy for genotype 1b HCV-infected patients.
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Affiliation(s)
- Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Jun Ito
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | | | | | | | | | - Katsumi Terashita
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.,Kushiro Rosai Hospital, Kushiro, Japan
| | - Tomoe Kobayashi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.,Tomakomai City Hospital, Tomakomai, Japan
| | | | | | | | - Masatsugu Ohara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Naoki Kawagishi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Megumi Kimura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Machiko Umemura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Takaaki Izumi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Yoko Tsukuda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.,Sapporo City General Hospital, Sapporo, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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Kaneko R, Nakazaki N, Omori R, Yano Y, Ogawa M, Sato Y. Efficacy of direct-acting antiviral treatment for chronic hepatitis C: A single hospital experience. World J Hepatol 2018; 10:88-94. [PMID: 29399282 PMCID: PMC5787689 DOI: 10.4254/wjh.v10.i1.88] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 12/04/2017] [Accepted: 12/13/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the efficacy of direct-acting antivirals (DAAs) in Kanto Rosai Hospital.
METHODS All patients with hepatitis C virus (HCV) who underwent DAA prescription were enrolled in this study. The present study was a single center retrospective analysis using patients infected with HCV genotype 1 or 2. Resistance analysis was performed by using direct sequencing and cycleave PCR in genotype 1 patients treated with interferon (IFN)-free DAA. The primary endpoint was sustained virologic response at 12 wk after therapy (SVR12).
RESULTS A total of 117 patients participated in the study, including 135 with genotype 1 and 42 with genotype 2. Of the 135 patients with genotype 1, 16 received protease inhibitor + IFN + ribavirin and all achieved SVR. Of the 119 patients who received IFN-free DAA (in different combinations), 102 achieved SVR and 9 failed (7/9 were on daclatasvir/asunaprevir and 2/9 on ledipasvir/sofosbuvir). Efficacy analysis was done only for 43 patients who received daclatasvir/asunaprevir. From this analysis, Y93 resistance-associated substitutions were significantly correlated with SVR.
CONCLUSION The SVR rate was 98% for genotype 1 and 100% for genotype 2. However, caution is needed for HCV NS5A resistance-associated substitutions that are selected by HCV NS5A inhibitors because cerebrovascular adverse events are induced by some DAA drugs.
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Affiliation(s)
- Rena Kaneko
- Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, Japan
| | - Natsuko Nakazaki
- Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, Japan
| | - Risa Omori
- Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, Japan
| | - Yuichiro Yano
- Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, Japan
| | - Masazumi Ogawa
- Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, Japan
| | - Yuzuru Sato
- Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, Japan
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24
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Kaneko R, Nakazaki N, Omori R, Yano Y, Ogawa M, Sato Y. The Effect of New Therapeutic and Diagnostic Agents on the Prognosis of Hepatocellular Carcinoma in Japan – An Analysis of Data from the Kanagawa Cancer Registry. Asian Pac J Cancer Prev 2017; 18:2471-2476. [PMID: 28952279 PMCID: PMC5720653 DOI: 10.22034/apjcp.2017.18.9.2471] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Objective: Notable advances in diagnostic imaging modalities and therapeutic agents have contributed to
improvement in the prognosis of hepatocellular carcinoma (HCC) over the past decade. However, knowledge concerning
their epidemiological contribution remains limited. The present study investigated the effect of emerging diagnostic
and therapeutic agents on HCC prognosis, using the largest regional cancer registry in Japan. Methods: Using data
from the Kanagawa Cancer Registry, the five-year survival rate of patients with liver cancer was estimated according
to the International Statistical Classification of Diseases and Related Health Problems (10th Edition). Result: A total of
40,276 cases of HCC (from 1976 to 2013) were identified. The prognosis markedly improved after the introduction of
new devices into the diagnosis and treatment of HCC (p<0.01). The trend of survival rate varied significantly between
institutions with many registered patients (high-volume centers) (p<0.01). Conclusion: The five-year survival rate of
patients with HCC in Kanagawa has markedly improved in recent years. This improvement in survival may be attributed
to the advances in surveillance and intervention for the treatment of HCC.
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Affiliation(s)
- Rena Kaneko
- Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Japan.
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Jakobsen JC, Nielsen EE, Feinberg J, Katakam KK, Fobian K, Hauser G, Poropat G, Djurisic S, Weiss KH, Bjelakovic M, Bjelakovic G, Klingenberg SL, Liu JP, Nikolova D, Koretz RL, Gluud C, Cochrane Hepato‐Biliary Group. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev 2017; 9:CD012143. [PMID: 28922704 PMCID: PMC6484376 DOI: 10.1002/14651858.cd012143.pub3] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs), e.g. sofosbuvir, are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). Sustained virological response (SVR) is used by investigators and regulatory agencies as a surrogate outcome for morbidity and mortality, based solely on observational evidence. However, there have been no randomised trials that have validated that usage. OBJECTIVES To assess the benefits and harms of DAAs in people with chronic HCV. SEARCH METHODS We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016. SELECTION CRITERIA Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and health-related quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and SVR. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. We evaluated the overall quality of the evidence, using GRADE. MAIN RESULTS We included a total of 138 trials randomising a total of 25,232 participants. The trials were generally short-term trials and designed primarily to assess the effect of treatment on SVR. The trials evaluated 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered DAAs that were discontinued or withdrawn from the market. Study populations were treatment-naive in 95 trials, had been exposed to treatment in 17 trials, and comprised both treatment-naive and treatment-experienced individuals in 24 trials. The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.We could not reliably determine the effect of DAAs on the market or under development on our primary outcome of hepatitis C-related morbidity or all-cause mortality. There were no data on hepatitis C-related morbidity and only limited data on mortality from 11 trials (DAA 15/2377 (0.63%) versus control 1/617 (0.16%); OR 3.72, 95% CI 0.53 to 26.18, very low-quality evidence). We did not perform Trial Sequential Analysis on this outcome.There is very low quality evidence that DAAs on the market or under development do not influence serious adverse events (DAA 5.2% versus control 5.6%; OR 0.93, 95% CI 0.75 to 1.15 , 15,817 participants, 43 trials). The Trial Sequential Analysis showed that there was sufficient information to rule out that DAAs reduce the relative risk of a serious adverse event by 20% when compared with placebo. The only DAA that showed a lower risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, the meta-analysis result showed no evidence of a difference.DAAs on the market or under development may reduce the risk of no SVR from 54.1% in untreated people to 23.8% in people treated with DAA (RR 0.44, 95% CI 0.37 to 0.52, 6886 participants, 32 trials, low quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).There was insufficient evidence from trials on withdrawn or discontinued DAAs to determine their effect on hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79; 5 trials, very low-quality evidence). However, these DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73; 29 trials, very low-quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). AUTHORS' CONCLUSIONS The evidence for our main outcomes of interest come from short-term trials, and we are unable to determine the effect of long-term treatment with DAAs. The rates of hepatitis C morbidity and mortality observed in the trials are relatively low and we are uncertain as to how DAAs affect this outcome. Overall, there is very low quality evidence that DAAs on the market or under development do not influence serious adverse events. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs may reduce the number of people with detectable virus in their blood, but we do not have sufficient evidence from randomised trials that enables us to understand how SVR affects long-term clinical outcomes. SVR is still an outcome that needs proper validation in randomised clinical trials.
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Affiliation(s)
- Janus C Jakobsen
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
- Holbaek HospitalDepartment of CardiologyHolbaekDenmark4300
| | - Emil Eik Nielsen
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Joshua Feinberg
- Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812Blegdamsvej 9CopenhagenDenmark2100
| | - Kiran Kumar Katakam
- Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812Blegdamsvej 9CopenhagenDenmark2100
| | - Kristina Fobian
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Goran Hauser
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Goran Poropat
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Snezana Djurisic
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagenDenmark
| | - Karl Heinz Weiss
- Heidelberg University HospitalInternal Medicine IV: Gastroenterology, Infectious Diseases, ToxicologyIm Neuenheimer Feld 410HeidelbergGermanyD‐69120
| | - Milica Bjelakovic
- University of NisMedical FacultyBoulevard Dr Zorana Djindjica 81NisSerbia18000
| | - Goran Bjelakovic
- Medical Faculty, University of NisDepartment of Internal MedicineZorana Djindjica 81NisSerbia18000
| | - Sarah Louise Klingenberg
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
| | - Jian Ping Liu
- Beijing University of Chinese MedicineCentre for Evidence‐Based Chinese Medicine11 Bei San Huan Dong Lu, Chaoyang DistrictBeijingChina100029
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
| | | | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
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Jakobsen JC, Nielsen EE, Feinberg J, Katakam KK, Fobian K, Hauser G, Poropat G, Djurisic S, Weiss KH, Bjelakovic M, Bjelakovic G, Klingenberg SL, Liu JP, Nikolova D, Koretz RL, Gluud C. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev 2017; 9:CD012143. [PMID: 28922704 PMCID: PMC6484383 DOI: 10.1002/14651858.cd012143.pub2] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs), e.g. sofosbuvir, are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). Sustained virological response (SVR) is used by investigators and regulatory agencies as a surrogate outcome for morbidity and mortality, based solely on observational evidence. However, there have been no randomised trials that have validated that usage. OBJECTIVES To assess the benefits and harms of DAAs in people with chronic HCV. SEARCH METHODS We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016. SELECTION CRITERIA Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and health-related quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and SVR. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. We evaluated the overall quality of the evidence, using GRADE. MAIN RESULTS We included a total of 138 trials randomising a total of 25,232 participants. The trials were generally short-term trials and designed primarily to assess the effect of treatment on SVR. The trials evaluated 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered DAAs that were discontinued or withdrawn from the market. Study populations were treatment-naive in 95 trials, had been exposed to treatment in 17 trials, and comprised both treatment-naive and treatment-experienced individuals in 24 trials. The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.We could not reliably determine the effect of DAAs on the market or under development on our primary outcome of hepatitis C-related morbidity or all-cause mortality. There were no data on hepatitis C-related morbidity and only limited data on mortality from 11 trials (DAA 15/2377 (0.63%) versus control 1/617 (0.16%); OR 3.72, 95% CI 0.53 to 26.18, very low-quality evidence). We did not perform Trial Sequential Analysis on this outcome.There is very low quality evidence that DAAs on the market or under development do not influence serious adverse events (DAA 5.2% versus control 5.6%; OR 0.93, 95% CI 0.75 to 1.15 , 15,817 participants, 43 trials). The Trial Sequential Analysis showed that there was sufficient information to rule out that DAAs reduce the relative risk of a serious adverse event by 20% when compared with placebo. The only DAA that showed a lower risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, the meta-analysis result showed no evidence of a difference.DAAs on the market or under development may reduce the risk of no SVR from 54.1% in untreated people to 23.8% in people treated with DAA (RR 0.44, 95% CI 0.37 to 0.52, 6886 participants, 32 trials, low quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).There was insufficient evidence from trials on withdrawn or discontinued DAAs to determine their effect on hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79; 5 trials, very low-quality evidence). However, these DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73; 29 trials, very low-quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). AUTHORS' CONCLUSIONS The evidence for our main outcomes of interest come from short-term trials, and we are unable to determine the effect of long-term treatment with DAAs. The rates of hepatitis C morbidity and mortality observed in the trials are relatively low and we are uncertain as to how DAAs affect this outcome. Overall, there is very low quality evidence that DAAs on the market or under development do not influence serious adverse events. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs may reduce the number of people with detectable virus in their blood, but we do not have sufficient evidence from randomised trials that enables us to understand how SVR affects long-term clinical outcomes. SVR is still an outcome that needs proper validation in randomised clinical trials.
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Affiliation(s)
| | - Emil Eik Nielsen
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Joshua Feinberg
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Kiran Kumar Katakam
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalBlegdamsvej 9CopenhagenDenmark2100
| | - Kristina Fobian
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Goran Hauser
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Goran Poropat
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Snezana Djurisic
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalBlegdamsvej 9CopenhagenDenmark2100
| | - Karl Heinz Weiss
- Heidelberg University HospitalInternal Medicine IV: Gastroenterology, Infectious Diseases, ToxicologyIm Neuenheimer Feld 410HeidelbergGermanyD‐69120
| | - Milica Bjelakovic
- University of NisMedical FacultyBoulevard Dr Zorana Djindjica 81NisSerbia18000
| | - Goran Bjelakovic
- Medical Faculty, University of NisDepartment of Internal MedicineZorana Djindjica 81NisSerbia18000
| | - Sarah Louise Klingenberg
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Jian Ping Liu
- Beijing University of Chinese MedicineCentre for Evidence‐Based Chinese Medicine11 Bei San Huan Dong Lu, Chaoyang DistrictBeijingChina100029
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | | | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
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Fujii H, Umemura A, Nishikawa T, Yamaguchi K, Moriguchi M, Nakamura H, Yasui K, Minami M, Tanaka S, Ishikawa H, Kimura H, Takami S, Nagao Y, Shima T, Itoh Y. Real-world efficacy of daclatasvir and asunaprevir with respect to resistance-associated substitutions. World J Hepatol 2017; 9:1064-1072. [PMID: 28951778 PMCID: PMC5596313 DOI: 10.4254/wjh.v9.i25.1064] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 05/17/2017] [Accepted: 07/17/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate daclatasvir (DCV) and asunaprevir (ASV) efficacy in hepatitis C (HCV) patients, with respect to resistance-associated substitutions (RASs).
METHODS A total of 392 HCV-infected patients from multiple centers were included in this study. We evaluated their clinical courses and sustained virologic responses (SVR) according to pretreatment factors (gender, age, history of interferon-based regimens, platelet counts, level of viremia, pretreatment NA5A:L31, and Y93 substitutions). We also analyzed the pretreatment and post-treatment major RASs of NS3:D168, NS5A:L31 and Y93 substitutions using a direct-sequencing method in 17 patients who were unable to achieve SVR at 12 wk after treatment completion (SVR12).
RESULTS The overall SVR12 rate was 88.3%. Thirty-one patients discontinued treatment before 24 wk because of adverse events, 23 of whom achieved SVR12. There were no significant differences in SVR12 rates with respect to gender, age, history of interferon-based regimens, and platelet counts. The SVR12 rate in patients with viral loads of ≥ 6.0 log IU/mL was significantly lower than those with viral loads of < 6.0 log IU/mL (P < 0.001). The SVR12 rate in patients with Y93 substitution-positive was significantly lower than those with Y93 substitution-negative (P < 0.001). The L31 substitution-positive group showed a lower SVR12 rate than the L31 substitution-negative group, but the difference was not statistically significant. Seventeen patients who did not achieve SVR12 and had available pretreatment and post-treatment sera had additional RASs in NS3:D168, NS5:L31, and Y93 substitution at treatment failure.
CONCLUSION Combination of DCV and ASV is associated with a high SVR rate. Baseline RASs should be thoroughly assessed to avoid additional RASs after treatment failure.
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Affiliation(s)
- Hideki Fujii
- Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto 6050981, Japan
| | | | | | | | | | - Hideki Nakamura
- Department of Gastroenterology and Hepatology, North Medical Center, Kyoto Prefectural University of Medicine, Kyoto 6292261, Japan
| | | | - Masahito Minami
- Department of Internal Medicine, Aiseikai Yamashina Hospital, Kyoto 6078086, Japan
| | - Saiyu Tanaka
- Center for Digestive and Liver Diseases, Nara City Hospital, Nara 6308305, Japan
| | - Hiroki Ishikawa
- Department of Gastroenterology and Hepatology, Omihachiman Community Medical Center, Shiga 5230082, Japan
| | - Hiroyuki Kimura
- Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto 6050981, Japan
| | - Shiro Takami
- Department of Gastroenterology, Otsu Municipal Hospital, Otsu 5200804, Japan
| | - Yasuyuki Nagao
- Department of Gastroenterology, Matsushita Memorial Hospital, Moriguchi 5708540, Japan
| | - Toshihide Shima
- Center of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita 5640013, Japan
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Tamori A, Hai H, Uchida-Kobayashi S, Enomoto M, Kozuka R, Motoyama H, Kawamura E, Hagihara A, Teranishi Y, Yoshida K, Morikawa H, Murakami Y, Kawada N. Outcomes for Cirrhotic Patients with Hepatitis C Virus 1b Treated with Asunaprevir and Daclatasvir Combination. Ann Hepatol 2017; 16:734-741. [PMID: 28809743 DOI: 10.5604/01.3001.0010.2732] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND The efficacy and safety of asunaprevir + daclatasvir combination therapy for treatment of hepatitis C virus (HCV) in compensated cirrhotic patients was not fully evaluated in real-world. Outcomes were assessed in cirrhotic patients with sustained viral response (SVR). MATERIAL AND METHODS A total of 145 patients without resistance-associated substitutions (RASs) at L31 and Y93 in the nonstructural protein 5A of HCV genotype 1b, consisting of 49 hepatic cirrhotic and 96 non-cirrhotic patients, were enrolled to the therapy. The patients were treated with 100 mg asunaprevir twice daily plus 60 mg daclatasvir once daily for 24 weeks. The primary endpoint was SVR 24 weeks after completing treatment. In addition, we evaluated the improvement of liver function and development of HCC for 1 year from the end of treatment (EOT). RESULTS The SVR24 rate was 96% (47/49) in the cirrhotic group and 96% (91/95) in the non-cirrhotic group (p = 0.69). During treatment, grade III/IV adverse events occurred more frequently in cirrhotic patients (10/49; 20.4%) than in non-cirrhotic patients (10/96; 10.4%) (p = 0.099). After EOT, alanine aminotransferase and AFP levels were significantly decreased in cirrhotic patients with SVR. In addition, serum levels of albumin and platelet counts were significantly increased. On the other hand, the rates of HCC recurrence (43%) and development (7.4%) were higher in cirrhotic patients than in the non-cirrhotic patients (12.5% and 1.1%, respectively). CONCLUSION RAS-oriented asunaprevir/daclatasvir therapy has a strong anti-HCV effect in patients with HCV genotype 1b. However, careful management is necessary in patients with cirrhosis.
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Affiliation(s)
- Akihiro Tamori
- Osaka City University Graduate School of Medicine, Osaka, Japan Department of Hepatology
| | - Hoang Hai
- Osaka City University Graduate School of Medicine, Osaka, Japan Department of Hepatology
| | | | - Masaru Enomoto
- Osaka City University Graduate School of Medicine, Osaka, Japan Department of Hepatology
| | - Ritsuzo Kozuka
- Osaka City University Graduate School of Medicine, Osaka, Japan Department of Hepatology
| | - Hiroyuki Motoyama
- Osaka City University Graduate School of Medicine, Osaka, Japan Department of Hepatology
| | - Etsushi Kawamura
- Osaka City University Graduate School of Medicine, Osaka, Japan Department of Hepatology
| | - Atsushi Hagihara
- Osaka City University Graduate School of Medicine, Osaka, Japan Department of Hepatology
| | - Yuga Teranishi
- Osaka City University Graduate School of Medicine, Osaka, Japan Department of Hepatology
| | - Kanako Yoshida
- Osaka City University Graduate School of Medicine, Osaka, Japan Department of Hepatology
| | - Hiroyasu Morikawa
- Osaka City University Graduate School of Medicine, Osaka, Japan Department of Hepatology
| | - Yoshiki Murakami
- Osaka City University Graduate School of Medicine, Osaka, Japan Department of Hepatology
| | - Norifumi Kawada
- Osaka City University Graduate School of Medicine, Osaka, Japan Department of Hepatology
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Elsharkawy A, Eletreby R, Fouad R, Soliman Z, Abdallah M, Negm M, Mohey M, Esmat G. Impact of different sofosbuvir based treatment regimens on the biochemical profile of chronic hepatitis C genotype 4 patients. Expert Rev Gastroenterol Hepatol 2017; 11:773-778. [PMID: 28480808 DOI: 10.1080/17474124.2017.1326816] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Huge efforts have been made to control chronic HCV in Egypt with introduction of Direct-Acting Antivirals (DAAs). Current study aims at evaluating effect of various DAA regimens on liver biochemical profile and haematological indices during treatment. METHODS 272 patients with chronic HCV genotype 4 treated by different DAA regimens (SOF/RBV, SOF/DAC ± RBV, SOF/SIM) for a duration of 12 or 24 weeks in Kasr Alainy Viral Hepatitis Center, Cairo University were followed up for serum bilirubin (BIL), albumin (ALB), alanine transaminase (ALT), aspartate aminotransferase (AST), prothrombin concentration, international normalized ratio (INR), and CBC at baseline, week-4 and end of treatment. RESULTS Mean age was 54 years. Males comprised 64.7%, 72.4% were treatment-naïve, 39% were cirrhotic. Overall SVR12 rate was (93.4%). With all regimens, ALT and AST declined after treatment. In cirrhotics, there was a rise in BIL and INR; with no change in ALB and a decrease in White blood cells. Drop in Hemoglobin and platelets in cirrhotic patients were noted with SOF/RBV, while SOF/SIM showed rise in BIL. CONCLUSION DAAs are safe and effective in genotype 4 chronic HCV patients. It improves liver necro-inflammatory markers in cirrhotics and non-cirrhotics. Cirrhotic patients require careful observation being more vulnerable for treatment related complications.
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Affiliation(s)
- Aisha Elsharkawy
- a Endemic Medicine and Hepatogastroentrology Department, Faculty of medicine , Cairo University , Cairo , Egypt
| | - Rasha Eletreby
- a Endemic Medicine and Hepatogastroentrology Department, Faculty of medicine , Cairo University , Cairo , Egypt
| | - Rabab Fouad
- a Endemic Medicine and Hepatogastroentrology Department, Faculty of medicine , Cairo University , Cairo , Egypt
| | - Zeinab Soliman
- a Endemic Medicine and Hepatogastroentrology Department, Faculty of medicine , Cairo University , Cairo , Egypt
| | - Mohamed Abdallah
- b Medical research division , National research Centre , Cairo , Egypt
| | - Mohamed Negm
- c Kasr Al-Ainy Viral Hepatitis Center, Faculty of medicine , Cairo University , Cairo , Egypt
| | - Mohammad Mohey
- a Endemic Medicine and Hepatogastroentrology Department, Faculty of medicine , Cairo University , Cairo , Egypt
| | - Gamal Esmat
- a Endemic Medicine and Hepatogastroentrology Department, Faculty of medicine , Cairo University , Cairo , Egypt
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30
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Morishita N, Hiramatsu N, Oze T, Urabe A, Tahata Y, Yamada R, Yakushijin T, Hosui A, Iio S, Yamada A, Hagiwara H, Mita E, Yamada Y, Ito T, Inada M, Katayama K, Yabuuchi I, Imai Y, Hikita H, Sakamori R, Yoshida Y, Tatsumi T, Hayashi N, Takehara T. Ultra-deep sequencing analysis of resistance-associated variants during retreatment with simeprevir-based triple therapy after failure of telaprevir-based triple therapy in patients with genotype 1 hepatitis C virus infection. Hepatol Res 2017; 47:773-782. [PMID: 27593967 DOI: 10.1111/hepr.12817] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 07/15/2016] [Accepted: 08/31/2016] [Indexed: 01/13/2023]
Abstract
AIM Simeprevir (SMV)-based triple therapy is an effective retreatment option following failure of telaprevir (TVR)-based triple therapy. However, it is unclear whether the persistence of resistance-associated variants (RAVs) induced by TVR-based therapy may reduce the treatment effect of SMV-based therapy. METHODS The factors associated with the treatment effect, including RAVs in the NS3 region, were examined in 21 patients with genotype 1b HCV infection who were treated with SMV-based therapy after failure of TVR-based therapy. Ultra-deep sequencing was carried out to detect RAVs. RESULTS With the exception of one patient who discontinued treatment owing to adverse events, the sustained virologic response (SVR) rate was 50% (10/20). Ultra-deep sequencing at the start of SMV-based therapy revealed that TVR-resistant variants were detected in six patients (29%), and no variants were observed at position 168. Cross-resistance between TVR and SMV with low frequency was detected in only one patient, and this patient achieved SVR. Higher SVRs for SMV-based therapy were attained in patients who discontinued treatment owing to the adverse effects of prior TVR-based therapy (discontinuation 100% vs. non-discontinuation 29%, P = 0.005), and patients who relapsed following prior pegylated interferon plus ribavirin therapy (relapse 100% vs. non-response 20%, P = 0.007). CONCLUSIONS In this study, ultra-deep sequencing analysis revealed that TVR and/or SMV-resistant variants may have no influence on the effect of SMV-based therapy after failure of TVR-based therapy. Patients who discontinued treatment owing to adverse effects of TVR-based therapy and relapsers to previous pegylated interferon/ribavirin therapy would be good candidates for retreatment with SMV-based therapy.
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Affiliation(s)
- Naoki Morishita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Naoki Hiramatsu
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tsugiko Oze
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ayako Urabe
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yuki Tahata
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ryoko Yamada
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Takayuki Yakushijin
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | | | - Sadaharu Iio
- Higashiosaka City General Hospital, Higashiosaka, Japan
| | | | | | - Eiji Mita
- National Hospital Organization Osaka National Hospital, Osaka, Japan
| | | | - Toshifumi Ito
- Japan Community Health Care Organization Osaka Hospital, Osaka, Japan
| | | | - Kazuhiro Katayama
- Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
| | - Iwao Yabuuchi
- National Hospital Organization Minami Wakayama Medical Center, Tanabe, Japan
| | | | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yuichi Yoshida
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | | | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
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Campos GRF, Bittar C, Jardim ACG, Shimizu JF, Batista MN, Paganini ER, Ribeiro de Assis L, Bartlett C, Harris M, da Silva Bolzani V, Regasini LO, Rahal P. Hepatitis C virus in vitro replication is efficiently inhibited by acridone Fac4. J Gen Virol 2017; 98:1693-1701. [PMID: 28699869 PMCID: PMC7615702 DOI: 10.1099/jgv.0.000808] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hepatitis C virus (HCV) affects about 170 million people worldwide. The current treatment has a high cost and variable response rates according to the virus genotype. Acridones, a group of compounds extracted from natural sources, showed potential antiviral actions against HCV. Thus, this study aimed to evaluate the effect of a panel of 14 synthetic acridones on the HCV life cycle. The compounds were screened using an Huh7.5 cell line stably harbouring the HCV genotype 2a subgenomic replicon SGR-Feo-JFH-1. Cells were incubated in the presence or absence of compounds for 72 h and cell viability and replication levels were assessed by MTT and luciferase assays, respectively. At a concentration of 5 µM the acridone Fac4 exhibited a >90 % inhibition of HCV replication with no effect on cell viability. The effects of Fac4 on virus replication, entry and release steps were evaluated in Huh7.5 cells infected with the JFH-1 isolate of HCV (HCVcc). Fac4 inhibited JFH-1 replication to approximately 70 %, while no effect was observed on virus entry. The antiviral activity of Fac4 was also observed on viral release, with almost 80 % of inhibition. No inhibitory effect was observed against genotype 3 replication. Fac4 was able to intercalate into dsRNA, however did not inhibit NS5B polymerase activity or translation driven by the HCV IRES. Although its mode of action is partly understood, Fac4 presents significant inhibition of HCV replication and can therefore be considered as a candidate for the development of a future anti-HCV treatment.
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Affiliation(s)
| | - Cíntia Bittar
- Institute of Bioscience, Language and Exact Science, IBILCE, UNESP – São Paulo State University, São José do Rio Preto, SP, Brazil
| | - Ana Carolina Gomes Jardim
- Institute of Biomedical Science, ICBIM, UFU – Federal University of Uberlândia, Uberlândia, MG, Brazil
| | - Jacqueline Farinha Shimizu
- Institute of Bioscience, Language and Exact Science, IBILCE, UNESP – São Paulo State University, São José do Rio Preto, SP, Brazil
| | - Mariana Nogueira Batista
- Institute of Bioscience, Language and Exact Science, IBILCE, UNESP – São Paulo State University, São José do Rio Preto, SP, Brazil
| | - Eder Ramos Paganini
- Institute of Bioscience, Language and Exact Science, IBILCE, UNESP – São Paulo State University, São José do Rio Preto, SP, Brazil
| | - Letícia Ribeiro de Assis
- Institute of Bioscience, Language and Exact Science, IBILCE, UNESP – São Paulo State University, São José do Rio Preto, SP, Brazil
| | - Christopher Bartlett
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Mark Harris
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | | | - Luis Octavio Regasini
- Institute of Bioscience, Language and Exact Science, IBILCE, UNESP – São Paulo State University, São José do Rio Preto, SP, Brazil
- Institute of Chemistry, São Paulo State University, Araraquara, SP, Brazil
| | - Paula Rahal
- Institute of Bioscience, Language and Exact Science, IBILCE, UNESP – São Paulo State University, São José do Rio Preto, SP, Brazil
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Mawatari S, Oda K, Tabu K, Ijuin S, Kumagai K, Inada Y, Uto H, Hiramine Y, Kure T, Fujisaki K, Hashiguchi M, Hori T, Oshige A, Imanaka D, Saishoji A, Taniyama O, Sakae H, Tamai T, Moriuchi A, Ido A. New resistance-associated substitutions and failure of dual oral therapy with daclatasvir and asunaprevir. J Gastroenterol 2017; 52:855-867. [PMID: 28078469 DOI: 10.1007/s00535-016-1303-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Accepted: 11/22/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND Daclatasvir (DCV) and asunaprevir (ASV) combination therapy has been primarily used in patients without NS5A L31 or Y93 resistance-associated substitutions (RASs) before treatment. We examined the characteristics of patients without these baseline RASs who did not achieve hepatitis C virus eradication with DCV and ASV combination therapy and identified new baseline NS5A RASs that are closely associated with failure of combination therapy. METHODS Three hundred thirty-five patients with hepatitis C virus genotype 1 infection with no NS5A L31, NS5A Y93, and NS3 D168 RASs before DCV and ASV combination therapy and no history of protease inhibitor therapy were enrolled. All RASs were evaluated by direct sequencing. RESULTS Sustained virologic response at 12 weeks (SVR12) was achieved in 297 patients (89%). Patients with NS5A Q24, L28, and/or R30 RASs or concomitant NS5A F37 and Q54 RASs had a significantly lower SVR12 rate than patients without these RASs (70% vs 92%, p < 0.001 and 79% vs 92%, p = 0.002 respectively). Multivariate analysis showed that NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs were significantly associated with virologic failure. The SVR12 rate in patients without NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs was 96.2% (202/210). CONCLUSIONS In patients without NS5A L31 or Y93 RASs, the presence of NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs at the baseline was associated with failure of DCV and ASV combination therapy. The coexistence of baseline RASs other than NS5A L31 and Y93 may affect the therapeutic effectiveness of DCV and ASV combination therapy.
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Affiliation(s)
- Seiichi Mawatari
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
| | - Kohei Oda
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Kazuaki Tabu
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Sho Ijuin
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Kotaro Kumagai
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Yukiko Inada
- Center for Digestive and Liver Diseases, Miyazaki Medical Center Hospital, 2-16 Takamatsu-cho, Miyazaki, 880-0003, Japan
| | - Hirofumi Uto
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.,Center for Digestive and Liver Diseases, Miyazaki Medical Center Hospital, 2-16 Takamatsu-cho, Miyazaki, 880-0003, Japan
| | - Yasunari Hiramine
- Department of Internal Medicine, Kagoshima Kouseiren Hospital, 22-25 Tenpozan-cho, Kagoshima, 890-0061, Japan
| | - Takeshi Kure
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.,Department of Internal Medicine, Kagoshima Kouseiren Hospital, 22-25 Tenpozan-cho, Kagoshima, 890-0061, Japan
| | - Kunio Fujisaki
- Department of Hepatology, Kirishima Medical Center, 3320 Hayato-cho, Kirishima, Kagoshima, 899-5112, Japan
| | - Masafumi Hashiguchi
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.,Department of Hepatology, Kirishima Medical Center, 3320 Hayato-cho, Kirishima, Kagoshima, 899-5112, Japan
| | - Takeshi Hori
- Department of Gastroenterology and Hepatology, Kagoshima City Hospital, 37-1 Uearata-cho, Kagoshima, 890-8760, Japan
| | - Akihiko Oshige
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.,Department of Gastroenterology and Hepatology, Kagoshima City Hospital, 37-1 Uearata-cho, Kagoshima, 890-8760, Japan
| | - Dai Imanaka
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.,Department of Gastroenteroloby, Ikeda Hospital, 1830 Shimoharaigawa-cho, Kanoya, Kagoshima, 893-0024, Japan
| | - Akiko Saishoji
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.,Department of Hepatology, Kagoshima Teishin Hospital, 1-12-1 Shimoishiki, Kagoshima, 890-8798, Japan
| | - Oki Taniyama
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Haruka Sakae
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Tsutomu Tamai
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Akihiro Moriuchi
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Akio Ido
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
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A NEW HEALTH TECHNOLOGY ASSESSMENT SYSTEM FOR JAPAN? SIMULATING THE POTENTIAL IMPACT ON THE PRICE OF SIMEPREVIR. Int J Technol Assess Health Care 2017; 33:121-127. [DOI: 10.1017/s0266462317000174] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Objectives:Japanese authorities have announced a plan to introduce a health technology assessment (HTA) system in 2016. This study assessed the potential impact of such a policy on the price of the antivirologic drug simeprevir.Methods:Taking the antivirologic drug simeprevir as an example, we compared the current Japanese price with hypothetical prices that might result if a U.K. (cost-utility) or German (efficiency frontier) style HTA assessment was in place.Results:The simeprevir unit price under the current Japanese pricing scheme is 13,122 Japanese yen (equivalent to 109.35 U.S. dollars as of April 2015). Depending on the selection of comparators and the pricing method, and assuming that HTA will be used as a basis for price setting, the estimated prices of simeprevir vary up to four times higher than under the current Japanese pricing scheme.Conclusions:Although the analysis is based on only one drug, it cannot be taken for granted that a new HTA system would reduce public healthcare expenditure in Japan.
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Kumada H, Suzuki F, Kamiya N, Orihashi M, Nakayasu Y, Yamada I. Efficacy and safety of telaprevir with pegylated interferon α-2a and ribavirin in Japanese patients. Hepatol Res 2017; 47:514-521. [PMID: 27062488 DOI: 10.1111/hepr.12722] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 03/16/2016] [Accepted: 04/04/2016] [Indexed: 01/01/2023]
Abstract
AIM To assess the efficacy and safety of telaprevir (TVR) in combination with pegylated interferon α-2a (PEG-IFNα-2a) and ribavirin (RBV) for treatment-naïve patients and relapsed patients compared to previous TVR-based triple therapy in Japan. METHODS The study group included 35 treatment-naïve (median age, 55 years) and 19 relapsed (median age, 55 years) patients with genotype 1 hepatitis C virus infection. Patients received TVR (750 mg every 8 h) for 12 weeks, in combination with PEG-IFNα-2a and RBV. RESULTS The sustained virological response (SVR24 ) rates for naïve and relapsed patients were 85.7% (30/35) and 94.7% (18/19), respectively. The discontinuation rate of all study drugs due to adverse events was 5.6% (3/54). Among the 54 patients, grade 3 skin disorders and grade 3 anemia (<8.0 g/dL) were reported in 2 (3.7%) and 6 patients (11.1%), respectively. Although the overall safety profiles were similar for the TVR/PEG-IFNα-2a/RBV and TVR/PEG-IFNα-2b/RBV regimens (previous study), the proportion of patients discontinuing all study drugs due to adverse events was lower in the patients treated with the TVR/PEG-IFNα-2a/RBV regimen (3/54, 5.6%) than TVR/PEG-IFNα-2b/RBV regimen (44/267, 16.5%). CONCLUSION Telaprevir in combination with PEG-IFNα-2a/RBV provided a high sustained virological response rate for the treatment of genotype 1 hepatitis C virus in both treatment-naïve and relapsed patients in Japan. Telaprevir-based therapy may provide a useful treatment option for patients who are difficult to treat due to NS5A (Y93, L31) and NS3/4A (D168) variants.
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Affiliation(s)
| | | | - Naohiro Kamiya
- SOUYAKU, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Madori Orihashi
- SOUYAKU, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Yoshiyuki Nakayasu
- SOUYAKU, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Ichimaro Yamada
- IKUYAKU, Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
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Clements KM, Clark RE, Lavitas P, Kunte P, Graham CS, O'Connell E, Lenz K, Jeffrey P. Access to New Medications for Hepatitis C for Medicaid Members: A Retrospective Cohort Study. J Manag Care Spec Pharm 2017; 22:714-722b. [PMID: 27231798 PMCID: PMC10397595 DOI: 10.18553/jmcp.2016.22.6.714] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Sofosbuvir (SOF)- or simeprevir (SIM)-containing regimens are highly effective for treating chronic hepatitis C virus (HCV) infection. These regimens, however, are expensive. Most payers have implemented prior authorization (PA) requirements to ensure that patients who can benefit most have priority for these medications. While many Medicaid programs limit access to those with advanced disease or to members who do not have active substance use disorder (SUD), the Massachusetts Medicaid (MassHealth) Primary Care Clinician (PCC) plan does not limit access based on disease severity or presence of SUD. Evaluating PA requests for SOF and/or SIM among MassHealth members will offer a useful example of early uptake among Medicaid members and will identify patient groups who might face barriers to treatment at the provider or patient level. OBJECTIVES To (a) evaluate the percentage of MassHealth PCC members with HCV who had a PA request, along with the percentage of requests approved, and (b) identify characteristics associated with PA requests for SOF or SIM among Massachusetts Medicaid (MassHealth) members with HCV. METHODS This retrospective cohort study used enrollment, medical claims, and PA request data from MassHealth PCC members from December 6, 2012, to July 31, 2014. The sample included members with 1 or more claims with an ICD-9-CM code for HCV during this time who were continuously enrolled from December 6, 2013, to July 31, 2014. Enrollment and medical claims data for the cohort with HCV were linked to a database containing information collected from PA requests. The overall percentage of members with HCV and a PA request for SOF and/or SIM between December 6, 2013, and July 31, 2014, and the percentage of requests approved were calculated. Chi-square statistics were used to compare demographic and clinical characteristics among members with HCV who did and did not have a request. Logistic regression was used to estimate the strength of associations between patient characteristics and a PA treatment request, adjusting for clinical and demographic variables. RESULTS Of 6,849 members identified with HCV, 346 (5.1%) had a PA request for SOF and/or SIM submitted to MassHealth. Compared with members with HCV who did not have a PA request for SOF or SIM, those with a PA request for these new treatments were more likely to be male (P = 0.01), older (P < 0.001), white race (P = 0.04), have standard MassHealth insurance (P = 0.01), and less likely to be homeless (P < 0.001). Members with a PA request were also more likely to have been treated for HCV in the past year and have advanced disease (hepatic decompensation, cirrhosis, or liver transplant) but less likely to have SUD (P < 0.001 for each). Ninety percent of requests for SOF or SIM were approved; few demographic or clinical characteristics were associated with approval. In adjusted analyses, predictors of PA request were aged 50-64 years (odds ratio (OR) = 2.0, 95% CI = 1.1-3.7 vs. aged < 30 years); hepatic decompensation (OR = 1.6, 95% CI = 1.2-2.3); cirrhosis (OR = 3.0, 95% CI = 2.2-4.1); liver transplant (OR = 3.0, 95% CI = 1.4-6.5); substance use (OR = 0.6, 95% CI = 0.5-0.8); recent HCV treatment (OR = 1.6, 95% CI = 1.0-2.6); comorbidity (OR = 0.95, 95% CI = 0.91-0.98) for 1-unit increase in Diagnostic Cost Group score; and care at a hospital outpatient department (OR = 2.0, 95% CI = 1.2-3.2 vs. group practice). CONCLUSIONS Antiviral treatment with SOF and/or SIM was requested for a relatively small proportion of MassHealth members with HCV, with nearly all approved. Prescriber prioritization or patient barriers to care, rather than the PA process, determined access to treatment in this Medicaid population. Support may be needed to ensure patients with SUD benefit from advances in HCV treatment. DISCLOSURES No outside funding supported this research. Internal funding was provided by the Commonwealth of Massachusetts. Lavitas has received compensation from University of Tennessee Advanced Studies in Medicine for development of CPE activity. Graham has consulted for the National Viral Hepatitis Roundtable and the Department of Health and Human Services, has received payment from Medscape for CME development, and is employed by Trek Therapeutics. Jeffrey has received payment for guest lectures at Boston University and Harvard University. Study concept and design were primarily contributed by Clark and Clements, along with Graham, Lenz, and Jeffrey. Kunte collected the data, which were interpreted by Graham, Lenz, and Jeffrey, with assistance from Lavitas, Clark, and Clements. The manuscript was written primarily by Clements, along with O'Connell and assisted by Graham, and revised by all the authors.
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Affiliation(s)
- Karen M Clements
- 1 Center for Health Policy and Research, University of Massachusetts Medical School, Shrewsbury
| | - Robin E Clark
- 2 Department of Family Medicine and Community Health, University of Massachusetts Medical School, Shrewsbury
| | - Pavel Lavitas
- 3 Clinical Pharmacy Services, University of Massachusetts Medical School, Shrewsbury
| | - Parag Kunte
- 1 Center for Health Policy and Research, University of Massachusetts Medical School, Shrewsbury
| | - Camilla S Graham
- 4 Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Elizabeth O'Connell
- 1 Center for Health Policy and Research, University of Massachusetts Medical School, Shrewsbury
| | - Kimberly Lenz
- 5 Office of Clinical Affairs, University of Massachusetts Medical School, Shrewsbury
| | - Paul Jeffrey
- 6 Office of Clinical Affairs, University of Massachusetts Medical School, Shrewsbury
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Canadian Task Force on Preventive Health Care. Recommendations on hepatitis C screening for adults. CMAJ 2017; 189:E594-E604. [PMID: 28438952 PMCID: PMC5403642 DOI: 10.1503/cmaj.161521] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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Hayes CN, Chayama K. Why highly effective drugs are not enough: the need for an affordable solution to eliminating HCV. Expert Rev Clin Pharmacol 2017; 10:583-594. [PMID: 28374641 DOI: 10.1080/17512433.2017.1313111] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Because of the rapid pace of development of new direct-acting antiviral (DAA) drugs, chronic hepatitis C virus (HCV) infection is now increasingly considered curable. However, the emphasis on DAA therapies disregards key issues related to cost, availability, and antiviral resistance. Areas covered: This perspective provides an overview of current HCV therapies and the development of DAAs, followed by a discussion of the limitations of DAA therapy. A literature search was used to select relevant studies, and a web search for relevant news articles and press releases was conducted. Expert commentary: Despite cure rates exceeding 90%, now is not the time to declare victory against HCV but to reinforce recent progress by addressing the issues of cost and availability as well as by developing strategies to manage antiviral resistance. Future drug development efforts should place greater emphasis on targeting host factors required for HCV replication, for which the barrier to resistance is higher, and effort should continue to develop a vaccine against HCV. Finally, efforts should be made to facilitate large-scale screening in endemic areas to identify and treat patients as early as possible to reduce long-term risks of advanced liver disease and their attendant costs of management.
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Affiliation(s)
- C Nelson Hayes
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan
| | - Kazuaki Chayama
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan.,c Laboratory for Digestive Diseases, Center for Genomic Medicine , RIKEN , Hiroshima , Japan
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Alqahtani S, Ozaras R, Isakov V, Wyles D, Ferenci P, Feld JJ, Calinas F, Gschwantler M, Gane E, Crawford D, Jacobson IM, Dumas EO, King M, Sulkowski M. Time to viral suppression is not related to achievement of SVR12 in HCV GT1-infected patients treated with ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin. J Viral Hepat 2017; 24:280-286. [PMID: 27935166 DOI: 10.1111/jvh.12641] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 09/27/2016] [Indexed: 01/01/2023]
Abstract
High rates of sustained virologic response at post-treatment week 12 (SVR12) were achieved in six phase 3 trials of ombitasvir (OBV, an NS5A inhibitor), paritaprevir (an NS3/4A protease inhibitor) co-dosed with ritonavir (PTV/r) + dasabuvir (DSV, an NS5B RNA polymerase inhibitor) (ie, 3D regimen) with or without ribavirin (RBV) in adults with chronic genotype (GT) 1 hepatitis C virus (HCV) infection. We assessed whether time to first HCV RNA value below the lower limit of quantification in patients with and without cirrhosis was associated with achievement of SVR12. Data were analysed from GT1-infected patients enrolled in six phase 3 studies of 3D ± RBV. Patients who experienced non-virologic failure were excluded from analysis. HCV RNA was determined using the Roche COBAS TaqMan RT-PCR assay (lower limit of quantification, LLOQ =25 IU/mL). SVR12 was analysed by week of first HCV RNA suppression, defined as HCV RNA
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Affiliation(s)
- S Alqahtani
- Johns Hopkins University, Baltimore, MD, USA
| | - R Ozaras
- Cerrahpasa Medical School, Istanbul, Turkey
| | - V Isakov
- Institute of Nutrition, Moscow, Russia
| | - D Wyles
- University of Colorado School of Medicine, Denver, CO, USA
| | - P Ferenci
- Universitaetsklinik fuer Innere Medizin III, Vienna, Austria
| | - J J Feld
- University of Toronto, Toronto, ON, Canada
| | - F Calinas
- Central Lisbon Hospital Centre, Lisbon, Portugal
| | | | - E Gane
- Auckland City Hospital, Auckland, New Zealand
| | - D Crawford
- School of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | | | | | - M King
- AbbVie Inc., North Chicago, IL, USA
| | - M Sulkowski
- Johns Hopkins University, Baltimore, MD, USA
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Toyota J, Karino Y, Suzuki F, Ikeda F, Ido A, Tanaka K, Takaguchi K, Naganuma A, Tomita E, Chayama K, Fujiyama S, Inada Y, Yoshiji H, Watanabe H, Ishikawa H, Hu W, McPhee F, Linaberry M, Yin PD, Swenson ES, Kumada H. Daclatasvir/asunaprevir/beclabuvir fixed-dose combination in Japanese patients with HCV genotype 1 infection. J Gastroenterol 2017; 52:385-395. [PMID: 27502287 DOI: 10.1007/s00535-016-1245-6] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 07/16/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND DCV-TRIO, a fixed-dose combination of daclatasvir (pangenotypic NS5A inhibitor), asunaprevir (NS3/4A protease inhibitor), and beclabuvir (non-nucleoside NS5B inhibitor), has achieved high rates of sustained virologic response at post-treatment Week 12 (SVR12) in phase 3 studies. METHODS In this phase 3 study, DCV-TRIO for 12 weeks and daclatasvir plus asunaprevir (DUAL) for 24 weeks were studied in Japanese patients infected with HCV genotype 1 (99 % genotype 1b). RESULTS SVR12 rates ≥95 % were achieved in both treatment-naive (N = 152) and interferon-experienced (N = 65) cohorts treated with DCV-TRIO for 12 weeks and were comparable across patient subgroups, including patients aged ≥65 years and those with cirrhosis. DUAL recipients (N = 75) had an SVR12 rate of 87 %. In the absence of baseline resistance-associated polymorphisms at positions NS5A-Y93H or -L31, SVR12 rates were 98 % with DCV-TRIO or DUAL. Among genotype 1b-infected patients with baseline Y93H or L31 polymorphisms, 35/38 (92 %) DCV-TRIO recipients, and 7/16 (44 %) DUAL recipients achieved SVR12. Adverse events, mostly liver related, led to treatment discontinuation in 10 % of DCV-TRIO recipients. In this group, SVR12 was achieved by 3/9 patients who discontinued before Week 4 and by 12/12 patients who completed ≥4 weeks of DCV-TRIO. Treatment-related serious adverse events occurred in 4 and 3 % of DCV-TRIO and DUAL recipients, respectively. Seven patients (9 %) discontinued DUAL due to adverse events. No deaths occurred. CONCLUSION SVR12 was achieved by 96 % of Japanese patients with HCV genotype 1 infection after 12 weeks of treatment with the DCV-TRIO regimen. DCV-TRIO and DUAL exhibited comparable safety profiles.
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Affiliation(s)
- Joji Toyota
- Department of Gastroenterology, Sapporo-Kosei General Hospital, 8-5 Higashi Kita-3-jo Chuo-ku, Sapporo-shi, Hokkaido, Japan.
| | - Yoshiyasu Karino
- Department of Gastroenterology, Sapporo-Kosei General Hospital, 8-5 Higashi Kita-3-jo Chuo-ku, Sapporo-shi, Hokkaido, Japan
| | - Fumitaka Suzuki
- Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, Japan
| | - Fusao Ikeda
- Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, Japan
| | - Akio Ido
- Kagoshima University, 8-35-1 Sakuragoka, Kagoshima-shi, Kagoshima, Japan
| | - Katsuaki Tanaka
- Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa, Japan
| | - Koichi Takaguchi
- Kagawa Prefectural Central Hospital, 1-2-1 Asahimachi, Takamatsu-shi, Kagawa, Japan
| | - Atsushi Naganuma
- Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki-shi, Gunma, Japan
| | - Eiichi Tomita
- Gifu Municipal Hospital, 7-1 Kashima-cho, Gifu-shi, Gifu, Japan
| | - Kazuaki Chayama
- Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Hiroshima-shi, Hiroshima, Japan
| | - Shigetoshi Fujiyama
- Kumamoto Shinto General Hospital, 1-17-27 Shinyashiki, Chuo-ku, Kumamoto, Kumamoto, Japan
| | - Yukiko Inada
- Miyazaki Medical Center Hospital, 2-16 Takamatsu-cho, Miyazaki-shi, Miyazaki, Japan
| | - Hitoshi Yoshiji
- Nara Medical University, 840 Shijocho, Kashihara-shi, Nara, Japan
| | - Hideaki Watanabe
- Bristol-Myers Squibb K.K., 5-1 Nishi-Shinjuku 6-chome, Shinjuku-ku, Tokyo, Japan
| | - Hiroki Ishikawa
- Bristol-Myers Squibb K.K., 5-1 Nishi-Shinjuku 6-chome, Shinjuku-ku, Tokyo, Japan
| | - Wenhua Hu
- Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT, USA
| | - Fiona McPhee
- Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT, USA
| | - Misti Linaberry
- Bristol-Myers Squibb, 100 Nassau Park Blvd, Princeton, NJ, USA
| | - Philip D Yin
- Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT, USA
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Mori N, Imamura M, Kawakami Y, Nagaoki Y, Kawaoka T, Tsuge M, Hiramatsu A, Hayes CN, Aikata H, Miki D, Ochi H, Honda Y, Takaki S, Tsuji K, Chayama K. IFNL4 polymorphism effects on outcome of simeprevir, peginterferon, and ribavirin therapy for older patients with genotype 1 chronic hepatitis C. Hepatol Res 2017; 47:E5-E13. [PMID: 27027531 DOI: 10.1111/hepr.12715] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Revised: 03/09/2016] [Accepted: 03/25/2016] [Indexed: 12/17/2022]
Abstract
AIM Older patients with chronic hepatitis C have a lower virological response to interferon (IFN)-based treatments compared to younger patients. A single nucleotide polymorphism in the IFN-λ-4 (IFNL4) gene has a potent predictive effect on treatment response to IFN-based treatments. The efficacy of simeprevir (SMV) plus pegylated-IFN (PEG-IFN) and ribavirin therapy and the predictive value of IFNL4 on the outcome of therapy for older patients have not been addressed. METHODS This retrospective multicenter study included 234 consecutive Japanese patients with genotype 1 chronic hepatitis C. We assessed the predictive factors for sustained virological response (SVR) to SMV, PEG-IFN, and ribavirin triple therapy in 170 younger (<70 years) and 64 older (≥70 years) patients. IFNL4 polymorphism ss469415590 was analyzed by Invader assay. RESULTS The SVR rate for older patients was similar to that for younger patients (63.9% and 72.0%, respectively). The SVR rate for the IFNL4 TT/TT group was significantly higher than the IFNL4 TT/ΔG or ΔG/ΔG group both in younger (93.6% and 46.1%, respectively, P < 0.01) and older patients (84.4% and 33.3%, respectively, P < 0.001). In multivariate regression analysis, IFNL4 TT/TT genotype, response to previous treatment and IFNL4 TT/TT genotype were identified as independent predictive factors for SVR in older and younger patients, respectively. Decrease in hemoglobin level was similar between the two groups. CONCLUSION The virological response to SMV triple therapy in older patients was similar to that of younger patients. Analysis of IFNL4 polymorphisms is a valuable predictor in both younger and older patients.
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Affiliation(s)
- Nami Mori
- Department of Gastroenterology/Liver Center, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Yuko Nagaoki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Laboratory for Digestive Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
| | - Hidenori Ochi
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Laboratory for Digestive Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
| | - Yohji Honda
- Department of Gastroenterology/Liver Center, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Shintaro Takaki
- Department of Gastroenterology/Liver Center, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Keiji Tsuji
- Department of Gastroenterology/Liver Center, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Laboratory for Digestive Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
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Nishiguchi S, Urano Y, Suzaki K, Taniguchi A, Scherer J, Berger KL, Quinson AM, Stern JO, Omata M. Safety and efficacy of faldaprevir in combination with pegylated interferon α-2b and ribavirin in Japanese patients with genotype-1 chronic hepatitis C virus infection. Hepatol Res 2017; 47:E142-E151. [PMID: 27153246 DOI: 10.1111/hepr.12741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 04/07/2016] [Accepted: 05/02/2016] [Indexed: 02/08/2023]
Abstract
AIM We evaluated the safety and efficacy of the hepatitis C virus (HCV) NS3/4A A protease inhibitor faldaprevir plus pegylated interferon α-2b and ribavirin (PegIFNα-2b/RBV) in Japanese patients with HCV genotype-1 infection. METHODS Treatment-naïve patients were randomized (1:1) to faldaprevir 120 mg q.d. for 12 or 24 weeks (response-guided therapy [RGT], n = 44), or faldaprevir 240 mg q.d. for 12 weeks (n = 43), each combined with PegIFNα-2b/RBV for 24 or 48 weeks (RGT). Response-guided therapy was based on early treatment success (HCV RNA <25 IU/mL at week 4 and <25 IU/mL undetected at week 8). Treatment-experienced patients received 240 mg q.d. for 24 weeks, plus PegIFNα-2b/RBV RGT (24 or 48 weeks, prior relapsers, n = 29) or PegIFNα-2b/RBV (48 weeks, 5 prior partial responders/breakthroughs, 10 prior null responders). The primary objective was safety; sustained virologic response 12 weeks post-treatment (SVR12) was a secondary end-point. RESULTS All except one patient experienced drug-related adverse events. Adverse events led to faldaprevir discontinuation in 1 (2%), 13 (20%), and 3 (6.8%) patients on faldaprevir 120 mg, faldaprevir 240 mg 12 weeks, and faldaprevir 240 mg 24 weeks, respectively. The SVR12 rates were: 86% with faldaprevir 120 mg and 74% with faldaprevir 240 mg among treatment-naïve patients; and 86%, 60%, and 40% among prior relapsers, partial responders/breakthroughs, and null responders, respectively. CONCLUSIONS In treatment-naïve Japanese patients, faldaprevir 120 mg q.d. plus PegIFNα-2b/RBV was better tolerated than faldaprevir 240 mg q.d. plus PegIFNα-2b/RBV, with at least comparable efficacy. In treatment-experienced patients, most prior relapsers achieved SVR12 with 24 weeks of faldaprevir 240 mg q.d. plus PegIFNα-2b/RBV. Clinicaltrials.gov NCT01579474.
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Affiliation(s)
- Shuhei Nishiguchi
- Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | | | - Keiko Suzaki
- Nippon Boehringer Ingelheim Co., Ltd., Tokyo, Japan
| | | | - Joseph Scherer
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield Connecticut, USA
| | - Kristi L Berger
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield Connecticut, USA
| | | | - Jerry O Stern
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield Connecticut, USA
| | - Masao Omata
- Department of Gastroenterology, Yamanashi Prefectural Central Hospital, Kofu, Japan
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Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res 2017; 142:83-122. [PMID: 28238877 PMCID: PMC7172984 DOI: 10.1016/j.antiviral.2017.02.014] [Citation(s) in RCA: 126] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 02/07/2017] [Accepted: 02/22/2017] [Indexed: 12/12/2022]
Abstract
One of the most exciting developments in antiviral research has been the discovery of the direct-acting antivirals (DAAs) that effectively cure chronic hepatitis C virus (HCV) infections. Based on more than 100 clinical trials and real-world studies, we provide a comprehensive overview of FDA-approved therapies and newly discovered anti-HCV agents with a special focus on drug efficacy, mechanisms of action, and safety. We show that HCV drug development has advanced in multiple aspects: (i) interferon-based regimens were replaced by interferon-free regimens; (ii) genotype-specific drugs evolved to drugs for all HCV genotypes; (iii) therapies based upon multiple pills per day were simplified to a single pill per day; (iv) drug potency increased from moderate (∼60%) to high (>90%) levels of sustained virologic responses; (v) treatment durations were shortened from 48 to 12 or 8 weeks; and (vi) therapies could be administered orally regardless of prior treatment history and cirrhotic status. However, despite these remarkable achievements made in HCV drug discovery, challenges remain in the management of difficult-to-treat patients.
HCV genotype-specific drugs evolve to pan-genotypic drugs. Drug potency increases from moderate (∼60%) to high (>90%) levels of sustained virologic response. Treatment durations are shortened from a 48-week to 12-week or 8-week period. HCV therapies based upon multiple pills per day are simplified to a single pill per day. HCV therapies are administered orally regardless of prior treatment history and cirrhotic status.
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Hayes CN, Imamura M, Chayama K. The practical management of chronic hepatitis C infection in Japan - dual therapy of daclatasvir + asunaprevir. Expert Rev Gastroenterol Hepatol 2017; 11:103-113. [PMID: 27936974 DOI: 10.1080/17474124.2017.1270205] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Without treatment, many of the 200 million people worldwide with chronic hepatitis C virus (HCV) infection will develop cirrhosis or liver cancer. Japan was the first nation to approve an interferon-free therapy for HCV, and sustained viral response (SVR) rates >90% have been achieved with asunaprevir, a protease inhibitor, plus daclatasvir, an inhibitor of the non-structural 5A (NS5A) protein. Areas covered: This review provides an overview of the results from both clinical trials and real world experience with asunaprevir and daclatasvir therapy focused primarily on Japan. A literature search using the keywords 'asunaprevir,' 'daclatasvir,' 'interferon-free therapy,' and 'direct-acting antiviral drugs' was initially used to select relevant literature for inclusion in the review. Expert commentary: While not approved in the United States, dual therapy with asunaprevir plus daclatasvir has already been successfully used in Japan and throughout East Asia to treat many thousands of patients. Pre-existing or treatment-emergent NS5A-Y93 or -L31 resistance-associated variants (RAVs) may lead to viral breakthrough, and alternative therapies should be considered for these patients, but patients who harbor NS5A RAVs only at low frequency are likely to achieve SVR. The therapy has also been shown to be safe and effective with renal dysfunction or liver cirrhosis.
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Affiliation(s)
- C Nelson Hayes
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Minami-ku , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan
| | - Michio Imamura
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Minami-ku , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan
| | - Kazuaki Chayama
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Minami-ku , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan.,c Laboratory for Digestive Diseases , Center for Genomic Medicine, RIKEN , Hiroshima , Japan
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Genetic basis of hepatitis virus-associated hepatocellular carcinoma: linkage between infection, inflammation, and tumorigenesis. J Gastroenterol 2017; 52:26-38. [PMID: 27714455 DOI: 10.1007/s00535-016-1273-2] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 09/23/2016] [Indexed: 02/04/2023]
Abstract
Hepatitis virus infection is a leading cause of chronic liver disease, including cirrhosis and hepatocellular carcinoma (HCC). Although anti-viral therapies against hepatitis B virus (HBV) and hepatitis C virus (HCV) have dramatically progressed during the past decade, the estimated number of people chronically infected with HBV and/or HCV is ~370 million, and hepatitis virus-associated hepatocarcinogenesis is a serious health concern worldwide. Understanding the mechanism of virus-associated carcinogenesis is crucial toward both treatment and prevention, and the recently developed whole genome/exome sequencing analysis using next-generation sequencing technologies has contributed to unveiling the landscape of genetic and epigenetic aberrations in not only tumor tissues but also the background liver tissues underlying chronic liver damage caused by hepatitis virus infection. Several major mechanisms underlie the genetic and epigenetic aberrations in the hepatitis virus-infected liver, such as the generation of reactive oxidative stress, ectopic expression of DNA mutator enzymes, and dysfunction of the DNA repair system. In addition, direct oncogenic effects of hepatitis virus, represented by the integration of HBV-DNA, are observed in infected hepatocytes. Elucidating the whole picture of genetic and epigenetic alterations, as well as the mechanisms of tumorigenesis, will facilitate the development of efficient treatment and prevention strategies for hepatitis virus-associated HCC.
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Prediction of Hepatocellular Carcinoma Development after Hepatitis C Virus Eradication Using Serum Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein. Int J Mol Sci 2016; 17:ijms17122143. [PMID: 27999409 PMCID: PMC5187943 DOI: 10.3390/ijms17122143] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 11/30/2016] [Accepted: 12/14/2016] [Indexed: 01/06/2023] Open
Abstract
We aimed to clarify the association between a novel serum fibrosis marker, Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+-M2BP), and hepatocellular carcinoma (HCC) development in 355 patients with chronic hepatitis C who achieved sustained virologic response (SVR) through interferon-based antiviral therapy. Pretreatment serum WFA+-M2BP levels were quantified and the hazard ratios (HRs) for HCC development were retrospectively analyzed by Cox proportional hazard analysis. During the median follow-up time of 2.9 years, 12 patients developed HCC. Multivariate analysis demonstrated that high serum WFA+-M2BP (≥2.80 cut off index (COI), HR = 15.20, p = 0.013) and high fibrosis-4 (FIB-4) index (≥3.7, HR = 5.62, p = 0.034) were independent risk factors for HCC development. The three- and five-year cumulative incidence of HCC in patients with low WFA+-M2BP were 0.4% and 0.4%, respectively, whereas those of patients with high WFA+-M2BP were 7.7% and 17.6%, respectively (p < 0.001). In addition, combination of serum WFA+-M2BP and FIB-4 indices successfully stratified the risk of HCC: the five-year cumulative incidences of HCC were 26.9%, 6.8%, and 0.0% in patients with both, either, and none of these risk factors, respectively (p < 0.001). In conclusion, pretreatment serum WFA+-M2BP level is a useful predictor for HCC development after achieving SVR.
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Ueda Y, Ikegami T, Soyama A, Akamatsu N, Shinoda M, Ishiyama K, Honda M, Marubashi S, Okajima H, Yoshizumi T, Eguchi S, Kokudo N, Kitagawa Y, Ohdan H, Inomata Y, Nagano H, Shirabe K, Uemoto S, Maehara Y. Simeprevir or telaprevir with peginterferon and ribavirin for recurrent hepatitis C after living-donor liver transplantation: A Japanese multicenter experience. Hepatol Res 2016; 46:1285-1293. [PMID: 26899352 DOI: 10.1111/hepr.12684] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Revised: 02/10/2016] [Accepted: 02/12/2016] [Indexed: 02/08/2023]
Abstract
AIM This study aimed to clarify the efficacy and safety of simeprevir, a second-generation NS3/4A inhibitor, with peginterferon and ribavirin for recurrent hepatitis C after liver transplantation. METHODS A retrospective cohort study of living-donor liver transplant recipients with recurrent hepatitis C with the hepatitis C virus genotype 1 treated with either simeprevir- or telaprevir-based triple therapy was carried out at eight Japanese liver transplant centers. RESULTS Simeprevir- and telaprevir-based triple therapies were given to 79 and 36 patients, respectively. Of the 79 patients treated with simeprevir-based triple therapy, 44 (56%) achieved sustained virological response 12 weeks (SVR12) after treatment ended, and there was no significant difference in the SVR12 between the simeprevir- and telaprevir-based triple therapy groups (69%). The rates of adverse events were not significantly different between the simeprevir- and telaprevir-based triple therapy groups, although the rate of patients who received blood cell transfusion and erythropoietin due to anemia and had renal insufficiency were significantly higher in the telaprevir group than in the simeprevir group. Three baseline factors, the presence of prior dual therapy with peginterferon and ribavirin (P = 0.001), a non-responder to the prior dual therapy (P < 0.001), and male sex (P = 0.040), were identified as significant predictive factors for non-SVR with simeprevir-based triple therapy. CONCLUSION Simeprevir-based triple therapy for recurrent hepatitis C after living-donor liver transplantation resulted in a high SVR rate and good tolerability, especially in treatment-naïve patients.
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Affiliation(s)
- Yoshihide Ueda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University
| | - Toru Ikegami
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Akihiko Soyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki
| | - Nobuhisa Akamatsu
- Division of Artificial Organ and Transplantation, Department of Surgery, University of Tokyo
| | - Masahiro Shinoda
- Department of Surgery, Keio University School of Medicine, Tokyo
| | - Kohei Ishiyama
- Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masaki Honda
- Department of Transplantation and Pediatric Surgery, Kumamoto University, Kumamoto
| | - Shigeru Marubashi
- Department of Surgery, Osaka University Graduate School of Medicine, Osaka
| | - Hideaki Okajima
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki
| | - Norihiro Kokudo
- Division of Artificial Organ and Transplantation, Department of Surgery, University of Tokyo
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo
| | - Hideki Ohdan
- Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yukihiro Inomata
- Department of Transplantation and Pediatric Surgery, Kumamoto University, Kumamoto
| | - Hiroaki Nagano
- Department of Surgery, Osaka University Graduate School of Medicine, Osaka
| | - Ken Shirabe
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Shinji Uemoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka
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Tamori A, Yoshida K, Kurai O, Kioka K, Hai H, Kozuka R, Motoyama H, Kawamura E, Hagihara A, Uchida-Kobayashi S, Morikawa H, Enomoto M, Murakami Y, Kawada N. Randomized trial of combined triple therapy comprising two types of peginterferon with simeprevir in patients with hepatitis C virus genotype 1b. Hepatol Res 2016; 46:1311-1320. [PMID: 26932745 DOI: 10.1111/hepr.12689] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2015] [Revised: 02/16/2016] [Accepted: 02/29/2016] [Indexed: 02/08/2023]
Abstract
UNLABELLED Simeprevir (SMV) is a potent, macrocyclic hepatitis C virus (HCV) non-structural 3/4 A protease inhibitor. This prospective study compared the efficacy and safety of SMV in combination with peginterferon α2a + ribavirin (P2aR) and with peginterferon α2b + ribavirin (P2bR) in Japanese patients with HCV genotype 1b infection. METHODS Hepatitis C virus genotype 1b patients were randomly assigned to receive SMV (100 mg QD) with P2aR for 12 weeks, then P2aR alone for 12 or 36 weeks; or SMV (100 mg QD) with P2bR for 12 weeks, then P2bR alone for 12 or 36 weeks. The primary endpoint was a sustained virologic response 24 weeks after completing treatment (SVR24). RESULTS In total, 151 patients were randomly assigned to the P2aR (n = 76) or P2bR group (n = 75). Six patients dropped out. Sustained virologic response 24 weeks after completing treatment was achieved in 55 (75.3%) of 73 P2aR patients and 55 (76.4%) of 72 P2bR patients. There was no difference in the rate of SVR24 between the two groups (P = 0.88). No differences in the proportion of patients who became HCV RNA-negative were detected between the P2aR and P2bR groups. The two groups had comparable numbers of adverse events, which led to the discontinuation of treatment in 9.6% and 8.3% of participants in the P2aR and P2bR groups, respectively. CONCLUSION Peginterferon α2a or α2b in combination with SMV + ribavirin therapy showed identical antiviral effects in patients with chronic hepatitis C. Also, the incidence of adverse events was identical for both regimens.
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Affiliation(s)
- Akihiro Tamori
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kanako Yoshida
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Osamu Kurai
- Department of Gastroenterology, Osaka City Juso Hospital, Osaka, Japan
| | - Kiyohide Kioka
- Department of Hepatology, Osaka City General Hospital, Osaka, Japan
| | - Hoang Hai
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Ritsuzo Kozuka
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hiroyuki Motoyama
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Etsushi Kawamura
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Atsushi Hagihara
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | | | - Hiroyasu Morikawa
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masaru Enomoto
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yoshiki Murakami
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
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Obata F, Murakami T, Miyagi J, Ueda S, Inagaki T, Minato M, Ono H, Nishimura K, Shibata E, Tamaki M, Yoshimoto S, Kishi F, Kishi S, Matsuura M, Nagai K, Abe H, Doi T. A case of rapid amelioration of hepatitis C virus-associated cryoglobulinemic membranoproliferative glomerulonephritis treated by interferon-free directly acting antivirals for HCV in the absence of immunosuppressant. CEN Case Rep 2016; 6:55-60. [PMID: 28509128 DOI: 10.1007/s13730-016-0244-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 11/10/2016] [Indexed: 12/11/2022] Open
Abstract
Mixed cryoglobulinemic syndrome, which is a systemic vasculitis characterized by the immune complex deposition in small- and medium-sized arteries and most often due to chronic hepatitis C virus (HCV) infection, sometimes clinically manifests as refractory glomerulonephritis or nephritic syndrome. Patients with mixed cryoglobulinemic nephropathy who have a rapidly progressive glomerulonephritis should receive immunosuppressive therapy. After disease stabilization, patients should receive concurrent therapy for the underlying HCV infection. The standard therapy of a chronic HCV infection is IFN monotherapy or IFN combined with ribavirin; however, after the introduction of direct-acting antivirals (DAAs), the standard therapy for patients with HCV genotype 1 has dramatically changed. We report a case of HCV-associated cryoglobulinemic membranoproliferative glomerulonephritis (MPGN) successfully treated by daclatasvir and asunaprevir, which are IFN-free DAAs for HCV, in combination with angiotensin II receptor blocker without immunosuppressive therapy. The patient developed severe nephrotic syndrome with progressive kidney dysfunction. Blood examination revealed a high copy number of HCV-RNA (6.4 log IU/mL, type 1), cryoglobulinemia, paraproteinemia of IgM-κ, and hypocomplementemia. Histological analysis showed MPGN type 1. These findings were compatible with those observed in HCV-associated cryoglobulinemic MPGN. This case offers original evidence for the application of newer generation of IFN-free DAAs in the treatment of HCV-associated cryoglobulinemic nephropathy.
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Affiliation(s)
- Fumiaki Obata
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, 3-18-15 Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan
| | - Taichi Murakami
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, 3-18-15 Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan.
| | - Junko Miyagi
- Department of Internal Medicine, Local Incorporated Administrative Agency Tokushima Prefecture Naruto Hospital, 32 Kurozaki-aza-kotani, Muya-cho, Naruto, Tokushima, 772-8503, Japan
| | - Sayo Ueda
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, 3-18-15 Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan
| | - Taizo Inagaki
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, 3-18-15 Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan
| | - Masanori Minato
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, 3-18-15 Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan
| | - Hiroyuki Ono
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, 3-18-15 Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan
| | - Kenji Nishimura
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, 3-18-15 Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan
| | - Eriko Shibata
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, 3-18-15 Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan
| | - Masanori Tamaki
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, 3-18-15 Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan
| | - Sakiya Yoshimoto
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, 3-18-15 Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan
| | - Fumi Kishi
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, 3-18-15 Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan
| | - Seiji Kishi
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, 3-18-15 Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan
| | - Motokazu Matsuura
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, 3-18-15 Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan
| | - Kojiro Nagai
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, 3-18-15 Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan
| | - Hideharu Abe
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, 3-18-15 Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan
| | - Toshio Doi
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, 3-18-15 Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan
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Network meta-analysis of first- and second-generation protease inhibitors for chronic hepatitis C genotype 1: efficacy based on RVR and SVR 24. Eur J Clin Pharmacol 2016; 73:1-14. [PMID: 27757504 DOI: 10.1007/s00228-016-2146-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 10/07/2016] [Indexed: 12/17/2022]
Abstract
PURPOSE This study aimed to compare the efficacy among direct-acting antiviral agents (first and second-generation direct-acting antiviral agents (DAAs)) with placebo and with standard dual therapy (pegylated interferon + ribavirin (Peg-IFN + RBV)) in terms of rapid virologic response (RVR) and sustained virologic response (SVR) in chronic hepatitis C genotype 1 treatment. METHODS We performed a systematic review of randomized controlled trials (RCTs) in MEDLINE, International Pharmaceutical Abstracts, Cochrane Library, SCIELO, and Scopus and conducted a network meta-analysis to compare the efficacy of boceprevir (BOC), daclatasvir (DCV), grazoprevir, simeprevir (SMV) and telaprevir (TVR), in treatment-naive and treatment-experienced patients. RESULTS Sixteen studies encompassing 7171 patients were analysed. Associations between DAAs therapies (IFN-free regimens) could not be addressed since no common comparator was found in the RCTs among these associations and the other agents included in the present analysis. All agents were more efficacious than placebo or Peg-IFN + RBV in terms of RVR, while only BOC and SMV showed statistically significant superiority for the SVR outcome when compared to placebo or standard dual therapy. No significant differences between the DAAs were observed. The analysis prioritized treatment with DCV for both efficacy outcomes. Node-splitting analysis showed that our networks are robust (p > 0.05). CONCLUSIONS The superiority of DAAs over placebo or standard dual therapy with Peg-IFN + RBV was confirmed, indicating the greater efficacy of DCV. This study is the first network meta-analysis that included RVR as an outcome in the evaluation of these agents via indirect comparison. Further investigation should be carried out addressing safety and tolerability outcomes.
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Hagiwara S, Nishida N, Watanabe T, Sakurai T, Ida H, Minami Y, Takita M, Minami T, Iwanishi M, Chishina H, Ueshima K, Komeda Y, Arizumi T, Kudo M. Outcome of Asunaprevir/Daclatasvir Combination Therapy for Chronic Liver Disease Type C. Dig Dis 2016; 34:620-626. [PMID: 27750228 DOI: 10.1159/000448822] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Treatment for chronic hepatitis C has recently developed in a very rapid manner. In Japan, in September 2014, IFN-free asunaprevir (ASV) and daclatasvir (DCV) became available for combination therapy. We report the treatment outcomes achieved at our hospital using this combination therapy. METHODS Sustained virological response (SVR) 24 could be evaluated in 120 of 125 patients with chronic liver disease type C who visited our hospital and were treated with ASV/DCV after September 2014, and these patients were analyzed. RESULTS SVR24 was achieved in 106 patients (88%). End-of-treatment response was not achieved in 10 patients (8.3%). Five of them carried multiple-resistant NS3/4A or NS5A region, and administration was discontinued early in 4 patients due to adverse effects. After ASV/DCV treatment, hepatocellular carcinoma (HCC) developed in 2 patients (1.7%) and recurred in 5 (4.2%). CONCLUSIONS ASV/DCV treatment achieved favorable SVR in elderly and hepatic cirrhosis patients and patients in whom HCC was cured. However, an increase in the incidence of HCC development in patients who markedly respond to direct-acting antivirals treatment is expected and surveillance of HCC becomes more important.
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