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Lee J, Ahn SB, Yim SY, An J, Jun DW, Ko MJ, Park DA, Yoo JJ. Efficacy and safety of direct-acting antiviral therapy for hepatitis C virus in elderly patients (≥65 years old): A systematic review and meta-analysis. J Viral Hepat 2022; 29:496-517. [PMID: 35357774 DOI: 10.1111/jvh.13679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 02/07/2022] [Accepted: 03/11/2022] [Indexed: 12/09/2022]
Abstract
Direct-acting agents (DAAs) have launched a new era of hepatitis C virus (HCV) treatment. As aged individuals comprise a large percentage of HCV-infected patients, the effectiveness and safety of DAAs in the elderly have come under scrutiny. This meta-analysis aimed to evaluate the efficacy and safety of DAAs in elderly patients. After a systematic search in PubMed (MEDLINE), Embase, OVID MEDLINE, the Cochrane Library and other databases, two investigators reviewed relevant abstracts and selected manuscripts for examination. The sustained virologic response (SVR) and adverse event (AE) rates were calculated with a random-effects model. Ninety studies evaluating SVR rates of elderly patients (≥65 years old) receiving DAAs were selected. DAAs in elderly patients exhibited a notable SVR rate of 96% (95% confidence interval [CI]: 95%-97%), accompanied by comparable rates in subgroup analyses. The comparison of SVR rates in elderly and non-elderly patients indicated no significant discrepancy (odds ratio [OR] 1.01, 95% CI: 1.00-1.01). The overall event rate of AEs was 45% (95% CI: 31%-60%), though AE rates varied by subgroups. Furthermore, AEs were comparatively more frequent (OR 1.15, 95% CI: 1.04-1.28) in the elderly than non-elderly, especially in subgroups such as SAE (OR 1.89, 95% CI: 1.52-2.36) and dose reduction in ribavirin (OR 1.90, 95% CI: 1.53-2.36). However, in the ribavirin (RBV)-free regimen, there was no significant difference in the incidence of AEs between the elderly and non-elderly groups. DAAs have high efficacy in elderly patients. Considering the possibility of AE, the RBV-free regimen should be given prior consideration for the treatment of elderly patients with HCV.
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Affiliation(s)
- Jieun Lee
- College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Sang Bong Ahn
- Nowon Eulji Medical Center, Department of Internal Medicine, Eulji University College of Medicine, Seoul, Korea
| | - Sun Young Yim
- Department of Internal Medicine, Korea University Hospital, Seoul, Korea
| | - Jihyun An
- Gastroenterology and Hepatology, Hanyang University College of Medicine, Guri, Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Min Jung Ko
- Division of Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency (NECA), Seoul, Korea
| | - Dong Ah Park
- Division of Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency (NECA), Seoul, Korea
| | - Jeong-Ju Yoo
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
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Abstract
In the 1970s, an unknown virus was suspected for documented cases of transfusion-associated hepatitis, a phenomenon called non-A, non-B hepatitis. In 1989, the infectious transmissible agent was identified and named hepatitis C virus (HCV) and, soon enough, the first diagnostic HCV antibody test was developed, which led to a dramatic decrease in new infections. Today, HCV infection remains a global health burden and a major cause of liver cirrhosis, hepatocellular carcinoma and liver transplantation. However, tremendous advances have been made over the decades, and HCV became the first curable, chronic viral infection. The introduction of direct antiviral agents revolutionized antiviral treatment, leading to viral eradication in more than 98% of all patients infected with HCV. This Perspective discusses the history of HCV research, which reads like a role model for successful translational research: starting from a clinical observation, specific therapeutic agents were developed, which finally were implemented in national and global elimination programmes.
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Affiliation(s)
- Michael P. Manns
- grid.10423.340000 0000 9529 9877Hannover Medical School, Hannover, Germany
| | - Benjamin Maasoumy
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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Deng H, Guo F, Yu W, Li L, Xia Y, Guan Y, Li J. Dynamic changes of HCV genomes under selective pressure from DAAs therapy in relapsed patients. Virus Res 2021; 302:198453. [PMID: 33991622 DOI: 10.1016/j.virusres.2021.198453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/03/2021] [Accepted: 05/10/2021] [Indexed: 11/30/2022]
Abstract
Currently, direct-acting antiviral drugs (DAAs) are widely used as therapeutic methods for hepatitis C virus (HCV)-positive patients, however, patients may experience treatment failure, and the dynamic changes of HCV genomes in these patients are unknown. In this study, three real-world DAAs cohorts were enrolled to observe clinical efficacy. In addition, serum samples from treatment failure patients at baseline and relapse were used to analyze changes of the HCV genomes at near full-length genome level, including resistance-associated variants (RAVs), viral quasispecies diversity and selection analysis. Next-generation sequencing was used as the detection method. The overall sustained virological response at 12 w after the end of treatment was achieved in 91.9% (57/62) of HCV patients, and 3 paired samples obtained from relapsed patients. All the 3 patients harbored baseline NS5A RAVs, the frequency of NS5A RAVs increased in 2 patients and a new NS5A RAV emerged in 1 patient at relapse, and almost all the viral strains existed with NS5A RAVs at relapse. The results of the viral quasispecies diversity analysis revealed that viral quasispecies diversity decreased at relapse compared to baseline, and the results of selection analysis indicated that the virus population experienced a bottleneck phenomenon, recent selective sweep and population expansion or was under purification selection after DAAs treatment. This study indicated that the clinical efficacy was excellent in real-world DAAs cohorts, and the viral strains existed at relapse were selective by DAAs therapy.
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Affiliation(s)
- Haohui Deng
- Department of Infectious Disease Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Fengxia Guo
- Department of Infectious Disease Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Weihua Yu
- Department of Infectious Disease Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Linghua Li
- Department of Infectious Disease Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yang Xia
- Department of Infectious Disease Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yujuan Guan
- Department of Infectious Disease Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jianping Li
- Department of Infectious Disease Center, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China.
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Shen C, Fan H, Ge Z, Cai W, Shao J, Dong C, Xue H, Fu Z, Li J, Zhang Y, Yue M. Efficacy and Safety of Glecaprevir/Pibrentasvir in HCV Patients With Previous Direct-Acting Antiviral Therapy Failures: A Meta-Analysis. Front Med (Lausanne) 2020; 7:592472. [PMID: 33425940 PMCID: PMC7793883 DOI: 10.3389/fmed.2020.592472] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 11/13/2020] [Indexed: 11/19/2022] Open
Abstract
Background: Since a greater number of hepatitis C virus (HCV) patients have access to direct-acting antiviral (DAA) based therapies, the number of patients not properly responding to prior DAA regimens is increasing. The objective of this comprehensive analysis was to assess the efficacy and safety of glecaprevir/pibrentasvir (GLE/PIB) in HCV patients who experienced previous DAA therapy failures. Methods: Bibliographic databases were systematically searched for relevant articles published by November 2020. The main endpoints were sustained viral response after 12 weeks (SVR12), adverse events (AEs; any grade) and severe adverse events (SAEs). Publication bias assessment was performed using funnel plots and the Egger's test. Results: Fourteen studies consisting of a total of 1,294 subjects were included in this study and the pooled estimate of SVR12, AEs and SAEs rates were 96.8% (95%CI: 95.1–98.2), 47.1% (95%CI: 26.0–69.3), and 1.8% (95%CI: 0.7–3.4), respectively. Subgroup analysis showed that pooled SVR12 rates were 97.9% (95%CI: 96.7–98.9) for Japan and 91.1% (95%CI: 87.3–94.3) for the United States; 95.8% (95%CI: 93.9–97.4) for genotype (GT)1 and 100.0% (95%CI: 99.6–100.0) for GT2; 95.3% (95%CI: 92.4–97.2) for cirrhosis and 96.3% (95%CI: 94.2–97.7) for non-cirrhosis cases. There was no publication bias included this study. Conclusion: This comprehensive analysis revealed that GLE/PIB is an effective and secure retreatment option for patients who did not optimally respond to DAA treatment, especially the Asian population with GT1-2.
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Affiliation(s)
- Chao Shen
- Key Laboratory of Infectious Diseases, Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Haozhi Fan
- Department of Information, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhijun Ge
- Department of Critical Care Medicine, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Weihua Cai
- Department of General Surgery, Third Affiliated Hospital of Nantong University, Nantong, China
| | - Jianguo Shao
- Department of Digestive Medicine, Third Affiliated Hospital of Nantong University, Nantong, China
| | - Chen Dong
- Department of Epidemiology and Statistics, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Hong Xue
- Department of Severe Infectious Diseases, Third Affiliated Hospital of Nantong University, Nantong, China
| | - Zuqiang Fu
- Key Laboratory of Infectious Diseases, Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jun Li
- Department of Infectious Diseases, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yun Zhang
- Key Laboratory of Infectious Diseases, Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.,Institute of Epidemiology and Microbiology, Eastern Theater Command Centers for Disease Prevention and Control, Nanjing, China
| | - Ming Yue
- Department of Infectious Diseases, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Efficacy and safety of direct-acting antiviral agent regimens in a real-world cohort of adult Chinese patients with chronic hepatitis C virus infection. LIVER RESEARCH 2020. [DOI: 10.1016/j.livres.2020.05.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Park SJ, Kim AR, Choe WH, Kim JH, Yoo BC, Kwon SY. The Efficacy and Safety of Direct-acting Antiviral Treatment for Chronic Hepatitis C Patients: A Single Center Study. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2019; 72:197-204. [PMID: 30419644 DOI: 10.4166/kjg.2018.72.4.197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Background/Aims Direct-acting antiviral (DAA) therapy has been shown to achieve a high rate of sustained virologic response (SVR) and favorable outcomes in chronic hepatitis C (CHC) patients. We investigated the virologic response and its clinical impact in CHC patients. Methods CHC patients with compensated liver function treated with DAAs between 2016 and 2017 were included for retrospective analysis. We analyzed baseline characteristics and virologic and biochemical responses at on-treatment 4 weeks, end of treatment, and post-treatment 12 weeks. Fibrosis was measured as liver stiffness measurement by transient elastography (FibroScan). Adverse events were monitored during the treatment period. Results A total of 135 patients (61.5% with genotype [GT] 1b and 38.5% with GT 2a) were enrolled 47.4% were male, 79.3% were treatment naive, and 30.4% had cirrhosis. SVR 12 was observed in 97.6% (81/83) in the GT 1b and 98.1% (51/52) in the GT 2a; treatment with daclatasvir+asunaprevir was the most commonly used in GT 1b (55/83), and sofosbuvir+ribavirin was the most commonly used in GT 2a (49/52). The median change of liver stiffness measurement at two time points using the signed rank test was -3.2 kPa in patients who underwent transient elastography before treatment and at SVR 12 (n=25). The most common adverse events were anemia, dyspepsia, and insomnia. One GT 2a patient treated with sofosbuvir+ribavirin stopped the treatment at 8 weeks due to symptomatic bradyarrhythmia; however, he recovered spontaneously and achieved SVR 12. Conclusions DAA treatment of chronic hepatitis C genotype 1b and 2a resulted in a high rate of sustained virologic response and improvement of liver fibrosis score.
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Affiliation(s)
- Seong Jun Park
- Division of Gastroenterology, Department of Internal Medicine, Konkuk University Medical Center, Seoul, Korea
| | - Ah Ran Kim
- Division of Gastroenterology, Department of Internal Medicine, Konkuk University Medical Center, Seoul, Korea
| | - Won Hyeok Choe
- Division of Gastroenterology, Department of Internal Medicine, Konkuk University Medical Center, Seoul, Korea
| | - Jeong Han Kim
- Division of Gastroenterology, Department of Internal Medicine, Konkuk University Medical Center, Seoul, Korea
| | - Byung Chul Yoo
- Division of Gastroenterology, Department of Internal Medicine, Konkuk University Medical Center, Seoul, Korea
| | - So Young Kwon
- Division of Gastroenterology, Department of Internal Medicine, Konkuk University Medical Center, Seoul, Korea
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Abstract
OBJECTIVE Direct-acting antiviral agents (DAAs) have been approved for treating hepatitis C virus (HCV) infection in China. However, they are substantially more expensive. The current analysis will investigate the cost-effectiveness of novel regimens compared with pegylated interferon and ribavirin (PR) therapies for informing Chinese decision-makers. METHODS A Markov model was developed to measure economic and health outcomes of novel regimens for genotype 1b, 2, 3, and 6 HCV infections compared with PR treatment. Clinical, cost, and utility inputs were gathered from published sources. Discounted quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs) are shown. The uncertainty was facilitated by one-way and probabilistic sensitivity analyses. RESULTS For genotype 1b HCV infection, the combination of paritaprevir, ritonavir, ombitasvir and dasabuvir was cost-saving compared with four competing alternatives. The ICERs of sofosbuvir plus ribavirin for genotypes 2 and 3 were lower than the threshold ($18,234/QALY). Among available strategies for patients with genotype 6, sofosbuvir in combination with ribavirin was the cost-saving alternative compared with PR. The results were robust to sensitivity analyses. CONCLUSIONS For both genotype 1b and 6 HCV infections in the context of Chinese patients, there were combinations of DAAs that were cost-saving compared with the usual PR treatment, and cost-effective for genotypes 2 and 3.
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Affiliation(s)
- Bin Wu
- a Medical Decision and Economic Group, Department of Pharmacy , Ren Ji Hospital, South Campus , School of Medicine , Shanghai Jiaotong University , Shanghai , PR China
| | - Zhenhua Wang
- b Department of Gastroenterology , Ren Ji Hospital , School of Medicine , Shanghai Jiaotong University , Shanghai , PR China
| | - Qing Xie
- c Department of Infectious Diseases, Ruijin Hospital , Shanghai Jiaotong University School of Medicine , Shanghai , PR China
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8
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Liverton NJ. Evolution of HCV NS3/4a Protease Inhibitors. TOPICS IN MEDICINAL CHEMISTRY 2019. [DOI: 10.1007/7355_2018_39] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Osawa M, Ueno T, Shiozaki T, Li H, Garimella T. Safety Exposure-Response Analysis for Daclatasvir, Asunaprevir, and Beclabuvir Combinations in HCV-Infected Subjects. J Clin Pharmacol 2018; 59:557-565. [PMID: 30566237 PMCID: PMC6590348 DOI: 10.1002/jcph.1347] [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] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 11/01/2018] [Indexed: 12/15/2022]
Abstract
The combination regimen of daclatasvir, asunaprevir, and beclabuvir has been developed for the treatment of hepatitis C virus infection. The objectives of this analysis were to characterize the relationship between the exposures of the daclatasvir, asunaprevir, and beclabuvir regimen and liver‐related laboratory elevations (Grade 3 or 4 alanine aminotransferase [ALT] and total bilirubin [Tbili]), and to evaluate the impact of selected covariates on the exposure‐response relationships. The exposure‐response analysis was performed with data from 1 phase 2 and 3 phase 3 studies in hepatitis C virus–infected subjects. The probability of liver‐related laboratory elevations were modeled using linear logistic regression. Selected covariates were tested using a forward‐addition and backward‐elimination approach. The final model for ALT elevation included Asian race, body weight in non‐Asian subjects, and asunaprevir exposure. The final model for Tbili elevation included Asian race, fibrosis score (F0‐F3 or F4) and asupanprevir exposure. Asian subjects had greater the Grade 3 or 4 ALT and Tbili elevation rates than non‐Asians. The Grade 3 or 4 ALT elevation rate increased with decreasing body weight in non‐Asian subjects. Subjects with F4 fibrosis score had a higher rate of Grade 3 or 4 Tbili elevation compared to subjects with F0 to F3 fibrosis score. Higher asunaprevir exposure was associated with increases in Grade 3 or 4 ALT and Tbili elevation rates; however, the impact on the ALT elevation was not clinically relevant and the effect on Tbili elevation was smaller than the other significant covariates.
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Singh S, Nautiyal A, Loke YK. Oral direct-acting antivirals and the incidence or recurrence of hepatocellular carcinoma: a systematic review and meta-analysis. Frontline Gastroenterol 2018; 9:262-270. [PMID: 30245788 PMCID: PMC6145438 DOI: 10.1136/flgastro-2018-101017] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 06/26/2018] [Accepted: 07/09/2018] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The influence of direct-acting antiviral (DAA) therapy for chronic hepatitis C virus on the risk of hepatocellular carcinoma (HCC) is conflicting. METHODS We conducted a systematic review and meta-analysis to determine the incidence or recurrence of HCC associated with oral DAA therapy. We searched PubMed, Scopus, Embase from inception to August 2017 to identify observational studies reporting on HCC among patients treated with DAAs. Two independent reviewers extracted data and assessed the risk of bias. Data were pooled by random-effects model. The primary outcome was the proportion of participants with incidence or recurrence of HCC (PROSPERO number CRD42017057040). RESULTS After reviewing 2080 citations, we included 8 controlled studies and 36 uncontrolled studies. The pooled proportion for incident HCC was 1.5 % (95% CI 1.0% to 2.1%; I2=90.1%; n= 542/39 145) from 18 uncontrolled studies and 3.3% (95% CI 1.2% to 9%; I2 =96%; n=109/6909) from 5 controlled studies, respectively. The pooled proportion for recurrent HCC was 16.7% (95% CI 10.2% to 26%; I2=84.8%; n=136/867) from 12 uncontrolled studies and 20.1% (95% CI 5.5% to 52.1%; I2=87.5%; n=36/225) from 3 controlled studies, respectively. There was no statistically significant effect on the risk of recurrent HCC (OR 0.50, 95%CI 0.16 to 1.59; I2 =73.4%) in a meta-analysis of three studies. CONCLUSIONS Our findings show low proportion of incident HCC, but high proportion of recurrent HCC on treatment with DAAs. Continued active surveillance for HCC after treatment with DAAs remains prudent.
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Affiliation(s)
- Sonal Singh
- Department of Family Medicine and Community Health, University of Massachusetts School of Medicine, Worcester, Massachusetts, USA,Meyers Primary Care Institute, University of Massachusetts School of Medicine, Worcester, MA, USA
| | - Amit Nautiyal
- Department of Medicine, Pulmonary and Critical Care Medicine, Albany Medical College, Albany, New York, USA
| | - Yoon K Loke
- Norwich Medical School, University of East Anglia, Norwich, Norfolk, UK
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Potent viral suppression and improvements in alpha-fetoprotein and measures of fibrosis in Japanese patients receiving a daclatasvir/asunaprevir/beclabuvir fixed-dose combination for the treatment of HCV genotype-1 infection. J Gastroenterol 2018; 53:1089-1097. [PMID: 29500489 DOI: 10.1007/s00535-018-1445-3] [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: 09/25/2017] [Accepted: 02/22/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND In the UNITY-3 study, 96% sustained virologic response (SVR12) rate was observed in Japanese patients with hepatitis C virus (HCV) genotype (GT)-1 infection treated for 12 weeks with fixed-dose daclatasvir, asunaprevir, and beclabuvir (DCV-TRIO). As HCV clearance may improve liver outcomes, we assessed hepatic fibrosis and alpha-fetoprotein (AFP), a hepatocellular carcinoma risk marker, pre- and post-treatment in UNITY-3. METHODS Treatment-naive or interferon-experienced UNITY-3 patients with HCV GT-1 who received twice-daily DCV-TRIO were assessed for fibrosis [FibroTest; FibroScan; fibrosis-4 index (FIB-4), aspartate-aminotransferase-to-platelet-ratio index] and AFP at baseline and Weeks 4 (FIB-4 only), 12 or 24 post-treatment. RESULTS Of 217 patients, 99% had GT-1b infection, 46% were aged > 65 years, 21% had compensated cirrhosis, and 26% baseline HCV-RNA > 107 IU/mL. All GT-1b patients treated ≥ 4 weeks achieved SVR12 with (n = 54) or without (n = 144) baseline NS5A polymorphisms associated with DCV resistance (positions 28/30/31/93). Statistically significant post-treatment reductions from baseline were observed for all fibrosis measures and AFP, with numerically greater reductions in cirrhotic patients. FibroTest category improved in 44%, remained stable in 50%, and worsened in 6% of patients; 98% with baseline AFP < 6 μg/L remained < 6 μg/L and 51% with baseline AFP ≥ 6 μg/L were < 6 μg/L post-treatment. CONCLUSIONS DCV-TRIO administered for 12 weeks to Japanese patients with primarily GT-1b infection achieved a high SVR12 rate and resulted in improved measures of hepatic fibrosis and serum AFP that may reduce the risk of future liver disease progression and hepatocellular carcinoma, particularly in those with compensated cirrhosis.
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Liu Y, Wang Z, Tobe RG, Lin H, Wu B. Cost Effectiveness of Daclatasvir Plus Asunaprevir Therapy for Chinese Patients with Chronic Hepatitis C Virus Genotype 1b. Clin Drug Investig 2018; 38:427-437. [PMID: 29417464 DOI: 10.1007/s40261-018-0621-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND OBJECTIVES Daclatasvir plus asunaprevir has shown superior efficacy and safety for treating hepatitis C virus genotype 1b infection in comparison with pegylated interferon and ribavirin. The objective of this analysis is to investigate the cost effectiveness of daclatasvir plus asunaprevir compared with interferon-α-based therapies from the perspective of the Chinese healthcare system. METHODS A Markov model was established to measure economic and health outcomes of daclatasvir plus asunaprevir compared with general interferon-α plus ribavirin and pegylated interferon plus ribavirin for hepatitis C virus genotype 1b infection. We also considered the two following scenarios: 24 weeks of daclatasvir plus asunaprevir used as a second-line treatment for ineligible/intolerant and non-responding patients with HCV during 48 weeks of first-line interferon-α plus ribavirin (interferon-α plus ribavirin and daclatasvir plus asunaprevir) or pegylated interferon plus ribavirin (pegylated interferon plus ribavirin and daclatasvir plus asunaprevir) treatment. Clinical costs and utility inputs were derived from the published literature. The incremental cost-effectiveness ratio was shown as costs in US dollars per quality-adjusted life-years gained. Uncertainty was examined by one-way and probabilistic sensitivity analyses. RESULTS Compared with interferon-α plus ribavirin, pegylated interferon and ribavirin, interferon-α plus ribavirin plus daclatasvir plus asunaprevir, and pegylated interferon plus ribavirin plus daclatasvir plus asunaprevir strategies, daclatasvir plus asunaprevir gained an additional 0.62, 0.32, 0.20, and 0.15 quality-adjusted life-year with increasing costs of US$11,950, US$671, US$8366, and -$3783, respectively. The incremental cost-effectiveness ratios of pegylated interferon and ribavirin, daclatasvir plus asunaprevir, interferon-α plus ribavirin and daclatasvir plus asunaprevir, and pegylated interferon plus ribavirin and daclatasvir plus asunaprevir against the baseline interferon-α plus ribavirin strategy were US$37,930, US$19,233, US$8495, and US$33,031 per quality-adjusted life-year gained. Daclatasvir plus asunaprevir and interferon-α plus ribavirin plus daclatasvir plus asunaprevir were presented as the cost-effective alternatives, and pegylated interferon plus ribavirin and pegylated interferon plus ribavirin and daclatasvir plus asunaprevir strategies dominated. The model outputs were sensitive to a patient's age, discount rate, and the risk ratio between pegylated interferon plus ribavirin and interferon-α plus ribavirin. CONCLUSIONS Daclatasvir plus asunaprevir in the Chinese setting is likely to be cost effective for treating hepatitis C virus genotype 1b infection.
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Affiliation(s)
- Yuchen Liu
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China.,Medical Decision and Economic Group, Department of Pharmacy, Ren Ji Hospital, South Campus, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Zhenhua Wang
- Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Ruoyan Gai Tobe
- Department of Health Policy, National Center for Child Health and Development, Tokyo, Japan
| | - Houwen Lin
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China. .,Medical Decision and Economic Group, Department of Pharmacy, Ren Ji Hospital, South Campus, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
| | - Bin Wu
- Medical Decision and Economic Group, Department of Pharmacy, Ren Ji Hospital, South Campus, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
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Kao JH, Yu ML, Chen CY, Peng CY, Chen MY, Tang H, Chen Q, Wu JJ. Twelve-week ravidasvir plus ritonavir-boosted danoprevir and ribavirin for non-cirrhotic HCV genotype 1 patients: A phase 2 study. J Gastroenterol Hepatol 2018; 33:1507-1510. [PMID: 29346834 DOI: 10.1111/jgh.14096] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Revised: 12/05/2017] [Accepted: 01/09/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM The need for all-oral hepatitis C virus (HCV) treatments with higher response rates, improved tolerability, and lower pill burden compared with interferon-inclusive regimen has led to the development of new direct-acting antiviral agents. Ravidasvir (RDV) is a second-generation, pan-genotypic NS5A inhibitor with high barrier to resistance. The aim of this phase 2 study (EVEREST study) was to assess the efficacy and safety of interferon-free, 12-week RDV plus ritonavir-boosted danoprevir (DNVr) and ribavirin (RBV) regimen for treatment-naïve Asian HCV genotype 1 (GT1) patients without cirrhosis. METHODS A total of 38 treatment-naïve, non-cirrhotic adult HCV GT1 patients were enrolled in this multicenter, open-label, single-arm phase 2 study (NCT03020095). All patients received a combination of RDV 200 mg once daily (q.d.) plus DNVr 100 mg/100 mg twice daily (b.i.d.) and oral RBV 1000/1200 mg/day (body weight < 75/≥ 75 kg) for 12 weeks. The primary endpoint was the rate of sustained virologic response 12 weeks after the end of treatment (SVR12). RESULTS Of 38 patients, all (100%) achieved SVR12. During the study, no treatment-related serious adverse events, no patients discontinued treatment due to adverse events, and no deaths were reported. Six of 37 (16%) patients with available sequences had HCV NS5A resistance-associated variants at baseline. All patients (6/6) with baseline NS5A resistance-associated variants achieved SVR12. CONCLUSIONS Twelve-week RDV and DNVr in combination with RBV for 12 weeks achieves the SVR12 rate of 100% in treatment-naïve non-cirrhotic Asian patients with HCV GT1 infection. This interferon-free regimen is also safe and well tolerated.
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Affiliation(s)
- Jia-Horng Kao
- Graduate Institute of Clinical Medicine and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Min-Lung Yu
- Division of Hepatobiliary, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chi-Yi Chen
- Division of Gastroenterology, Department of Internal Medicine, Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Cheng-Yuan Peng
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Ming-Yao Chen
- Division of Gastroenterology, Department of Internal Medicine, Taipei Medical University Shuang Ho Hospital, Taipei, Taiwan
| | | | | | - Jinzi J Wu
- Ascletis BioScience Co., Ltd., Hangzhou, China
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14
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Ueno T, Osawa M, Imai Y, Ishikawa H, Garimella T. Exposure-Response (Efficacy) Analysis of Daclatasvir and Asunaprevir in Japanese Patients With Hepatitis C Virus Infection. J Clin Pharmacol 2018; 58:1479-1488. [PMID: 30063245 PMCID: PMC6175176 DOI: 10.1002/jcph.1262] [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] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 04/19/2018] [Indexed: 12/12/2022]
Abstract
The treatment of hepatitis C virus (HCV) infection has been revolutionized by the development of all-oral combination regimens of direct-acting antiviral agents. The current analysis characterized the relationship between exposures of daclatasvir (DCV; tablets) and asunaprevir (ASV; capsules) and sustained virologic response (SVR) in Japanese patients who are HCV genotype (GT) 1b nonresponders to pegylated interferon (IFN) α/ribavirin or IFNβ/ribavirin, and IFN-based therapy-ineligible naive/intolerant patients receiving DCV and ASV, and provided insight into patient covariates that were most closely associated with efficacy. The relationship between the probability of achieving SVR at 12 weeks after treatment (SVR12) and average steady-state plasma concentrations estimated from population pharmacokinetic models for DCV and ASV is described using a logistic regression model with data from a phase 2 and a phase 3 study in Japanese patients infected with HCV GT 1b (N=265). The functional form characterization, which describes a relationship between DCV and ASV average steady-state plasma concentrations and SVR12, as well as covariate identification (demographic, laboratory, and prognostic and treatment covariates) were investigated during model development. The presence of the signature nonstructural protein 5A Y93H mutation at baseline was the only significant parameter of SVR12 in the final exposure-response model. Model evaluation plots demonstrate that the final model was able to predict the observed SVR rates. Exposure-response analysis supports the clinical utility of the combination regimen of 60-mg once-daily DCV and 100-mg twice-daily ASV in Japanese patients infected with HCV GT 1b.
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15
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Safety and effectiveness of daclatasvir and asunaprevir dual therapy in patients with genotype 1 chronic hepatitis C: results from postmarketing surveillance in Japan. Hepatol Int 2018; 12:244-253. [DOI: 10.1007/s12072-018-9872-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 05/16/2018] [Indexed: 12/26/2022]
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16
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Chen W, Ward T, Tan MP, Yan J, Wang PF, Wygant GD, Gordon J. Daclatasvir combined with asunaprevir is a cost-effective and cost-saving treatment for hepatitis C infection in China. J Comp Eff Res 2018; 7:785-795. [PMID: 29860879 DOI: 10.2217/cer-2018-0005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: To evaluate the cost-effectiveness of the novel all-oral direct-acting antiviral regimen daclatasvir + asunaprevir (DUAL), versus interferon-based regimens for the treatment of chronic hepatitis C virus genotype 1b infection. Methods: Inputs for a lifetime Markov model were sourced from clinical trials and published literature. Outputs include disease management costs, life expectancy, quality-adjusted life-years and cost-effectiveness. Sensitivity analyses assessed the drivers of cost-effectiveness and sustained virologic response thresholds at which DUAL is cost-saving. Results: DUAL was associated with discounted incremental quality-adjusted life-years of 1.29-3.85 and incremental life-years of 0.85-2.59 per patient, with discounted lifetime cost savings of USD$1415-8525. Associated sustained virologic response rates could fall to 45.1-84.8%, while remaining dominant. Conclusion: Treatment with DUAL provides significant clinical benefit, while accruing lower lifetime costs.
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Affiliation(s)
- Wen Chen
- Department of Health Economics, Fudan University, Shanghai, China
| | - Thomas Ward
- Health Economics and Outcomes Research Ltd, Cardiff, UK
| | - Mai Ping Tan
- Health Economics and Outcomes Research Ltd, Cardiff, UK
| | - Jing Yan
- Health Economics & Outcomes Research, Bristol-Myers Squibb Pharmaceuticals Ltd, Shanghai, China
| | - Peter Feng Wang
- World Wide Health Economics & Outcomes Research, Bristol-Myers Squibb Company, Princeton, New Jersey, USA
| | - Gail D Wygant
- World Wide Health Economics & Outcomes Research, Bristol-Myers Squibb Company, Princeton, New Jersey, USA
| | - Jason Gordon
- Health Economics and Outcomes Research Ltd, Cardiff, UK.,School of Medicine, University of Nottingham, Nottingham, United Kingdom
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17
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Reddy KR, Pol S, Thuluvath PJ, Kumada H, Toyota J, Chayama K, Levin J, Lawitz EJ, Gadano A, Ghesquiere W, Gerken G, Brunetto MR, Peng C, Silva M, Strasser SI, Heo J, McPhee F, Liu Z, Yang R, Linaberry M, Noviello S. Long-term follow-up of clinical trial patients treated for chronic HCV infection with daclatasvir-based regimens. Liver Int 2018; 38:821-833. [PMID: 28941023 PMCID: PMC5947593 DOI: 10.1111/liv.13596] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 09/18/2017] [Indexed: 12/29/2022]
Abstract
BACKGROUND & AIMS Daclatasvir has achieved high sustained virologic response (SVR) rates in diverse hepatitis C virus (HCV) populations. This study evaluated the long-term efficacy and safety of daclatasvir-based regimens administered during clinical studies. METHODS Patients enrolled within 6 months of parent study completion or protocol availability at the study sites. The primary objective was durability of SVR at follow-up Week 12 (SVR12). Secondary objectives included analysing HCV sequences in non-responders or responders who relapsed, and characterization of liver disease progression. RESULTS Between 24 February 2012 and 17 July 2015, this study enrolled and began following 1503 recipients of daclatasvir-based regimens (follow-up cut-off, 13 October 2015); 60% were male, 18% aged ≥65 years, 87% had genotype-1a (42%) or -1b (45%) infection, and 18% had cirrhosis. Median follow-up from parent study follow-up Week 12 was 111 (range, 11-246) weeks. 1329/1489 evaluable patients were SVR12 responders; 1316/1329 maintained SVR until their latest visit. Twelve responders relapsed by (n = 9) or after (n = 3) parent study follow-up Week 24; one was reinfected. Relapse occurred in 3/842 (0.4%) and 9/487 (2%) responders treated with interferon-free or interferon-containing regimens, respectively. Hepatic disease progression and new hepatocellular carcinoma were diagnosed in 15 and 23 patients, respectively. Among non-responders, emergent non-structural protein-5A (NS5A) and -3 (NS3) substitutions were replaced by wild-type sequences in 27/157 (17%) and 35/47 (74%) patients, respectively. CONCLUSIONS SVR12 was durable in 99% of recipients of daclatasvir-based regimens. Hepatic disease progression and new hepatocellular carcinoma were infrequent. Emergent NS5A substitutions persisted longer than NS3 substitutions among non-responders.
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Affiliation(s)
| | | | | | | | | | | | | | - Eric J. Lawitz
- Texas Liver InstituteUniversity of Texas Health Sciences CenterSan AntonioTXUSA
| | - Adrian Gadano
- Hospital Italiano de Buenos AiresBuenos AiresArgentina
| | - Wayne Ghesquiere
- Vancouver Island Health AuthorityUniversity of British ColumbiaVictoriaBCCanada
| | | | | | | | | | | | - Jeong Heo
- College of MedicineMedical Research InstitutePusan National University HospitalPusan National UniversityBusanKorea
| | | | | | - Rong Yang
- Bristol‐Myers SquibbWallingfordCTUSA
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18
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Wei L, Wang FS, Zhang MX, Jia JD, Yakovlev AA, Xie W, Burnevich E, Niu JQ, Jung YJ, Jiang XJ, Xu M, Chen XY, Xie Q, Li J, Hou JL, Tang H, Dou XG, Gandhi Y, Hu WH, McPhee F, Noviello S, Treitel M, Mo L, Deng J. Daclatasvir plus asunaprevir in treatment-naïve patients with hepatitis C virus genotype 1b infection. World J Gastroenterol 2018; 24:1361-1372. [PMID: 29599611 PMCID: PMC5871831 DOI: 10.3748/wjg.v24.i12.1361] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 02/09/2018] [Accepted: 02/25/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To assess daclatasvir plus asunaprevir (DUAL) in treatment-naïve patients from mainland China, Russia and South Korea with hepatitis C virus (HCV) genotype 1b infection.
METHODS Patients were randomly assigned (3:1) to receive 24 wk of treatment with DUAL (daclatasvir 60 mg once daily and asunaprevir 100 mg twice daily) beginning on day 1 of the treatment period (immediate treatment arm) or following 12 wk of matching placebo (placebo-deferred treatment arm). The primary endpoint was a comparison of sustained virologic response at posttreatment week 12 (SVR12) compared with the historical SVR rate for peg-interferon plus ribavirin (70%) among patients in the immediate treatment arm. The first 12 wk of the study were blinded. Safety was assessed in DUAL-treated patients compared with placebo patients during the first 12 wk (double-blind phase), and during 24 wk of DUAL in both arms combined.
RESULTS In total, 207 patients were randomly assigned to immediate (n = 155) or placebo-deferred (n = 52) treatment. Most patients were Asian (86%), female (59%) and aged < 65 years (90%). Among them, 13% had cirrhosis, 32% had IL28B non-CC genotypes and 53% had baseline HCV RNA levels of ≥ 6 million IU/mL. Among patients in the immediate treatment arm, SVR12 was achieved by 92% (95% confidence interval: 87.2-96.0), which was significantly higher than the historical comparator rate (70%). SVR12 was largely unaffected by cirrhosis (89%), age ≥ 65 years (92%), male sex (90%), baseline HCV RNA ≥ 6 million (89%) or IL28B non-CC genotypes (96%), although SVR12 was higher among patients without (96%) than among those with (53%) baseline NS5A resistance-associated polymorphisms (at L31 or Y93H). During the double-blind phase, aminotransferase elevations were more common among placebo recipients than among patients receiving DUAL. During 24 wk of DUAL therapy (combined arms), the most common adverse events (≥ 10%) were elevated alanine aminotransferase and upper respiratory tract infection; emergent grade 3-4 laboratory abnormalities were infrequently observed, and all grade 3-4 aminotransferase abnormalities (alanine aminotransferase, n = 9; aspartate transaminase, n = 6) reversed within 8-11 d. Two patients discontinued DUAL treatment; one due to aminotransferase elevations, nausea, and jaundice and the other due to a fatal adverse event unrelated to treatment. There were no treatment-related deaths.
CONCLUSION DUAL was well-tolerated during this phase 3 study, and SVR12 with DUAL treatment (92%) exceeded the historical SVR rate for peg-interferon plus ribavirin of 70%.
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Affiliation(s)
- Lai Wei
- Peking University People’s Hospital and Peking University Hepatology Institute, Beijing 100044, China
| | - Fu-Sheng Wang
- 302 Military Hospital of China, Beijing 100039, China
| | - Ming-Xiang Zhang
- the Sixth People’s Hospital of Shenyang, Shenyang 110006, Liaoning Province, China
| | - Ji-Dong Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Alexey A Yakovlev
- Saint-Petersburg State Healthcare Institution ‘Clinical Infectious Hospital n.a. S.P. Botkin’, Saint-Petersburg 191167, Russia
| | - Wen Xie
- Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Eduard Burnevich
- I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia
| | - Jun-Qi Niu
- The First Hospital of Jilin University, Jilin 1300021, Jilin Province, China
| | - Yong Jin Jung
- SMG-SNU Boramae Medical Center, Seoul 07061, South Korea
| | - Xiang-Jun Jiang
- Qingdao Municipal Hospital, Qingdao 266011, Shandong Province, China
| | - Min Xu
- Guangzhou No. 8 People’s Hospital, Guangzhou 510060, Guangdong Province, China
| | - Xin-Yue Chen
- Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Qing Xie
- Shanghai Ruijin Hospital, Jiaotong University School of Medicine, Shenyang 200025, Liaoning Province, China
| | - Jun Li
- TheFirst Affiliated Hospital with Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Jin-Lin Hou
- Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Hong Tang
- West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xiao-Guang Dou
- China Medical University, Shengjing Hospital, Shenyang 110004, Liaoning Province, China
| | - Yash Gandhi
- Bristol-Myers Squibb, Princeton, NJ 08540, United States
| | - Wen-Hua Hu
- Bristol-Myers Squibb, Princeton, NJ 08540, United States
| | - Fiona McPhee
- Bristol-Myers Squibb, Wallingford, CT 06492, United States
| | | | | | - Ling Mo
- Bristol-Myers Squibb, Shanghai 200040, China
| | - Jun Deng
- Bristol-Myers Squibb, Shanghai 200040, China
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19
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Ji F, Wei B, Yeo YH, Ogawa E, Zou B, Stave CD, Li Z, Dang S, Furusyo N, Cheung RC, Nguyen MH. Systematic review with meta-analysis: effectiveness and tolerability of interferon-free direct-acting antiviral regimens for chronic hepatitis C genotype 1 in routine clinical practice in Asia. Aliment Pharmacol Ther 2018; 47:550-562. [PMID: 29327780 DOI: 10.1111/apt.14507] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Revised: 11/22/2017] [Accepted: 12/17/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Direct-acting antiviral (DAA) regimens have shown high efficacy and tolerability for patients with HCV genotype 1/1b (GT1/1b) in clinical trials. However, robust real-world evidence of interferon (IFN)-free DAA treatment for HCV GT1-infected patients in Asia is still lacking. AIM To systematically review and meta-analyse the effectiveness and tolerability of IFN-free DAA therapy for HCV GT1 infection in Asia. METHODS We included studies that enrolled adult patients with HCV GT1 infection in routine clinical practice in Asia, using IFN-free DAA regimens, and reported sustained virological response (SVR) after 12/24 weeks end-of-treatment by 31 May 2017. The pooled SVR rates were computed with a random-effects model. Subgroup analysis and meta-regression as previously registered in PROSPERO were performed to determine how pre-planned variables might have affected the pooled estimates. RESULTS We included 41 studies from eight countries and regions, comprising of 8574 individuals. The pooled SVR rates for GT1 were 89.9% (95% CI 88.6-91.1, I2 = 55.1%) with daclatasvir/asunaprevir (DCV/ASV) and 98.1% (95% CI 97.0-99.0, I2 = 41.0%) with ledipasvir/sofosbuvir ± ribavirin (LDV/SOF ± RBV). Baseline cirrhosis but not prior treatment history and age, attenuated the effectiveness of both regimens. Baseline resistance associated substitutions (RASs) severely attenuated SVR of DCV/ASV (65.4% vs 94.3%, P < 0.001) and only minimally with LDV/SOF ± RBV (94.5% vs 99.2%, P = 0.003). Patients with renal dysfunction treated with DCV/ASV showed a higher SVR rate (93.9% vs 89.8%, P = 0.046). Patients with hepatocellular carcinoma (HCC) LDV/SOF ± RBV achieved a lower SVR than those without HCC (94.1% vs 98.7%, P = 0.001). CONCLUSION All oral DAA treatment of HCV GT1 resulted in high cure rates in Asian patients in routine clinical practice setting including elderly patients and those with end-stage renal disease.
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Affiliation(s)
- F Ji
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA.,Department of Infectious Diseases, The Second Affiliated Hospital of Xi' an Jiaotong University, Xi'an, China.,Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - B Wei
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
| | - Y H Yeo
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
| | - E Ogawa
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA.,Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - B Zou
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
| | - C D Stave
- Department of Lane Medical Library, Stanford University Medical Center, Palo Alto, CA, USA
| | - Z Li
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - S Dang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi' an Jiaotong University, Xi'an, China
| | - N Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - R C Cheung
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA.,Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
| | - M H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
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20
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Wei L, Xie Q, Hou JL, Tang H, Ning Q, Cheng J, Nan Y, Zhang L, Li J, Jiang J, McNabb B, Zhang F, Camus G, Mo H, Osinusi A, Brainard DM, Gong G, Mou Z, Wu S, Wang G, Hu P, Gao Y, Jia J, Duan Z. Ledipasvir/sofosbuvir for treatment-naive and treatment-experienced Chinese patients with genotype 1 HCV: an open-label, phase 3b study. Hepatol Int 2018; 12:126-132. [PMID: 29637511 PMCID: PMC5904238 DOI: 10.1007/s12072-018-9856-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 03/15/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Chronic hepatitis C virus (HCV) infection is a significant medical burden in China, affecting more than 10 million persons. In clinical trials and real-world settings, treatment with ledipasvir/sofosbuvir in patients with genotype 1 HCV infection resulted in high sustained virologic response rates. Ledipasvir/sofosbuvir may provide a highly effective, short-duration, single-tablet regimen for Chinese patients with HCV infection. METHODS Chinese patients with genotype 1 HCV infection who were HCV treatment naive or treatment experienced, without cirrhosis or with compensated cirrhosis, were treated with open-label ledipasvir/sofosbuvir for 12 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after completing treatment (SVR12). For treatment-naive patients, SVR12 was compared to a historical rate of 57%. The primary safety endpoint was adverse events leading to permanent discontinuation of study drug; serious adverse events were also evaluated. The presence of resistance-associated substitutions (RASs) was evaluated by viral sequencing. RESULTS All 206 enrolled patients achieved SVR12 (100%; 95% CI 98-100%), including 106 treatment-naive patients (100%; 95% CI 97-100%), which was superior to a historical SVR rate of 57% (p < 0.001). All patients with baseline NS5A and NS5B RASs (14 and 1% of patients, respectively) achieved SVR12. The most common adverse events were viral upper respiratory tract infection (17%), upper respiratory tract infection (14%), and cough (6%). There were no discontinuations due to adverse events; and no treatment-related serious adverse events were reported. CONCLUSION Ledipasvir/sofosbuvir is a well tolerated and highly effective treatment for Chinese patients with genotype 1 HCV, regardless of prior treatment experience, cirrhosis status, or the presence of pretreatment RASs.
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Affiliation(s)
- Lai Wei
- Beijing Key Lab for Hepatitis C and Immunologic Liver Disease, Peking University Hepatology Institute, Peking University People's Hospital, 11 Xizhimen S St, Xicheng District, Beijing, 100044, China.
| | - Qing Xie
- Ruijin Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Jin Lin Hou
- Nanfang Hospital of Southern Medical University, Guangzhou, China
| | - Hong Tang
- West China Hospital, Sichuan University, Chengdu, China
| | - Qin Ning
- Tongji Hospital of Tongji Medical College, Huanzhong University of Science and Technology, Wuhan, China
| | - Jun Cheng
- Beijing Ditan Hospital Affiliated to Capital Medical University, Beijing, China
| | - Yuemin Nan
- The Third Hospital of Hebei Medical University, Hebei, China
| | - Lunli Zhang
- The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jun Li
- The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Jianning Jiang
- The First Affiliated Hospital of Guangxi Medical University, Guangxi, China
| | | | | | | | | | | | | | - Guozhong Gong
- The Second Xiangya Hospital of Central South University, Changsha, China
| | | | - Shanming Wu
- Clinical Center of Shanghai Public Health, Shanghai, China
| | | | - Peng Hu
- The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yanhang Gao
- The First Hospital of Jilin University, Changchun, China
| | - Jidong Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhongping Duan
- Beijing You-An Hospital, Capital Medical University, Beijing, China
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21
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Integrated pharmacokinetic/viral dynamic model for daclatasvir/asunaprevir in treatment of patients with genotype 1 chronic hepatitis C. Acta Pharmacol Sin 2018; 39:140-153. [PMID: 28880015 DOI: 10.1038/aps.2017.84] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 04/27/2017] [Indexed: 12/12/2022]
Abstract
In order to develop an integrated pharmacokinetic/viral dynamic (PK/VD) model to predict long-term virological response rates to daclatasvir (DCV) and asunaprevir (ASV) combination therapy in patients infected with genotype 1 (GT1) chronic hepatitis C virus (HCV), a systematic publication search was conducted for DCV and ASV administered alone and/or in combination in healthy subjects or patients with GT1 HCV infection. On the basis of a constructed meta-database, an integrated PK/VD model was developed, which adequately described both DCV and ASV PK profiles and viral load time curves. The IC50 values of DCV and ASV were estimated to be 0.041 and 2.45 μg/L, respectively, in GT1A patients. A sigmoid Emax function was applied to describe the antiviral effects of DCV and ASV, depending on the drug concentrations in the effect compartment. An empirical exponential function revealed that IC50 changing over time described drug resistance in HCV GT1A patients during DCV or ASV monotherapy. Finally, the PK/VD model was evaluated externally by comparing the expected and observed virological response rates during and post-treatment with DCV and ASV combination therapy in HCV GT1B patients. Both the rates were in general agreement. Our PK/VD model provides a useful platform for the characterization of pharmacokinetic/pharmacodynamic relationships and the prediction of long-term virological response rates to aid future development of direct acting antiviral drugs.
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22
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Kao JH, Yu ML, Peng CY, Heo J, Chu CJ, Chang TT, Lee YJ, Hu TH, Yoon KT, Paik SW, Lim YS, Ahn SH, Isakov V, McPhee F, Hu W, Scott Swenson E, Yin PD, Treitel M. Daclatasvir/asunaprevir/beclabuvir, all-oral, fixed-dose combination for patients with chronic hepatitis C virus genotype 1. J Gastroenterol Hepatol 2017; 32:1998-2005. [PMID: 28370350 DOI: 10.1111/jgh.13796] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Revised: 03/17/2017] [Accepted: 03/23/2017] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIM This multinational (Taiwan, South Korea, Russia) phase 3 study evaluated the all-oral, ribavirin-free, fixed-dose combination (DCV-TRIO) of daclatasvir (NS5A inhibitor) 30 mg, asunaprevir (NS3 inhibitor) 200 mg, and beclabuvir (NS5B inhibitor) 75 mg, in patients with chronic hepatitis C virus genotype-1 infection, with or without compensated cirrhosis. METHODS UNITY-4 (NCT02170727) was an open-label, two-cohort study in which 169 patients, treatment-naive (n = 138) or treatment-experienced (n = 31), received twice-daily DCV-TRIO for 12 weeks with 24 weeks of post-treatment follow-up. The primary efficacy end point was sustained virologic response at post-treatment week 12 (SVR12) in treatment-naive patients. RESULTS Eighty-eight (52%) patients were men, 81 (48%) Taiwanese, 78 (46%) Korean, and 10 (6%) Russian; 23 (14%) had compensated cirrhosis, and 52 (31%) were IL28B (rs1297860) non-CC genotype. Baseline resistance-associated NS5A polymorphisms (L31 and/or Y93) were detected in 25/165 (15%) patients with available genotype-1 sequencing data. SVR12 was achieved by 98.6% (136/138; 95% confidence interval: 94.9-99.8%) of treatment-naive and 100% (31/31; 95% confidence interval: 88.8-100%) of treatment-experienced patients. Both virologic failures were found to be infected with hepatitis C virus genotype-6g; 100% SVR12 was observed for genotype-1a (n = 8) and genotype-1b (n = 157). Two patients experienced serious adverse events. Eight (5%) patients experienced reversible grade 3/4 alanine aminotransferase or aspartate aminotransferase elevations, leading to discontinuation in four (2%); all achieved SVR12. There were no grade 3/4 total bilirubin increases and no deaths. CONCLUSIONS Twelve weeks of DCV-TRIO was well tolerated and provided 100% SVR12 in treatment-naive and treatment-experienced patients with genotype-1 infection, with or without cirrhosis, including those with baseline NS5A-L31 or NS5A-Y93 resistance-associated substitutions.
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Affiliation(s)
| | - Ming-Lung Yu
- Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Cheng-Yuan Peng
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Jeong Heo
- College of Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Chi-Jen Chu
- Taipei Veterans General Hospital, Taipei, Taiwan
| | | | - Youn-Jae Lee
- Inje University Busan Paik Hospital, Busan, Korea
| | - Tsung-Hui Hu
- Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung City, Taiwan
| | - Ki Tae Yoon
- Pusan National University School of Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea
| | | | | | - Sang Hoon Ahn
- Yonsei University College of Medicine, Seoul, South Korea
| | | | - Fiona McPhee
- Bristol-Myers Squibb, Princeton, New Jersey, USA
| | - Wenhua Hu
- Bristol-Myers Squibb, Princeton, New Jersey, USA
| | | | - Philip D Yin
- Bristol-Myers Squibb, Princeton, New Jersey, USA
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Ji F, Wang W, Dang S, Wang S, Li B, Bai D, Zhao W, Deng H, Tian C, Li Z. Outcomes after sofosbuvir-containing regimens for hepatitis C virus in patients with decompensated cirrhosis: a real-world study. Infect Agent Cancer 2017; 12:48. [PMID: 28924449 PMCID: PMC5598030 DOI: 10.1186/s13027-017-0158-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 09/05/2017] [Indexed: 02/06/2023] Open
Abstract
Background Direct-acting antivirals have been used for decompensated cirrhotic patients with hepatitis C virus (HCV) infection. However, the benefits in Chinese patients with decompensated cirrhosis are unclear. Methods Thirty patients with HCV infection and decompensated cirrhosis were administered sofosbuvir-containing regimens at our hospital between April and December 2015. The efficacy and safety of the treatments was determined by sustained virological response at week 12 (SVR 12), change of liver function and adverse events. Results The cohort included 13 treatment-experienced and 17 treatment-naïve patients. A total of 27 patients (90%) achieved SVR 12. No baseline characteristics (sex, age, treatment-experience, genotype, viral load, liver function or splenectomy) was association with achievement of SVR 12. Patients achieved SVR 12 had significantly improved liver function by post-treatment week 12 (P < 0.05). Of the 30 patients, six developed anemia, one developed hepatic decompensation, two developed impaired renal function and one developed a severe upper respiratory tract infection during the treatment. There was no death or HCC development during 12 months of follow-up off-therapy. Two patients (7.4%) with SVR 12 experienced new decompensated episodes during the follow-up. Conclusion Sofosbuvir-containing regimens are effective in Chinese HCV patients with decompensated cirrhosis, regardless of baseline characteristics, as demonstrated by a high rate of SVR 12, as well as improvement in liver function. Although antiviral therapy is generally well tolerated, a vigilant monitoring of anemia and renal function should be mandatory.
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Affiliation(s)
- Fanpu Ji
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xi Wu Road, Xi'an, 710004 Shaanxi Province People's Republic of China.,Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wenjun Wang
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xi Wu Road, Xi'an, 710004 Shaanxi Province People's Republic of China
| | - Shuangsuo Dang
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xi Wu Road, Xi'an, 710004 Shaanxi Province People's Republic of China
| | - Shengbang Wang
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xi Wu Road, Xi'an, 710004 Shaanxi Province People's Republic of China
| | - Burong Li
- Department of Clinical Laboratory, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Dan Bai
- Department of Biochemistry and Molecular Biology, Medical College of Xi'an Jiaotong University, Xi'an, China
| | - Wenxue Zhao
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xi Wu Road, Xi'an, 710004 Shaanxi Province People's Republic of China
| | - Hong Deng
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xi Wu Road, Xi'an, 710004 Shaanxi Province People's Republic of China
| | - Changyin Tian
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xi Wu Road, Xi'an, 710004 Shaanxi Province People's Republic of China
| | - Zongfang Li
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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24
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Yu JH, Lee JI, Lee KS, Kim JK. Real-life prevalence of resistance-associated variants against non-structural protein 5A inhibitors and efficiency of Daclatasvir + Asunaprevir therapy in Korean patients with genotype 1b hepatitis C. Virol J 2017; 14:164. [PMID: 28836992 PMCID: PMC5571669 DOI: 10.1186/s12985-017-0826-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 08/14/2017] [Indexed: 02/08/2023] Open
Abstract
Background Direct-acting antivirals (DAAs) for chronic hepatitis C (CHC) treatment are tolerable and highly effective in a shorter period of time than before. However, resistance-associated variants (RAVs) can affect the efficacy of DAAs. The aim of this study was to investigate the real-life prevalence of RAVs against non-structural protein 5A (NS5A) inhibitors in Korean patients with genotype 1b chronic hepatitis C. Methods All consecutive patients with CHC genotype 1b who underwent a RAV test at a single referral hospital were enrolled. Results A total of 142 patients (male 53, female 89) were tested for RAVs. The average age of the patients was 58 years. Liver cirrhosis was found in 34.5% (49/142) of patients, and 19.0% (29/142) of patients had previously undergone interferon-based treatment. Twenty-nine patients (20.4%) had RAVs (Y93 or L31). Y93H, L31, or Y93H with L31 were detected in 22 (15.5%), 8 (5.6%), and 1 (0.7%) patients, respectively. The presence of RAV was not affected by previous interferon-based treatment or by the existence of liver cirrhosis. Among 113 patients without baseline NS5A RAVs, 72 patients started daclatasvir (DCV) + asunaprevir (ASV) treatment and 95% (68/72) patients achieved virologic response at week 4. Virologic response at end of treatment and sustained virologic response at 12 weeks after treatment were achieved by 94% (68/72) and 94% (68/72), respectively. Conclusions In Korean patients with genotype 1b CHC, 20.4% (29 of 142) of patients showed RAVs against NS5A inhibitors. Patient without RAVs who received treatment with DCV + ASV showed high virologic response rates in Korea.
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Affiliation(s)
- Jung Hwan Yu
- Gangnam Severance Hospital, Department of Internal Medicine, Yonsei University College of Medicine, 20, 63-gil, Eonju-ro Gangnam-gu, Seoul, 06229, South Korea
| | - Jung Il Lee
- Gangnam Severance Hospital, Department of Internal Medicine, Yonsei University College of Medicine, 20, 63-gil, Eonju-ro Gangnam-gu, Seoul, 06229, South Korea
| | - Kwan Sik Lee
- Gangnam Severance Hospital, Department of Internal Medicine, Yonsei University College of Medicine, 20, 63-gil, Eonju-ro Gangnam-gu, Seoul, 06229, South Korea
| | - Ja Kyung Kim
- Gangnam Severance Hospital, Department of Internal Medicine, Yonsei University College of Medicine, 20, 63-gil, Eonju-ro Gangnam-gu, Seoul, 06229, South Korea.
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25
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Kan H, Imamura M, Kawakami Y, Daijo K, Teraoka Y, Honda F, Nakamura Y, Morio K, Kobayashi T, Nakahara T, Nagaoki Y, Kawaoka T, Tsuge M, Aikata H, Hayes CN, Miki D, Ochi H, Honda Y, Mori N, Takaki S, Tsuji K, Chayama K. Emergence of drug resistance-associated variants and changes in serum lipid profiles in sofosbuvir plus ledipasvir-treated chronic hepatitis C patients. J Med Virol 2017; 89:1963-1972. [PMID: 28657143 DOI: 10.1002/jmv.24885] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 06/08/2017] [Indexed: 12/22/2022]
Abstract
Combination of sofosbuvir plus ledipasvir therapy has been expected to enhance sustained virological response (SVR) rates in hepatitis C virus (HCV) genotype 1 chronic infected patients. We analyzed the emergence of drug resistance-associated variants (RAVs) in treatment failure and changes in lipid profiles in sofosbuvir/ledipasvir-treated patients. A total of 176 patients with chronic HCV genotype 1 infection without decompensated liver cirrhosis were treated with sofosbuvir/ledipasvir for 12 weeks. NS5A and NS5B RAVs were determined by either Invader assay or direct sequencing. Serum lipid-related markers were measured at the start of treatment and at week 4 in patients who received sofosbuvir/ledipasvir and ombitasvir/paritaprevir/ritonavir therapies. SVR was achieved in 94.9% (167 out of 176) of patients. SVR12 rate was 97.1% for patietns with low frequncy (<25%) of baseline NS5A RAVs, but 82.8% for patients with high frequency (>75%) of NS5A RAVs. In multivariate regression analysis, higher albumin (odds ratio [OR] = 0.020 for presence; P = 0.007), and NS5A-L31/Y93 RAVs with a population frequency <75% (OR = 29.860 for presence; P = 0.023) were identified as significant independent predictors for SVR12. NS5A-Y93H substitutions were detected in all nine treatment failures at HCV relapse, and three out of six patients with NS5A inhibitor-naïve patients achieved additional NS5A RAVs. Serum low-density lipoprotein cholesterol and apolipoprotein B levels were significantly elevated at week 4 in sofosbuvir/ledipasvir-treated patients. These elevations were greater than in ombitasvir/paritaprevir/ritonavir-treated patients. In conclusion, NS5A multi-RAVs are likely to develop in patients who fail to respond to sofosbuvir/ledipasvir therapy. Inhibition of HCV replication with sofosbuvir might affect lipid metabolism.
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Affiliation(s)
- Hiromi Kan
- 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
| | - Yoshiiku Kawakami
- 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
| | - Tomoki Kobayashi
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuko Nagaoki
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Clair Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Laboratory for Digestive Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
| | - Hidenori Ochi
- Laboratory for Digestive Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
| | - Yoji Honda
- Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Nami Mori
- Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Shintaro Takaki
- Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Keiji Tsuji
- Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Laboratory for Digestive Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
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26
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Morio R, Imamura M, Kawakami Y, Morio K, Kobayashi T, Yokoyama S, Kimura Y, Nagaoki Y, Kawaoka T, Tsuge M, Hiramatsu A, Nelson Hayes C, Aikata H, Takahashi S, Miki D, Ochi H, Mori N, Takaki S, Tsuji K, Chayama K. Safety and efficacy of dual therapy with daclatasvir and asunaprevir for older patients with chronic hepatitis C. J Gastroenterol 2017; 52:504-511. [PMID: 27631593 DOI: 10.1007/s00535-016-1255-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2016] [Accepted: 08/25/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND Daclatasvir and asunaprevir combination therapy has shown a high virological response for chronic genotype 1 hepatitis C virus (HCV)-infected patients. However, the safety and efficacy of the therapy for older patients are unknown. METHODS One hundred seventy patients younger than 75 years and 139 patients aged 75 years or older with genotype 1 HCV infection were treated for 24 weeks with daclatasvir plus asunaprevir. Pretreatment drug-resistance-associated variants at NS5A-L31 and NS5A-Y93 were determined by the Invader assay. Virological response and adverse events according to age were analyzed. RESULTS The sustained virological response (SVR) rate for older patients was similar to that for younger patients (97.1 and 92.4 % respectively). In multivariate regression analysis, prior simeprevir treatment (odds ratio 56.6 for absence; P < 0.001) was identified as a significant independent predictor of SVR. The SVR rate for patients with pretreatment resistance-associated variants (RAVs) at a low population frequency (less than 25 %) was similar to that for patients with no detectable RAVs. The frequency of adverse events was similar between younger and older patients. All 19 very elderly patients (85 years or older) completed the 24 weeks of treatment and achieved SVR. CONCLUSIONS Older patients have a virological response and tolerance of daclatasvir plus asunaprevir therapy similar to those of younger patients. Even though RAVs were detected, virological response similar to that for patients with no detectable RAVs may still be expected for patients with RAVs as long as the population frequency is low.
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Affiliation(s)
- Reona Morio
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Tomoki Kobayashi
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Satoe Yokoyama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yuki Kimura
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yuko Nagaoki
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Shoichi Takahashi
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Daiki Miki
- Laboratory for Digestive Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
| | - Hidenori Ochi
- Laboratory for Digestive Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
| | - Nami Mori
- Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Shintaro Takaki
- Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Keiji Tsuji
- Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan. .,Laboratory for Digestive Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan.
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27
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Wang HL, Lu X, Yang X, Xu N. Effectiveness and safety of daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: Systematic review and meta-analysis. J Gastroenterol Hepatol 2017; 32:45-52. [PMID: 27597318 DOI: 10.1111/jgh.13587] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 07/29/2016] [Accepted: 08/24/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Daclatasvir plus asunaprevir (DCV + ASV) has demonstrated potent antiviral activity in patients with hepatitis C virus (HCV) genotype 1b infection. A definite conclusion about efficacy and safety of DCV + ASV in patients with HCV genotype 1b is not available. A meta-analysis was conducted to evaluate outcomes of all-oral treatment with DCV + ASV in terms of sustained virological response at 12 (SVR12 ) and 24 (SVR24 ) weeks and adverse effects after the end of treatment. METHODS PUBMED, MEDLINE, and EMBASE databases were searched in May 2016. The data were analyzed with Review Manager 5.3. RESULTS Nine trials (n = 1690) met entry criteria. SVR12 was achieved by 89.9% of treatment-naïve patients, 84.7% of interferon-ineligible/intolerant patients, and 81.9% of nonresponder patients. Moreover, 89.0% of interferon-ineligible/intolerant patients and 83.1% of nonresponder patients achieved SVR24 . Baseline characteristics, including gender, race, advanced age, non-CC IL28B genotype, and cirrhosis, did not appear to impact SVR rates. However, the rate of SVR12 in all patients with viral load < 8 × 105 was higher than that of all those with viral load ≥ 8 × 105 (151/162 vs 625/753). Moreover, pre-existing nonstructural protein 5A resistance-associated variants (RAVs) were associated with virological failure during DCV + ASV therapy, resulting in the emergence of multiple RAVs. Treatment with DCV + ASV was well tolerated, with low incidences of serious adverse effects, discontinuations, and grade 3 or 4 laboratory abnormalities in all patients. CONCLUSIONS Daclatasvir plus asunaprevir provides a highly effective and well-tolerated treatment option for patients with HCV genotype 1b. However, patients with nonstructural protein 5A RAVs at baseline should be assessed to optimize more potent direct antiviral agent therapies.
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Affiliation(s)
- Hui-Lian Wang
- Department of Genetics and Molecular Biology, Xi'an Jiaotong University School of Medicine, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
| | - Xi Lu
- School of Mechanical Engineering, Xi'an Jiaotong University, Xi'an, China
| | - Xudong Yang
- Department of Genetics and Molecular Biology, Xi'an Jiaotong University School of Medicine, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
| | - Nan Xu
- 2nd Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, China
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Kohli A, Alshati A, Georgie F, Manch R, Gish RG. Direct-acting antivirals for the treatment of chronic hepatitis C in patients with chronic kidney disease. Therap Adv Gastroenterol 2016; 9:887-897. [PMID: 27803742 PMCID: PMC5076774 DOI: 10.1177/1756283x16665254] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
All-oral, direct-acting antivirals (DAAs) have significantly improved the efficacy and safety of chronic hepatitis C (CHC) treatment but their effectiveness and safety among patients with chronic kidney disease (CKD) remains poorly understood. Our aim was to assess the efficacy and safety of DAAs for treatment of CKD patients. The National Library of Medicine through PubMed was searched for studies evaluating the efficacy of DAAs for the treatment of patients with CKD stages 4 or 5, as defined by the Kidney Disease Outcomes Quality Initiative guidelines [i.e. glomerular filtration rate (GFR) 15-29 ml/min per 1.73 m2 and GFR <15 ml/min per 1.73 m2, respectively, or hemodialysis or peritoneal dialysis]. Randomized clinical trials (RCTs) and relevant cohort studies were included if they were published in English and included sustained viral response after 12 weeks (SVR12) as a primary or secondary endpoint. After applying inclusion and exclusion criteria, eight studies (one RCT and seven cohort studies) following 350 patients were selected. For patients with CKD stage 4 or 5, ± hemodialysis, the overwhelming majority of DAA regimens were well-tolerated and resulted in SVR12 rates of 90-100%. Most studies were small, with the exception of one RCT evaluating elbasvir and grazoprevir. Overall, treatment of CHC in patients with CKD is highly effective with SVR12 rates similar to those seen in patients without CKD and with acceptable adverse event profiles. In patients with hepatitis C virus (HCV) genotype (GT) 1a, 1b or 4 and Stage 4 or 5 CKD, the best evidence available is for the use of elbasvir and grazoprevir. This combination as well as the combination of paritaprevir/ritonavir/ombitasvir/dasabuvir for HCV GT-1b are recommended. More studies are needed to assess efficacy and adverse effects of DAAs and their impact on CKD patients and to fully elucidate the effect of curing CHC on the natural history and sequelae of renal disease in CHC patients with CKD.
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Affiliation(s)
- Anita Kohli
- Dignity Health, St. Joseph’s Hospital and Medical Center, Division of Hepatology and Division of Infectious Disease, Phoenix, AZ, USA
| | - Ali Alshati
- Dignity Health, St. Joseph’s Hospital and Medical Center, Division of Hepatology, Phoenix, AZ, USA
| | - Fawaz Georgie
- Dignity Health, St. Joseph’s Hospital and Medical Center, Division of Hepatology, Phoenix, AZ, USA
| | - Richard Manch
- Dignity Health, St. Joseph’s Hospital and Medical Center, Division of Hepatology, Phoenix, AZ, USA
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Hernandez D, Yu F, Huang X, Kirov S, Pant S, McPhee F. Impact of Pre-existing NS5A-L31 or -Y93H Minor Variants on Response Rates in Patients Infected with HCV Genotype-1b Treated with Daclatasvir/Asunaprevir. Adv Ther 2016; 33:1169-79. [PMID: 27287851 DOI: 10.1007/s12325-016-0354-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Indexed: 12/21/2022]
Abstract
INTRODUCTION The combination of daclatasvir (DCV, pan-genotypic NS5A inhibitor) plus asunaprevir (ASV; NS3 protease inhibitor) is approved in Japan, Korea and other countries for the treatment of chronic hepatitis C virus (HCV) genotype (GT)-1. A high (~90 to 100%) sustained virologic response (SVR) with DCV/ASV therapy has been achieved by excluding patients infected with HCV GT-1b with baseline NS5A resistance-associated variants (RAVs) at L31 or Y93H detected by direct sequencing (DS). We set out to determine whether patients with minor variants at NS5A-L31 or -Y93H, detected by next-generation sequencing (NGS), impacted SVR rates with DCV/ASV therapy. METHODS Baseline samples from 222 interferon (IFN)-ineligible/intolerant (N = 135) and prior non-responder (N = 87) patients infected with GT-1b who were treated with DCV/ASV for 24 weeks in the Phase 3 clinical study AI447026 were prepared for NGS (Ion-Torrent platform). The prevalence of baseline NS5A RAVs and their impact on SVR when observed at ≥1% by NGS in a patient's virus population were examined. NGS and DS (sensitivity ≥20%) data were compared. RESULTS The prevalence of baseline NS5A RAVs at L31 or Y93H was 29% (63/219) and 18% (39/214) by NGS and DS, respectively. SVR24 rates were comparable in patients without observed baseline L31 or Y93H polymorphisms whether assessed by NGS (96%; 148/154) or by the less sensitive DS platform (95%; 164/173). CONCLUSION Optimal SVR rates (≥95%) to DCV/ASV treatment were achieved using DS to exclude patients infected with GT-1b with NS5A RAVs at L31 or Y93H representing ≥20% of their virus population. Exclusion by NGS of patients with minor variants in NS5A (<20%) did not enhance SVR rates. These results suggest that the presence of minor variants in NS5A does not appear to impact the overall SVR rate in patients with GT-1b treated with DCV/ASV. FUNDING This study was sponsored by Bristol-Myers Squibb. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01497834.
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Affiliation(s)
- Dennis Hernandez
- Bristol-Myers Squibb, Research and Development, Wallingford, CT, USA
| | - Fei Yu
- Bristol-Myers Squibb, Research and Development, Wallingford, CT, USA
| | - Xin Huang
- Bristol-Myers Squibb, Research and Development, Hopewell, NJ, USA
| | - Stefan Kirov
- Bristol-Myers Squibb, Research and Development, Hopewell, NJ, USA
| | - Saumya Pant
- Bristol-Myers Squibb, Research and Development, Hopewell, NJ, USA
| | - Fiona McPhee
- Bristol-Myers Squibb, Research and Development, Wallingford, CT, USA.
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