|
1
|
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.
Collapse
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
| |
Collapse
|
|
2
|
Sabry N, Kamel AM, Cordie A, Esmat G. Daclatasvir as a hepatitis C infection treatment option: an up-to-date evaluation. Expert Opin Pharmacother 2023; 24:159-170. [PMID: 36369914 DOI: 10.1080/14656566.2022.2145883] [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: 11/15/2022]
Abstract
INTRODUCTION Globally, it is estimated that 290,000 patients infected with hepatitis C virus (HCV) died from hepatitis C consequences, including cirrhosis and hepatocellular carcinoma in 2019. Although daclatasvir (DCV), combined with sofosbuvir (SOF), is effective in HCV patients, the new pan-genotypic combinations are considered by many as more cost-effective and successful in eradicating HCV infection. AREAS COVERED This review discusses the safety, efficacy, and cost-effectiveness of DCV as an HCV treatment option based on real-world studies and pharmacoeconomic evaluations. EXPERT OPINION Real-life studies suggest that SOF/DCV has acceptable sustained virological response and can be used successfully to manage HCV. Nonetheless, the use of SOF/DCV is limited by the longer treatment duration in genotype (GT)-3 patients and the need for ribavirin (RBV) in treatment-experienced patients which increases the likelihood of adverse effects. DCV is likely to remain as a therapeutic option for the management of GT-1, GT-2, and GT-4 patients in resource limited settings, while GT-3 patients are more likely to benefit from RBV-free direct-acting antiviral combinations such as SOF/velpatasvir for 12 weeks or glecaprevir/pibrentasvir for 8 weeks. The introduction of generics for these new pan-genotypic drugs would likely eliminate the need for SOF/DCV in the near future.
Collapse
Affiliation(s)
- Nirmeen Sabry
- Clinical Pharmacy Department, College of Pharmacy, Cairo University, Cairo, 11562, Egypt
| | - Ahmed M Kamel
- Clinical Pharmacy Department, College of Pharmacy, Cairo University, Cairo, 11562, Egypt
| | - Ahmed Cordie
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, 11562, Egypt.,Kasr Alaini HIV and Viral Hepatitis Fighting Group, Faculty of Medicine, Cairo University, Cairo, 11562, Egypt
| | - Gamal Esmat
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, 11562, Egypt
| |
Collapse
|
|
3
|
Affiliation(s)
- Nicholas A Meanwell
- Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, P.O. Box 4000, Princeton, New Jersey 08543-4000, United States
| | - Gunda I Georg
- College of Pharmacy, University of Minnesota, 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States
| | - Shaomeng Wang
- University of Michigan, Departments of Internal Medicine, Pharmacology and Medicinal Chemistry and Michigan Center for Therapeutic Innovation, Ann Arbor, Michigan 48109, United States
| |
Collapse
|
|
4
|
Pawlotsky JM, Negro F, Aghemo A, Berenguer M, Dalgard O, Dusheiko G, Marra F, Puoti M, Wedemeyer H. EASL recommendations on treatment of hepatitis C: Final update of the series ☆. J Hepatol 2020; 73:1170-1218. [PMID: 32956768 DOI: 10.1016/j.jhep.2020.08.018] [Citation(s) in RCA: 748] [Impact Index Per Article: 149.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 08/18/2020] [Indexed: 02/08/2023]
Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, with approximately 71 million chronically infected individuals worldwide. Clinical care for patients with HCV-related liver disease has advanced considerably thanks to an enhanced understanding of the pathophysiology of the disease, as well as developments in diagnostic procedures and improvements in therapy and prevention. These therapies make it possible to eliminate hepatitis C as a major public health threat, as per the World Health Organization target, although the timeline and feasibility vary from region to region. These European Association for the Study of the Liver recommendations on treatment of hepatitis C describe the optimal management of patients with recently acquired and chronic HCV infections in 2020 and onwards.
Collapse
|
|
5
|
Jiang X, Lv X, Chang L, Yan Y, Ji H, Sun H, Guo F, Rodgers MA, Yin P, Wang L. Molecular characterization of hepatitis C virus for subtype determination and resistance-associated substitutions detection among Chinese voluntary blood donors. Antiviral Res 2020; 181:104871. [PMID: 32717286 DOI: 10.1016/j.antiviral.2020.104871] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 05/28/2020] [Accepted: 07/01/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND The high prevalence of hepatitis C virus (HCV) infection and the resulting burden of the disease are significant issues to public health worldwide. Although direct-acting antiviral drugs (DAAs) with good tolerance and bioavailability are available, resistance-associated substitutions (RASs) often jeopardize the successful sustainment of virological responses in HCV treatment. High-frequency baseline RASs in treatment-naïve patients can lead to failures in DAA treatment. Clinical data on HCV RASs in patients from China are limited and require investigations. METHODS 262 HCV RNA positive plasma from Chinese blood donors were genotyped and amplified with subtype-specific primers for NS3 and NS5A regions. RASs were analyzed using Geno2pheno. The codon usage of each resistance-associated substitution was calculated for genetic barrier analysis. RESULTS The two main subtypes in mainland China were 1b and 2a, followed by subtype 6a, 3b, 3a, and 1a. In NS3 region of 1b subtype, substitutions (T54S, V55A, Y56F, Q80 K/L, S122 G/T, R117 H/C, V170I and S174A) were present in 89.7% (96/107) of the samples. Other RASs (M28L, R30Q, P58 L/S and Y93H) were observed in 22.1% (25/113) of the samples in NS5A region. A crucial RAS, Q80K, and two other mutations (S122G + V170I) was identified in the same sequence, which reduced its susceptibility to protease inhibitor ASV and resulted in resistance to SMV. In NS5A, Y93H was detected in 9.7% (11/113) of the 1b samples, leading to medium-to-high level resistance to all six commercialized NS5A inhibitors. S122G-NS3 and Y93H-NS5A occurred simultaneously in 38.1% (7/22) of the samples with mutations in both two regions. Moreover, codon usage of S122G-NS3 and Y93H-NS5A revealed that both variants had the lowest genetic barrier and required only one transition to confer resistance. CONCLUSIONS Low genetic barriers facilitated the generation of resistance mutants and threated the efficacy of DAA regimens. The baseline RASs posed a great challenge to real-world DAA application.
Collapse
Affiliation(s)
- Xinyi Jiang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, PR China; Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, PR China; Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China.
| | - Xiaoting Lv
- Abbott Laboratories, Research and Development, Shanghai, PR China.
| | - Le Chang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, PR China; Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, PR China.
| | - Ying Yan
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, PR China; Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, PR China.
| | - Huimin Ji
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, PR China; Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, PR China.
| | - Huizhen Sun
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, PR China; Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, PR China; Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China.
| | - Fei Guo
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, PR China; Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, PR China.
| | - Mary A Rodgers
- Abbott Laboratories, Infectious Disease Research, Abbott Park, IL, USA.
| | - Peng Yin
- Abbott Laboratories, Infectious Disease Research, Abbott Park, IL, USA.
| | - Lunan Wang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, PR China; Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, PR China; Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China.
| |
Collapse
|
|
6
|
Costa VD, Pellegrini P, Rotman V, Pittella AM, Nunes EP, Lago BV, Lampe E, Mello FCA. Resistance Mutations A30K and Y93N Associated with Treatment Failure with Sofosbuvir and Daclatasvir for Hepatitis C Virus Infection Non-Responder Patients: Case Reports. Viruses 2019; 11:v11111004. [PMID: 31683616 PMCID: PMC6893792 DOI: 10.3390/v11111004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 08/28/2019] [Accepted: 09/05/2019] [Indexed: 12/13/2022] Open
Abstract
In Brazil, hepatitis C treatment has been evolving significantly with the licensing of direct-acting antivirals (DAAs). However, viral determinants (amino acid substitutions in hepatitis C virus (HCV) genome and infective genotype) associated with host factors (hepatic condition and prior HCV therapy) might limit the achievement of sustained virologic response (SVR). Here, we described two case reports in which the occurrence of HCV NS5A mutations A30K (subtype 3a) and Y93N (subtype 1a) might have influenced daclatasvir (DCV)/sofosbuvir (SOF) combined therapy non-response. Despite high response rates for DAA combined therapies in Brazil, these case reports stated the importance of an investigation about how to manage a DAA treatment failure since a combination of factors, especially the occurrence of resistance substitutions, could impact a rescue therapy with new available antivirals in clinical routine.
Collapse
Affiliation(s)
- Vanessa D Costa
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, Avenida Brasil, 4365-Manguinhos, 21040-900 Rio de Janeiro, RJ, Brazil.
| | - Patricia Pellegrini
- Serviço de Hepatologia, Universidade Federal do Rio de Janeiro, Rua Professor Paulo Rodolpho Rocco, 255, Cidade Universitária, 21044-020 Rio de Janeiro, RJ, Brazil.
| | - Vivian Rotman
- Serviço de Hepatologia, Universidade Federal do Rio de Janeiro, Rua Professor Paulo Rodolpho Rocco, 255, Cidade Universitária, 21044-020 Rio de Janeiro, RJ, Brazil.
| | - Ana Maria Pittella
- Hospital Quinta D'Or. Rua Almirante Baltazar, 435, São Cristóvão, 20941-150 Rio de Janeiro, RJ, Brazil.
| | - Estevão P Nunes
- Instituto Nacional de Infectologia Evandro Chagas, INI/FIOCRUZ, Avenida Brasil, 4365-Manguinhos, 21040-360 Rio de Janeiro, RJ, Brazil.
| | - Barbara V Lago
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, Avenida Brasil, 4365-Manguinhos, 21040-900 Rio de Janeiro, RJ, Brazil.
| | - Elisabeth Lampe
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, Avenida Brasil, 4365-Manguinhos, 21040-900 Rio de Janeiro, RJ, Brazil.
| | - Francisco C A Mello
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, Avenida Brasil, 4365-Manguinhos, 21040-900 Rio de Janeiro, RJ, Brazil.
| |
Collapse
|
|
7
|
Zhu X, Wang M, Liu M, Yu X, Huang P. Efficacy and safety of direct-acting antivirals for treatment-naive patients with genotype 1 hepatitis C virus infection. Per Med 2019; 16:421-429. [PMID: 31591934 DOI: 10.2217/pme-2018-0121] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This systematic review was performed on the basis of Preferred Reporting Items for Systematic Reviews and Meta-analyses and Cochrane recommendations to compare sustained virological response (SVR12) and the serious adverse events in patients treated by directing-acting antivirals. We conducted a literature search in PubMed/Medline, EBSCO, Embase and the Cochrane Library until 2018. A consistency model was used to get the relative effect of odds ratio among regimens and the possibility for the efficacy and safety of 13 regimen, and we divided these regimens into DUAL or TRIO regimens to conduct integrated data analysis. The results demonstrated that dual or triple directing-acting antiviral-combined regimens had higher SVR12 rates, Daclatasvir plus Asunaprevir may be a good choice for genotype 1 patients, and regimens without Ribavirin and interferon are safer.
Collapse
Affiliation(s)
- Xiaobo Zhu
- Department of Pharmacy, People's Hospital of Danyang, Danyang 212300, China
| | - Mingqi Wang
- Department of Epidemiology, Xu Zhou Medical University, Xuzhou 221000, China
| | - Mei Liu
- Department of Epidemiology, Nanjing Medical University, Nanjing 211166, China
| | - Xinghao Yu
- Department of Epidemiology, Xu Zhou Medical University, Xuzhou 221000, China
| | - Peng Huang
- Department of Epidemiology, Nanjing Medical University, Nanjing 211166, China.,Key Laboratory of Infectious Diseases, Nanjing Medical University, Nanjing 211166, China
| |
Collapse
|
|
8
|
Sofia MJ. The Discovery and Development of Daclatasvir: An Inhibitor of the Hepatitis C Virus NS5A Replication Complex. ACTA ACUST UNITED AC 2019. [PMCID: PMC7122418 DOI: 10.1007/7355_2018_47] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
|
|
9
|
Takeda H, Yamashita T, Ueda Y, Sekine A. Exploring the hepatitis C virus genome using single molecule real-time sequencing. World J Gastroenterol 2019; 25:4661-4672. [PMID: 31528092 PMCID: PMC6718035 DOI: 10.3748/wjg.v25.i32.4661] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 07/04/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Single molecular real-time (SMRT) sequencing, also called third-generation sequencing, is a novel sequencing technique capable of generating extremely long contiguous sequence reads. While conventional short-read sequencing cannot evaluate the linkage of nucleotide substitutions distant from one another, SMRT sequencing can directly demonstrate linkage of nucleotide changes over a span of more than 20 kbp, and thus can be applied to directly examine the haplotypes of viruses or bacteria whose genome structures are changing in real time. In addition, an error correction method (circular consensus sequencing) has been established and repeated sequencing of a single-molecule DNA template can result in extremely high accuracy. The advantages of long read sequencing enable accurate determination of the haplotypes of individual viral clones. SMRT sequencing has been applied in various studies of viral genomes including determination of the full-length contiguous genome sequence of hepatitis C virus (HCV), targeted deep sequencing of the HCV NS5A gene, and assessment of heterogeneity among viral populations. Recently, the emergence of multi-drug resistant HCV viruses has become a significant clinical issue and has been also demonstrated using SMRT sequencing. In this review, we introduce the novel third-generation PacBio RSII/Sequel systems, compare them with conventional next-generation sequencers, and summarize previous studies in which SMRT sequencing technology has been applied for HCV genome analysis. We also refer to another long-read sequencing platform, nanopore sequencing technology, and discuss the advantages, limitations and future perspectives in using these third-generation sequencers for HCV genome analysis.
Collapse
Affiliation(s)
- Haruhiko Takeda
- Department of Omics-based Medicine, Center for Preventive Medical Science, Chiba University, Chiba 260-0856, Japan
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Taiki Yamashita
- Department of Omics-based Medicine, Center for Preventive Medical Science, Chiba University, Chiba 260-0856, Japan
| | - Yoshihide Ueda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Akihiro Sekine
- Department of Omics-based Medicine, Center for Preventive Medical Science, Chiba University, Chiba 260-0856, Japan
| |
Collapse
|
|
10
|
Sofia MJ. The Discovery and Early Clinical Evaluation of the HCV NS3/4A Protease Inhibitor Asunaprevir (BMS-650032). TOPICS IN MEDICINAL CHEMISTRY 2019. [PMCID: PMC7123690 DOI: 10.1007/7355_2018_58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
The discovery of asunaprevir (1) began with the concept of engaging the small and well-defined S1’ pocket of the hepatitis C virus (HCV) NS3/4A protease that was explored in the context of tripeptide carboxylic acid-based inhibitors. A cyclopropyl-acyl sulfonamide moiety was found to be the optimal element at the P1-P1’ interface enhancing the potency of carboxylic acid-based prototypes by 10- to >100-fold, dependent upon the specific background. Optimization for oral bioavailability identified a 1-substituted isoquinoline-based P2* element that conferred a significant exposure advantage in rats compared to the matched 4-substituted quinoline isomer. BMS-605339 (30) was the first cyclopropyl-acyl sulfonamide derivative advanced into clinical trials that demonstrated dose-related reductions in plasma viral RNA in HCV-infected patients. However, 30 was associated with cardiac events observed in a normal healthy volunteer (NHV) and an HCV-infected patient that led to the suspension of the development program. Using a Langendorff rabbit heart model, a limited structure-cardiac liability relationship was quickly established that led to the discovery of 1. This compound, which differs from 30 only by changes in the substitution pattern of the P2* isoquinoline heterocycle and the addition of a single chlorine atom to the molecular formula, gave a dose-dependent reduction in plasma viral RNA following oral administration to HCV-infected patients without the burden of the cardiac events that had been observed with 30. A small clinical trial of the combination of 1 with the HCV NS5A inhibitor daclatasvir (2) established for the first time that a chronic genotype 1 (GT-1) HCV infection could be cured by therapy with two direct-acting antiviral agents in the absence of exogenous immune-stimulating agents. Development of the combination of 1 and 2 was initially focused on Japan where the patient population is predominantly infected with GT-1b virus, culminating in marketing approval which was granted on July 4, 2014. In order to broaden therapy to include GT-1a infections, a fixed dose triple combination of 1, 2, and the allosteric NS5B inhibitor beclabuvir (3) was developed, approved by the Japanese health authorities for the treatment of HCV GT-1 infection on December 20, 2016 and marketed as Ximency®.
Collapse
|
|
11
|
Zhai PB, Qing J, Li B, Zhang LQ, Ma L, Chen L. GP205, a new hepatitis C virus NS3/4A protease inhibitor, displays higher metabolic stability in vitro and drug exposure in vivo. Acta Pharmacol Sin 2018; 39:1746-1752. [PMID: 29930277 DOI: 10.1038/s41401-018-0046-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 05/12/2018] [Indexed: 12/14/2022]
Abstract
NS3/4A serine protease is a prime target for direct-acting antiviral therapies against hepatitis C virus (HCV) infection. Several NS3/4A inhibitors have been widely used in clinic, while new inhibitors with better characteristics are still urgently needed. GP205 is a new macrocyclic inhibitor of NS3/4A with low nanomolar activities against HCV replicons of genotypes 1b, 2a, 4a, and 5a, with EC50 values ranging from 1.5 to 12.8 nmol/L. In resistance selection study in vitro, we found resistance-associated substitutions on D168: The activity of GP205 was significantly attenuated against 1b replicon with D168V or D168A mutation, similar as simeprevir. No cross resistance of GP205 with NS5B or NS5A inhibitor was observed. Combination of GP205 with sofosbuvir or daclatasvir displayed additive or synergistic efficacy. The pharmacokinetic profile of GP205 was characterized in rats and dogs after oral administration, which revealed good drug exposure both in plasma and in liver and long plasma half-life. The in vitro stability test showed ideal microsomal and hepatic cells stability of GP205. The preclinical profiles of GP205 support further research on this NS3/4A inhibitor to expand the existing HCV infection therapies.
Collapse
|
|
12
|
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.
Collapse
|
|
13
|
Knops E, Sierra S, Kalaghatgi P, Heger E, Kaiser R, Kalinina OV. Epistatic Interactions in NS5A of Hepatitis C Virus Suggest Drug Resistance Mechanisms. Genes (Basel) 2018; 9:E343. [PMID: 29986475 PMCID: PMC6071292 DOI: 10.3390/genes9070343] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 06/29/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) causes a major health burden and can be effectively treated by direct-acting antivirals (DAAs). The non-structural protein 5A (NS5A), which plays a role in the viral genome replication, is one of the DAAs’ targets. Resistance-associated viruses (RAVs) harbouring NS5A resistance-associated mutations (RAMs) have been described at baseline and after therapy failure. A mutation from glutamine to arginine at position 30 (Q30R) is a characteristic RAM for the HCV sub/genotype (GT) 1a, but arginine corresponds to the wild type in the GT-1b; still, GT-1b strains are susceptible to NS5A-inhibitors. In this study, we show that GT-1b strains with R30Q often display other specific NS5A substitutions, particularly in positions 24 and 34. We demonstrate that in GT-1b secondary substitutions usually happen after initial R30Q development in the phylogeny, and that the chemical properties of the corresponding amino acids serve to restore the positive charge in this region, acting as compensatory mutations. These findings may have implications for RAVs treatment.
Collapse
Affiliation(s)
- Elena Knops
- Institute of Virology, University of Cologne, 50935 Cologne, Germany.
| | - Saleta Sierra
- Institute of Virology, University of Cologne, 50935 Cologne, Germany.
- German Center for Infection Research (DZIF)-Cologne-Bonn Partner Site, 50935 Cologne, Germany.
| | - Prabhav Kalaghatgi
- Department of Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, 66123 Saarbrücken, Germany.
- German Center for Infection Research (DZIF)-Saarbrücken Partner Site, 66123 Saarbrücken, Germany.
| | - Eva Heger
- Institute of Virology, University of Cologne, 50935 Cologne, Germany.
| | - Rolf Kaiser
- Institute of Virology, University of Cologne, 50935 Cologne, Germany.
- German Center for Infection Research (DZIF)-Cologne-Bonn Partner Site, 50935 Cologne, Germany.
| | - Olga V Kalinina
- Department of Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, 66123 Saarbrücken, Germany.
| |
Collapse
|
|
14
|
Esposito I, Marciano S, Trinks J. Pharmacokinetic and pharmacodynamic evaluation of daclatasvir, asunaprevir plus beclabuvir as a fixed-dose co-formulation for the treatment of hepatitis C. Expert Opin Drug Metab Toxicol 2018; 14:649-657. [PMID: 29855221 DOI: 10.1080/17425255.2018.1483336] [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: 12/18/2022]
Abstract
INTRODUCTION Many reports have evaluated the clinical efficacy and safety of the fixed-dose all-oral combination of daclatasvir, asunaprevir, and beclabuvir (DCV-TRIO), which was approved in Japan in December 2016 for the treatment of hepatitis C genotype (GT)-1 infection. Areas covered: This article reviews the pharmacodynamic and pharmacokinetic properties of the DCV-TRIO combination. The topics covered include data regarding the drug's absorption, distribution, metabolism, excretion, and antiviral activity strategies. Its therapeutic efficacy and safety in GT-1 infection from phase 2/3 clinical trials are also discussed. Expert opinion: The ideal regimen for the treatment of Hepatitis C virus infection should be potent, pangenotypic, Ribavirin-free, safe, co-formulated, and affordable. Considering these characteristics, DCV-TRIO is neither pangenotypic nor potent enough against GT-1a, regardless of the presence or absence of cirrhosis. Other potential limitations of this regimen are its dosification (twice-daily), and the fact that since it includes a protease inhibitor, it is contraindicated in decompensated cirrhosis. For these reasons, it has only been approved in Japan, where more than 70% of the patients are infected with GT-1b. However, this co-formulation might still have a place in the treatment of non-cirrhotic patients infected with GT-1b provided that massive access to treatment is facilitated.
Collapse
Affiliation(s)
- Isabella Esposito
- a Instituto de Ciencias Básicas y Medicina Experimental (ICBME), Instituto Universitario del Hospital Italiano , Buenos Aires , Argentina
| | - Sebastián Marciano
- b Hepatology Unit , Hospital Italiano de Buenos Aires , Buenos Aires , Argentina.,c Department of Research , Hospital Italiano de Buenos Aires , Buenos Aires , Argentina
| | - Julieta Trinks
- a Instituto de Ciencias Básicas y Medicina Experimental (ICBME), Instituto Universitario del Hospital Italiano , Buenos Aires , Argentina.,d National Council of Scientific and Technical Research (CONICET) , Buenos Aires , Argentina
| |
Collapse
|
|
15
|
Eley T, Garimella T, Li W, Bertz RJ. Asunaprevir: An HCV Protease Inhibitor With Preferential Liver Distribution. Clin Pharmacol Drug Dev 2018; 6:195-200. [PMID: 28263460 DOI: 10.1002/cpdd.315] [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: 09/03/2015] [Accepted: 09/15/2016] [Indexed: 12/24/2022]
Abstract
Asunaprevir is an inhibitor of the hepatitis C virus (HCV) NS3/4A protease, demonstrating efficacy in clinical studies in patients infected with HCV genotype 1 or 4, with either peginterferon/ribavirin or combinations of direct-acting antivirals. Because of preferential distribution of asunaprevir to the liver via organic anion-transporting polypeptide (OATP)-mediated transport, asunaprevir demonstrates high apparent oral clearance and very low plasma concentrations. Asunaprevir plasma concentrations are markedly increased by single-dose rifampin (an OATP inhibitor) and in subjects with moderate to severe hepatic impairment. In addition, modestly higher plasma concentrations of asunaprevir have been noted in subjects infected with HCV relative to healthy subjects and in Asian subjects relative to whites. At the marketed dose, infrequent hepatic transaminase abnormalities were poorly predicted by plasma concentrations. For a compound with these characteristics, hepatic concentrations may have provided an improved understanding of the in vivo pharmacokinetic and pharmacodynamic data to support decision making during development.
Collapse
Affiliation(s)
- Timothy Eley
- Research and Development, Bristol-Myers Squibb, Princeton, NJ, USA
| | - Tushar Garimella
- Research and Development, Bristol-Myers Squibb, Princeton, NJ, USA
| | - Wenying Li
- Research and Development, Bristol-Myers Squibb, Princeton, NJ, USA
| | - Richard J Bertz
- Research and Development, Bristol-Myers Squibb, Princeton, NJ, USA
| |
Collapse
|
|
16
|
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%.
Collapse
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
| |
Collapse
|
|
17
|
Honda K, Seike M, Oribe J, Endo M, Arakawa M, Tokoro M, Iwao M, Mori T, Nishimura J, Takahashi Y, Omori K, Yamashita T, Muro T, Murakami K. Usefulness of semiquantitative PCR-Invader assay for selecting candidates for daclatasvir plus asunaprevir combination therapy among patients with hepatitis C virus genotype 1b. Hepatol Res 2018; 48:255-263. [PMID: 29080280 DOI: 10.1111/hepr.12994] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2017] [Revised: 10/13/2017] [Accepted: 10/24/2017] [Indexed: 02/06/2023]
Abstract
AIMS PCR-Invader is a highly sensitive assay for detecting non-structural protein 5A (NS5A) resistance-associated variants (RAVs) of hepatitis C virus (HCV). Here, we validated the accuracy of the semiquantitative PCR-Invader (SQ-PI) assay compared to direct sequencing (DS) for identifying NS5A RAVs, and we evaluated the treatment efficacy of daclatasvir plus asunaprevir (DCV + ASV) for patients judged to be non-positive for NS5A RAVs by SQ-PI. METHODS Detection rates of NS5A RAVs by SQ-PI and DS were compared for 204 patients with HCV genotype 1b. Patients with non-positive results for NS5A RAVs by SQ-PI were treated by DCV + ASV, and the efficacy of this treatment was examined. RESULTS All samples judged as negative for NS5A RAVs by SQ-PI were similarly judged by DS. However, 29.7% of samples judged as negative for Y93H by DS were judged as weakly positive or positive by SQ-PI. Among 108 patients who were judged as negative by SQ-PI and treated by DCV + ASV, rates of sustained virologic response at 24 weeks (SVR24) were 96.3% in intention-to-treat analysis and 99.0% in patients who completed treatment. Among patients who were weakly positive for Y93H on SQ-PI, the SVR24 rate was 95.0% (19/20). This rate was 100% (78/78) in patients who were negative for Y93H on SQ-PI and completed treatment. CONCLUSION Treatment efficacy of DCV + ASV was extremely high among patients who were non-positive for NS5A RAVs on SQ-PI, especially for patients with negative results.
Collapse
Affiliation(s)
- Koichi Honda
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu City, Japan
| | - Masataka Seike
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu City, Japan
| | - Junya Oribe
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu City, Japan
| | - Mizuki Endo
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu City, Japan
| | - Mie Arakawa
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu City, Japan
| | - Masanori Tokoro
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu City, Japan
| | - Masao Iwao
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu City, Japan
| | | | - Junko Nishimura
- Department of Gastroenterology, Oita Cardiovascular Hospital, Oita City, Japan
| | - Yukou Takahashi
- Department of Gastroenterology, Oita Cardiovascular Hospital, Oita City, Japan
| | - Kaoru Omori
- Department of Internal Medicine, Sato Daiichi Hospital, Usa City, Japan
| | - Tsutomu Yamashita
- Department of Gastroenterology and Hepatology, National Hospital Organization Oita Medical Center, Oita City, Japan
| | - Toyokichi Muro
- Department of Gastroenterology and Hepatology, National Hospital Organization Oita Medical Center, Oita City, Japan
| | - Kazunari Murakami
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu City, Japan
| |
Collapse
|
|
18
|
Ahmed AM, Doheim MF, Mattar OM, Sherif NA, Truong DH, Hoa PTL, Hirayama K, Huy NT. Beclabuvir in combination with asunaprevir and daclatasvir for hepatitis C virus genotype 1 infection: A systematic review and meta-analysis. J Med Virol 2018; 90:907-918. [PMID: 28892235 DOI: 10.1002/jmv.24947] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2017] [Accepted: 08/29/2017] [Indexed: 01/12/2023]
Abstract
Daclatasvir, asunaprevir (ASV), and beclabuvir (BCV) are direct-acting antivirals (DAAs) for patients with hepatitis C virus genotype 1 infection. This systematic review and meta-analysis investigating the efficacy and safety of this three-drug combination in HCV genotype 1 infection. Eleven electronic search engines were searched for relevant publications. Studies were screened for eligibility and data was extracted. The outcomes were pooled as event rate and risk ratio (RR). The protocol was registered in PROSPERO (CRD42017054391). Among the included six studies, five studies were included for the meta-analysis (n = 1261). The three-drug combination showed a high response rate in naïve patients with sustained virologic response at week-12 posttreatment (SVR12 ) rate = 95.7% (95%CI [93.8-97.1]) and no difference detected by adding ribavirin (RBV) (the pooled RR = 0.98, 95%CI [0.90-1.08], P = 0.70) or comparing with interferon-experienced patients (RR = 1.02, 95%CI [0.98-1.07], P = 0.31) regardless the genotype 1 subtypes or IL28B genotype. Treatment failure was minimal and showed no difference regarding the previous comparisons. Increasing the dose or the duration did not show a significant increase in the efficacy. In conclusion, this analysis showed high response rates in HCV genotype 1-infected patients treated with daclatasvir, ASV, and BCV irrespective of RBV use, prior interferon-based therapy, or restriction on non-cirrhotic patients, IL28B genotype, or baseline resistance-associated variants.
Collapse
Affiliation(s)
| | | | | | | | - Duy Hieu Truong
- Quang Binh Pharmaceutical Joint-Stock Company, Quang Binh, Vietnam
| | - Pham T L Hoa
- Department of Tropical Diseases, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Kenji Hirayama
- Department of Immunogenetics, Institute of Tropical Medicine (NEKKEN), Leading Graduate School Program, and Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Nguyen Tien Huy
- Evidence Based Medicine Research Group & Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam.,Department of Clinical Product Development, Institute of Tropical Medicine (NEKKEN), Leading Graduate School Program, and Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| |
Collapse
|
|
19
|
Kitrinos KM, Corsa AC, Worth A, Hedskog C, Brainard DM, Miller MD, Mo H. Nonstructural protein 5A resistance profile in patients with chronic hepatitis C treated with ledipasvir-containing regimens without sofosbuvir. J Viral Hepat 2018; 25:126-133. [PMID: 28833932 DOI: 10.1111/jvh.12783] [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: 05/03/2017] [Accepted: 07/21/2017] [Indexed: 01/16/2023]
Abstract
The study aimed to evaluate the effects of baseline hepatitis C virus (HCV) nonstructural protein 5A (NS5A) resistance-associated substitutions (RASs) on sustained virologic response to ledipasvir (LDV)-containing regimens in the absence of sofosbuvir (SOF) in patients with HCV genotype (GT) 1 infection across 6 phase 2 clinical studies. We analysed data from 1103 patients who received either LDV + vedroprevir (NS3 protease inhibitor) + tegobuvir (NS5B inhibitor) ± ribavirin or LDV + ribavirin + pegylated interferon. Population sequencing of HCV NS5A was performed at baseline and at virologic failure from patient plasma samples. Of 1045 patients with available baseline sequences, 747 (67.7%) had GT1a, and 298 (26.9%) had GT1b infection. The overall prevalence of NS5A RASs at baseline was 9.4%; 7.6% (57/747) and 13.8% (41/298) of patients with GT1a and GT1b infection, respectively. The majority of GT1a-infected patients with NS5A RASs at baseline had a single NS5A RAS (78.9%) at NS5A positions K24R, M28T, Q30H/L, L31M and Y93H/N/C/S. The spectrum of NS5A RASs detected in GT1b patients was much less diverse compared to GT1a patients, with all patients harbouring a single NS5A RAS either L31M or Y93H/C. For patients treated with LDV-containing regimens in the absence of SOF, the presence of baseline NS5A RASs was associated with low SVR rates. In patients with virologic failure, nearly all had either pre-existing and/or emergent NS5A RASs: 287/287 (100%) and 40/42 (95.2%) patients with GT1a and GT1b infection, respectively. Three novel NS5A substitutions were identified as emergent NS5A RASs: K26E and S38F in GT1a; and L31I in GT1b. In conclusion, the presence of NS5A RASs at baseline reduced the SVR rate in patients treated with LDV in combination vedroprevir + tegobuvir ± ribavirin or ribavirin + pegylated interferon. Virologic failure was associated with the detection of NS5A RASs in nearly all patients. These results suggest that the resistance barrier may differ depending on HCV drug combination and may be more important than that of the individual DAAs.
Collapse
Affiliation(s)
| | - A C Corsa
- Gilead Sciences, Inc., Foster City, CA, USA
| | - A Worth
- Gilead Sciences, Inc., Foster City, CA, USA
| | - C Hedskog
- Gilead Sciences, Inc., Foster City, CA, USA
| | | | - M D Miller
- Gilead Sciences, Inc., Foster City, CA, USA
| | - H Mo
- Gilead Sciences, Inc., Foster City, CA, USA
| |
Collapse
|
|
20
|
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.
Collapse
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
| |
Collapse
|
|
21
|
Suda G, Furusyo N, Toyoda H, Kawakami Y, Ikeda H, Suzuki M, Arataki K, Mori N, Tsuji K, Katamura Y, Takaguchi K, Ishikawa T, Tsuji K, Shimada N, Hiraoka A, Yamsaki S, Nakai M, Sho T, Morikawa K, Ogawa K, Kudo M, Nagasaka A, Furuya K, Yamamoto Y, Kato K, Ueno Y, Iio E, Tanaka Y, Kurosaki M, Kumada T, Chayama K, Sakamoto N. Daclatasvir and asunaprevir in hemodialysis patients with hepatitis C virus infection: a nationwide retrospective study in Japan. J Gastroenterol 2018; 53:119-128. [PMID: 28560477 DOI: 10.1007/s00535-017-1353-y] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 05/22/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is common in hemodialysis patients and worsens their prognosis, while antiviral therapy options are limited. Recently, clinical trial and real-world, small-scale studies have reported excellent responses to direct-acting antivirals in patients with advanced chronic kidney diseases. However, real-world, large-scale data were lacking. This large multicenter analysis included HCV-infected hemodialysis patients receiving combination therapy with a nonstructural protein 5A (NS5A) inhibitor, daclatasvir (DCV), and a protease inhibitor, asunaprevir (ASV). METHODS Twenty-three centers in Japan participated in this study of 123 hemodialysis patients with genotype 1 HCV infection, who received DCV/ASV combination therapy between November 2014 and March 2016. We collected and analyzed data relating to treatment outcome, baseline clinical information, laboratory measurements (during and after the treatment), and adverse events. RESULTS Thirty-nine patients (31.7%) had advanced liver fibrosis, 12 (9.8%) had histories of hepatocellular carcinoma (HCC), and 18 (14.6%) had baseline resistance-associated variants (RAVs) of NS5A. The overall sustained virological response (SVR)12 rate was 95.9% (118/123). Notably, all patients with HCC and 94.4% (17/18) of those with NS5A RAVs achieved SVR12. Significant factors associated with non-SVR were advanced fibrosis and the interleukin-28B non-TT genotype at rs8099917. Four patients (3.3%) discontinued therapy because of adverse events including elevated serum alanine transaminase levels (n = 2), rash (n = 1), and HCC (n = 1); all of these achieved SVR12. CONCLUSIONS This real-world, nationwide study revealed that DCV/ASV combination therapy was safe and highly effective for hemodialysis patients with genotype 1 HCV infections. This study was registered at the UMIN Clinical Trials Registry (UMIN000024227).
Collapse
Affiliation(s)
- Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Gifu, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Hiroki Ikeda
- Division of Gastroenterology and Hepatology, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Michihiro Suzuki
- Division of Gastroenterology and Hepatology, St. Marianna University School of Medicine, Kanagawa, Japan
| | | | - Nami Mori
- 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
| | - Yoshio Katamura
- Department of Gastroenterology, Onomichi General Hospital, Hiroshima, Japan
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Toru Ishikawa
- Department of Gastroenterology and Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Japan
| | - Kunihiko Tsuji
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Noritomo Shimada
- Division of Gastroenterology and Hepatology, Ootakanomori Hospital, Chiba, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Sho Yamsaki
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Mineo Kudo
- Sapporo Hokuyu Hospital, Hokkaido, Japan
| | | | - Ken Furuya
- Department of Gastroenterology and Hepatology, Japan Community Health Care Organization (JCHO) Hokkaido Hospital, Hokkaido, Japan
| | | | - Kanji Kato
- Iwamisawa Manicipal General Hospital, Hokkaido, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, Japan
| | - Etsuko Iio
- Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yasuhito Tanaka
- Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Takashi Kumada
- Department of Gastroenterology, Ogaki Municipal Hospital, Gifu, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
| |
Collapse
|
|
22
|
Canini L, Imamura M, Kawakami Y, Uprichard SL, Cotler SJ, Dahari H, Chayama K. HCV kinetic and modeling analyses project shorter durations to cure under combined therapy with daclatasvir and asunaprevir in chronic HCV-infected patients. PLoS One 2017; 12:e0187409. [PMID: 29216198 PMCID: PMC5720697 DOI: 10.1371/journal.pone.0187409] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 10/19/2017] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND & AIMS High cure rates are achieved in HCV genotype-1b patients treated with daclatasvir and asunaprevir, DCV/ASV. Here we analyzed early HCV kinetics in genotype-1b infected Japanese subjects treated with DCV/ASV and retrospectively projected, using mathematical modeling, whether shorter treatment durations might be effective. METHODS HCV RNA levels were measured frequently during DCV/ASV therapy in 95 consecutively treated patients at a single center in Japan. Mathematical modeling was used to predict the time to cure, i.e, <1 virus copy in the extracellular body fluid. Patients with HCV<15 IU/ml at week 1 (n = 27) were excluded from modeling analysis due to insufficient HCV RNA data points. RESULTS Eighty nine of the 95 included patients (94%) achieved cure, 3 (3%) relapsed due to treatment-emergent resistance, and 3 (3%) completed therapy but were lost during follow up. Model fits from 68 patients with sufficient data points indicate that after a short pharmacological delay (15.4 min [relative standard error, rse = 26%]), DCV/ASV effectiveness in blocking HCV production was 0.999 [rse~0%], HCV half-life in blood was t1/2 = 1.7 hr [rse = 21%], and HCV-infected cell loss rate was 0.391/d [rse = 5%]. Modeling predicted that 100% and 98.5% of patients who had HCV<15 IU/ml at days 14 and 28 might have been cured with 6 and 8 weeks of therapy, respectively. There was a trend (p = 0.058) between younger age and shorter time to cure. CONCLUSION Modeling early HCV kinetics under DCV/ASV predicts that most patients would achieve cure with short treatment durations, suggesting that 24 weeks of DCV/ASV treatment can be significantly shortened.
Collapse
Affiliation(s)
- Laetitia Canini
- The program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, Illinois, United States of America
- Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Susan L. Uprichard
- The program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, Illinois, United States of America
| | - Scott J. Cotler
- The program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, Illinois, United States of America
| | - Harel Dahari
- The program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, Illinois, United States of America
- * E-mail: (KC); (HD)
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
- * E-mail: (KC); (HD)
| |
Collapse
|
|
23
|
Jakobsen JC, Nielsen EE, Feinberg J, Katakam KK, Fobian K, Hauser G, Poropat G, Djurisic S, Weiss KH, Bjelakovic M, Bjelakovic G, Klingenberg SL, Liu JP, Nikolova D, Koretz RL, Gluud C. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev 2017; 9:CD012143. [PMID: 28922704 PMCID: PMC6484376 DOI: 10.1002/14651858.cd012143.pub3] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs), e.g. sofosbuvir, are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). Sustained virological response (SVR) is used by investigators and regulatory agencies as a surrogate outcome for morbidity and mortality, based solely on observational evidence. However, there have been no randomised trials that have validated that usage. OBJECTIVES To assess the benefits and harms of DAAs in people with chronic HCV. SEARCH METHODS We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016. SELECTION CRITERIA Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and health-related quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and SVR. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. We evaluated the overall quality of the evidence, using GRADE. MAIN RESULTS We included a total of 138 trials randomising a total of 25,232 participants. The trials were generally short-term trials and designed primarily to assess the effect of treatment on SVR. The trials evaluated 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered DAAs that were discontinued or withdrawn from the market. Study populations were treatment-naive in 95 trials, had been exposed to treatment in 17 trials, and comprised both treatment-naive and treatment-experienced individuals in 24 trials. The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.We could not reliably determine the effect of DAAs on the market or under development on our primary outcome of hepatitis C-related morbidity or all-cause mortality. There were no data on hepatitis C-related morbidity and only limited data on mortality from 11 trials (DAA 15/2377 (0.63%) versus control 1/617 (0.16%); OR 3.72, 95% CI 0.53 to 26.18, very low-quality evidence). We did not perform Trial Sequential Analysis on this outcome.There is very low quality evidence that DAAs on the market or under development do not influence serious adverse events (DAA 5.2% versus control 5.6%; OR 0.93, 95% CI 0.75 to 1.15 , 15,817 participants, 43 trials). The Trial Sequential Analysis showed that there was sufficient information to rule out that DAAs reduce the relative risk of a serious adverse event by 20% when compared with placebo. The only DAA that showed a lower risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, the meta-analysis result showed no evidence of a difference.DAAs on the market or under development may reduce the risk of no SVR from 54.1% in untreated people to 23.8% in people treated with DAA (RR 0.44, 95% CI 0.37 to 0.52, 6886 participants, 32 trials, low quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).There was insufficient evidence from trials on withdrawn or discontinued DAAs to determine their effect on hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79; 5 trials, very low-quality evidence). However, these DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73; 29 trials, very low-quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). AUTHORS' CONCLUSIONS The evidence for our main outcomes of interest come from short-term trials, and we are unable to determine the effect of long-term treatment with DAAs. The rates of hepatitis C morbidity and mortality observed in the trials are relatively low and we are uncertain as to how DAAs affect this outcome. Overall, there is very low quality evidence that DAAs on the market or under development do not influence serious adverse events. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs may reduce the number of people with detectable virus in their blood, but we do not have sufficient evidence from randomised trials that enables us to understand how SVR affects long-term clinical outcomes. SVR is still an outcome that needs proper validation in randomised clinical trials.
Collapse
Affiliation(s)
- Janus C Jakobsen
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
- Holbaek HospitalDepartment of CardiologyHolbaekDenmark4300
| | - Emil Eik Nielsen
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Joshua Feinberg
- Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812Blegdamsvej 9CopenhagenDenmark2100
| | - Kiran Kumar Katakam
- Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812Blegdamsvej 9CopenhagenDenmark2100
| | - Kristina Fobian
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Goran Hauser
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Goran Poropat
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Snezana Djurisic
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagenDenmark
| | - Karl Heinz Weiss
- Heidelberg University HospitalInternal Medicine IV: Gastroenterology, Infectious Diseases, ToxicologyIm Neuenheimer Feld 410HeidelbergGermanyD‐69120
| | - Milica Bjelakovic
- University of NisMedical FacultyBoulevard Dr Zorana Djindjica 81NisSerbia18000
| | - Goran Bjelakovic
- Medical Faculty, University of NisDepartment of Internal MedicineZorana Djindjica 81NisSerbia18000
| | - Sarah Louise Klingenberg
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
| | - Jian Ping Liu
- Beijing University of Chinese MedicineCentre for Evidence‐Based Chinese Medicine11 Bei San Huan Dong Lu, Chaoyang DistrictBeijingChina100029
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
| | | | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
| | | |
Collapse
|
|
24
|
Jakobsen JC, Nielsen EE, Feinberg J, Katakam KK, Fobian K, Hauser G, Poropat G, Djurisic S, Weiss KH, Bjelakovic M, Bjelakovic G, Klingenberg SL, Liu JP, Nikolova D, Koretz RL, Gluud C. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev 2017; 9:CD012143. [PMID: 28922704 PMCID: PMC6484383 DOI: 10.1002/14651858.cd012143.pub2] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs), e.g. sofosbuvir, are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). Sustained virological response (SVR) is used by investigators and regulatory agencies as a surrogate outcome for morbidity and mortality, based solely on observational evidence. However, there have been no randomised trials that have validated that usage. OBJECTIVES To assess the benefits and harms of DAAs in people with chronic HCV. SEARCH METHODS We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016. SELECTION CRITERIA Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and health-related quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and SVR. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. We evaluated the overall quality of the evidence, using GRADE. MAIN RESULTS We included a total of 138 trials randomising a total of 25,232 participants. The trials were generally short-term trials and designed primarily to assess the effect of treatment on SVR. The trials evaluated 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered DAAs that were discontinued or withdrawn from the market. Study populations were treatment-naive in 95 trials, had been exposed to treatment in 17 trials, and comprised both treatment-naive and treatment-experienced individuals in 24 trials. The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.We could not reliably determine the effect of DAAs on the market or under development on our primary outcome of hepatitis C-related morbidity or all-cause mortality. There were no data on hepatitis C-related morbidity and only limited data on mortality from 11 trials (DAA 15/2377 (0.63%) versus control 1/617 (0.16%); OR 3.72, 95% CI 0.53 to 26.18, very low-quality evidence). We did not perform Trial Sequential Analysis on this outcome.There is very low quality evidence that DAAs on the market or under development do not influence serious adverse events (DAA 5.2% versus control 5.6%; OR 0.93, 95% CI 0.75 to 1.15 , 15,817 participants, 43 trials). The Trial Sequential Analysis showed that there was sufficient information to rule out that DAAs reduce the relative risk of a serious adverse event by 20% when compared with placebo. The only DAA that showed a lower risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, the meta-analysis result showed no evidence of a difference.DAAs on the market or under development may reduce the risk of no SVR from 54.1% in untreated people to 23.8% in people treated with DAA (RR 0.44, 95% CI 0.37 to 0.52, 6886 participants, 32 trials, low quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).There was insufficient evidence from trials on withdrawn or discontinued DAAs to determine their effect on hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79; 5 trials, very low-quality evidence). However, these DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73; 29 trials, very low-quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). AUTHORS' CONCLUSIONS The evidence for our main outcomes of interest come from short-term trials, and we are unable to determine the effect of long-term treatment with DAAs. The rates of hepatitis C morbidity and mortality observed in the trials are relatively low and we are uncertain as to how DAAs affect this outcome. Overall, there is very low quality evidence that DAAs on the market or under development do not influence serious adverse events. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs may reduce the number of people with detectable virus in their blood, but we do not have sufficient evidence from randomised trials that enables us to understand how SVR affects long-term clinical outcomes. SVR is still an outcome that needs proper validation in randomised clinical trials.
Collapse
Affiliation(s)
| | - Emil Eik Nielsen
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Joshua Feinberg
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Kiran Kumar Katakam
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalBlegdamsvej 9CopenhagenDenmark2100
| | - Kristina Fobian
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Goran Hauser
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Goran Poropat
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Snezana Djurisic
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalBlegdamsvej 9CopenhagenDenmark2100
| | - Karl Heinz Weiss
- Heidelberg University HospitalInternal Medicine IV: Gastroenterology, Infectious Diseases, ToxicologyIm Neuenheimer Feld 410HeidelbergGermanyD‐69120
| | - Milica Bjelakovic
- University of NisMedical FacultyBoulevard Dr Zorana Djindjica 81NisSerbia18000
| | - Goran Bjelakovic
- Medical Faculty, University of NisDepartment of Internal MedicineZorana Djindjica 81NisSerbia18000
| | - Sarah Louise Klingenberg
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Jian Ping Liu
- Beijing University of Chinese MedicineCentre for Evidence‐Based Chinese Medicine11 Bei San Huan Dong Lu, Chaoyang DistrictBeijingChina100029
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | | | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| |
Collapse
|
|
25
|
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.
Collapse
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
| |
Collapse
|
|
26
|
Serti E, Park H, Keane M, O’Keefe AC, Rivera E, Liang TJ, Ghany M, Rehermann B. Rapid decrease in hepatitis C viremia by direct acting antivirals improves the natural killer cell response to IFNα. Gut 2017; 66:724-735. [PMID: 26733671 PMCID: PMC6886885 DOI: 10.1136/gutjnl-2015-310033] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Revised: 11/23/2015] [Accepted: 11/24/2015] [Indexed: 12/26/2022]
Abstract
OBJECTIVE Chronic HCV infection is characterised by innate immune activation with increased interferon-stimulated genes (ISG) expression and by an altered phenotype of interferon-responsive natural killer (NK) cells. Here, we asked whether a rapid reduction in viremia by daclatasvir (DCV) and asunaprevir (ASV) improves the response to pegylated interferon (PegIFN) in patients who had previously failed a standard course of PegIFN/ribavirin (RBV) therapy. DESIGN Twenty-two HCV-infected non-responders to previous PegIFN/RBV therapy were studied for IFN-responsiveness of NK cells during quadruple (QUAD) therapy with DCV, ASV, PegIFN and RBV. A direct comparison of early NK cell responses in PegIFN/RBV therapy and QUAD therapy was performed for seven patients using paired cryopreserved peripheral blood mononuclear cells (PBMC) from both treatment courses. As a validation cohort, nine DCV/ASV-treated patients were studied for their NK cell response to in vitro stimulation with IFNα. RESULTS The 24 h virological response to QUAD therapy correlated with an increase in signal transducer and activator of transcription 1 (STAT1), phosphorylated STAT1 (pSTAT1) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in NK cells, and the STAT1/pSTAT1/TRAIL induction was greater during QUAD therapy than during previous PegIFN/RBV therapy. Successful QUAD therapy as well as successful IFN-free DCV/ASV regimen resulted in an improved functional NK cell response (degranulation and TRAIL expression) to in vitro stimulation with IFNα. CONCLUSIONS IFN-responsiveness can be improved by inhibiting HCV replication and reducing the HCV-induced activation of the innate immune response. This may provide a rationale for clinical trials of a brief period of direct acting antiviral therapy followed by PegIFN/RBV therapy to reduce the overall treatment costs in low-income and middle-income countries. TRIAL REGISTRATION NUMBERS NCT01888900 and NCT00718172.
Collapse
Affiliation(s)
- Elisavet Serti
- Immunology Section, National Institutes of Health, DHHS, Bethesda, MD, USA
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA
| | - Heiyoung Park
- Immunology Section, National Institutes of Health, DHHS, Bethesda, MD, USA
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA
| | - Meghan Keane
- Immunology Section, National Institutes of Health, DHHS, Bethesda, MD, USA
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA
| | - Ashley C. O’Keefe
- Immunology Section, National Institutes of Health, DHHS, Bethesda, MD, USA
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA
| | - Elenita Rivera
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA
| | - T. Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA
| | - Marc Ghany
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA
| | - Barbara Rehermann
- Immunology Section, National Institutes of Health, DHHS, Bethesda, MD, USA
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA
| |
Collapse
|
|
27
|
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.
Collapse
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.
| |
Collapse
|
|
28
|
Gitto S, Gamal N, Andreone P. NS5A inhibitors for the treatment of hepatitis C infection. J Viral Hepat 2017; 24:180-186. [PMID: 27925362 DOI: 10.1111/jvh.12657] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 10/24/2016] [Indexed: 12/12/2022]
Abstract
Today, we are witnessing a new era for the treatment of hepatitis C with excellent rates of virologic response and very good safety profiles. Among the many classes of direct-acting antivirals, the inhibitors of nonstructural protein 5A are particularly interesting. NS5A is a phosphorylated protein with a relevant role in viral replication. HCV-NS5A inhibitors show high potency, very good safety profile and high barrier to resistance. The amazing in vitro effectiveness of this class is associated with great efficacy in clinical trials in combination protocols with antivirals of other classes, with sustained virological response (SVR) obtained in more than 90% of patients. Herein, we sought to review the current knowledge regarding the NS5A protease complex inhibitors with special emphasis on clinical efficacy and development of viral resistance.
Collapse
Affiliation(s)
- Stefano Gitto
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Nesrine Gamal
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Pietro Andreone
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| |
Collapse
|
|
29
|
Mull ES, Sun LQ, Zhao Q, Eggers B, Pokornowski K, Zhai G, Rajamani R, Jenkins S, Kramer M, Wang YK, Fang H, Tenney D, Baldick CJ, Cockett MI, Meanwell NA, Scola PM. Functionalized triazines as potent HCV entry inhibitors. Bioorg Med Chem Lett 2017; 27:1089-1093. [PMID: 28089701 DOI: 10.1016/j.bmcl.2016.12.038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Revised: 12/13/2016] [Accepted: 12/14/2016] [Indexed: 01/29/2023]
Abstract
A series of potent and novel acylsulfonamide-bearing triazines were synthesized and the structure-activity relationships (SARs) as HCV entry inhibitors were evaluated. This acylsulfonamide series was derived from an early lead, 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid wherein the carboxylic acid was replaced with an acylsulfonamide moiety. This structural modification provided a class of compounds which projected an additional vector off the terminus of the acylsulfonamide functionality as a means to drive activity. This effort led to the discovery of potent analogues within this series that demonstrated sub-nanomolar EC50 values in the HCV pseudotype particle (HCVpp) assay.
Collapse
Affiliation(s)
- Eric S Mull
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
| | - Li-Qiang Sun
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Qian Zhao
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Betsy Eggers
- Department of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Kevin Pokornowski
- Department of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Guangzhi Zhai
- Department of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Ramkumar Rajamani
- Department of Computer-Assisted Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Susan Jenkins
- Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Melissa Kramer
- Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Ying-Kai Wang
- Department of Lead Evaluation, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Hua Fang
- Department of Lead Evaluation, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Daniel Tenney
- Department of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Carl J Baldick
- Department of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Mark I Cockett
- Department of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Nicholas A Meanwell
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Paul M Scola
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| |
Collapse
|
|
30
|
Hayes CN, Imamura M, Chayama K. The practical management of chronic hepatitis C infection in Japan - dual therapy of daclatasvir + asunaprevir. Expert Rev Gastroenterol Hepatol 2017; 11:103-113. [PMID: 27936974 DOI: 10.1080/17474124.2017.1270205] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Without treatment, many of the 200 million people worldwide with chronic hepatitis C virus (HCV) infection will develop cirrhosis or liver cancer. Japan was the first nation to approve an interferon-free therapy for HCV, and sustained viral response (SVR) rates >90% have been achieved with asunaprevir, a protease inhibitor, plus daclatasvir, an inhibitor of the non-structural 5A (NS5A) protein. Areas covered: This review provides an overview of the results from both clinical trials and real world experience with asunaprevir and daclatasvir therapy focused primarily on Japan. A literature search using the keywords 'asunaprevir,' 'daclatasvir,' 'interferon-free therapy,' and 'direct-acting antiviral drugs' was initially used to select relevant literature for inclusion in the review. Expert commentary: While not approved in the United States, dual therapy with asunaprevir plus daclatasvir has already been successfully used in Japan and throughout East Asia to treat many thousands of patients. Pre-existing or treatment-emergent NS5A-Y93 or -L31 resistance-associated variants (RAVs) may lead to viral breakthrough, and alternative therapies should be considered for these patients, but patients who harbor NS5A RAVs only at low frequency are likely to achieve SVR. The therapy has also been shown to be safe and effective with renal dysfunction or liver cirrhosis.
Collapse
Affiliation(s)
- C Nelson Hayes
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Minami-ku , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan
| | - Michio Imamura
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Minami-ku , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan
| | - Kazuaki Chayama
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Minami-ku , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan.,c Laboratory for Digestive Diseases , Center for Genomic Medicine, RIKEN , Hiroshima , Japan
| |
Collapse
|
|
31
|
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]
|
|
32
|
Wilson EM, Rosenthal ES, Kattakuzhy S, Tang L, Kottilil S. Clinical Laboratory Testing in the Era of Directly Acting Antiviral Therapies for Hepatitis C. Clin Microbiol Rev 2017; 30:23-42. [PMID: 27795306 PMCID: PMC5217793 DOI: 10.1128/cmr.00037-16] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Directly acting antiviral (DAA) combination therapies for chronic hepatitis C virus (HCV) infection are highly effective, but treatment decisions remain complex. Laboratory testing is important to evaluate a range of viral, host, and pharmacological factors when considering HCV treatment, and patients must be monitored during and after therapy for safety and to assess the viral response. In this review, we discuss the laboratory tests relevant for the treatment of HCV infection in the era of DAA therapy, grouped according to viral and host factors.
Collapse
Affiliation(s)
- Eleanor M Wilson
- Institute of Human Virology, University of Maryland School of Medicine, University of Maryland, Baltimore, Maryland, USA
- Critical Care Medicine Department of the NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Elana S Rosenthal
- Critical Care Medicine Department of the NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Sarah Kattakuzhy
- Institute of Human Virology, University of Maryland School of Medicine, University of Maryland, Baltimore, Maryland, USA
- Critical Care Medicine Department of the NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Lydia Tang
- Institute of Human Virology, University of Maryland School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - Shyam Kottilil
- Institute of Human Virology, University of Maryland School of Medicine, University of Maryland, Baltimore, Maryland, USA
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| |
Collapse
|
|
33
|
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.
Collapse
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
| |
Collapse
|
|
34
|
Gamal N, Gitto S, Andreone P. Efficacy and Safety of Daclatasvir in Hepatitis C: An Overview. J Clin Transl Hepatol 2016; 4:336-344. [PMID: 28097103 PMCID: PMC5225154 DOI: 10.14218/jcth.2016.00038] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 10/10/2016] [Accepted: 10/14/2016] [Indexed: 12/15/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a growing public health concern, with 184 million people infected worldwide. During the past decade, interferon has been the backbone of HCV treatment, even though it remains far from ideal. The latest development of the new direct antivirals has drastically changed the treatment approach for chronic hepatitis C (CHC). Inhibitors of the HCV NS5A region have garnered remarkable interest among treating physicians, due to their high potency and favourable safety profile. In particular, treatment with daclatasvir (DCV) has yielded high rates of vriologic response in patients infected with genotype (Gt) 1 and Gt 3, when used in combination with other antivirals of a different class, such as sofosbuvir. Although few data are available for DCV treatment of the other Gts, the results in patients with Gt 2 and Gt 4 infection appear promising, as do those for unique patient populations. NS5A-resistant viral variants can pre-exist or emerge after treatment failure for the HCV NS5A inhibitors. Nonetheless, DCV-resistant viral variants continue to be sensitive to interferon and other classes of antivirals such as NS3/4A and NS5B inhibitors. Herein, we aimed to provide an overview of the current knowledge about DCV in the treatment of CHC.
Collapse
Affiliation(s)
- Nesrine Gamal
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Stefano Gitto
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Pietro Andreone
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| |
Collapse
|
|
35
|
Scavone C, Sportiello L, Rafaniello C, Mascolo A, Sessa M, Rossi F, Capuano A. New era in treatment options of chronic hepatitis C: focus on safety of new direct-acting antivirals (DAAs). Expert Opin Drug Saf 2016; 15:85-100. [DOI: 10.1080/14740338.2016.1221396] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Cristina Scavone
- Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy
| | - Liberata Sportiello
- Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy
| | - Concetta Rafaniello
- Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy
| | - Annamaria Mascolo
- Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy
| | - Maurizio Sessa
- Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy
| | - Francesco Rossi
- Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy
| | - Annalisa Capuano
- Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy
| |
Collapse
|
|
36
|
Kawakami Y, Imamura M, Ikeda H, Suzuki M, Arataki K, Moriishi M, Mori N, Kokoroishi K, Katamura Y, Ezaki T, Ueno T, Ide K, Masaki T, Ohdan H, Chayama K. Pharmacokinetics, efficacy and safety of daclatasvir plus asunaprevir in dialysis patients with chronic hepatitis C: pilot study. J Viral Hepat 2016; 23:850-856. [PMID: 27346670 DOI: 10.1111/jvh.12553] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 04/26/2016] [Indexed: 12/23/2022]
Abstract
The aim of this study was to evaluate the pharmacokinetic profile of daclatasvir (DCV) and asunaprevir (ASV) dual therapy in haemodialysis patients infected with hepatitis C virus (HCV). Eighteen haemodialysis patients and 54 patients with normal renal function were treated with DCV and ASV dual therapy for 24 weeks. We evaluated the pharmacokinetic profiles of DCV and ASV and examined the rate of sustained virological response 12 weeks after the end of treatment (SVR12 ) and incidence of adverse events during treatment of haemodialysis patients infected with chronic HCV genotype 1 infection. To adjust for potential differences in baseline characteristics between haemodialysis patients and patients with normal renal function, we used propensity scores case-control matching methods. Area under the plasma concentration time curve from 0 to 6 h (AUC0-6 h ) of DCV was slightly lower in haemodialysis patients than in patients with normal renal function (P > 0.6). AUC0-6 h of ASV was significantly lower in haemodialysis patients (P = 0.012). SVR12 rates were 100% (18/18) for haemodialysis and 96.2% (52/54) for patients with normal renal function. Changes in mean log10 HCV RNA levels and viral response were higher in haemodialysis patients compared to patients with normal renal function. No discontinuations due to adverse events occurred. In conclusion, DCV and ASV dual therapy for HCV infection is effective and safe with similar results in haemodialysis patients compared to patients with normal renal function.
Collapse
Affiliation(s)
- Y Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - M Imamura
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - H Ikeda
- Division of Gastroenterology and Hepatology, St. Marianna University School of Medicine, Kanagawa, Japan
| | - M Suzuki
- Division of Gastroenterology and Hepatology, St. Marianna University School of Medicine, Kanagawa, Japan
| | - K Arataki
- Tsuchiya General Hospital, Hiroshima, Japan
| | - M Moriishi
- Tsuchiya General Hospital, Hiroshima, Japan
| | - N Mori
- Department of Gastroenterology/Liver Center, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - K Kokoroishi
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Y Katamura
- Department of Gastroenterology, Onomichi General Hospital, Hiroshima, Japan
| | - T Ezaki
- Department of Nephrology, Onomichi General Hospital, Hiroshima, Japan
| | - T Ueno
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - K Ide
- Department of Surgery, Division of Frontier Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | - T Masaki
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - H Ohdan
- Department of Surgery, Division of Frontier Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | - K Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan. .,Liver Research Project Center, Hiroshima University, Hiroshima, Japan. .,Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan.
| |
Collapse
|
|
37
|
Morio K, Imamura M, Kawakami Y, Morio R, Hatooka M, Kan H, Fujino H, Fukuhara T, Kobayashi T, Masaki K, Ono A, Nakahara T, Urabe A, Yokoyama S, Nagaoki Y, Kawaoka T, Hiraga N, Tsuge M, Hiramatsu A, Hayes CN, Aikata H, Ochi H, Chayama K. Effects of ITPA polymorphism on decrease of hemoglobin during simeprevir, peg-interferon, and ribavirin combination treatment for chronic hepatitis C. Hepatol Res 2016; 46:1256-1263. [PMID: 26916827 DOI: 10.1111/hepr.12681] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 02/14/2016] [Accepted: 02/15/2016] [Indexed: 02/08/2023]
Abstract
AIM Polymorphisms in the ITPA gene influence anemia during peg-interferon (PEG-IFN) and ribavirin (RBV) therapy, but their effects during triple therapy with simeprevir, PEG-IFN, and RBV are not sufficiently known. METHODS We analyzed 212 patients with genotype 1 chronic hepatitis C, who were treated with simeprevir plus PEG-IFN/RBV triple therapy, and assessed the effect of the ITPA polymorphism on hemoglobin levels and RBV dose reduction. ITPA (rs1127354) and IFNL4 (ss469415590) polymorphisms were genotyped using the Invader assay. A stepwise multivariate regression analysis was carried out to identify factors associated with outcome of the therapy. RESULTS Reduction of hemoglobin levels was similar between patients treated with simeprevir plus PEG-IFN/RBV and those treated with PEG-IFN/RBV therapy. In simeprevir plus PEG-IFN/RBV-treated patients, decreases in hemoglobin levels were faster and greater, and the cumulative proportion of patients with ribavirin dose reduction was significantly greater in ITPA genotype CC patients than in CA/AA patients. The total dose of simeprevir and PEG-IFN was similar between ITPA genotype CC and CA/AA patients. In contrast, the total dose of RBV was lower in patients with the CC genotype. Multivariate analysis showed that the IFNL4 TT/TT genotype, but not the ITPA SNP genotype, treatment history (treatment-naive or relapse during prior treatment), and treatment completion were significantly associated with outcome of therapy. CONCLUSION ITPA polymorphism influences hemoglobin levels and incidence of RVB dose reduction during simeprevir triple therapy, indicating the importance of monitoring anemia during treatment, particularly for ITPA genotype CC patients.
Collapse
Affiliation(s)
- Kei Morio
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Reona Morio
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masahiro Hatooka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiromi Kan
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takayuki Fukuhara
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomoki Kobayashi
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Keiichi Masaki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Ayako Urabe
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Satoe Yokoyama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuko Nagaoki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Nobuhiko Hiraga
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hidenori Ochi
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Laboratory for Digestive Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Laboratory for Digestive Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
| | | |
Collapse
|
|
38
|
Flisiak R, Kawazoe S, Znoyko O, Assy N, Gadano A, Kao JH, Lee KS, Zwirtes R, Portsmouth S, Dong Y, Xu D, Kumada H, Srinivasan S. Peginterferon Lambda-1a/Ribavirin with Daclatasvir or Peginterferon Alfa-2a/Ribavirin with Telaprevir for Chronic Hepatitis C Genotype 1b. J Interferon Cytokine Res 2016; 36:635-643. [DOI: 10.1089/jir.2015.0173] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Affiliation(s)
- Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland
| | - Seiji Kawazoe
- Department of Hepatobiliary and Pancreatology, Saga Prefectural Hospital Koseikan, Saga, Japan
| | - Olga Znoyko
- Moscow State University of Medicine and Dentistry, Moscow, Russia
| | - Nimer Assy
- Department of Liver, Ziv Medical Center and Bar-Ilan University, Safed, Israel
| | - Adrian Gadano
- Liver Unit, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Jia-Horng Kao
- Hepatitis Research Center, National Taiwan University, Taipei, Taiwan
| | - Kwan-Sik Lee
- Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | - Ricardo Zwirtes
- Research and Development, Bristol-Myers Squibb, Inc., Wallingford, Connecticut
| | - Simon Portsmouth
- Research and Development, Bristol-Myers Squibb, Inc., Wallingford, Connecticut
| | - Yuping Dong
- Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey
| | - Dong Xu
- Research and Development, Bristol-Myers Squibb, Inc., Wallingford, Connecticut
| | | | - Subasree Srinivasan
- Research and Development, Bristol-Myers Squibb, Inc., Wallingford, Connecticut
| |
Collapse
|
|
39
|
Wei L, Zhang M, Xu M, Chuang WL, Lu W, Xie W, Jia Z, Gong G, Li Y, Bae SH, Yang YF, Xie Q, Lin S, Chen X, Niu J, Jia J, Garimella T, Torbeyns A, McPhee F, Treitel M, Yin PD, Mo L. A phase 3, open-label study of daclatasvir plus asunaprevir in Asian patients with chronic hepatitis C virus genotype 1b infection who are ineligible for or intolerant to interferon alfa therapies with or without ribavirin. J Gastroenterol Hepatol 2016; 31:1860-1867. [PMID: 27003037 DOI: 10.1111/jgh.13379] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Revised: 03/08/2016] [Accepted: 03/11/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIM Daclatasvir plus asunaprevir has demonstrated efficacy and safety in patients with chronic hepatitis C virus genotype 1b infection. This study focused on evaluating daclatasvir plus asunaprevir in interferon (±ribavirin)-ineligible or -intolerant Asian patients with genotype 1b infection from mainland China, Korea, and Taiwan. METHODS Interferon (±ribavirin)-ineligible and -intolerant patients with genotype 1b infection received daclatasvir 60 mg tablets once daily plus asunaprevir 100 mg soft capsules twice daily for 24 weeks. The primary endpoint was sustained virologic response at post-treatment week 24 (SVR24). RESULTS Of the 159 patients treated, 89.3% were Chinese, 65.4% were female, and 73.6% were interferon-intolerant. Cirrhosis was present in 32.7% of patients, and 40.3% had IL28B non-CC genotypes. SVR24 was achieved by 145/159 (91.2%) patients (100% concordance with SVR12) and was similarly high in cirrhotic patients (47/52, 90.4%). SVR24 was higher in patients without baseline NS5A (L31M or Y93H) resistance-associated variants (RAVs) (137/139, 98.6%), including those with cirrhosis (43/44, 97.7%). Prevalence of baseline NS5A RAVs was low (19/159, 11.9%), particularly in mainland China (10/127, 7.9%). One death (0.6%), five serious adverse events (3.1%), and three grade 4 laboratory abnormalities (1.9%) occurred on treatment; none were considered related to study drugs. Two patients (1.3%) discontinued because of adverse events. Treatment was generally well tolerated regardless of cirrhosis status. CONCLUSIONS Daclatasvir plus asunaprevir achieved a SVR24 rate of 91.2%, rising to 98.6% in patients without baseline NS5A RAVs, and was generally well tolerated in interferon (±ribavirin)-ineligible or -intolerant patients with genotype 1b infection from mainland China, Korea, and Taiwan.
Collapse
Affiliation(s)
- Lai Wei
- Peking University People's Hospital and Peking University Hepatology Institute, Beijing
| | | | - Min Xu
- Guangzhou No.8 People's Hospital, Guangzhou
| | - Wan-Long Chuang
- Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung
| | - Wei Lu
- Tianjin Second People's Hospital, Tianjin
| | - Wen Xie
- Beijing Ditan Hospital, Capital Medical University, Beijing
| | | | - Guozhong Gong
- The Second Xiangya Hospital of Central South University, Changsha
| | - Yueqi Li
- 302 Military Hospital of China, Beijing
| | - Si Hyun Bae
- Seoul St. Mary Hospital, The Catholic University of Korea, Seoul
| | - Yong-Feng Yang
- The 2nd Hospital of Nanjing, Affiliated to Medical School of South East University, Nanjing
| | - Qing Xie
- Shanghai Ruijin Hospital, Jiaotong University School of Medicine, Guangzhou
| | - Shumei Lin
- The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an
| | - Xinyue Chen
- Beijing Youan Hospital, Capital Medical University, Beijing
| | - Junqi Niu
- First Hospital of Jilin University, Changchun
| | - Jidong Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing
| | | | | | | | | | | | - Ling Mo
- Bristol-Myers Squibb, Shanghai
| |
Collapse
|
|
40
|
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
|
|
41
|
Alavian SM, Rezaee-Zavareh MS. Daclatasvir-based Treatment Regimens for Hepatitis C Virus Infection: A Systematic Review and Meta-Analysis. HEPATITIS MONTHLY 2016; 16:e41077. [PMID: 27826322 PMCID: PMC5097339 DOI: 10.5812/hepatmon.41077] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 08/07/2016] [Accepted: 08/14/2016] [Indexed: 12/11/2022]
Abstract
CONTEXT Direct acting antivirals (DAAs) have recently emerged as a promising therapeutic regimen for the treatment of hepatitis C virus (HCV) infection, which is a major public health problem. Among the known DAAs, daclatasvir (DCV), an inhibitor of the non-structural 5A protein, has been used in combination with several drugs for treatment of infection with HCV of different genotypes under different conditions. We conducted a systematic review and meta-analysis of combination therapy with DCV. EVIDENCE ACQUISITION We performed a systematic search in PubMed, Scopus, Science Direct and Web of Science with appropriate keywords for DCV. Studies that evaluated any regimen containing DCV and reported the sustained virological response (SVR) 12 weeks after therapy based on the HCV genotype, treatment duration and use of ribavirin (RBV) were included. The selected studies were considered for meta-analysis using STATA 11.0. RESULTS We found six different regimens containing DCV: DCV/asunaprevir (ASV), DCV/ASV/beclubavir, DCV/pegylated interferon lambda or alpha/RBV with or without ASV, DCV/simeprevir, DCV/VX-135 and DCV/sofosbuvir (SOF). Most of these regimens were used for the treatment of HCV genotype 1 infections, and in most cases, treatment failure was noted in subtype 1a infections. Among all these regimens, DCV/SOF with or without RBV for 12 or 24 weeks was found to be an efficacious approach for treatment of different types of patients with infections with different HCV genotypes. CONCLUSIONS Among the treatment regimens containing DCV, DCV/SOF has the highest SVR rate for the treatment of infection with different HCV genotypes in different patient contexts; thus, this regimen shows promise for the treatment of HCV infections.
Collapse
Affiliation(s)
- Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Middle East Liver Diseases (MELD) Center, Tehran, IR Iran
- Meta-analysis Study Group for Treatment of Hepatitis C, Iran Hepatitis Network, Tehran, IR Iran
| | - Mohammad Saeid Rezaee-Zavareh
- Middle East Liver Diseases (MELD) Center, Tehran, IR Iran
- Meta-analysis Study Group for Treatment of Hepatitis C, Iran Hepatitis Network, Tehran, IR Iran
- Students’ Research Committee, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| |
Collapse
|
|
42
|
Santagostino E, Pol S, Olveira A, Reesink HW, van Erpecum K, Bogomolov P, Xu D, Critelli L, Srinivasan S, Cooney E. Daclatasvir/peginterferon lambda-1a/ribavirin in patients with chronic HCV infection and haemophilia who are treatment naïve or prior relapsers to peginterferon alfa-2a/ribavirin. Haemophilia 2016; 22:692-9. [PMID: 27339614 DOI: 10.1111/hae.12947] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/03/2016] [Indexed: 12/28/2022]
Abstract
AIM This study explores the potential role of a novel interferon-containing regimen for treatment of patients with chronic hepatitis C (CHC) and underlying haemophilia. METHODS This trial (NCT01741545) was an open-label, non-randomized phase 3 study, which included adult haemophiliacs with hepatitis C virus (HCV). Patients with HCV genotypes (GT)-2 or -3 were treated with Lambda-IFN/ribavirin (RBV)/daclatasvir (DCV) for 12 weeks (cohort A). Patients with HCV GT-1b or -4 were treated with Lambda-IFN/RBV/DCV for 12 weeks, followed by Lambda-IFN/RBV for an additional 12 weeks (cohort B). The primary endpoint was the proportion of patients with a sustained virologic response at post-treatment follow-up week 12 (SVR12). Clinical development of Lambda-IFN was discontinued during this trial leading to study termination before a 24-week post-treatment follow-up was obtained for all participants. RESULTS Overall, 51 patients were treated (cohort A, n = 12; cohort B, n = 39). The proportion of patients achieving SVR12 was 92% in cohort A and 90% in cohort B. Therapy was generally well tolerated. The most common adverse events (AEs) were related to elevations in serum transaminases and/or bilirubin. Five serious AEs, four discontinuations due to AEs, and no deaths were reported. The rate of grade 3-4 bilirubin elevations was 17-18% across cohorts. CONCLUSION Lambda-IFN/RBV/DCV treatment demonstrated a high SVR rate and was generally well tolerated with a safety profile consistent with expectations for this special patient population. This study supports use of DCV as part of a combination treatment regimen for haemophiliacs with CHC.
Collapse
Affiliation(s)
- E Santagostino
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Ca' Granda Foundation, Maggiore Hospital Policlinico, Milan, Italy.
| | - S Pol
- Hôpital Cochin, Université Paris Descartes, Inserm U-818, Institut Pasteur, Paris, France
| | - A Olveira
- Hospital Universitario La Paz, Madrid, Spain
| | - H W Reesink
- Academic Medical Center, Amsterdam, the Netherlands
| | - K van Erpecum
- Universitair Medisch Centrum Utrecht, Utrecht, the Netherlands
| | - P Bogomolov
- Clinical Hospital of Tsentrosoyuz, Moscow, Russia
| | - D Xu
- Bristol-Myers Squibb, Inc., Wallingford, CT, USA
| | - L Critelli
- Bristol-Myers Squibb, Inc., Wallingford, CT, USA
| | - S Srinivasan
- Bristol-Myers Squibb, Inc., Wallingford, CT, USA
| | - E Cooney
- Bristol-Myers Squibb, Inc., Wallingford, CT, USA
| |
Collapse
|
|
43
|
Sun LQ, Mull E, Zheng B, D'Andrea S, Zhao Q, Wang AX, Sin N, Venables BL, Sit SY, Chen Y, Chen J, Cocuzza A, Bilder DM, Mathur A, Rampulla R, Chen BC, Palani T, Ganesan S, Arunachalam PN, Falk P, Levine S, Chen C, Friborg J, Yu F, Hernandez D, Sheaffer AK, Knipe JO, Han YH, Schartman R, Donoso M, Mosure K, Sinz MW, Zvyaga T, Rajamani R, Kish K, Tredup J, Klei HE, Gao Q, Ng A, Mueller L, Grasela DM, Adams S, Loy J, Levesque PC, Sun H, Shi H, Sun L, Warner W, Li D, Zhu J, Wang YK, Fang H, Cockett MI, Meanwell NA, McPhee F, Scola PM. Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing. J Med Chem 2016; 59:8042-60. [PMID: 27564532 DOI: 10.1021/acs.jmedchem.6b00821] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Arvind Mathur
- Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development , Route 206 and Provinceline Road, Princeton, New Jersey 08543, United States
| | - Richard Rampulla
- Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development , Route 206 and Provinceline Road, Princeton, New Jersey 08543, United States
| | - Bang-Chi Chen
- Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development , Route 206 and Provinceline Road, Princeton, New Jersey 08543, United States
| | - Theerthagiri Palani
- Biocon Bristol-Myers Squibb R&D Center , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India
| | - Sivakumar Ganesan
- Biocon Bristol-Myers Squibb R&D Center , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India
| | - Pirama Nayagam Arunachalam
- Biocon Bristol-Myers Squibb R&D Center , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Qi Gao
- Department of Pharmaceutical Development, Bristol-Myers Squibb Research and Development , 1 Squibb Drive, New Brunswick, New Jersey 08903, United States
| | - Alicia Ng
- Department of Pharmaceutical Development, Bristol-Myers Squibb Research and Development , 1 Squibb Drive, New Brunswick, New Jersey 08903, United States
| | | | | | - Stephen Adams
- Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States
| | | | - Paul C Levesque
- Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States
| | - Huabin Sun
- Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States
| | - Hong Shi
- Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States
| | - Lucy Sun
- Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States
| | - William Warner
- Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States
| | - Danshi Li
- Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States
| | - Jialong Zhu
- Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States
| | | | | | | | | | | | | |
Collapse
|
|
44
|
Meanwell NA. 2015 Philip S. Portoghese Medicinal Chemistry Lectureship. Curing Hepatitis C Virus Infection with Direct-Acting Antiviral Agents: The Arc of a Medicinal Chemistry Triumph. J Med Chem 2016; 59:7311-51. [PMID: 27501244 DOI: 10.1021/acs.jmedchem.6b00915] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The development of direct-acting antiviral agents that can cure a chronic hepatitis C virus (HCV) infection after 8-12 weeks of daily, well-tolerated therapy has revolutionized the treatment of this insidious disease. In this article, three of Bristol-Myers Squibb's HCV programs are summarized, each of which produced a clinical candidate: the NS3 protease inhibitor asunaprevir (64), marketed as Sunvepra, the NS5A replication complex inhibitor daclatasvir (117), marketed as Daklinza, and the allosteric NS5B polymerase inhibitor beclabuvir (142), which is in late stage clinical studies. A clinical study with 64 and 117 established for the first time that a chronic HCV infection could be cured by treatment with direct-acting antiviral agents alone in the absence of interferon. The development of small molecule HCV therapeutics, designed by medicinal chemists, has been hailed as "the arc of a medical triumph" but may equally well be described as "the arc of a medicinal chemistry triumph".
Collapse
Affiliation(s)
- Nicholas A Meanwell
- Department of Discovery Chemistry, Bristol-Myers Squibb Research & Development , Wallingford, Connecticut 06492, United States
| |
Collapse
|
|
45
|
Ferreira VL, Assis Jarek NA, Tonin FS, Borba HHL, Wiens A, Pontarolo R. Safety of interferon-free therapies for chronic hepatitis C: a network meta-analysis. J Clin Pharm Ther 2016; 41:478-85. [PMID: 27440554 DOI: 10.1111/jcpt.12426] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 06/27/2016] [Indexed: 12/24/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Interferon-free (IFN-free) therapies for hepatitis C virus (HCV) have been developed to provide more effective, tolerable and safer therapeutic strategies. To date, no network meta-analysis (NMA) evaluating the safety profile of these regimens has been performed. This systematic review and NMA aimed to evaluate safety outcomes of IFN-free treatment options for chronic hepatitis C. METHODS A systematic review was performed according to PRISMA and Cochrane recommendations. A literature search was conducted in PubMed/Medline, Scopus, Cochrane Library, International Pharmaceutical Abstracts and Web of Science electronic databases and included only randomized clinical trials that provided safety outcomes of interest of evaluated second-generation direct-acting antivirals: incidence of any adverse events (AEs) and serious AE. NMA allowed estimating probability for the relative safety of the interventions. A consistency model was used to draw conclusions about relative safety of treatments, presented as odds ratio (OR) and corresponding 95% credible interval (CrI). RESULTS Fifty-one clinical trials were included (13 089 participants). Most participants had hepatitis C genotype 1 virus (76%) and were treated for 12 weeks. Two NMAs were built to investigate the incidence of AEs and serious AEs, comparing 13 and 10 IFN-free treatment options, respectively. For the outcome incidence of AEs, few significant differences were observed, which were explained by the presence of RBV. Elbasvir with grazoprevir and placebo were both safer than ombitasvir in combination with paritaprevir, ritonavir, daclatasvir plus RBV [ORs with 95% Crl of 4·09 (1·17-14·09) and 2·40 (1·19-4·77), respectively] and sofosbuvir with RBV [ORs with 95% Crl of 0·22 (0·07-0·72) and 2·69 (1·53-4·80), respectively]. Furthermore, elbasvir with grazoprevir was safer than sofosbuvir used with velpatasvir and RBV [OR 0·19 (95% CrI 0·03-0·98)]; ombitasvir in combination with paritaprevir, ritonavir, daclatasvir was safer than the same therapy but combined with RBV [OR 2·14 (95% CrI 1·09-4·44)]; and sofosbuvir used with velpatasvir was safer than sofosbuvir with RBV [OR 2·07 (95% CrI 1·13-3·79)]. Elbasvir with grazoprevir (50%) followed by placebo (28%) had the highest probabilities of less AEs. No significant differences were observed for serious AE outcomes. WHAT IS NEW AND CONCLUSION This meta-analysis included a large number of therapies. Small differences were observed in any AEs, but not in serious AEs.
Collapse
Affiliation(s)
- V L Ferreira
- Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Curitiba, Brazil
| | - N A Assis Jarek
- Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Curitiba, Brazil
| | - F S Tonin
- Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Curitiba, Brazil
| | - H H L Borba
- Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Curitiba, Brazil
| | - A Wiens
- Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Curitiba, Brazil
| | - R Pontarolo
- Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Curitiba, Brazil
| |
Collapse
|
|
46
|
Cuypers L, Ceccherini-Silberstein F, Van Laethem K, Li G, Vandamme AM, Rockstroh JK. Impact of HCV genotype on treatment regimens and drug resistance: a snapshot in time. Rev Med Virol 2016; 26:408-434. [PMID: 27401933 DOI: 10.1002/rmv.1895] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 06/11/2016] [Accepted: 06/15/2016] [Indexed: 12/11/2022]
Abstract
The introduction of highly potent direct-acting antivirals (DAAs) has revolutionized hepatitis C virus treatment. Nevertheless, viral eradication worldwide remains a challenge also in the era of DAA treatment, because of the high associated costs, high numbers of undiagnosed patients, high re-infection rates in some risk groups and suboptimal drug efficacies associated with host and viral factors as well as advanced stages of liver disease. A correct determination of the HCV genotype allows administration of the most appropriate antiviral regimen. Additionally, HCV genetic sequencing improves our understanding of resistance-associated variants, either naturally occurring before treatment, acquired by transmission at HCV infection, or emerging after virological failure. Because treatment response rates, and the prevalence and development of drug resistance variants differ for each DAA regimen and HCV genotype, this review summarizes treatment opportunities per HCV genotype, and focuses on viral genetic sequencing to guide clinical decision making. Although approval of the first pan-genotypic DAA-only regimen is expected soon, HCV genetic sequencing will remain important because when DAA therapies fail, genotyping and resistance testing to select a new active DAA combination will be essential. Copyright © 2016 John Wiley & Sons, Ltd.
Collapse
Affiliation(s)
- Lize Cuypers
- KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Leuven, Belgium
| | | | - Kristel Van Laethem
- KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Leuven, Belgium
| | - Guangdi Li
- KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Leuven, Belgium.,Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Anne-Mieke Vandamme
- KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Leuven, Belgium.,Center for Global Health and Tropical Medicine, Microbiology Unit, Institute for Hygiene and Tropical Medicine, University Nova de Lisboa, Lisbon, Portugal
| | | |
Collapse
|
|
47
|
Kao JH, Jensen DM, Manns MP, Jacobson I, Kumada H, Toyota J, Heo J, Yoffe B, Sievert W, Bessone F, Peng CY, Roberts SK, Lee YJ, Bhore R, Mendez P, Hughes E, Noviello S. Daclatasvir plus asunaprevir for HCV genotype 1b infection in patients with or without compensated cirrhosis: a pooled analysis. Liver Int 2016; 36:954-962. [PMID: 26683763 DOI: 10.1111/liv.13049] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 12/08/2015] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS We compared outcomes by cirrhosis status across studies of the all-oral combination of daclatasvir (DCV) plus asunaprevir (ASV). METHODS Outcomes from global and Japanese phase 2 and 3 clinical studies of DCV+ASV in patients with genotype (GT) 1b infection were assessed by cirrhosis status. Sustained virological response (SVR) was assessed in individual phase 3 studies; a pooled analysis was carried out for safety outcomes. RESULTS In the Japanese phase 3 study, SVR12 was achieved by 91% of patients with cirrhosis (n = 22) and 84% of patients without cirrhosis (n = 200); in the global phase 3 study, SVR12 was achieved by 84% of patients with cirrhosis (n = 206) and by 85% of patients without cirrhosis (n = 437). The frequency of serious adverse events, adverse events leading to treatment discontinuation and treatment-emergent grade 3/4 laboratory abnormalities was low (<10%) and similar among patients with (n = 229) or without (n = 689) compensated cirrhosis receiving DCV+ASV. Grade 3/4 reductions in platelets and neutrophils were more common among patients with cirrhosis (1.3 and 2.2%, respectively) compared with those without cirrhosis (both 0.6%). Grade 3/4 liver function test abnormalities were less common among patients with cirrhosis (1.8%) compared with those without cirrhosis (3.5-4.7%). Alanine aminotransferase elevations were not associated with hepatic decompensation. CONCLUSIONS The safety and efficacy of DCV+ASV were similar in patients with or without compensated cirrhosis. This all-oral, interferon- and ribavirin-free combination is an effective and well-tolerated treatment option for patients with HCV GT1b infection and cirrhosis. Trial registrations numbers: Clinicaltrials.gov identifiers: NCT01012895; NCT01051414; NCT01581203; NCT01497834.
Collapse
Affiliation(s)
- Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Donald M Jensen
- Center for Liver Diseases, University of Chicago Medical Center, Chicago, IL, USA
| | - Michael P Manns
- Hannover Medical School, Hannover, Germany
- German Center for Infection Research, Hannover-Braunschweig, Germany
| | - Ira Jacobson
- Department of Medicine at Mount Sinai Beth Israel Medical Center, New York, NY, USA
| | | | - Joji Toyota
- Sapporo-Kosei General Hospital, Sapporo, Japan
| | - Jeong Heo
- College of Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Busan, South Korea
| | - Boris Yoffe
- Veterans Affairs Medical Center, Baylor College of Medicine, Houston, TX, USA
| | - William Sievert
- Monash Health and Monash University, Melbourne, Victoria, Australia
| | - Fernando Bessone
- Hospital Provincial del Centenario, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - Cheng-Yuan Peng
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Stuart K Roberts
- Alfred Hospital and Monash University, Melbourne, Victoria, Australia
| | - Youn-Jae Lee
- Inje University Busan Paik Hospital, Busan, South Korea
| | - Rafia Bhore
- Bristol-Myers Squibb Research and Development, Princeton, NJ, USA
| | - Patricia Mendez
- Bristol-Myers Squibb Research and Development, Princeton, NJ, USA
| | - Eric Hughes
- Bristol-Myers Squibb Research and Development, Princeton, NJ, USA
| | | |
Collapse
|
|
48
|
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.
Collapse
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.
| |
Collapse
|
|
49
|
Abstract
INTRODUCTION The direct acting antiviral daclatasvir is an NS5A replication inhibitor active against the entire range of hepatitis C virus genotypes. It is a key step in establishing the goal of an all-oral, ribavirin-free, pan-genotypic regimen against hepatitis C. AREAS COVERED We review current literature including published abstracts and manuscripts. Evidence was obtained through PubMed/Medline search using listed keywords and through review of published abstracts. EXPERT OPINION Daclatasvir introduces a degree of pangenotypic potency currently lacking in other NS5A agents. Emerging literature suggests that daclatasvir in combination with other DAAs will represent a promising option in this difficult to treat populations including posttransplant, genotype 3 and HIV patients.
Collapse
Affiliation(s)
- Syed-Mohammed Jafri
- a Division of Gastroenterology , Henry Ford Hospital , Detroit , MI 48202 , USA
| | - Stuart C Gordon
- a Division of Gastroenterology , Henry Ford Hospital , Detroit , MI 48202 , USA
| |
Collapse
|
|
50
|
Nam HC, Lee HL, Yang H, Song MJ. Efficacy and safety of daclatasvir and asunaprevir for hepatitis C virus genotype 1b infection. Clin Mol Hepatol 2016; 22:259-266. [PMID: 27377910 PMCID: PMC4946403 DOI: 10.3350/cmh.2016.0020] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2016] [Revised: 06/13/2016] [Accepted: 06/13/2016] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND/AIMS The treatment strategy for hepatitis C virus (HCV) has been changing rapidly since the introduction of direct-acting antivirals such as daclatasvir (DCV) and asunaprevir (ASV). We evaluated the efficacy and safety of DCV and ASV for HCV in real-life practice. METHODS Patients were treated with 60 mg of DCV once daily plus 200 mg of ASV twice daily for 24 weeks, and followed for 12 weeks. The primary endpoint was a sustained virological response at 12 weeks after treatment (SVR12) and safety. RESULTS This retrospective study included eight patients with chronic HCV genotype 1b infection. All of the enrolled patients were diagnosed with liver cirrhosis, and their mean age was 65.75 years. One patient was a nonresponder and two patients relapsed with previous pegylated interferon (PegIFN) and ribavirin (RBV) treatment. None of the patient showed NS5A mutation. An SVR12 was achieved in 88% of cases by the DCV and ASV combination therapy. The serum transaminase level and the aspartate-aminotransferase-to-platelet ratio were improved after the treatment. DCV and ASV were well tolerated in most of the patients, with treatment discontinuation due to adverse events (elevated liver enzyme and decompensation) occurring in two patients. CONCLUSION In this study, combination of DCV and ASV treatment achieved a high sustained virological response with few adverse events even in those with cirrhosis, advanced age, and nonresponse/relapse to previous interferon-based therapy. Close monitoring of safety issues may be necessary when treating chronic HCV patients receiving DCV and ASV, especially in older patient and those with cirrhosis.
Collapse
Affiliation(s)
- Hee Chul Nam
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hae Lim Lee
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hyun Yang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Myeong Jun Song
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Division of Hepatology, Department of Internal Medicine, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Korea
| |
Collapse
|