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Jose-Abrego A, Laguna-Meraz S, Roman S, Mariscal-Martinez IM, Panduro A. Hepatitis C Virus Resistance-Associated Substitutions in Mexico. Viruses 2025; 17:169. [PMID: 40006924 PMCID: PMC11860613 DOI: 10.3390/v17020169] [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: 12/21/2024] [Revised: 01/10/2025] [Accepted: 01/13/2025] [Indexed: 02/27/2025] Open
Abstract
Hepatitis C virus (HCV) is susceptible to resistance-associated substitutions (RASs) in the NS3, NS5A, and NS5B nonstructural genes, key targets of the direct-acting antivirals (DAAs). This study aimed to assess the prevalence and distribution of RASs across different HCV subtypes in Mexico. A Genbank dataset of 566 HCV sequences was analyzed. Most sequences were from Mexico City (49.1%, 278/566) and Jalisco (39.4%, 223/566). The NS5B region was the most sequenced (59.7%, 338/566). The most frequent HCV subtypes were 1a (44.0%, 249/566), 1b (28.6%, 162/566), 2b (9.5%, 54/566), and 3a (6.2%, 35/566). Subtypes 1a (57.4%, 128/223) and 3a (12.6%, 28/223) were significantly higher in Jalisco than in Mexico City (34.2%, 95/278 and 2.5%, 7/278), whereas subtype 1b was higher in Mexico City (34.5%, 96/278 vs. 14.8%, 33/223). Subtype 1a increased from 2019 to 2024, representing 49.4% (123/249) of all reported cases. RASs were detected in NS3 (6.7%, 1/15), NS5A (2.9%, 3/102), and NS5B (0.3%, 1/349), with the most frequent mutations being Q80K, Y93H, and S282T, respectively, and detected in subtypes 1b (n = 3), 1a (n = 1), and 2a (n = 1). In conclusion, Mexico's HCV sequencing-based surveillance is limited. Subtype 1a predominated, but frequencies varied across states. The prevalence of RASs varied by gene from 0.3% to 6.7%. Establishing regional sequencing centers for NS3, NS5A, and NS5B is crucial to monitoring Mexico's DAA-resistant mutations and HCV subtype genetic diversity.
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Affiliation(s)
- Alexis Jose-Abrego
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara 44280, Mexico; (A.J.-A.); (S.L.-M.); (S.R.); (I.M.M.-M.)
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Mexico
| | - Saul Laguna-Meraz
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara 44280, Mexico; (A.J.-A.); (S.L.-M.); (S.R.); (I.M.M.-M.)
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Mexico
| | - Sonia Roman
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara 44280, Mexico; (A.J.-A.); (S.L.-M.); (S.R.); (I.M.M.-M.)
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Mexico
| | - Irene M. Mariscal-Martinez
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara 44280, Mexico; (A.J.-A.); (S.L.-M.); (S.R.); (I.M.M.-M.)
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Mexico
- Doctoral Program Molecular Biology in Medicine, Health Sciences Center, University of Guadalajara, Guadalajara 44340, Mexico
| | - Arturo Panduro
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara 44280, Mexico; (A.J.-A.); (S.L.-M.); (S.R.); (I.M.M.-M.)
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Mexico
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Kamal S, Shahzad A, Rehman K, Tariq K, Akash MSH, Imran M, Assiri MA. Therapeutic Intervention of Serine Protease Inhibitors against Hepatitis C Virus. Curr Med Chem 2024; 31:2052-2072. [PMID: 37855348 DOI: 10.2174/0109298673234823230921090431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 05/12/2023] [Accepted: 05/23/2023] [Indexed: 10/20/2023]
Abstract
Hepatitis C virus (HCV) is a globally prevalent and hazardous disorder that is responsible for inducing several persistent and potentially fatal liver diseases. Current treatment strategies offer limited efficacy, often accompanied by severe and debilitating adverse effects. Consequently, there is an urgent and compelling need to develop novel therapeutic interventions that can provide maximum efficacy in combating HCV while minimizing the burden of adverse effects on patients. One promising target against HCV is the NS3-4A serine protease, a complex composed of two HCV-encoded proteins. This non-covalent heterodimer is crucial in the viral life cycle and has become a primary focus for therapeutic interventions. Although peginterferon, combined with ribavirin, is commonly employed for HCV treatment, its efficacy is hampered by significant adverse effects that can profoundly impact patients' quality of life. In recent years, the development of direct-acting antiviral agents (DAAs) has emerged as a breakthrough in HCV therapy. These agents exhibit remarkable potency against the virus and have demonstrated fewer adverse effects when combined with other DAAs. However, it is important to note that there is a potential for developing resistance to DAAs due to alterations in the amino acid position of the NS3-4A protease. This emphasizes the need for ongoing research to identify strategies that can minimize the emergence of resistance and ensure long-term effectiveness. While the combination of DAAs holds promise for HCV treatment, it is crucial to consider the possibility of drug-drug interactions. These interactions may occur when different DAAs are used concurrently, potentially compromising their therapeutic efficacy. Therefore, carefully evaluating and monitoring potential drug interactions are vital to optimize treatment outcomes. In the pursuit of novel therapeutic interventions for HCV, the field of computational biology and bioinformatics has emerged as a valuable tool. These advanced technologies and methodologies enable the development and design of new drugs and therapeutic agents that exhibit maximum efficacy, reduced risk of resistance, and minimal adverse effects. By leveraging computational approaches, researchers can efficiently screen and optimize potential candidates, accelerating the discovery and development of highly effective treatments for HCV, treatments.
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Affiliation(s)
- Shagufta Kamal
- Department of Biochemistry, Government College University, Faisalabad, Pakistan
| | - Asif Shahzad
- Department of Biochemistry, Government College University, Faisalabad, Pakistan
| | - Kanwal Rehman
- Department of Pharmacy, The Women University, Multan, Pakistan
| | - Komal Tariq
- Department of Biochemistry, Government College University, Faisalabad, Pakistan
| | | | - Muhammad Imran
- Research center for Advanced Materials Science (RCAMS), King Khalid University, Abha, Saudi Arabia
- Department of Chemistry, Faculty of Science, King Khalid University, Abha, Saudi Arabia
| | - Mohammed Ali Assiri
- Research center for Advanced Materials Science (RCAMS), King Khalid University, Abha, Saudi Arabia
- Department of Chemistry, Faculty of Science, King Khalid University, Abha, Saudi Arabia
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El-Marakby MG, Solayman MH, Sabri NA. Evaluation of the Safety Profile of Direct-Acting Antivirals on Patients with Hepatitis C Virus: A Pharmacovigilance Study. Ther Innov Regul Sci 2023:10.1007/s43441-023-00537-x. [PMID: 37227588 PMCID: PMC10400676 DOI: 10.1007/s43441-023-00537-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 05/05/2023] [Indexed: 05/26/2023]
Abstract
BACKGROUND Hepatitis C virus (HCV) is the primary contributor to chronic hepatic diseases. A rapid change in the situation took place with the advent of oral direct-acting antivirals (DAAs). However, a comprehensive review of the adverse event (AE) profile of the DAAs is lacking. This cross-sectional study aimed to analyze the reported Adverse Drug Reactions (ADRs) with DAA treatment using data from VigiBase, the WHO Individual Case Safety Report (ICSR) database. METHODS All ICSRs reported to VigiBase with sofosbuvir (SOF), daclatasvir (DCV), sofosbuvir /ledipasvir (SOF/LDV) and ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) in Egypt were extracted. Descriptive analysis was performed to summarize patients' and reactions' characteristics. Information components (ICs) and proportional reporting ratios (PRRs) for all reported ADRs were calculated to identify signals of disproportionate reporting. Logistic regression analysis was performed to identify the DAAs association with serious events of concern while adjusting for age, gender, pre-existing cirrhosis, and ribavirin use. RESULTS Out of 2925 reports, 1131 (38.6%) were serious. The most commonly reported reactions; anaemia (21.3%), HCV relapse (14.5%) and headache (14%). For the disproportionality signals; HCV relapse was reported with SOF/DCV (IC 3.65, 95% CrI 3.47-3.79) and SOF/RBV (IC 3.69, 95% CrI 3.37-3.92), while anaemia (IC 2.85, 95% CrI 2.26-3.27) and renal impairment (IC 2.12, 95% CrI 0.7-3.03) were reported with OBV/PTV/r. CONCLUSION The highest severity index and seriousness were reported with SOF/RBV regimen. A significant association was found for OBV/PTV/r with renal impairment and anaemia although being the superior regimen in terms of efficacy. The study findings call for further population-based studies for clinical validation.
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Affiliation(s)
- Mai G El-Marakby
- Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
| | - Mohamed H Solayman
- Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Nagwa A Sabri
- Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
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Nirei K, Kanda T, Masuzaki R, Mizutani T, Moriyama M. Follow-Up of Patients Who Achieved Sustained Virologic Response after Interferon-Free Treatment against Hepatitis C Virus: Focus on Older Patients. ACTA ACUST UNITED AC 2021; 57:medicina57080761. [PMID: 34440967 PMCID: PMC8399286 DOI: 10.3390/medicina57080761] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/24/2021] [Accepted: 07/26/2021] [Indexed: 11/16/2022]
Abstract
Background and Objectives: Direct-acting antiviral agents (DAAs) have improved sustained virologic response (SVR) rates in patients with chronic hepatitis C virus (HCV) infection. Our aim was to elucidate the occurrence of hepatocellular carcinoma (HCC) and to compare the outcomes of patients aged 75 years or older (older group) with those of patients younger than 75 years (younger group) after SVR. Materials and Methods: Among 441 patients treated with interferon-free DAA combinations, a total of 409 SVR patients were analyzed. We compared the two age groups in terms of HCC incidence and mortality rates. Results: Older and younger groups consisted of 68 and 341 patients, respectively. Occurrence of HCC after SVR did not differ between the two groups of patients with a history of HCC. Occurrence of HCC after SVR was observed more in younger patients without a history of HCC (p < 0.01). Although older patients without a history of HCC had a higher mortality rate (p < 0.01), their causes of death were not associated with liver diseases. Among younger patients without a history of HCC, none died. Conclusions: After SVR, liver disease may not be a prognostic factor in older HCV patients without a history of HCC.
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Okano H, Asakawa H, Nose K, Tsuruga S, Tochio T, Kumazawa H, Sakuno T, Isono Y, Tanaka H, Matsusaki S, Sase T, Saito T, Mukai K, Nishimura A. Characteristics of patients unaware of their chronic hepatitis virus infection. WORLD ACADEMY OF SCIENCES JOURNAL 2021; 3:29. [DOI: 10.3892/wasj.2021.100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Affiliation(s)
- Hiroshi Okano
- Department of Gastroenterology, Suzuka General Hospital, Suzuka, Mie 513‑8630, Japan
| | - Hiroki Asakawa
- Department of Gastroenterology, Suzuka General Hospital, Suzuka, Mie 513‑8630, Japan
| | - Kenji Nose
- Department of Gastroenterology, Suzuka General Hospital, Suzuka, Mie 513‑8630, Japan
| | - Satomi Tsuruga
- Department of Gastroenterology, Suzuka General Hospital, Suzuka, Mie 513‑8630, Japan
| | - Tomomasa Tochio
- Department of Gastroenterology, Suzuka General Hospital, Suzuka, Mie 513‑8630, Japan
| | - Hiroaki Kumazawa
- Department of Gastroenterology, Suzuka General Hospital, Suzuka, Mie 513‑8630, Japan
| | - Takashi Sakuno
- Department of Gastroenterology, Suzuka General Hospital, Suzuka, Mie 513‑8630, Japan
| | - Yoshiaki Isono
- Department of Gastroenterology, Suzuka General Hospital, Suzuka, Mie 513‑8630, Japan
| | - Hiroki Tanaka
- Department of Gastroenterology, Suzuka General Hospital, Suzuka, Mie 513‑8630, Japan
| | - Shimpei Matsusaki
- Department of Gastroenterology, Suzuka General Hospital, Suzuka, Mie 513‑8630, Japan
| | - Tomohiro Sase
- Department of Gastroenterology, Suzuka General Hospital, Suzuka, Mie 513‑8630, Japan
| | - Tomonori Saito
- Department of Gastroenterology, Suzuka General Hospital, Suzuka, Mie 513‑8630, Japan
| | - Katsumi Mukai
- Department of Gastroenterology, Suzuka General Hospital, Suzuka, Mie 513‑8630, Japan
| | - Akira Nishimura
- Department of Gastroenterology, Suzuka General Hospital, Suzuka, Mie 513‑8630, Japan
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Masaki N, Kawasaki Y, Nozaki Y, Yanase M. Characteristics of patients aged over 75 years with hepatitis C virus infection treated with direct-acting antivirals in Japan: Evidence based on the nationwide, real-world database in Japan. Hepatol Res 2021; 51:417-425. [PMID: 33217105 DOI: 10.1111/hepr.13596] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/16/2020] [Accepted: 11/09/2020] [Indexed: 01/01/2023]
Abstract
AIM Direct-acting antivirals (DAAs) have dramatically changed the treatment of chronic hepatitis C. Their high efficacy helps in eradicating hepatitis C virus with few adverse events. Information on real-world use of DAAs therapy in patients aged 75 years and older is inadequate. METHODS The Japanese DAAs database was constructed in 2014 as a cooperative system between 18 prefectures. The medical reports filled in by doctors and anonymized at the local government office were collected. The patients' demographic features, viral factors, and treatment characteristics were compared among three groups stratified by age when therapy was initiated: Group A (<60 years old), Group B (60-74 years old), and Group C (≥75 years old). RESULTS Out of the 22,454 patients whose age upon starting therapy could be identified, 24.8% (n = 5597) belonged to Group C, which was ten times the number in the Japanese Interferon Database. Female patients, advanced stages of liver fibrosis, and past history of hepatocellular carcinoma treatment were significantly higher in the older age groups (Group A < B < C), whereas sustained virologic response (SVR) rates were not different (91%-93%). In Group C, multivariate logistic regression analysis revealed that predicting factors for virologic response varied among DAAs regimens. However, the completion of DAAs therapy commonly contributed to SVR, regardless of DAAs regimen. CONCLUSIONS DAAs therapy is associated with high SVR rates, even in the oldest age group, and therapy should not be withheld on the basis of old age.
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Affiliation(s)
- Naohiko Masaki
- Laboratory Testing Department, National Center for Global Health and Medicine, Tokyo, Japan
| | - Youhei Kawasaki
- Biostatistics Section, Clinical Research Center, Chiba University Hospital, Chiba, Japan
- Faculty of Nursing, Japanese Red Cross College of Nursing, Tokyo, Japan
| | - Yuichi Nozaki
- Department of Gastroenterology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Mikio Yanase
- Department of Gastroenterology, National Center for Global Health and Medicine, Tokyo, Japan
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Tarao K, Nozaki A, Komatsu H. A Hepatitis C Virus-Associated Decompensated Cirrhotic Patient Who Showed the Disappearance of Hepatic Encephalopathy, Ascites, and Pleural Effusion by Antiviral Therapy with Sofosbuvir/Velpatasvir. Case Rep Gastroenterol 2021; 15:436-442. [PMID: 34054397 PMCID: PMC8138198 DOI: 10.1159/000511749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 09/18/2020] [Indexed: 11/19/2022] Open
Abstract
Oral direct-acting antivirals (DAAs) are the main therapy for hepatitis C virus (HCV)-associated liver disease in Japan. Moreover, many DAAs include an indication for compensated liver cirrhosis. However, patients with decompensated HCV-associated cirrhosis have hitherto not been indicated for therapy with DAAs. Recently, a new DAA, sofosbuvir/velpatasvir (SOF/VEL), was indicated for decompensated HCV-associated cirrhotic patients. Actually, it has been shown to eradicate HCV in many cases. However, it is not clear whether hepatic encephalopathy, ascites, and pleural effusion in patients with decompensated HCV-associated cirrhosis disappear by SOF/VEL treatment. Recently, we encountered a decompensated HCV-associated cirrhosis patient who showed the disappearance of hepatic encephalopathy, ascites, and pleural effusion with marked improvement of serum ammonia level, albumin level, prothrombin time, and platelet count after the eradication of HCV by the administration of SOF/VEL. Her consciousness was cloudy and it took many hours for the preparation of each meal just before SOF/VEL treatment, but after the disappearance of HCV-RNA by the therapy, her consciousness became clear and she could prepare meals in a short time. This case suggests the possibility of improvement from decompensated HCV-associated liver cirrhosis to compensated liver cirrhosis with disappearance of hepatic encephalopathy, ascites, and pleural effusion by SOF/VEL therapy.
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Affiliation(s)
- Kazuo Tarao
- Tarao's Gastroenterological Clinic, Yokohama, Japan
| | - Akito Nozaki
- Department of Gastroenterology, Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Hirokazu Komatsu
- Department of Gastroenterology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan
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Abe K, Wakabayashi H, Nakayama H, Suzuki T, Kuroda M, Yoshida N, Tojo J, Kogure A, Rai T, Saito H, Mukai S, Fujita M, Hayashi M, Takahashi A, Ohira H. Factors associated with hepatocellular carcinoma occurrence after HCV eradication in patients without cirrhosis or with compensated cirrhosis. PLoS One 2020; 15:e0243473. [PMID: 33284844 PMCID: PMC7721183 DOI: 10.1371/journal.pone.0243473] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 11/21/2020] [Indexed: 02/08/2023] Open
Abstract
The present study aimed to investigate the incidence of hepatocellular carcinoma (HCC) and factors related to HCC occurrence after direct-acting antiviral (DAA) treatment in the Fukushima Liver Academic Group (FLAG). We conducted a multicenter retrospective cohort study of 1068 patients without cirrhosis (NC) or with compensated liver cirrhosis (LC) who achieved a sustained virologic response (SVR). First, we compared the cumulative HCC incidence and survival rates in NC (n = 880) and LC (n = 188) patients without a history of HCC treatment. Second, we performed multivariate analysis of factors related to HCC occurrence after DAA treatment. Overall, the average age was 65 years, and the male/female ratio was 511/557. Thirty-nine (4%) patients developed HCC. The cumulative 4-year HCC incidence and survival rates were 3.0% and 99.8% in NC patients and 11.5% and 98.5% in LC patients, respectively. The independent factors affecting HCC occurrence identified by multivariate analysis were the serum albumin (ALB) level before SVR for NC patients and the ALBI score, platelet count, and diabetes before SVR for LC patients. The factors related to HCC occurrence differed between NC and LC patients. Careful surveillance of post-SVR patients with these risk factors is needed.
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Affiliation(s)
- Kazumichi Abe
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
- Department of Internal Medicine, Hanawa Kosei Hospital, Higashishirakawa, Japan
- * E-mail:
| | - Hiroto Wakabayashi
- Department of Gastroenterology, Takeda General Hospital, Aizuwakamatsu, Japan
| | - Haruo Nakayama
- Department of Gastroenterology, Iwaki City Medical Center, Iwaki, Japan
| | - Tomohiro Suzuki
- Department of Gastroenterology, Fukushima Rosai Hospital, Iwaki, Japan
| | - Masahito Kuroda
- Department of Gastroenterology, Fukushima Red Cross Hospital, Fukushima, Japan
| | - Naoe Yoshida
- Department of Internal Medicine, Iwase General Hospital, Sukagawa, Japan
| | | | - Atsuko Kogure
- Department of Gastroenterology, Fujita General Hospital, Date, Japan
| | | | | | - Shinji Mukai
- Department of Gastroenterology, Ohta Nishinouchi Hospital, Koriyama, Japan
| | - Masashi Fujita
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Manabu Hayashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Atsushi Takahashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
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Fukuda H, Yano Y, Sato D, Ohde S, Noto S, Watanabe R, Takahashi O. Healthcare Expenditures for the Treatment of Patients Infected with Hepatitis C Virus in Japan. PHARMACOECONOMICS 2020; 38:297-306. [PMID: 31761994 DOI: 10.1007/s40273-019-00861-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
AIM The recently developed direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infections are costly. Cost-effectiveness analyses of DAAs require accurate healthcare expenditure estimates for the various HCV disease states, but few studies have produced such estimates using national-level data. This study utilized nationally representative data to estimate the healthcare expenditure for each HCV disease state. METHODS We identified all patients infected with HCV between April 2010 and March 2018 from a nationwide administrative claims database in Japan. Monthly patient-level healthcare expenditures were calculated for the following disease states: chronic hepatitis C (CHC), compensated cirrhosis (CC), decompensated cirrhosis (DC), and hepatocellular carcinoma (HCC). The expenditures for the CHC and CC states were also compared before DAA treatment and after sustained virologic response (SVR) was achieved. A longitudinal two-part model was employed to estimate the healthcare expenditures for each state. RESULTS During the study period, 1,564,043 patients with 146,488,137 patient-months of data met the inclusion criteria. The year of valuation was 2017. The mean monthly healthcare expenditures per patient (95% confidence intervals) for the pre-DAA CHC, CC, DC, and HCC states were US$267 (US$267-268), US$428 (US$427-429), US$666 (US$663-669), and US$969 (US$966-972), respectively. The mean monthly healthcare expenditures per patient for the post-SVR (≥ 2 years) CHC and CC states were US$176 (US$176-177) and US$238 (US$236-240), respectively. Healthcare expenditure increased with increasing age in all disease states (P < 0.05). CONCLUSIONS These healthcare expenditure estimates from a nationally representative sample have potential applications in cost-effectiveness analyses of DAAs.
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Affiliation(s)
- Haruhisa Fukuda
- Department of Health Care Administration and Management, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
| | - Yoshihiko Yano
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Daisuke Sato
- National Institute of Public Health, Saitama, Japan
| | - Sachiko Ohde
- St. Luke's International University Graduate School of Public Health, Tokyo, Japan
| | - Shinichi Noto
- Department of Occupational Therapy, Niigata University of Health and Welfare, Niigata, Japan
| | - Ryo Watanabe
- Faculty of Health and Social Services, Kanagawa University of Human Services, Kanagawa, Japan
| | - Osamu Takahashi
- St. Luke's International University Graduate School of Public Health, Tokyo, Japan
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Kondo Y, Kogure T, Ninomiya M, Fukuda R, Monma N, Ikeo K, Tanaka Y. The reduction of miR146b-5p in monocytes and T cells could contribute to the immunopathogenesis of hepatitis C virus infection. Sci Rep 2019; 9:13393. [PMID: 31527804 PMCID: PMC6746729 DOI: 10.1038/s41598-019-49706-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 08/30/2019] [Indexed: 02/06/2023] Open
Abstract
It has been reported that various kinds of miRNAs could affect the pathogenesis of hepatitis C virus infection. Recently, our group reported that deep-sequencing analysis was useful to detect disease-specific miRNAs. The aim of this study is to identify the HCV-specific miRNAs that could contribute to the immunopathogenesis of HCV by using clinical samples and in vitro analysis. Five miRNAs (hsa-miR181a-2-3p, hsa-miR-374a-3p, hsa-miR374a-5p, hsa-miR-204-5p and hsa-miR146b-5p) were shown to be significantly downregulated in CH-C by deep sequence analysis. The average ratio (PBMCs miRNAs/serum miRNAs) of hsa-miR146b-5p was highest among all the miRNAs. Moreover, serum hsa-miR146b-5p was significantly down-regulated in CH-C patients in comparison to CH-B patients and healthy subjects. The expression of hsa-miR146b-5p in CD3+ T cells and CD14+ monocytes of CH-C patients was significantly lower than that of the other groups. The hsa-miR146b-5p expression in CD14+ monocytes of SVR patients treated with Peg-IFN/RBV was significantly higher than in those of non-SVR patients treated with Peg IFN/RBV. However, the hsa-miR146b-5p expression in CD14+ monocytes of SVR patients treated with DCV and ASV was comparable to that in monocytes of non-SVR patients treated with DCV and ASV. Moreover, the expression levels of hsa-miR146b-5p in CD14+ monocytes were significantly increased after achieving SVR and 1(OH)Vitamin D3 treatment. Further, the expression of HCV-Core could suppress miR146b-5p expression in immune cells and affect the expression of various kinds of cytokines by affecting the NF-κB signaling. In conclusion, the reduction of miR146b-5p in monocytes and T cells could contribute to the immunopathogenesis of hepatitis C virus infection.
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Affiliation(s)
- Yasuteru Kondo
- Department of Hepatology, Sendai Kousei Hospital, 4-15 Hirose, Aoba, Sendai City, Miyagi, Japan.
- Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, 467-8601, Japan.
| | - Takayuki Kogure
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo, Aoba, Sendai City, Miyagi, Japan
| | - Masashi Ninomiya
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo, Aoba, Sendai City, Miyagi, Japan
| | - Ryo Fukuda
- Department of Hepatology, Sendai Kousei Hospital, 4-15 Hirose, Aoba, Sendai City, Miyagi, Japan
| | - Norikazu Monma
- Center for information Biology, National Institute of Genetics, Mishima, Japan
| | - Kazuho Ikeo
- Center for information Biology, National Institute of Genetics, Mishima, Japan
| | - Yasuhito Tanaka
- Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, 467-8601, Japan
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Macken L, Gelson W, Priest M, Abouda G, Barclay S, Fraser A, Healy B, Irving W, Verma S. Efficacy of direct-acting antivirals: UK real-world data from a well-characterised predominantly cirrhotic HCV cohort. J Med Virol 2019; 91:1979-1988. [PMID: 31329295 DOI: 10.1002/jmv.25552] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 07/15/2019] [Indexed: 12/16/2022]
Abstract
Direct-acting antivirals (DAAs) have revolutionised the management of chronic hepatitis C virus (HCV) infection. We describe UK real-world DAA experience. Individuals commencing HCV treatment containing a DAA regimen (Mar 2014-Nov 2016), participating in the National HCV Research UK (HCVRUK) Cohort Study were recruited from 33 UK HCV centers. The data were prospectively entered at sites onto a centralised database. The data were reported as median (Q1-Q3). Of the 1448 treated patients, 1054 (73%) were males, the median age being 54 years (47-60), 900 (62%) being genotype 1 and 455 (31%) genotype 3. The majority, 887 (61%) had cirrhosis, and 590 (41%) were treatment-experienced. DAA regimens utilised: genotype1 sofosbuvir (SOF)/Ledipasvir/±Ribavirin (625/900, 69%) and Ombitasvir/Paritaprevir/Dasabuvir/±RBV (220/900, 24%), and in genotype 3 SOF/Daclatasvir + RBV (256/455, 56%) and SOF/pegylated interferon/RBV (157/455, 35%). Overall, 1321 (91%) achieved sustained virological response (SVR12), genotype 1 vs 3, 93% vs 87%, P < .001. Prior treatment, presence of cirrhosis and treatment regimen did not impact SVR12. Predictors of treatment failure were genotype 3 infection, OR, 2.015 (95% CI: 1.279-3.176, P = .003), and male sex, OR, 1.878 (95% CI: 1.071-3.291, P = .028). Of those with hepatic decompensation at baseline (n = 39), 51% (n = 20) recompensated post-treatment, lower baseline serum creatinine being associated with recompensation (P = .029). There were two liver-related deaths, both having decompensated disease. This real-world UK data, comprising of a predominantly cirrhotic HCV genotype 1/3 cohort, confirms DAA efficacy with an overall 91% SVR12, with 51% recompensating post-treatment. Genotype 3 infection was a predictor of treatment failure.
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Affiliation(s)
- Lucia Macken
- Department of Clinical and Experimental Medicine, Brighton and Sussex Medical School (BSMS), Brighton, UK.,Department of Gastroenterology and Hepatology, Brighton and Sussex University Hospital (BSUH) NHS Trust, Brighton, UK
| | - William Gelson
- Cambridge Liver Unit, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - Matthew Priest
- Department of Gastroenterology and Hepatology, Greater Glasgow and Clyde Hospitals NHS Trust, Scotland
| | - George Abouda
- Department of Gastroenterology and Hepatology, Hull and East Yorkshire Hospitals NHS Trust, Hull, UK
| | - Stephen Barclay
- Department of Gastroenterology and Hepatology, Greater Glasgow and Clyde Hospitals NHS Trust, Scotland.,School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, Scotland
| | - Andrew Fraser
- Department of Gastroenterology and Hepatology, Grampian Hospitals NHS Trust, Scotland
| | - Brendan Healy
- Department of Gastroenterology and Hepatology, GIG CYMRU NHS Wales, Wales
| | - Will Irving
- National Institute for Health Research (NIHR) Nottingham BioMedical Research Unit, Nottingham University Hospitals NHS Trust and the University of Nottingham, UK
| | - Sumita Verma
- Department of Clinical and Experimental Medicine, Brighton and Sussex Medical School (BSMS), Brighton, UK.,Department of Gastroenterology and Hepatology, Brighton and Sussex University Hospital (BSUH) NHS Trust, Brighton, UK
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12
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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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13
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Nagaoki Y, Imamura M, Nishida Y, Daijo K, Teraoka Y, Honda F, Nakamura Y, Morio K, Fujino H, Nakahara T, Kawaoka T, Tsuge M, Hiramatsu A, Kawakami Y, Miki D, Hiyama Y, Ochi H, Chayama K, Aikata H. The impact of interferon-free direct-acting antivirals on clinical outcome after curative treatment for hepatitis C virus-associated hepatocellular carcinoma: Comparison with interferon-based therapy. J Med Virol 2019; 91:650-658. [PMID: 30381831 DOI: 10.1002/jmv.25352] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 10/23/2018] [Indexed: 01/04/2025]
Abstract
BACKGROUND AND AIM To examine the effect on recurrence and survival of treatment by interferon (IFN)-free direct-acting antivirals (DAA) for patients with hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) who underwent primary curative treatment. METHODS This was a retrospective cohort study of 250 patients with HCV who had received curative treatment for primary HCC. As anti-HCV treatment after HCC treatment, 38 patients received IFN-free DAA therapy (DAA patients) and 94 received IFN-based therapy (IFN patients). The recurrence of HCC and overall survival of the patient groups were compared in a case-control study. RESULTS The cumulative HCC recurrence rates at 1, 3, and 5 years were 5%, 39%, and 39% for DAA patients and 0%, 46%, and 62% for IFN patients, respectively (P = 0.370). Multivariate analysis of the HCC recurrence identified treatment responses (sustained virological response [SVR]: hazard ratio [HR] 2.237; P = 0.003) as an independent predictive factor. The cumulative overall survival rates at 3 and 5 years were 96%, 96% for DAA patients and 93%, 73% for IFN patients, respectively ( P = 0.163). Multivariate analysis identified treatment responses (SVR: HR 8.742; P < 0.001) as independent predictors of overall survival. Propensity score matching analysis showed no significant difference in HCC development rates and overall survival rates in the two groups. CONCLUSIONS We found that SVR obtained after curative treatment for primary HCC suppressed recurrence and improved overall survival. And, IFN-free DAA therapy after curative treatment for primary HCC could predict improving overall survival and suppressed HCC recurrence.
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Affiliation(s)
- Yuko Nagaoki
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Yuno Nishida
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kana Daijo
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Fumi Honda
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuki Nakamura
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Yuichi Hiyama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University
| | - Hidenori Ochi
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
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14
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Watanabe T, Tokumoto Y, Joko K, Michitaka K, Horiike N, Tanaka Y, Tada F, Kisaka Y, Nakanishi S, Yamauchi K, Yukimoto A, Hirooka M, Abe M, Hiasa Y. Predictors of hepatocellular carcinoma occurrence after direct-acting antiviral therapy in patients with hepatitis C virus infection. Hepatol Res 2019; 49:136-146. [PMID: 30335208 DOI: 10.1111/hepr.13278] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 10/13/2018] [Accepted: 10/13/2018] [Indexed: 12/17/2022]
Abstract
AIM The predictors for the development of hepatocellular carcinoma (HCC) after direct-acting antiviral (DAA) treatment were investigated. METHODS A total of 1174 patients with chronic hepatitis C virus infection were treated with DAA therapy (sofosbuvir and ledipasvir [n = 615], sofosbuvir and ribavirin [n = 380], and daclatasvir and asunaprevir [n = 179]) and achieved sustained virologic response (SVR). The HCC development rate and the factors that might contribute to the development of HCC after the end of DAA treatment were analyzed. RESULTS During the median observation period of 537 days, HCC developed in 33 cases. The incidence of HCC was 1.9%, 3.2%, and 4.1% at 1, 1.5, and 2 years after the end of DAA therapy, respectively. Multivariate analysis with pre- and post-treatment factors identified the Fibrosis-4 (FIB-4) index (hazard ratio [HR] = 1.09; 95% confidence interval [CI], 1.021-1.178; P = 0.011) and post-treatment α-fetoprotein (AFP) (HR = 1.11; 95% CI, 1.054-1.172; P < 0.001) as independent factors that contributed to the development of HCC after DAA therapy. Using these identified parameters, a new scoring system (0 to 2 points) was established. Patients in the high-score group (2 points) could be identified as having a significantly higher risk of HCC development, and the respective 1- and 2-year cumulative incidence rates of HCC were 6.1% and 14.4%. CONCLUSIONS A high FIB-4 index and a high post-treatment AFP at the end of DAA treatment were the independent predictors for developing HCC after DAA treatment. For patients with these risk factors, extra attention to the possibility of HCC development is needed.
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Affiliation(s)
- Takao Watanabe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Yoshio Tokumoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Kouji Joko
- Center for Liver-Biliary-Pancreatic Diseases, Matsuyama Red Cross Hospital, Matsuyama, Japan
| | - Kojiro Michitaka
- Department of Gastroenterology, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Norio Horiike
- Department of Gastroenterology, Saiseikai Imabari Hospital, Imabari, Japan
| | - Yoshinori Tanaka
- Department of Gastroenterology, Matsuyama Shimin Hospital, Matsuyama, Japan
| | - Fujimasa Tada
- Department of Internal Medicine, Saiseikai Matsuyama Hospital, Matsuyama, Japan
| | - Yoshiyasu Kisaka
- Department of Gastroenterology, Uwajima City Hospital, Uwajima, Japan
| | - Seiji Nakanishi
- Department of Gastroenterology, Ehime Prefectural Imabari Hospital, Imabari, Japan
| | - Kazuhiko Yamauchi
- Department of Gastroenterology, National Hospital Organization Ehime Medical Center, Toon, Japan
| | - Atsushi Yukimoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
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15
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Ishida K, Shimakami T, Kaneko S. The use of direct-acting antivirals in the treatment of elderly patients with hepatitis C Virus infection. Nihon Ronen Igakkai Zasshi 2019; 54:375-380. [PMID: 28855462 DOI: 10.3143/geriatrics.54.375] [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: 11/11/2022]
Abstract
AIM Antiviral treatment for hepatitis C infection in elderly patients has been dramatically improved by direct-acting antivirals (DAAs). DAAs are easy to use as they are administered orally and the treatment periods are shorter. Furthermore, they are associated with fewer adverse effects. In this study, we sought to analyze the efficacy and safety of DAAs in HCV-infected elderly patients. METHOD We analyzed 223 HCV-infected patients who were treated with DAAs in Kanazawa University Hospital, Japan. As of August 31, 2016, all of the patients were observed to have achieved a sustained viral response by the 12th week of treatment (SVR12). We categorized patients into two groups. Group one included 79 patients (average age 75.5 years; range 70-85 years). Group two included 144 patients (average age, 58.1 years; range 27-69 years). Group one included more female patients. RESULTS The platelet count of Group one was significantly lower than that of Group two. The FIB-4 index of Group one was significantly higher than that of Group two. Group one included a greater number of patients with a history of hepatocellular carcinoma (HCC) before the administration of DAAs. The SVR12 rate and rate of drop-out due to adverse effects did not differ between the two groups to a statistically significant extent. The rate of HCC occurrence after SVR in Group one was higher than that in Group two. CONCLUSION Our study shows that DAAs can be used for older patients and that the antiviral efficacy and safety are similar to the efficacy and safety in younger patients.
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Affiliation(s)
- Kosuke Ishida
- Department of Gastroenterology, Kanazawa University Hospital
| | | | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Hospital
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16
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Complex Association of Virus- and Host-Related Factors with Hepatocellular Carcinoma Rate following Hepatitis C Virus Clearance. J Clin Microbiol 2019; 57:JCM.01463-18. [PMID: 30381417 DOI: 10.1128/jcm.01463-18] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 10/23/2018] [Indexed: 02/07/2023] Open
Abstract
Little is known about the effects of virus- and host-related factors on hepatocarcinogenesis in patients who show viral clearance after HCV RNA eradication by direct-acting antivirals (DAAs). The subjects of this retrospective study were 1,922 patients with HCV genotype 1 (HCV-1)- or HCV-2-related chronic liver disease who showed a sustained virological response (SVR; defined as negative results for HCV RNA at 12 weeks after the cessation of all-oral DAAs). All patients were confirmed to be hepatocellular carcinoma (HCC) free before and during DAAs. HCC was diagnosed in 43 patients during the follow-up, with an incidence rate per 1,000 person years of 9.44. The cumulative HCC rates were 1.2, 2.0, and 3.1% at the end of 1, 2, and 3 years, respectively. The annual rate of HCC during the first 3 years was 1.0%. The incidence rate was significantly higher in patients infected with the HCV-1b core amino acid (aa) 70 mutant than in those infected with HCV-2a/2b, and the rate in patients infected with the HCV-1b core aa 70 wild type tended to be higher than that in patients infected with HCV-2a/2b. The rate in patients infected with the HCV-1b NS5A aa 93 mutant was significantly higher than that in patients infected with HCV-2a/2b. However, the rate was not different between patients infected with the IL28B rs8099917 TT genotype and patients infected with the non-TT genotype. Multivariate analysis identified a Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+M2BP) cutoff index (COI) of ≥2.5 and infection with the HCV-1b core aa 70 mutant subgroup to be pretreatment predictors of posttreatment HCC. The same analysis identified an alpha-fetoprotein concentration of ≥5 μg/liter and an WFA+M2BP COI of ≥1.0 to be predictors of HCC at 24 weeks after the end of antiviral therapy. We conclude that both virus- and host-related factors seem to influence the development of HCC after HCV RNA eradication.
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17
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Miyasaka A, Yoshida Y, Yoshida T, Murakami A, Abe K, Ohuchi K, Kawakami T, Watanabe D, Hoshino T, Sawara K, Takikawa Y. The Real-world Efficacy and Safety of Ombitasvir/Paritaprevir/Ritonavir for Hepatitis C Genotype 1. Intern Med 2018; 57:2807-2812. [PMID: 29780135 PMCID: PMC6207834 DOI: 10.2169/internalmedicine.0810-18] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Objective There are few reports on the outcomes of 12-week paritaprevir, ombitasvir, and ritonavir (PTV/OBV/r) treatment in real-world clinical settings. We aimed to evaluate the efficacy and safety of 12-week treatment with ritonavir-boosted paritaprevir and ombitasvir in patients with hepatitis C virus (HCV) genotype 1 infection in a real-world setting. Methods Fifty-eight patients with chronic hepatitis or compensated hepatic cirrhosis and genotype-1 HCV infection were treated with PTV/OBV/r and followed for 24 weeks after the completion of treatment in 10 centers in northern Tohoku. The efficacy and safety of this 12-week treatment regimen was analyzed. Results Among the 58 treated patients, 18 (31%) had compensated liver cirrhosis, while 11 (19%) patients had experienced treatment failure with another treatment regimen. NS5A resistance-associated variants (RAVs) were detected at baseline in 3 patients (5.2%), including Y93H in two patients and L31M in two patients. One patient had NS5A RAVs at both positions 93 and 31. The overall sustained virological response (SVR) 24 rate was 96.6%. Three patients with NS5A RAVs also achieved an SVR24. The SVR24 rate was not significantly affected by age, sex, prior treatment, prior history of HCC, or liver stiffness. The mean alanine aminotransferase (ALT) levels decreased significantly during this treatment. Adverse events occurred in 15 patients (26%), 26% of which were grade 1 or 2. No severe adverse events occurred. Conclusion In this real-world study, 12-week PTV/OBV/r treatment was effective and safe for treating patients with HCV-1 infection who had chronic hepatitis or compensated hepatic cirrhosis.
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Affiliation(s)
- Akio Miyasaka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Japan
| | - Yuichi Yoshida
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Japan
| | | | - Akihiko Murakami
- Department of Gastroenterology, Iwate Prefectural Miyako Hospital, Japan
| | | | | | | | - Daisuke Watanabe
- Department of Gastroenterology, Noshiro Yamamoto Medical Association Hospital, Japan
| | - Takao Hoshino
- Department of Gastroenterology, Akita Kosei Medical Center, Japan
| | - Kei Sawara
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Japan
- Department of Gastroenterology, Iwate Prefectural Kamaishi Hospital, Japan
| | - Yasuhiro Takikawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Japan
- Department of Hepatology, San-ai Hospital, Japan
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18
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Menon RM, Polepally AR, Khatri A, Awni WM, Dutta S. Clinical Pharmacokinetics of Paritaprevir. Clin Pharmacokinet 2018; 56:1125-1137. [PMID: 28236252 DOI: 10.1007/s40262-017-0520-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Paritaprevir is a potent hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor that is used in combination with other direct-acting antivirals (DAAs) for the treatment of chronic HCV infection. Paritaprevir is primarily metabolized by cytochrome P450 (CYP) 3A4 and is administered with a low dose of ritonavir to achieve drug concentrations suitable for once-daily dosing. Coadministration of paritaprevir with ritonavir increases the half-life of single-dose paritaprevir from approximately 3 h to 5-8 h, doubles the time to maximum plasma concentration (T max) from 2.3 to 4.7 h, and increases exposures 30-fold for maximum observed plasma concentration (C max), 50-fold for area under the plasma concentration-time curve (AUC), and >300-fold for trough concentration (C 24). Paritaprevir displays highly variable, nonlinear pharmacokinetics, with C max and AUC increasing in a greater than dose proportional manner when administered with or without ritonavir. In the presence of ritonavir, paritaprevir is excreted mostly unchanged in feces via biliary excretion. Paritaprevir exposures are higher in Japanese subjects compared with Caucasian subjects; however, no dose adjustment is needed for Japanese patients as the higher exposures are safe and well tolerated. The pharmacokinetic characteristics of paritaprevir are similar between healthy subjects and HCV-infected patients, and are not appreciably altered by mild or moderate hepatic impairment or mild, moderate, or severe renal impairment, including those on dialysis. Paritaprevir exposures are increased in patients with severe hepatic impairment. Although the presence of a low dose of ritonavir in paritaprevir-containing regimens increases the likelihood of drug-drug interactions, results from several drug interaction studies demonstrated that paritaprevir-containing regimens can be coadministered with many comedications that are commonly prescribed in HCV-infected patients.
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Affiliation(s)
- Rajeev M Menon
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., Dept. R4PK, Bldg. AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
| | - Akshanth R Polepally
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., Dept. R4PK, Bldg. AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA
| | - Amit Khatri
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., Dept. R4PK, Bldg. AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA
| | - Walid M Awni
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., Dept. R4PK, Bldg. AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA
| | - Sandeep Dutta
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., Dept. R4PK, Bldg. AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA
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19
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Abstract
Ombitasvir is a potent, nonstructural protein 5A inhibitor of the hepatitis C virus (HCV) that is used in combination with other direct-acting antivirals for the treatment of chronic HCV infection. Ombitasvir is predominantly metabolized by amide hydrolysis followed by oxidative metabolism and is a substrate of P-glycoprotein. Ombitasvir displays linear pharmacokinetics with minimal accumulation and is eliminated via metabolism and biliary excretion. A negligible amount of unchanged drug is excreted in urine. Exposures are comparable across Chinese, Japanese, and non-Asian subjects. The pharmacokinetic characteristics of ombitasvir are similar in healthy subjects and HCV-infected patients, and are not appreciably altered by hepatic or renal impairment. Results from several drug interaction studies demonstrated that ombitasvir has a low potential for drug interactions.
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Affiliation(s)
- Prajakta S Badri
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., Dept. R4PK, Bldg. AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA
| | - Diana L Shuster
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., Dept. R4PK, Bldg. AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA
| | - Sandeep Dutta
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., Dept. R4PK, Bldg. AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA
| | - Rajeev M Menon
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., Dept. R4PK, Bldg. AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
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20
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Teraoka Y, Uchida T, Imamura M, Hiraga N, Osawa M, Kan H, Saito Y, Tsuge M, Abe-Chayama H, Hayes CN, Makokha GN, Aikata H, Miki D, Ochi H, Ishida Y, Tateno C, Chayama K. Limitations of daclatasvir/asunaprevir plus beclabuvir treatment in cases of NS5A inhibitor treatment failure. J Gen Virol 2018; 99:1058-1065. [PMID: 29916799 DOI: 10.1099/jgv.0.001091] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Combined daclatasvir (DCV)/asunaprevir (ASV) plus beclabuvir (BCV) treatment shows a high virological response for genotype 1b chronic hepatitis C patients. However, its efficacy for patients for whom previous direct-acting antiviral (DAA) therapy failed is not known. We analysed the efficacy of DCV/ASV/BCV treatment for HCV-infected mice and chronic hepatitis patients. Human hepatocyte chimaeric mice were injected with serum samples obtained from either a DAA-naïve patient or a DCV/ASV treatment failure and were then treated with DCV/ASV alone or in combination with BCV for 4 weeks. DCV/ASV treatment successfully eliminated the virus in DAA-naïve-patient HCV-infected mice. DCV/ASV treatment failure HCV-infected mice developed viral breakthrough during DCV/ASV treatment, with the emergence of NS5A-L31V/Y93H HCV resistance-associated variants (RAVs) being observed by direct sequencing. DCV/ASV/BCV treatment inhibited viral breakthrough in NS5A-L31V/Y93H-mutated HCV-infected mice, but HCV relapsed with the emergence of NS5B-P495S variants after the cessation of the treatment. The efficacy of the triple therapy was also analysed in HCV-infected patients; one DAA-naïve patient and four prior DAA treatment failures were treated with 12 weeks of DCV/ASV/BCV therapy. Sustained virological response was achieved in a DAA-naïve patient and one of the DCV/ASV treatment failures through DCV/ASV/BCV therapy; however, HCV relapse occurred in the other patients with prior DCV/ASV and/or sofosbuvir/ledipasvir treatment failures. DCV/ASV/BCV therapy seems to have limited efficacy for patients with NS5A RAVs for whom prior DAA treatment has failed.
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Affiliation(s)
- Yuji Teraoka
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Takuro Uchida
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Nobuhiko Hiraga
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Mitsutaka Osawa
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hiromi Kan
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Yuhei Saito
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,3Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Hiromi Abe-Chayama
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,4Center for Medical Specialist Graduate Education and Research, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - C Nelson Hayes
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Grace Naswa Makokha
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- 2Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,5Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Hidenori Ochi
- 2Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,5Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Yuji Ishida
- 2Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,6PhoenixBio Co., Ltd, Higashihiroshima, Japan
| | - Chise Tateno
- 2Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,6PhoenixBio Co., Ltd, Higashihiroshima, Japan
| | - Kazuaki Chayama
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,5Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
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21
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Sho T, Suda G, Nagasaka A, Yamamoto Y, Furuya K, Kumagai K, Uebayashi M, Terashita K, Kobayashi T, Tsunematsu I, Onodera M, Meguro T, Kimura M, Ito J, Umemura M, Izumi T, Kawagishi N, Ohara M, Ono Y, Nakai M, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N. Safety and efficacy of sofosbuvir and ribavirin for genotype 2 hepatitis C Japanese patients with renal dysfunction. Hepatol Res 2018; 48:529-538. [PMID: 29316051 DOI: 10.1111/hepr.13056] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 12/15/2017] [Accepted: 01/04/2018] [Indexed: 12/12/2022]
Abstract
AIM The safety and efficacy of sofosbuvir (SOF) and ribavirin (RBV) have not been well clarified in patients with renal dysfunction because clinical trials have not included such patients. We evaluated the safety and efficacy of SOF and RBV for genotype 2 hepatitis C virus (HCV)-infected patients with renal dysfunction. METHODS The study included genotype 2 HCV-infected patients who received SOF and RBV between July 2014 and May 2017. The sustained virologic response (SVR) after the treatment and safety during the therapy were evaluated according to renal function. RESULTS A total of 231 patients were included in this study. The median age was 62 years old, and 45.9% (106/231) were men. Of the 231 patients, 191 (82.8%) and 40 (17.2%) were classified as having chronic kidney disease (CKD) stages G1/2 and G3, respectively. The overall SVR rate was 97% (224/231). The SVR rates in patients with CKD stages G1, 2, G3a, and G3b were 98.1%, 98.6%, 87.9%, and 100%, respectively, and this therapy was tolerated. Multivariate analysis indicated that renal dysfunction was significantly associated with a non-SVR (odds ratio, 6.963; 95% confidence interval, 1.494-32.41; P = 0.013). The patients with renal dysfunction were older, had advanced liver fibrosis, lower baseline platelet and hemoglobin levels, and a higher rate of RBV dose reduction. CONCLUSIONS Sofosbuvir and RBV therapy is highly effective and safe for genotype 2 HCV-infected Japanese patients. However, attention should be paid to baseline renal function when SOF- and RBV-containing regimens are used for patients with renal dysfunction.
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Affiliation(s)
- Takuya Sho
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | | | | | | | | | | | - Katsumi Terashita
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.,Kushiro Rosai Hospital, Hokkaido, Japan
| | - Tomoe Kobayashi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.,Tomakomai City Hospital, Hokkaido, Japan
| | | | | | | | - Megumi Kimura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Jun Ito
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Machiko Umemura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Takaaki Izumi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Naoki Kawagishi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Masatsugu Ohara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Yuji Ono
- Sapporo City General Hospital, Hokkaido, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
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22
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Arai T, Atsukawa M, Tsubota A, Ikegami T, Shimada N, Kato K, Abe H, Okubo T, Itokawa N, Kondo C, Mikami S, Asano T, Chuganji Y, Matsuzaki Y, Toyoda H, Kumada T, Iio E, Tanaka Y, Iwakiri K. Efficacy and safety of ombitasvir/paritaprevir/ritonavir combination therapy for genotype 1b chronic hepatitis C patients complicated with chronic kidney disease. Hepatol Res 2018; 48:549-555. [PMID: 29316062 DOI: 10.1111/hepr.13058] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 01/05/2018] [Accepted: 01/05/2018] [Indexed: 02/08/2023]
Abstract
AIM The aim of this study was to clarify the effects and safety of ombitasvir/paritaprevir/ritonavir (OBT/PTV/r) therapy in genotype 1b chronic hepatitis C patients with non-dialysis chronic kidney disease (CKD). METHODS This retrospective, multicenter study of 12-week OBT/PTV/r therapy included genotype 1b patients with non-dialysis CKD. Chronic kidney disease was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 . Virologic responses and treatment-emergent adverse events (TEAEs) in patients with CKD were compared with those in patients without CKD. RESULTS Two hundred and thirty-five patients with a median age of 67 years (range, 27-89 years) were enrolled, consisting of 181 patients without CKD and 54 patients with CKD. Overall, the rates of rapid virologic response (RVR), end of treatment response (ETR), and sustained virologic response (SVR) were 78.7%, 98.7%, and 98.7%, respectively. Among the 181 non-CKD patients, the rates were 77.3% (140/181), 98.9% (179/181), and 98.9% (179/181), respectively. Among the 54 CKD patients, the rates were 83.3% (45/54), 98.1% (53/54), and 98.1% (53/54), respectively. There were no significant differences in the virologic response rates between the two groups (P = 0.449 for RVR, 0.545 for ETR, and 0.545 for SVR). In the CKD group, the eGFR level did not significantly change throughout the treatment period. There was no significant difference in the incidence of TEAEs or treatment discontinuation due to TEAEs between the two groups. CONCLUSION The present study showed that the effects and safety of OBV/PTV/r therapy in genotype 1b chronic hepatitis C patients with non-dialysis CKD were not inferior to those in patients without CKD.
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Affiliation(s)
- Taeang Arai
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
| | - Masanori Atsukawa
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Akihito Tsubota
- Core Research Facilities for Basic Science, The Jikei University School of Medicine, Tokyo, Japan
| | - Tadashi Ikegami
- Department of Internal Medicine, Division of Hepatology and Gastroenterology, Tokyo Medical University, Ibaraki Medical Center, Ibaraki, Japan
| | - Noritomo Shimada
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Otakanomori Hospital, Kashiwa, Japan
| | - Keizo Kato
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Japan
| | - Hiroshi Abe
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Japan
| | - Tomomi Okubo
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
| | - Norio Itokawa
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
| | - Chisa Kondo
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Shigeru Mikami
- Department of Internal Medicine, Division of Gastroenterology, Kikkoman General Hospital, Noda, Japan
| | - Toru Asano
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan
| | - Yoshimichi Chuganji
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan
| | - Yasushi Matsuzaki
- Department of Internal Medicine, Division of Hepatology and Gastroenterology, Tokyo Medical University, Ibaraki Medical Center, Ibaraki, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Takashi Kumada
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Etsuko Iio
- Department of Virology and Liver Unit, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan
| | - Katsuhiko Iwakiri
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
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23
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Crouchet E, Wrensch F, Schuster C, Zeisel MB, Baumert TF. Host-targeting therapies for hepatitis C virus infection: current developments and future applications. Therap Adv Gastroenterol 2018; 11:1756284818759483. [PMID: 29619090 PMCID: PMC5871046 DOI: 10.1177/1756284818759483] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 01/15/2018] [Indexed: 02/04/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a leading cause of chronic liver diseases and hepatocellular carcinoma (HCC) worldwide. In the past few years, anti-HCV therapies have undergone a revolution with the approval of multiple direct-acting antivirals (DAAs), which enable interferon-free treatments with considerable improvement of sustained virologic response in patients. Today, DAAs have become the standard of care for HCV therapy. However, several limitations remain, which include access to therapy, treatment failure in a subset of patients and persistent risk of HCC development following cure in patients with advanced fibrosis. By targeting conserved host proteins involved in the HCV life cycle, host-targeting agents (HTAs) offer opportunities for pan-genotypic antiviral approaches with a high barrier to drug resistance. Moreover, when applied in combination with DAAs, HTAs could improve the management of difficult-to-treat patients by acting through a complementary mechanism of action. In this review, we summarize the different HTAs evaluated in preclinical and clinical development and discuss their potential role for anti-HCV therapies.
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Affiliation(s)
- Emilie Crouchet
- Institut National de la Santé et de la Recherche Médicale (Inserm), U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France Université de Strasbourg, Strasbourg, France
| | - Florian Wrensch
- Institut National de la Santé et de la Recherche Médicale (Inserm), U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France Université de Strasbourg, Strasbourg, France
| | - Catherine Schuster
- Institut National de la Santé et de la Recherche Médicale (Inserm), U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France Université de Strasbourg, Strasbourg, France
| | - Mirjam B. Zeisel
- Institut National de la Santé et de la Recherche Médicale (Inserm), U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France Université de Strasbourg, Strasbourg, France Inserm U1052, CNRS UMR 5286, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL), Lyon, France
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24
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Ogata F, Akuta N, Kobayashi M, Fujiyama S, Kawamura Y, Sezaki H, Hosaka T, Kobayashi M, Saitoh S, Suzuki Y, Suzuki F, Arase Y, Ikeda K, Kumada H. Amino acid substitutions in the hepatitis C virus core region predict hepatocarcinogenesis following eradication of HCV RNA by all-oral direct-acting antiviral regimens. J Med Virol 2018; 90:1087-1093. [PMID: 29427443 DOI: 10.1002/jmv.25047] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 01/17/2018] [Indexed: 01/01/2023]
Abstract
Impact of substitution of aa70 in the core region (Core aa70) in HCV genotype 1b (HCV-1b) on hepatocarcinogenesis following eradication of HCV RNA by direct-acting antiviral therapy is not clear. In a retrospective study, 533 patients with HCV-related chronic liver disease, with sustained virological response defined as negative HCV RNA at 12 weeks after cessation of direct-acting antiviral therapy, were examined to evaluate the relationship between Core aa70 substitution and hepatocarcinogenesis. Twelve patients developed hepatocellular carcinoma during the follow-up period. The cumulative hepatocarcinogenesis rates were 1.7% and 2.4% at the end of 1 and 2 years, respectively. Overall, multivariate analysis identified HCV subgroup (HCV-1b with Gln70(His70); P = 0.003) and age (>65 years; P = 0.049), as pretreatment predictors of hepatocarcinogenesis. In HCV-1b patients, multivariate analysis identified post-treatment Wisteria floribunda agglutinin positive Mac-2 binding protein (>1.8 COI; P = 0.042) and HCV subgroup (HCV-1b with Gln70(His70); P = 0.071), as predictors of hepatocarcinogenesis, including post-treatment parameter. In conclusion, Core aa70 substitution in HCV-1b at the start of direct-acting antiviral therapy is an important predictor of hepatocarcinogenesis following eradication of HCV RNA. This study emphasizes the importance of detection of Core aa70 substitution before initiating antiviral therapy.
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Affiliation(s)
- Fumihiro Ogata
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Norio Akuta
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | | | | | | | - Hitomi Sezaki
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Tetsuya Hosaka
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | | | - Satoshi Saitoh
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | | | | | - Yasuji Arase
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Kenji Ikeda
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
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25
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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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26
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Kumada H, Mochida S, Nakamuta M, Suzuki F, Yagi T, Takasaki R, Okai M, Kamiya N, Okada Y, Hirota S, Orihashi M, Ochi M, Chayama K. Efficacy and safety of telaprevir with natural human interferon-β and ribavirin in Japanese chronic hepatitis C patients with depression. Hepatol Res 2018; 48:184-192. [PMID: 28497489 DOI: 10.1111/hepr.12914] [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: 11/06/2016] [Revised: 03/16/2017] [Accepted: 05/09/2017] [Indexed: 12/16/2022]
Abstract
AIM To assess the efficacy and safety of telaprevir (TVR) when used in combination with natural human interferon-β (IFN-β) and ribavirin (RBV) for genotype 1 patients with depression compared to IFN-β/RBV therapy in Japan. We also examined the efficacy of the TVR/IFN-β/RBV therapy in treatment failure genotype 2 patients with depression. METHODS For the genotype 1 patients, 30 patients received TVR (750 mg every 8 h) for 12 weeks combined with IFN-β and RBV for 24 weeks (Group A), and 30 received IFN-β and RBV for 48 weeks (Group B). For the genotype 2 patients, 14 patients were dosed only with the TVR-based regimen. RESULTS The sustained virologic response (SVR) rates for Group A and Group B were 63.3% and 20.0%, respectively (P = 0.001, likelihood ratio test). The SVR rate for genotype 2 patients previously treated with pegylated IFN and/or RBV was 71.4%. No patient dropped out due to exacerbation of depression. The trend of platelet counts after the drugs were given was similar in the TVR/IFN-β/RBV therapy group and the IFN-β/RBV therapy group. Common resistance-associated variants of TVR were identified in 4 of the 13 patients who did not achieve SVR. CONCLUSION This study showed that an addition of TVR to IFN-β/RBV therapy raised SVR in previously treated and untreated genotype 1 patients and previously treated genotype 2 patients with chronic hepatitis C and depression.
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Affiliation(s)
| | - Satoshi Mochida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Makoto Nakamuta
- Department of Gastroenterology, Kyushu Medical Center, Clinical Research Center, National Hospital Organization, Fukuoka, Japan
| | | | - Takashi Yagi
- Pharmaceutical Clinical Research Department, Toray Industries, Inc., Tokyo, Japan
| | - Ryuji Takasaki
- Pharmaceutical Clinical Research Department, Toray Industries, Inc., Tokyo, Japan
| | - Masao Okai
- Pharmaceutical Clinical Research Department, Toray Industries, Inc., Tokyo, Japan
| | - Naohiro Kamiya
- SOHYAKU. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Yasushi Okada
- IKUYAKU. Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Saya Hirota
- SOHYAKU. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Madori Orihashi
- SOHYAKU. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Miyoko Ochi
- SOHYAKU. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
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Ferreira VL, Tonin FS, Assis Jarek NA, Ramires Y, Pontarolo R. Efficacy of Interferon-Free Therapies for Chronic Hepatitis C: A Systematic Review of All Randomized Clinical Trials. Clin Drug Investig 2018; 37:635-646. [PMID: 28409482 DOI: 10.1007/s40261-017-0521-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND AND OBJECTIVES Second-generation direct-acting antivirals (DAAs) have recently arisen as more effective and safer treatments for chronic hepatitis C. These drugs can be combined into treatments without interferon (IFN), and are therefore called IFN-free therapies. OBJECTIVE The objective of this study systematic review was to evaluate the efficacy of IFN-free therapies for the treatment of chronic hepatitis C, and thus increase the clinical evidence for these therapies. METHODS A systematic review was conducted in accordance with Cochrane Collaboration recommendations. A search was performed in six different electronic databases using 'clinical trials', 'hepatitis C' and 'interferon-free' as the main descriptors, and studies that conformed to the inclusion criteria had their data extracted, including study information, baseline characteristics, and efficacy outcomes (sustained virologic response, rapid virologic response, and virologic failure). RESULTS Sixty-four randomized clinical trials including 15 different therapies were included in a total of 15,731 patients infected with the hepatitis C virus, mostly with genotype 1, and mainly treated for 12 or 24 weeks. The sustained virologic response rate after 12 weeks of treatment was approximately 89%, while the virologic failure rate was below 5%. CONCLUSIONS Second-generation DAAs presented several advantages: virologic response values higher than the average achieved by previous IFN-based therapies, reduced treatment duration, and the possibility of different combinations of therapies to meet patient needs. Thus, IFN-free therapies appear to be valuable alternatives for the treatment of chronic hepatitis C.
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Affiliation(s)
- Vinicius L Ferreira
- Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Av. Pref. Lothario Meissner, 632, Jardim Botânico, Curitiba, PR, 80210170, Brazil.
| | - Fernanda S Tonin
- Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Av. Pref. Lothario Meissner, 632, Jardim Botânico, Curitiba, PR, 80210170, Brazil
| | - Nayara A Assis Jarek
- Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Av. Pref. Lothario Meissner, 632, Jardim Botânico, Curitiba, PR, 80210170, Brazil
| | - Yohanna Ramires
- Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Av. Pref. Lothario Meissner, 632, Jardim Botânico, Curitiba, PR, 80210170, Brazil
| | - Roberto Pontarolo
- Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Av. Pref. Lothario Meissner, 632, Jardim Botânico, Curitiba, PR, 80210170, Brazil
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Ohashi K, Ishikawa T, Suzuki M, Abe H, Koyama F, Nakano T, Ueki A, Noguchi H, Hasegawa E, Hirosawa S, Kobayashi M, Hirosawa H, Sato K, Fukazawa T, Maruyama Y, Yoshida T. Health-related quality of life on the clinical course of patients with chronic hepatitis C receiving daclatasvir/asunaprevir therapy: A prospective observational study comparing younger (<70) and elderly (≥70) patients. Exp Ther Med 2018; 15:970-976. [PMID: 29399105 PMCID: PMC5772754 DOI: 10.3892/etm.2017.5488] [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] [Received: 06/04/2017] [Accepted: 10/18/2017] [Indexed: 12/20/2022] Open
Abstract
Interferon-free direct acting antiviral agent regimens for chronic hepatitis C (CHC) have been developed. These regimens have shown a high rate of sustained virologic response (SVR), and a reduction in side effects during treatment is also anticipated. However, the impact of the regimens on health-related quality of life (HRQOL) and side effects during treatment is not fully understood. The purpose of the present study was to evaluate HRQOL in the clinical course of patients with CHC receiving daclatasvir/asunaprevir (DCV/ASV) therapy using the Short Form-36 (SF-36) method. Twenty-eight patients with CHC receiving DCV/ASV therapy were analyzed in the present study, and HRQOL was measured by SF-36. Patients were asked to fill out the SF-36 prior to therapy (baseline), following 12 weeks of therapy, at the end of treatment and at SVR week 24 (SVR24) to evaluate HRQOL. Laboratory data were also investigated during the same period, and associations between these results and SF-36 were investigated. Aspartate aminotransferase, alanine aminotransferase, serum albumin, α-fetoprotein, platelet counts and Fibrosis (Fib)-4 index were all significantly improved at each time point when compared with baseline. With regard to alterations in HRQOL during therapy, the ≥70-year-old group displayed a significantly greater improvement in physical functioning during the period between baseline and 12 weeks when compared with the <70-year-old group. In the analysis of the SF-36 differences within each group, general health improved significantly in the ≥70-year-old group, as well as albumin levels. In addition, Fib-4-index significantly improved at all time points (12 and 24 weeks, and SVR24) when compared with baseline in the ≥70-year-old group. Therefore, DCV/ASV therapy may improve HRQOL and hepatic functional reserve, particularly in elderly patients.
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Affiliation(s)
- Kazuki Ohashi
- Department of Nursing, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Toru Ishikawa
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
- Department of Gastroenterology and Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Mitsuyuki Suzuki
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
- Department of Pharmacology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Hiroko Abe
- Department of Nursing, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Fujiko Koyama
- Department of Nursing, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Tomomi Nakano
- Department of Nursing, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Aya Ueki
- Department of Nursing, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Hirohito Noguchi
- Department of Nursing, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Erina Hasegawa
- Department of Nursing, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Shiori Hirosawa
- Department of Nursing, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Miki Kobayashi
- Department of Nursing, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Hiroshi Hirosawa
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
- Department of Clinical Engineering, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Kaede Sato
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
- Department of Nutrition, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Takako Fukazawa
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
- Department of Nutrition, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Yuka Maruyama
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
- Department of Secretary, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Toshiaki Yoshida
- Department of Gastroenterology and Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
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Atsukawa M, Tsubota A, Koushima Y, Ikegami T, Watanabe K, Shimada N, Sato S, Kato K, Abe H, Okubo T, Arai T, Itokawa N, Kondo C, Mikami S, Asano T, Chuganji Y, Matsuzaki Y, Iwakiri K. Efficacy and safety of ombitasvir/paritaprevir/ritonavir in dialysis patients with genotype 1b chronic hepatitis C. Hepatol Res 2017; 47:1429-1437. [PMID: 28457003 DOI: 10.1111/hepr.12910] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 04/26/2017] [Accepted: 04/27/2017] [Indexed: 02/08/2023]
Abstract
AIM From a pharmacokinetic viewpoint, the use of ombitasvir/paritaprevir/ritonavir, one of the standards of care for genotype 1b chronic hepatitis C in Japan, could be possible in patients with impaired renal function. The aim of this study was to assess the efficacy and safety of this combination that have not yet been addressed in patients undergoing dialysis. METHODS A retrospective, multicenter study evaluated the outcome of 12-week ombitasvir (non-structural protein [NS]5A inhibitor)/paritaprevir (NS3/4A protease inhibitor)/ritonavir combination therapy for dialysis patients. The primary end-point was sustained virologic response 12 weeks after therapy (SVR12). RESULTS The subjects were 31 patients with a median age of 64 years (range, 49-85 years), including 10 cirrhotic patients. All of the 31 patients had an estimated glomerular filtration rate level <15 mL/min/1.73 m2 , defined as end-stage renal disease (ESRD). Pre-existing resistance-associated substitutions at position L31 and Y93 of the NS5A region were detected in 0% and 3.6% (1/28), respectively. The rates of rapid virologic response, end-of-treatment response, and SVR12 were 93.5% (29/31), 100% (31/31), and 96.8% (30/31), respectively. The incidence of adverse events was 35.5% (11/31). Of the 11 patients, one discontinued the treatment due to erythema multiforme and thereafter relapsed. The most frequent adverse event was pruritus (6.5%; 2/31). CONCLUSIONS The present study suggests that ombitasvir/paritaprevir/ritonavir combination therapy is effective and safe for genotype 1b chronic hepatitis C patients undergoing dialysis due to ESRD.
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Affiliation(s)
- Masanori Atsukawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.,Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
| | - Akihito Tsubota
- Core Research Facilities for Basic Science, Jikei University School of Medicine, Tokyo, Japan
| | - Yohei Koushima
- Division of Gastroenterology and Hepatology, Japanese Red Cross Saitama Hospital, Saitama, Japan
| | - Tadashi Ikegami
- Department of Internal Medicine, Division of Hepatology and Gastroenterology, Tokyo Medical University, Ibaraki Medical Center, Ibaraki, Japan
| | - Kouji Watanabe
- Department of Internal Medicine, Division of Gastroenterology, Mito Saiseikai General Hospital, Ibaraki, Japan
| | - Noritomo Shimada
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Otakanomori Hospital, Chiba, Japan
| | - Shinichi Sato
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Seirei Sakura Citizen Hospital, Chiba, Japan
| | - Keizo Kato
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Chiba, Japan
| | - Hiroshi Abe
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Chiba, Japan
| | - Tomomi Okubo
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
| | - Taeang Arai
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
| | - Norio Itokawa
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
| | - Chisa Kondo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Shigeru Mikami
- Department of Internal Medicine, Division of Gastroenterology, Kikkoman General Hospital, Chiba, Japan
| | - Toru Asano
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan
| | - Yoshimichi Chuganji
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan
| | - Yasushi Matsuzaki
- Department of Internal Medicine, Division of Hepatology and Gastroenterology, Tokyo Medical University, Ibaraki Medical Center, Ibaraki, Japan
| | - Katsuhiko Iwakiri
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
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Pharmacokinetics and Tolerability of Anti-Hepatitis C Virus Treatment with Ombitasvir, Paritaprevir, Ritonavir, with or Without Dasabuvir, in Subjects with Renal Impairment. Clin Pharmacokinet 2017; 56:153-163. [PMID: 27389403 DOI: 10.1007/s40262-016-0429-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND The direct-acting antiviral agent (DAA) combination of ombitasvir and paritaprevir (administered with ritonavir) with (3D regimen) or without (2D regimen) dasabuvir has shown very high efficacy rates in the treatment of chronic hepatitis C virus (HCV) infection. Renal impairment, a common comorbidity in patients with chronic HCV infection, can influence the pharmacokinetics of antiviral agents and hence their efficacy and safety profiles. OBJECTIVE The aim of this study was to evaluate the influence of renal impairment on the pharmacokinetics and tolerability of the 3D and 2D regimens. METHODS Overall, 24 subjects, six in each of four renal function groups (normal, mild, moderate, and severe), received a single dose of the 3D and 2D regimens in separate dosing periods. Plasma and urine were analyzed to assess the effect of renal impairment on drug exposure. RESULTS DAA exposures changed by up to 21, 37, and 50 % in subjects with mild, moderate, and severe renal impairment, respectively, versus subjects with normal renal function. Ritonavir exposure increased with the degree of renal impairment (maximum 114 %). The half-lives of DAAs and ritonavir in subjects with renal impairment were generally comparable with those in healthy subjects. No safety or tolerability concerns arose in this study. CONCLUSION The 3D and 2D regimens do not require dose adjustment for patients with HCV infection and concomitant renal impairment.
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Ahmed H, Abushouk AI, Menshawy A, Mohamed A, Negida A, Loutfy SA, Abdel-Daim MM. Safety and Efficacy of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir with or without Ribavirin for Treatment of Hepatitis C Virus Genotype 1: A Systematic Review and Meta-analysis. Clin Drug Investig 2017; 37:1009-1023. [PMID: 28871475 DOI: 10.1007/s40261-017-0565-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND OBJECTIVE Interferon-free regimens are rapidly evolving for patients with chronic hepatitis C virus (HCV) infection. We performed this meta-analysis to investigate the safety and efficacy of a combination regimen (ombitasvir [OBV]/paritaprevir [PTV]/ritonavir [r] ± dasabuvir [DSV]) for the treatment of patients with HCV genotype 1 infection. METHODS A computerized literature search for relevant clinical trials was conducted during May 2017. Data on sustained virological response (SVR), virological relapse, and safety outcomes were extracted and calculated as pooled proportion (PP) or risk ratio (RR) with their 95% confidence interval (CI), using StatsDirect and RevMan software. RESULTS The final analysis included 13 studies for HCV genotype 1 (3115 patients). The pooled effect estimate showed that 12-week treatment of genotype 1 patients with the OBV/PTV/r regimen achieved a high SVR rate (PP = 94%, 95% CI 92-96) that increased to (PP = 97%, 95% CI 96-98) upon the addition of DSV. These results were consistent when independent subgroup analyses were conducted based on viral subgenotypes, the presence of cirrhosis, or former treatment failure. Adding ribavirin (RBV) to this regimen was not associated with increased SVR rates (risk ratio = 1, 95% CI 0.98-1.02), while it increased the risk of serious adverse events (p = 0.02), insomnia (p = 0.001), and pruritus (p < 0.001). CONCLUSION The current meta-analysis showed a high efficacy for the OBV/PTV/r regimen in the treatment of HCV genotype 1 (with DSV) infection, regardless of the presence of cirrhosis or former treatment failure. Adding RBV to this regimen slightly decreased the relapse rate. Future studies with larger sample sizes are required to investigate the efficacy of this regimen in other HCV genotypes and to establish the evidence about the effect of adding RBV to OBV/PTV/r + DSV.
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Affiliation(s)
- Hussien Ahmed
- Faculty of Medicine, Zagazig University, Zagazig, El-Sharkia, Egypt.
- Medical Research Group of Egypt, Cairo, Egypt.
- Student Research Unit, Zagazig University, Zagazig, El-Sharkia, Egypt.
| | | | - Amr Menshawy
- Medical Research Group of Egypt, Cairo, Egypt
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Arwa Mohamed
- Faculty of Medicine, Zagazig University, Zagazig, El-Sharkia, Egypt
- Medical Research Group of Egypt, Cairo, Egypt
| | - Ahmed Negida
- Faculty of Medicine, Zagazig University, Zagazig, El-Sharkia, Egypt
- Medical Research Group of Egypt, Cairo, Egypt
- Student Research Unit, Zagazig University, Zagazig, El-Sharkia, Egypt
| | - Samah A Loutfy
- National Cancer Institute, Cairo University, Cairo, Egypt
| | - Mohamed M Abdel-Daim
- Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, 41522, Egypt.
- Department of Ophthalmology and Micro-Technology, Yokohama City University, Yokohama, Japan.
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Drug-Drug Interactions Between the Anti-Hepatitis C Virus 3D Regimen of Ombitasvir, Paritaprevir/Ritonavir, and Dasabuvir and Eight Commonly Used Medications in Healthy Volunteers. Clin Pharmacokinet 2017; 55:1003-14. [PMID: 26895022 PMCID: PMC4933729 DOI: 10.1007/s40262-016-0373-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Background and Aims The three direct-acting antiviral regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir (3D regimen) is approved for treatment of hepatitis C virus (HCV) genotype 1 infection. Drug–drug interaction (DDI) studies of the 3D regimen and commonly used medications were conducted in healthy volunteers to provide information on coadministering these medications with or without dose adjustments. Methods Three phase I studies evaluated DDIs between the 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily + dasabuvir 250 mg twice daily) and hydrocodone bitartrate/acetaminophen (5/300 mg), metformin hydrochloride (500 mg), diazepam (2 mg), cyclobenzaprine hydrochloride (5 mg), carisoprodol (250 mg), or sulfamethoxazole/trimethoprim (SMZ/TMP) (800/160 mg twice daily), all administered orally. DDI magnitude was determined using geometric mean ratios and 90 % confidence intervals for the maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC). Results Changes in exposures (Cmax and AUC geometric mean ratios) of acetaminophen, metformin, sulfamethoxazole, trimethoprim, and diazepam were ≤25 % upon coadministration with the 3D regimen. The Cmax and AUC of nordiazepam, an active metabolite of diazepam, increased by 10 % and decreased by 44 %, respectively. Exposures of cyclobenzaprine and carisoprodol decreased by ≤40 and ≤46 %, respectively, whereas exposures of hydrocodone increased up to 90 %. Ombitasvir, paritaprevir, ritonavir, and dasabuvir exposures changed by ≤25 %, except for a 37 % decrease in paritaprevir Cmax with metformin and a 33 % increase in dasabuvir AUC with SMZ/TMP. Conclusions Acetaminophen, metformin, sulfamethoxazole, and trimethoprim can be coadministered with the 3D regimen without dose adjustment. Higher doses may be needed for diazepam, cyclobenzaprine, and carisoprodol based on clinical monitoring. A 50 % lower dose and/or clinical monitoring should be considered for hydrocodone. No dose adjustment is necessary for the 3D regimen.
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Suda G, Nagasaka A, Yamamoto Y, Furuya K, Kumagai K, Kudo M, Terashita K, Kobayashi T, Tsunematsu I, Yoshida J, Meguro T, Kimura M, Ito J, Umemura M, Izumi T, Tsunematsu S, Sato F, Tsukuda Y, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N. Safety and efficacy of daclatasvir and asunaprevir in hepatitis C virus-infected patients with renal impairment. Hepatol Res 2017; 47:1127-1136. [PMID: 27943523 DOI: 10.1111/hepr.12851] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 11/01/2016] [Accepted: 12/08/2016] [Indexed: 12/15/2022]
Abstract
AIM Hepatitis C virus (HCV) infection is a risk factor for end-stage renal disease, renal graft failure, and hemodialysis patient mortality. However, the efficacy of direct-acting antiviral therapy for HCV-infected patients with renal impairment is unclear. Additionally, the promising NS5B inhibitor sofosbuvir has not been recommended for patients with severe renal impairment. In this prospective, multicenter study, we evaluated the efficacy and safety of daclatasvir and asunaprevir combination therapy, with a focus on patients with renal impairment. METHODS The study included 322 genotype 1 HCV-infected patients who received daclatasvir and asunaprevir combination therapy. The safety and sustained virological response was examined at 12 weeks after the end of treatment and safety was evaluated according to renal function. RESULTS Of 322 patients, 5% (16/322) and 2.5% (8/322) had chronic kidney disease stage G3b (estimated glomerular filtration rate [eGFR], 30-44 mL/min/1.73 m2 ) and stage G4/5 (eGFR, 15-29/<15 mL/min/1.73 m2 ), respectively. Baseline presence of the NS5A resistance-associated variant, previous simeprevir treatment, and HCV RNA titers, which were predictors of a sustained viral response, were similar between patients with eGFR <45 mL/min/1.73 m2 and eGFR >45 mL/min/1.73 m2 . Notably, the 12-week sustained viral response rate was comparable in patients with eGFR <45 mL/min/1.73 m2 (100%, 24/24) and those with eGFR >45 mL/min/1.73 m2 (88.9%, 265/298; P = 0.07). Treatment discontinuation rates and adverse events, including alanine aminotransferase elevation, anemia, and renal disorders, were similar between the two groups. CONCLUSION Daclatasvir and asunaprevir combination therapy for patients with renal dysfunction was highly effective and safe.
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Affiliation(s)
- Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Atsushi Nagasaka
- Department of Gastroenterology and Hepatology, Sapporo City General Hospital, Sapporo, Japan
| | - Yoshiya Yamamoto
- Department of Gastroenterology and Hepatology, Hakodate City General Hospital, Hakodate, Japan
| | - Ken Furuya
- Department of Gastroenterology and Hepatology, JCHO Hokkaido Hospital, Sapporo, Japan
| | - Kenichi Kumagai
- Department of Gastroenterology and Hepatology, Hakodate Medical Association Hospital, Hakodate, Japan
| | - Mineo Kudo
- Department of Gastroenterology and Hepatology, Sapporo Hokuyu Hospital, Sapporo, Japan
| | - Katsumi Terashita
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.,Department of Gastroenterology and Hepatology, Kushiro Rosai Hospital, Kushiro, Japan
| | - Tomoe Kobayashi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.,Department of Gastroenterology and Hepatology, Tomakomai City Hospital, Tomakomai, Japan
| | - Izumi Tsunematsu
- Department of Gastroenterology and Hepatology, Touei Hospital, Sapporo, Japan
| | - Junichi Yoshida
- Department of Gastroenterology and Hepatology, JCHO Sapporo Hokushin Hospital
| | - Takashi Meguro
- Department of Gastroenterology and Hepatology, Hokkaido Gastroenterology Hospital, Sapporo, Japan
| | - Megumi Kimura
- 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
| | - 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
| | - Seiji Tsunematsu
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Fumiyuki Sato
- 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.,Department of Gastroenterology and Hepatology, 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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Schnell G, Tripathi R, Krishnan P, Beyer J, Reisch T, Irvin M, Dekhtyar T, Setze C, Rodrigues L, Alves K, Burroughs M, Redman R, Chayama K, Kumada H, Collins C, Pilot-Matias T. Resistance characterization of hepatitis C virus genotype 2 from Japanese patients treated with ombitasvir and paritaprevir/ritonavir. J Med Virol 2017; 90:109-119. [PMID: 28842997 PMCID: PMC6680211 DOI: 10.1002/jmv.24923] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 08/10/2017] [Indexed: 01/02/2023]
Abstract
Treatment of HCV genotype (GT) 2‐infected Japanese patients with paritaprevir (NS3/4A inhibitor boosted with ritonavir) and ombitasvir (NS5A inhibitor) without ribavirin for 12 weeks in the phase 2 study M12‐536, and with ribavirin for 16 weeks in phase 3 study GIFT II resulted in SVR rates of 72.2% to 91.5%. Overall, 11 out of 125 patients with GT2a and 37 out of 79 patients with GT2b infection experienced virologic failure. The prevalence of baseline polymorphisms in NS3 and NS5A and their the impact on treatment outcome, as well as the development of viral resistance in GT2‐infected patients experiencing virologic failure were evaluated by HCV NS3 and NS5A population and clonal sequence analyses. Baseline polymorphisms in NS3 that confer resistance to paritaprevir were rare in both GT2a‐ and GT2b‐infected patients, while baseline polymorphisms in NS5A that confer resistance to ombitasvir were detected in 11.2% and 14.1% of the GT2a‐ and GT2b‐infected patients, respectively. There was no significant impact of baseline polymorphisms on treatment outcome in Japanese patients. The most common treatment‐emergent substitutions at the time of virologic failure occurred at amino acid positions 168 in NS3 and 28 in NS5A in both GT2a‐ and GT2b‐infected patients. Although there was a higher rate of virologic failure in patients with GT2b infection, the resistance analyses presented in this report support the conclusion that testing for baseline resistance‐associated polymorphisms is not warranted for HCV GT2‐infected patients treated with a regimen of ombitasvir/paritaprevir/ritonavir + ribavirin for 16 weeks.
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Affiliation(s)
- Gretja Schnell
- Research & Development, AbbVie Inc., North Chicago, Illinois
| | - Rakesh Tripathi
- Research & Development, AbbVie Inc., North Chicago, Illinois
| | | | - Jill Beyer
- Research & Development, AbbVie Inc., North Chicago, Illinois
| | - Thomas Reisch
- Research & Development, AbbVie Inc., North Chicago, Illinois
| | - Michelle Irvin
- Research & Development, AbbVie Inc., North Chicago, Illinois
| | | | - Carolyn Setze
- Research & Development, AbbVie Inc., North Chicago, Illinois
| | - Lino Rodrigues
- Research & Development, AbbVie Inc., North Chicago, Illinois
| | - Katia Alves
- Research & Development, AbbVie Inc., North Chicago, Illinois
| | | | - Rebecca Redman
- Research & Development, AbbVie Inc., North Chicago, Illinois
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan
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Nakano R, Ohira M, Ishiyama K, Ide K, Kobayashi T, Tahara H, Shimizu S, Arihiro K, Imamura M, Chayama K, Tanaka Y, Ohdan H. Acute Graft Rejection and Formation of De Novo Donor-Specific Antibodies Triggered by Low Cyclosporine Levels and Interferon Therapy for Recurrent Hepatitis C Infection After Liver Transplantation: A Case Report. Transplant Proc 2017; 49:1634-1638. [PMID: 28838454 DOI: 10.1016/j.transproceed.2017.05.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 05/13/2017] [Indexed: 12/20/2022]
Abstract
BACKGROUND We report a case of acute rejection of a liver graft, together with the occurrence of de novo donor-specific antibodies (DSAs), in a 53-year-old Japanese man who had undergone deceased-donor liver transplantation. METHODS The graft rejection was triggered by low cyclosporine levels and pegylated interferon treatment for the recurrence of hepatitis C virus (HCV) infection 18 months after transplantation. Although the graft was ABO-compatible, pre-formed DSA B51 was detected; therefore, total plasma exchange was performed and intravenous rituximab (500 mg/body) was administered before transplantation. RESULTS DSA was absent 6 months after transplantation. HCV recurrence was treated with pegylated interferon-α-2a. Renal function deteriorated with this anti-HCV therapy, with serum cyclosporine levels decreasing to 50 ng/mL. A rapid virologic response was achieved, but liver function deteriorated after 3 months of anti-HCV therapy, with histologic evidence of acute cellular rejection and formation of de novo DSAs. Anti-thymocyte globulin was administered for 5 days, which led to immediate improvement in liver function. However, renal function declined, warranting hemodialysis. The patient recovered 2 months after acute rejection, although de novo DSAs persisted. CONCLUSIONS Careful immunologic monitoring may be required for patients receiving interferon therapy for HCV infection to maintain sufficient blood levels of immunosuppressive agents and to prevent acute liver graft rejection.
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Affiliation(s)
- R Nakano
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - M Ohira
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
| | - K Ishiyama
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - K Ide
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - T Kobayashi
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - H Tahara
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - S Shimizu
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - K Arihiro
- Department of Pathology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | - M Imamura
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - K Chayama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Y Tanaka
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - H Ohdan
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Tarao K, Sato A. A Hepatitis C Virus-Associated Chronic Hepatitis Patient Developing Various Adverse Events Including Severe Gingivitis, Gingival Bleeding, and Inflammation of Genital Vulva during the Course of Antiviral Therapy with Elbasvir/Grazoprevir. Case Rep Gastroenterol 2017; 11:736-741. [PMID: 29430226 PMCID: PMC5803708 DOI: 10.1159/000484135] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 10/10/2017] [Indexed: 12/27/2022] Open
Abstract
Oral direct-acting antivirals comprise the main therapy for hepatitis C virus (HCV)-associated liver disease in Japan. Daclatasvir/asunaprevir is the primary agent and sofosbuvir/ledipasvir is the secondary agent for HCV genotype 1b. Ombitasvir/paritaprevir/ritonavir was also recommended as a therapy for HCV genotype 1b. More recently, elbasvir (NS5A inhibitor)/grazoprevir (NS3/4A protease inhibitor) was also recommended as a potent therapy for HCV genotype 1b infection. This agent achieved an SVR12 as high as 96.5% for HCV virus-associated chronic hepatitis. We recently encountered a case treated with this agent and the female patient showed various adverse events, such as severe gingivitis, gingival bleeding, severe tonsillitis, inflammation of the genital vulva, and the sustained sensation of being hungry. In spite of the gingival bleeding, there was no depletion of the platelet count, nor elongation of the prothrombin time. She tolerated these adverse events and finally completed the therapy and achieved SVR12.
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Affiliation(s)
- Kazuo Tarao
- Tarao's Gastroenterological Clinic, Yokohama, Japan
| | - Akira Sato
- Division of Gastroenterology, Department of Internal Medicine, St. Marianna University, Yokohama City Seibu Hospital, Yokohama, Japan
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Sezaki H, Suzuki F, Hosaka T, Akuta N, Fujiyama S, Kawamura Y, Kobayashi M, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Kobayashi M, Kumada H. The efficacy and safety of dual oral therapy with daclatasvir and asunaprevir for genotype 1b in Japanese real-life settings. Liver Int 2017; 37:1325-1333. [PMID: 28178397 DOI: 10.1111/liv.13384] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 02/01/2017] [Indexed: 01/17/2023]
Abstract
BACKGROUND & AIMS It is important to investigate the treatment outcomes in patients excluded from clinical trials (CTR). The aims of this study were to evaluate the efficacy and safety of a 24-week daclatasvir (DCV) and asunaprevir (ASV) therapy for patients with chronic hepatitis C virus (HCV)-1b infection. METHODS A total of 651 HCV-1b patients started dual oral therapy with DCV and ASV for 24 weeks in Toranomon Hospital, Tokyo. Among them, 276 patients met phase III CTR inclusion criteria. The sustained virological response (SVR) rate after treatment and the adverse events during therapy were compared between CTR-met (patients who met the inclusion criteria) and CTR-unmet (patients who did not meet the inclusion criteria) groups. RESULTS SVR12 was achieved in 87.0% (240/276) and 86.7% (325/375) in CTR-met and CTR-unmet patients respectively. SVR12 rate in simeprevir-experienced patients was 52.9% (9/17). SVR12 rate in patients without resistance-associated variant (RAV) of NS3 or NS5A loci was 93.7% (416/444). However, the SVR12 rates in patients with NS3-D168, NS5A-L31 and Y93 single RAV at baseline were 55.0% (11/20), 73.9% (17/23) and 65.6% (63/96) respectively. The safety profiles in both CTR-met and CTR-unmet patients were similar. The discontinuation rate as a result of alanine aminotransferase (ALT) elevation was only 2.9%. Seven (2.5%) patients in CTR-met group and 20 (5.3%) in CTR-unmet group discontinued therapy because of adverse events other than the ALT elevation. CONCLUSIONS Dual oral therapy with DCV and ASV in real-life settings was well tolerated with a similar safety profile and achieved similar SVR12 rates as that of CTR.
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Affiliation(s)
- Hitomi Sezaki
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Fumitaka Suzuki
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan.,Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Tetsuya Hosaka
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Norio Akuta
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | | | | | | | | | - Satoshi Saitoh
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Yasuji Arase
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Kenji Ikeda
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Mariko Kobayashi
- Research Institute for Hepatology, Toranomon Hospital, Tokyo, Japan
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38
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Gopalakrishnan SM, Polepally AR, Mensing S, Khatri A, Menon RM. Population Pharmacokinetics of Paritaprevir, Ombitasvir, and Ritonavir in Japanese Patients with Hepatitis C Virus Genotype 1b Infection. Clin Pharmacokinet 2017; 56:1-10. [PMID: 27314261 DOI: 10.1007/s40262-016-0423-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND OBJECTIVE Hepatitis C virus (HCV) infection is of considerable clinical concern in Japan. We modeled the population pharmacokinetics of an oral interferon-free, direct-acting antiviral agent (DAA) regimen (i.e., the 2D regimen) recently approved for the treatment of chronic HCV genotype 1 infection as a new option for affected Japanese patients. METHODS Using data from a phase III clinical trial (GIFT-I) that enrolled Japanese patients with HCV genotype 1b infection, population pharmacokinetic models were developed for the drugs that comprise the 2D regimen: paritaprevir, ombitasvir, and ritonavir. Demographic and clinical covariates with potential to influence 2D pharmacokinetics were evaluated for their effects on drug exposures. Proposed models were assessed using goodness-of-fit plots, visual predictive checks, and bootstrap evaluations. RESULTS One-compartment models with first-order absorption and elimination adequately described the population pharmacokinetics of paritaprevir, ombitasvir, and ritonavir. On average, patients with cirrhosis had approximately 95-145 % higher, 19-24 % lower, and 58-68 % higher exposures of paritaprevir, ombitasvir, and ritonavir, respectively. Female patients had 58-81 % higher ombitasvir exposures, whereas patients with mild renal impairment (creatinine clearance 75 mL/min) had 9-14 % higher ombitasvir exposures than did patients with normal renal function (creatinine clearance 105 mL/min). The DAA exposure values were comparable between responders and non-responders. CONCLUSION Population pharmacokinetic modeling did not reveal any patient-related or clinical parameters that would require dose adjustment of the 2D regimen when used for the treatment of HCV genotype 1b infection in Japanese patients.
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Affiliation(s)
- Sathej M Gopalakrishnan
- Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061, Ludwigshafen am Rhein, Germany.
| | | | - Sven Mensing
- Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061, Ludwigshafen am Rhein, Germany
| | - Amit Khatri
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA
| | - Rajeev M Menon
- Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA
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Nagaoki Y, Imamura M, Aikata H, Daijo K, Teraoka Y, Honda F, Nakamura Y, Hatooka M, Morio R, Morio K, Kan H, Fujino H, Kobayashi T, Masaki K, Ono A, Nakahara T, Kawaoka T, Tsuge M, Hiramatsu A, Kawakami Y, Hayes CN, Miki D, Ochi H, Chayama K. The risks of hepatocellular carcinoma development after HCV eradication are similar between patients treated with peg-interferon plus ribavirin and direct-acting antiviral therapy. PLoS One 2017; 12:e0182710. [PMID: 28797106 PMCID: PMC5552231 DOI: 10.1371/journal.pone.0182710] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2017] [Accepted: 07/24/2017] [Indexed: 02/06/2023] Open
Abstract
The risk of hepatocellular carcinoma (HCC) development is reduced following viral elimination by interferon therapy in chronic hepatitis C patients. However, the risk in patients treated with interferon-free direct-acting antivirals (DAAs) is unknown. We evaluated chronic hepatitis C patients who achieved viral eradication by pegylated-interferon plus ribavirin (PEG-IFN/RBV, n = 244) or daclatasvir plus asunaprevir (DCV/ASV, n = 154) therapy. None of the patients had prior history of HCC or antiviral therapy. The median observation period after the end of treatment for the PEG-IFN/RBV and DCV/ASV groups were 96 (range 10–196) and 23 (range 4–78) months, respectively. During the observation period, HCC developed in 13 (5.3%) and 7 (4.5%) patients in the PEG-IFN/RBV and DCV/ASV groups, respectively. The cumulative HCC development rate after 1-, 3- and 5-years (0.4%, 3% and 5% for the PEG-IFN/RBV group and 0.6%, 9% and 9% for the DAA group, respectively) were similar between the two groups. Propensity score matching analysis also showed no significant difference in HCC development rates between the two groups. Serum AFP levels decreased to similar levels between PEG-IFN/RBV and DCV/ASV groups following the achievement of viral eradication. The risk for HCC development following viral eradication by IFN-free DAA therapy may be similar to that in IFN-based therapy.
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Affiliation(s)
- Yuko Nagaoki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Kana Daijo
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Fumi Honda
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Yuki Nakamura
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Masahiro Hatooka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Reona Morio
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Hiromi Kan
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Tomoki Kobayashi
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Keiichi Masaki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - C. Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Hidenori Ochi
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
- * E-mail:
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Han MS, Park Y, Kim HS. Comparison of Abbott RealTime genotype II, GeneMatrix restriction fragment mass polymorphism and Sysmex HISCL HCV Gr assays for hepatitis C virus genotyping. ACTA ACUST UNITED AC 2017; 55:1122-1128. [DOI: 10.1515/cclm-2016-0130] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 11/29/2016] [Indexed: 12/13/2022]
Abstract
AbstractBackground:Hepatitis C virus (HCV) genotype is a predictive marker for treatment response. We sequentially evaluated the performances of two nucleic acid amplification tests (NAATs) and one serology assay for HCV genotype: Abbott RealTimegenotype II (RealTimeII), GeneMatrix restriction fragment mass polymorphism (RFMP), and Sysmex HISCL HCV Gr (HISCL Gr).Methods:We examined 281 clinical samples with three assays. The accuracy was assessed using the HCV Genotype Performance Panel PHW204 (SeraCare Life Sciences) for two NAATs. Discrepant cases were re-genotyped by the Versant HCV v.2.0 (line probe 2.0) assay.Results:With the RealTimeII assay, clinic samples were analyzed as follows: genotypes 1b (43.1%), 2 (40.2%), 1 subtypes other than 1a and 1b (12.5%), 3 (1.8%), 4 (1.4%), 1a (0.7%), 6 (0.4%), and mixed (1.1%). The RealTimeII and RFMP assays showed a type concordance rate of 97.5% (274/281) (κ=0.80) and no significant discordance (p=0.25). Both assays accurately genotyped all samples in the Performance Panel by the subtype level. The HISCL Gr assay showed concordance rates of about 91% (κ<0.40) and statistically significant discordances with two NAATs (p<0.05). In confirmation tests, the results of RFMP assay were the most consistent with those of Versant 2.0 assay.Conclusions:The three HCV assays provided genotyping and serotyping results with good concordance rates. The two NAATs (RealTimeII and RFMP) showed comparable performance and good agreement. However, the results of the HISCL Gr assay showed statistically significant differences with those of the NAATs.
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Sato K, Chayama K, Alves K, Toyoda H, Suzuki F, Kato K, Rodrigues L, Zhang X, Setze C, Pilot-Matias T, Burroughs M, Redman R, Kumada H. Randomized Phase 3 Trial of Ombitasvir/Paritaprevir/Ritonavir and Ribavirin for Hepatitis C Virus Genotype 2-Infected Japanese Patients. Adv Ther 2017; 34:1449-1465. [PMID: 28536999 DOI: 10.1007/s12325-017-0506-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Indexed: 12/11/2022]
Abstract
INTRODUCTION In Japan, hepatitis C virus (HCV) genotype (GT) 2 accounts for approximately 32% of HCV infections. Limited treatment options exist in Japan for HCV GT2-infected patients. GIFT-II was a phase 3, randomized, open-label study evaluating the efficacy and safety of 16- and 12-week regimens of co-formulated ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus ribavirin (RBV) in Japanese adults with HCV GT2 infection. METHODS Patients were randomized in a 1:1 ratio to once-daily, co-formulated OBV/PTV/r (25/150/100 mg) with weight-based RBV for 16 or 12 weeks. The primary efficacy endpoint was the sustained virologic response at 12 weeks post-treatment (SVR12) rate in the primary efficacy population of non-cirrhotic treatment-naive patients. RESULTS A total of 171 patients were randomized to OBV/PTV/r + RBV. In the primary efficacy population, SVR12 rates were 91.5% (43/47; 95% confidence interval 83.5-99.5%) and 75.0% (36/48; 95% confidence interval 62.8-87.2%) in the 16-week arm and 12-week arm, respectively. No patient in the 16-week arm relapsed by post-treatment week 12. Among non-cirrhotic treatment-experienced patients, the overall SVR rate in the 16-week arm was 75.8% (25/33) and was highest [93.8% (15/16)] among those who had relapsed after previous interferon-based therapy. SVR12 rates were consistently higher in patients with HCV GT2a infection versus HCV GT2b infection [16-week treatment arm: 93.9% (31/33) versus 85.7% (12/14) and 93.8% (15/16) versus 56.3% (9/16) among non-cirrhotic treatment-naive and treatment-experienced patients, respectively]. No patient discontinued treatment because of an adverse event. The most common adverse events were anemia, increased blood bilirubin, and nasopharyngitis. CONCLUSIONS OBV/PTV/r + RBV for 16 weeks resulted in high SVR12 rates in non-cirrhotic Japanese patients infected with HCV GT2 who were treatment-naive or who had relapsed after an interferon-based therapy. Higher SVR12 rates were observed among patients with HCV GT2a infection versus those with GT2b infection. This regimen demonstrated a favorable safety profile. TRIAL REGISTRATION ClinicalTrials.gov identifier, NCT02023112. FUNDING AbbVie.
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Affiliation(s)
- Ken Sato
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | | | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Gifu, Japan
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Tarao K, Yamada K. A Hepatitis C Virus-Associated Cirrhotic Patient Developing Interstitial Pneumonia during the Course of Antiviral Therapy with Ombitasvir/Paritaprevir/Ritonavir. Case Rep Gastroenterol 2017; 11:369-376. [PMID: 28690490 PMCID: PMC5498963 DOI: 10.1159/000462965] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 02/09/2017] [Indexed: 12/12/2022] Open
Abstract
Oral direct-acting antivirals (DAAs) are the main therapy for hepatitis C virus (HCV)-associated liver disease in Japan. Daclatasvir/asunaprevir is the first agent and sofosbuvir/ledipasvir is the secondary agent for HCV genotype 1b. More recently, ombitasvir/paritaprevir/ritonavir is also recommended as a potent therapy for HCV genotype 1b. Among the adverse events associated with these oral DAAs, interstitial pneumonia is one of the most severe ones. Regarding treatment with daclatasvir plus asunaprevir or sofosbuvir plus ledipasvir, a few cases have already been reported in a postmarketing surveillance. Recently, we have encountered a HCV-associated genotype 1b cirrhosis patient who developed interstitial pneumonia during treatment with ombitasvir/paritaprevir/ritonavir and who recovered after drug discontinuation without corticosteroid therapy. Interstitial pneumonia was confirmed by chest x-ray and chest computed tomography. The serum KL-6 level was elevated to 1,180 U/mL. The total duration of the drug administration was 7 weeks, and she achieved SVR24. This is the first detailed report in the literature on the development of interstitial pneumonia during treatment with ombitasvir/paritaprevir/ritonavir. When dry cough appeared in the treatment with DAAs, chest computed tomography and the evaluation of serum KL-6 level were recommended.
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Affiliation(s)
- Kazuo Tarao
- Tarao's Gastroenterological Clinic, Yokohama, Japan
| | - Kouzo Yamada
- Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, 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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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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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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Iwata H, Ishikawa H. [Pharmacological properties and clinical efficacy of Ximency ® Combination Tablets]. Nihon Yakurigaku Zasshi 2017; 150:153-164. [PMID: 28890478 DOI: 10.1254/fpj.150.153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
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Chayama K, Hayes CN. Treatment of HCV patients on hemodialysis with daclatasvir and asunaprevir. J Gastroenterol 2017; 52:125-126. [PMID: 27541041 DOI: 10.1007/s00535-016-1252-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 07/20/2016] [Indexed: 02/04/2023]
Affiliation(s)
- Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan. .,Liver Research Project Center, Hiroshima University, Hiroshima, Japan. .,Laboratory for Digestive Diseases, RIKEN Center for Genomic Medicine, Hiroshima, Japan.
| | - Clair Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
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Sato K, Hosonuma K, Yamazaki Y, Kobayashi T, Takakusagi S, Horiguchi N, Kakizaki S, Kusano M, Ohnishi H, Okamoto H, Yamada M. Combination Therapy with Ombitasvir/Paritaprevir/Ritonavir for Dialysis Patients Infected with Hepatitis C Virus: A Prospective Multi-Institutional Study. TOHOKU J EXP MED 2017; 241:45-53. [PMID: 28090038 DOI: 10.1620/tjem.241.45] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Hepatitis C virus (HCV) infection is common in dialysis patients worldwide and nosocomial HCV spread within dialysis facilities continues to develop. Combination therapy with daclatasvir and asunaprevir (DCV/ASV) that has proven efficacy for dialysis patients infected with genotype 1b HCV (HCV/1b) has several concerns in Japan. The recently available combination therapy with ombitasvir, paritaprevir, and ritonavir (OBV/PTV/r) is not contraindicated in patients with chronic renal failure and has more safety profile and shorter treatment period than that with DCV/ASV. We evaluated the effects of combination therapy with OBV/PTV/r in four dialysis patients infected with HCV/1b, who were eligible for our study. On-treatment assessments included standard laboratory testing, serum HCV RNA and symptom-directed physical examinations. Three patients had a sustained virological response at 12 weeks after treatment, but one remaining patient had viral breakthrough. Notably, the patient with viral breakthrough had been coinfected with HCV/1b and HCV/2b; namely, HCV/2b with resistance-associated variations was not eradicated by the combination therapy. Among the three patients responsive to the combination therapy, one patient complained of appetite loss and itching, while in another patient the therapy was discontinued due to itching, exacerbation of wamble, and a falling tendency probably due to interaction with valsartan. These AEs were ameliorated or disappeared after the completion of the therapy. The significance of our study is persuasive virological evaluation associated to the combination therapy and reasonable interpretation of AEs. In conclusion, combination therapy with OBV/PTV/r may have promise as an efficacious therapy, but caution regarding AEs should be practiced.
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Affiliation(s)
- Ken Sato
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine
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Akuta N, Kobayashi M, Suzuki F, Sezaki H, Fujiyama S, Kawamura Y, Hosaka T, Kobayashi M, Saitoh S, Suzuki Y, Arase Y, Ikeda K, Kumada H. Liver Fibrosis and Body Mass Index Predict Hepatocarcinogenesis following Eradication of Hepatitis C Virus RNA by Direct-Acting Antivirals. Oncology 2016; 91:341-347. [DOI: 10.1159/000450551] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 08/28/2016] [Indexed: 01/14/2023]
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Protease Inhibitor Resistance Remains Even After Mutant Strains Become Undetectable by Deep Sequencing. J Infect Dis 2016; 214:1687-1694. [DOI: 10.1093/infdis/jiw437] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 09/09/2016] [Indexed: 12/13/2022] Open
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