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Di Marco L, Cannova S, Ferrigno E, Landro G, Nonni R, Mantia CL, Cartabellotta F, Calvaruso V, Di Marco V. A Comprehensive Review of Antiviral Therapy for Hepatitis C: The Long Journey from Interferon to Pan-Genotypic Direct-Acting Antivirals (DAAs). Viruses 2025; 17:163. [PMID: 40006918 PMCID: PMC11860415 DOI: 10.3390/v17020163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/19/2025] [Accepted: 01/20/2025] [Indexed: 02/27/2025] Open
Abstract
The treatment landscape for hepatitis C virus (HCV) infection has transformed over the past few decades, evolving from the limited efficacy of interferon (IFN) monotherapy to the highly successful pan-genotypic direct-acting antivirals (DAAs) used today. Initially, alpha-interferon monotherapy, introduced in the 1990s, was the standard treatment, yet it provided low sustained virological response (SVR) rates and caused significant adverse effects, limiting its utility. The development of pegylated interferon (peg-IFN) improved the pharmacokinetic profile of IFN, allowing for less frequent dosing and modestly improved response rates. When combined with ribavirin, peg-IFN achieved higher SVR rates, especially in non-genotype 1 HCV infections, but the combination also brought additional side effects, such as anemia and depression. The advent of the first-generation DAAs, such as telaprevir and boceprevir, marked a significant milestone. Combined with peg-IFN and ribavirin, these protease inhibitors boosted response rates in patients with genotype 1 HCV. However, high rates of adverse effects and drug resistance remained challenges. Second-generation DAAs, like sofosbuvir and ledipasvir, introduced IFN-free regimens with improved safety profiles and efficacy. The most recent advances are pan-genotypic DAAs, including glecaprevir-pibrentasvir and sofosbuvir-velpatasvir, which offer high SVR rates across all genotypes, shorter treatment durations, and fewer side effects. Current pan-genotypic regimens represent a cornerstone in HCV therapy, providing an accessible and effective solution globally.
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Affiliation(s)
- Lorenza Di Marco
- SIcilian Network for Therapy, Epidemiology and Screening In Hepatology (SINTESI), 90127 Palermo, Italy; (L.D.M.); (F.C.); (V.C.)
- Department of Oncology and Hematology, Azienda Ospedaliero-University Hospital of Mod, 41124 Modena, Italy
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41100 Modena, Italy
| | - Simona Cannova
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
| | - Emanuele Ferrigno
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
| | - Giuseppe Landro
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
| | - Rosario Nonni
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
| | - Claudia La Mantia
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
| | - Fabio Cartabellotta
- SIcilian Network for Therapy, Epidemiology and Screening In Hepatology (SINTESI), 90127 Palermo, Italy; (L.D.M.); (F.C.); (V.C.)
- Department of Medicine, Buccheri-La Ferla Hospital, 90123 Palermo, Italy
| | - Vincenza Calvaruso
- SIcilian Network for Therapy, Epidemiology and Screening In Hepatology (SINTESI), 90127 Palermo, Italy; (L.D.M.); (F.C.); (V.C.)
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
| | - Vito Di Marco
- SIcilian Network for Therapy, Epidemiology and Screening In Hepatology (SINTESI), 90127 Palermo, Italy; (L.D.M.); (F.C.); (V.C.)
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (S.C.); (E.F.); (G.L.); (R.N.); (C.L.M.)
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Direct-Acting Antiviral Agents for Hepatitis C Virus Infection-From Drug Discovery to Successful Implementation in Clinical Practice. Viruses 2022; 14:v14061325. [PMID: 35746796 PMCID: PMC9231290 DOI: 10.3390/v14061325] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/13/2022] [Accepted: 06/15/2022] [Indexed: 12/13/2022] Open
Abstract
Today, hepatitis C virus infection affects up to 1.5 million people per year and is responsible for 29 thousand deaths per year. In the 1970s, the clinical observation of unclear, transfusion-related cases of hepatitis ignited scientific curiosity, and after years of intensive, basic research, the hepatitis C virus was discovered and described as the causative agent for these cases of unclear hepatitis in 1989. Even before the description of the hepatitis C virus, clinicians had started treating infected individuals with interferon. However, intense side effects and limited antiviral efficacy have been major challenges, shaping the aim for the development of more suitable and specific treatments. Before direct-acting antiviral agents could be developed, a detailed understanding of viral properties was necessary. In the years after the discovery of the new virus, several research groups had been working on the hepatitis C virus biology and finally revealed the replication cycle. This knowledge was the basis for the later development of specific antiviral drugs referred to as direct-acting antiviral agents. In 2011, roughly 22 years after the discovery of the hepatitis C virus, the first two drugs became available and paved the way for a revolution in hepatitis C therapy. Today, the treatment of chronic hepatitis C virus infection does not rely on interferon anymore, and the treatment response rate is above 90% in most cases, including those with unsuccessful pretreatments. Regardless of the clinical and scientific success story, some challenges remain until the HCV elimination goals announced by the World Health Organization are met.
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Xu X, Zhang QY, Chu XY, Quan Y, Lv BM, Zhang HY. Facilitating Antiviral Drug Discovery Using Genetic and Evolutionary Knowledge. Viruses 2021; 13:v13112117. [PMID: 34834924 PMCID: PMC8626054 DOI: 10.3390/v13112117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 10/19/2021] [Accepted: 10/19/2021] [Indexed: 12/15/2022] Open
Abstract
Over the course of human history, billions of people worldwide have been infected by various viruses. Despite rapid progress in the development of biomedical techniques, it is still a significant challenge to find promising new antiviral targets and drugs. In the past, antiviral drugs mainly targeted viral proteins when they were used as part of treatment strategies. Since the virus mutation rate is much faster than that of the host, such drugs feature drug resistance and narrow-spectrum antiviral problems. Therefore, the targeting of host molecules has gradually become an important area of research for the development of antiviral drugs. In recent years, rapid advances in high-throughput sequencing techniques have enabled numerous genetic studies (such as genome-wide association studies (GWAS), clustered regularly interspersed short palindromic repeats (CRISPR) screening, etc.) for human diseases, providing valuable genetic and evolutionary resources. Furthermore, it has been revealed that successful drug targets exhibit similar genetic and evolutionary features, which are of great value in identifying promising drug targets and discovering new drugs. Considering these developments, in this article the authors propose a host-targeted antiviral drug discovery strategy based on knowledge of genetics and evolution. We first comprehensively summarized the genetic, subcellular location, and evolutionary features of the human genes that have been successfully used as antiviral targets. Next, the summarized features were used to screen novel druggable antiviral targets and to find potential antiviral drugs, in an attempt to promote the discovery of new antiviral drugs.
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Affiliation(s)
| | - Qing-Ye Zhang
- Correspondence: (Q.-Y.Z.); (H.-Y.Z.); Tel.: +86-27-8728-0877 (H.-Y.Z.)
| | | | | | | | - Hong-Yu Zhang
- Correspondence: (Q.-Y.Z.); (H.-Y.Z.); Tel.: +86-27-8728-0877 (H.-Y.Z.)
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Yoshioka M, Sawada Y, Saito-Sasaki N, Yoshioka H, Hama K, Omoto D, Ohmori S, Okada E, Nakamura M. High S100A2 expression in keratinocytes in patients with drug eruption. Sci Rep 2021; 11:5493. [PMID: 33750880 PMCID: PMC7943585 DOI: 10.1038/s41598-021-85009-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 02/17/2021] [Indexed: 11/09/2022] Open
Abstract
Telaprevir used as a protease inhibitor against hepatitis C virus is frequently associated with cutaneous adverse reactions. To explore a histological biomarker of cutaneous adverse events induced by telaprevir, we systematically searched for genes that were dysregulated by telaprevir in normal human epidermal keratinocytes (NHEKs). Microarray analysis and real-time polymerase chain reaction (PCR) revealed the significant increase in the expression of S100 calcium-binding protein A2 (S100A2) gene following treatment of NHEKs with telaprevir. Immunohistochemical analysis demonstrated that the expression of S100A2 was dominant in the spinous layer of the epidermis in patients with telaprevir-mediated severe-type drug eruptions and limited to the basal layer of the epidermis in healthy subjects. Furthermore, S100A2 expression increased after treatment with trichloroethylene and other medications, and the degree of S100A2 expression correlated with the severity of cutaneous adverse events. S100A2 expression also significantly increased in the skin of patients with atopic dermatitis and psoriasis. Taken together, S100A2 is highly expressed in the epidermis under inflammatory conditions and drug eruptions and may serve as a marker for keratinocyte damage in response to any inflammatory or toxic condition.
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Affiliation(s)
- Manabu Yoshioka
- Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Yu Sawada
- Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
| | - Natsuko Saito-Sasaki
- Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Haruna Yoshioka
- Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Kayo Hama
- Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Daisuke Omoto
- Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Shun Ohmori
- Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Etsuko Okada
- Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Motonobu Nakamura
- Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
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Murugan NA, Raja KMP, Saraswathi NT. Peptide-Based Antiviral Drugs. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1322:261-284. [PMID: 34258744 DOI: 10.1007/978-981-16-0267-2_10] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Three types of chemical entities, namely, small organic molecules (organics), peptides, and biologics, are mainly used as drug candidates for the treatment of various diseases. Even though the peptide drugs are known since 1920 in association with the clinical use of insulin, only a limited number of peptides are currently used for therapeutics due to various disadvantages associated with them such as limited serum and blood stability, oral bioavailability, and permeability. Since, through chemical modifications and structure tuning, many of these limitations can be overcome, peptide-based drugs are gaining attention in pharmaceutical research. As of today, there are more than 60 peptide-based drugs approved by FDA, and over 150 peptides are in the advanced clinical studies. In this book chapter, the peptide-based lead compounds and drugs available for treating various viral diseases and their advantages and disadvantages when compared to small molecules drugs are discussed.
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Affiliation(s)
- N Arul Murugan
- Department of Theoretical Chemistry and Biology, School of Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, Sweden.
| | - K Muruga Poopathi Raja
- Chemical Biology and Biophysics Laboratory, Department of Physical Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai, Tamilnadu, India.
| | - N T Saraswathi
- School of Chemical & Biotechnology, Sastra Deemed University, Thanjavur, Tamil Nadu, India
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Abstract
Antiviral drugs have traditionally been developed by directly targeting essential viral components. However, this strategy often fails due to the rapid generation of drug-resistant viruses. Recent genome-wide approaches, such as those employing small interfering RNA (siRNA) or clustered regularly interspaced short palindromic repeats (CRISPR) or those using small molecule chemical inhibitors targeting the cellular "kinome," have been used successfully to identify cellular factors that can support virus replication. Since some of these cellular factors are critical for virus replication, but are dispensable for the host, they can serve as novel targets for antiviral drug development. In addition, potentiation of immune responses, regulation of cytokine storms, and modulation of epigenetic changes upon virus infections are also feasible approaches to control infections. Because it is less likely that viruses will mutate to replace missing cellular functions, the chance of generating drug-resistant mutants with host-targeted inhibitor approaches is minimized. However, drug resistance against some host-directed agents can, in fact, occur under certain circumstances, such as long-term selection pressure of a host-directed antiviral agent that can allow the virus the opportunity to adapt to use an alternate host factor or to alter its affinity toward the target that confers resistance. This review describes novel approaches for antiviral drug development with a focus on host-directed therapies and the potential mechanisms that may account for the acquisition of antiviral drug resistance against host-directed agents.
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Raja R, Baral S, Dixit NM. Interferon at the cellular, individual, and population level in hepatitis C virus infection: Its role in the interferon-free treatment era. Immunol Rev 2019; 285:55-71. [PMID: 30129199 DOI: 10.1111/imr.12689] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The advent of powerful direct-acting antiviral agents (DAAs) has revolutionized the treatment of hepatitis C. DAAs cure nearly all patients with short duration, oral treatments. Significant efforts are now underway to optimize DAA-based treatments. We discuss the potential role of interferon in this optimization. Clinical studies present compelling evidence that DAAs perform better in treatment-naive individuals than in individuals who previously failed treatment with interferon, a surprising correlation because interferon and DAAs are thought to act independently. Recent mathematical models explore a mechanistic hypothesis underlying this correlation. The hypothesis invokes the action of interferon at the cellular, individual, and population levels. Strong interferon responses prevent the productive infection of cells, reduce viral replication, and impede the development of resistance to DAAs in infected individuals and improve cure rates elicited by DAAs in treated populations. The models develop descriptions of these processes, integrate them into a comprehensive framework, and capture clinical data quantitatively, providing a successful test of the hypothesis. Individuals with strong endogenous interferon responses thus present a promising subpopulation for reducing DAA treatment durations. This review discusses the conceptual advances made by the models, highlights the new insights they unravel, and examines their applicability to optimize DAA-based treatments.
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Affiliation(s)
- Rubesh Raja
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, India
| | - Subhasish Baral
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, India
| | - Narendra M Dixit
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, India.,Centre for Biosystems Science and Engineering, Indian Institute of Science, Bangalore, India
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Gul M, Eryılmaz S. Synthesis, Antioxidant Activity and Theoretical Investigation of Isoxazolines Derivatives of Monoterpenoids. LETT ORG CHEM 2019. [DOI: 10.2174/1570178616666181226154540] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The 3+2 cycloaddition reactions are important to generate five-membered heterocyclic compounds
as well as altering biological activity effects based on structure. In the study, we synthesized
new isoxazoline derivatives of different monoterpenoids and examined the structure analysis using
spectroscopical analysis methods, reveal changes in the theoretical analysis related to the biological activity.
These new compounds exhibit antioxidant activities; DPPH radical scavenging, ferric reducing,
metal chelating activities which are significantly higher than the related commercial monoterpenoids.
Theoretical approaches on the compounds containing isoxazole moiety have been performed by the
DFT/B3LYP/method, 6-31G(d,p) basis set in the ground state. The global and local chemical reactivity
properties of the compounds were investigated by considering the values of electronegativity, global
hardness-softness, electronic chemical potential, electrophilicity index and condensed Fukui functions,
local softness and local electrophilicity index. Furthermore, total energy, FMOs energy values and the
dipole moment (µ), mean polarizability (α), and first order hyperpolarizability (β) values were analysed
at the theoretical level to examine the polarizability characteristics of the compounds. The antioxidant
activity values of the newly synthesized compounds were compared with a finding of the computational
study. The results obtained exhibited good correlation on some parameters.
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Affiliation(s)
- Melek Gul
- Department of Chemistry, Science-Art Faculty, Amasya University, Amasya, Turkey
| | - Serpil Eryılmaz
- Department of Physics, Science-Art Faculty, Amasya University, Amasya, Turkey
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In Vitro Susceptibility of Hepatitis C Virus Genotype 1 through 6 Clinical Isolates to the Pangenotypic NS3/4A Inhibitor Voxilaprevir. J Clin Microbiol 2019; 57:JCM.01844-18. [PMID: 30728196 DOI: 10.1128/jcm.01844-18] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 01/28/2019] [Indexed: 02/06/2023] Open
Abstract
Voxilaprevir is a direct-acting antiviral agent (DAA) that targets the NS3/4A protease of hepatitis C virus (HCV). High sequence diversity of HCV and inadequate drug exposure during unsuccessful treatment may lead to the accumulation of variants with reduced susceptibility to DAAs, including NS3/4A protease inhibitors such as voxilaprevir. The voxilaprevir susceptibility of clinical and laboratory strains of HCV was assessed. The NS3 protease regions of viruses belonging to 6 genotypes and 29 subtypes from 345 DAA-naive or -experienced (including protease inhibitor) patients and 344 genotype 1 to 6 replicons bearing engineered NS3 resistance-associated substitutions (RASs) were tested in transient-transfection assays. The median voxilaprevir 50% effective concentration against NS3 from protease inhibitor-naive patient samples ranged from 0.38 nM for genotype 1 to 5.8 nM for genotype 3. Voxilaprevir susceptibilities of HCV replicons with NS3 RASs were dependent on subtype background and the type and number of substitutions introduced. The majority of RASs known to confer resistance to other protease inhibitors had little to no impact on voxilaprevir susceptibility, except A156L, T, or V in genotype 1 to 4 which conferred >100-fold reductions but exhibited low replication capacity in most genotypes. These data support the use of voxilaprevir in combination with other DAAs in DAA-naive and DAA-experienced patients infected with any subtype of HCV.
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Ruiz I, Pawlotsky JM. Hepatitis B Reactivation or Hepatitis C Exacerbation in Patients with Hematological Malignancies. Ann Hepatol 2019; 16:179-181. [PMID: 28233738 DOI: 10.5604/16652681.1231595] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- Isaac Ruiz
- INSERM U955 Team 18, Hôpital Henri Mondor, Créteil, France
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Hepatitis C Infection in Hemodialysis Patients. CURRENT HEALTH SCIENCES JOURNAL 2019; 44:107-112. [PMID: 30746156 PMCID: PMC6320456 DOI: 10.12865/chsj.44.02.02] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 03/27/2018] [Indexed: 01/01/2023]
Abstract
Three centuries after the identification of hepatitis C virus (HCV), specialized literature has outlined the epidemiology, viral kinetics and clinical manifestations of this infection. A major cause of morbidity-mortality in patients with renal transplantation and in hemodialysis patients is HCV infection. In high seroprevalence countries, internal accounts are not uniform. The European trend is to decrease the incidence and prevalence of HCV in hemodialysis patients. In Europe, the prevalence of HCV infection among hemodialysis patients tends to be higher than that of the general population, but it is variable by region. Some studies indicate a decrease in incidence in parallel with prevalence in dialysis centers over the last 10 years, while others maintain a high incidence. In some countries, as is the case with Romania, both prevalence and incidence remain high, with the major route of transmission being nosocomial, probably due to limited resources for a rapidly growing dialyzed population. Some authors recommend more isolation measures to be taken in centers with high prevalence of infection.
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Sharafi H, Maleki S, Alavian SM. Prevalence of hepatitis C virus NS5A resistance-associated substitutions in chronic infection with genotype 1: A pooled analysis based on deposited sequences in GenBank. Virus Res 2018; 259:54-61. [PMID: 30401643 DOI: 10.1016/j.virusres.2018.10.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 09/18/2018] [Accepted: 10/18/2018] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Resistance-associated substitutions (RASs) in the NS5A gene of hepatitis C virus (HCV) has been studied as one of the predictors of response to NS5A inhibitor-containing regimens. This study aimed to evaluate the prevalence of pre-treatment naturally-occurring NS5A RASs in HCV isolates from patients with chronic HCV genotype 1 (HCV-1) infection retrieved from GenBank. METHODS In the search procedure, the studies with published HCV-1 NS5A sequence in GenBank were screened and evaluated for inclusion in the pooled analysis. The sequences of the included studies were retrieved from GenBank and evaluated for substitutions in amino acid positions24, 26, 28, 29, 30, 31, 32, 38, 58, 62, 92 and 93 of HCV NS5A including RASs and RASs conferring >100 resistance fold change (RASs >100X). RESULTS In the pooled analysis, 2409 isolates from patients with HCV-1 infection were included, consisting 1305 (54.2%) HCV-1a and 1104 (45.8%) HCV-1b isolates. The prevalence of NS5A RASs and RASs >100X were 16.0% (95%CI = 14.6%-17.5%) and 4.7% (95%CI = 3.9%-5.6%), respectively. The NS5A RASs were more frequently observed in HCV-1b isolates than in HCV-1a isolates (P < 0.001). CONCLUSION The naturally-occurring HCV NS5A RASs especially those with clinical relevance (RASs >100X) are observed in a small (4.7%) number of patients with HCV-1 infection.
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Affiliation(s)
- Heidar Sharafi
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran; Middle East Liver Diseases (MELD) Center, Tehran, Iran
| | | | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran; Middle East Liver Diseases (MELD) Center, Tehran, Iran.
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Liu Z, Qin Q, Wu C, Li H, Shou J, Yang Y, Gu M, Ma C, Lin W, Zou Y, Zhang Y, Ma F, Sun J, Wang X. Downregulated NDR1 protein kinase inhibits innate immune response by initiating an miR146a-STAT1 feedback loop. Nat Commun 2018; 9:2789. [PMID: 30018336 PMCID: PMC6050289 DOI: 10.1038/s41467-018-05176-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 06/15/2018] [Indexed: 01/06/2023] Open
Abstract
Interferon (IFN)-stimulated genes (ISGs) play crucial roles in the antiviral immune response; however, IFNs also induce negative regulators that attenuate the antiviral response. Here, we show that both viral and bacterial invasion downregulate Nuclear Dbf2-related kinase 1 (NDR1) expression via the type I IFN signaling pathway. NDR1 promotes the virus-induced production of type I IFN, proinflammatory cytokines and ISGs in a kinase-independent manner. NDR1 deficiency also renders mice more susceptible to viral and bacterial infections. Mechanistically, NDR1 enhances STAT1 translation by directly binding to the intergenic region of miR146a, thereby inhibiting miR146a expression and liberating STAT1 from miR146a-mediated translational inhibition. Furthermore, STAT1 binds to the miR146a promoter, thus decreasing its expression. Together, our results suggest that NDR1 promotion of STAT1 translation is an important event for IFN-dependent antiviral immune response, and suggest that NDR1 has an important role in controlling viral infections. The authors show that NDR1 promotion of STAT1 translation is an important event for IFN-dependent antiviral immune response. These data suggest that NDR1 has an important role in controlling viral infections.
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Affiliation(s)
- Zhiyong Liu
- Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, 310058, PR China
| | - Qiang Qin
- Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, 310058, PR China
| | - Cheng Wu
- Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, 310058, PR China
| | - Hui Li
- Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, 310022, PR China
| | - Jia'nan Shou
- Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, 310058, PR China
| | - Yuting Yang
- Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, 310058, PR China
| | - Meidi Gu
- Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, 310058, PR China
| | - Chunmei Ma
- Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, 310058, PR China
| | - Wenlong Lin
- Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, 310058, PR China
| | - Yan Zou
- Medical Science Laboratory, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, 545005, PR China
| | - Yuanyuan Zhang
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, PR China
| | - Feng Ma
- Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, PR China
| | - Jihong Sun
- Department of Radiology, Sir Run Run Shaw Hospital School of Medicine, Zhejiang University, Hangzhou, 310058, PR China.
| | - Xiaojian Wang
- Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, 310058, PR China.
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Chachá SGF, Rodrigues JPV, Araújo RC, Pereira LRL, Villanova MG, Souza FF, Santana RDC, Martinelli ADLC. First-wave protease inhibitors for hepatitis C genotype 1 treatment: a real-life experience in Brazilian patients. Rev Soc Bras Med Trop 2018; 51:146-154. [PMID: 29768546 DOI: 10.1590/0037-8682-0153-2017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 03/28/2018] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION Licensed for chronic hepatitis C treatment in 2011, the protease inhibitors (PIs) telaprevir (TVR) and boceprevir (BOC), which have high sustained viral responses (SVR), ushered a new era characterized by the development of direct-action drugs against the hepatitis C virus (HCV). The aim of this study was to analyze the effectiveness and safety of BOC and TVR administered with pegylated interferon and ribavirin and to share the experience of a Brazilian reference center. METHODS A retrospective descriptive study was conducted in patients with HCV genotype 1 infection who started treatment between July 2013 and December 2015. Data were collected using a computerized system. RESULTS A total of 115 subjects were included, of which 58 (50.4 %) had liver cirrhosis and 103 (89.6 %) used TVR. The overall SVR rate was 61.7 % (62.1 % for TVR and 58.3 % for BOC). The presence of cirrhosis was associated with a lower SVR rate, whereas patients who relapsed after prior therapy had a greater chance of showing SVR than did non-responders. The incidence of adverse drug reactions (ADRs) was high. Almost all patients (~100 %) presented with hematologic events. Furthermore, treatment had to be discontinued in 15 subjects (13 %) due to severe ADRs. CONCLUSIONS In conclusion, the SVR rates in our study were lower than those reported in pre-marketing studies but were comparable to real-life data. ADRs, particularly hematological ADRs, were more common compared to those in previous studies and resulted in a high rate of treatment discontinuity.
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Affiliation(s)
- Silvana Gama Florencio Chachá
- Departamento de Medicina, Universidade Federal de São Carlos, São Carlos, SP, Brasil.,Divisão de Gastroenterologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - João Paulo Vilela Rodrigues
- Centro de Pesquisa em Assistência Farmacêutica e Farmácia Clínica, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Roberta Chaves Araújo
- Divisão de Gastroenterologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Leonardo Régis Leira Pereira
- Centro de Pesquisa em Assistência Farmacêutica e Farmácia Clínica, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Márcia Guimarães Villanova
- Divisão de Gastroenterologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Fernanda Fernandes Souza
- Divisão de Gastroenterologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Rodrigo de Carvalho Santana
- Divisão de Moléstias Infecciosas, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Ana de Lourdes Candolo Martinelli
- Divisão de Gastroenterologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
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Wei S, Lei Y, Yang J, Wang X, Shu F, Wei X, Lin F, Li B, Cui Y, Zhang H, Wei S. Neutralization effects of antibody elicited by chimeric HBV S antigen viral-like particles presenting HCV neutralization epitopes. Vaccine 2018; 36:2273-2281. [PMID: 29576303 DOI: 10.1016/j.vaccine.2018.03.036] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Revised: 02/23/2018] [Accepted: 03/14/2018] [Indexed: 01/29/2023]
Abstract
Hepatitis C virus (HCV) infection is a major public health problem despite effectual direct-acting antivirals (DAAs) therapy. Development of a prophylactic vaccine is essential to block spread of HCV infection. The HBV small surface antigen (HBsAg-S) can self-assemble into virus-like particles (VLPs), has higher immunogenicity and is used as a vaccine against HBV infections. Chimeric HBsAg-S proteins with foreign epitopes allow VLP formation and induce the specific humoral and cellular immune responses against the foreign proteins. In this study, we investigated the immune responses induced by chimeric VLPs with HCV neutralizing epitopes and HBV S antigen in mice. The chimeric HCV-HBV VLPs expressing neutralizing epitopes were prepared and purified. BALB/c mice were immunized with purified chimeric VLPs and the serum neutralizing antibodies were analyzed. We found that these chimeric VLPs induced neutralizing antibodies against HCV in mice. Additionally, the murine serum neutralized infections with HCV pseudoparticles and cell-cultured viruses derived from different heterologous 1a, 1b and 2a genotypes. We also found that immunization with chimeric VLPs induced anti-HBsAg antibodies. This study provides a novel strategy for development of a HCV prophylactic neutralizing epitope vaccine and a HCV-HBV bivalent prophylactic vaccine.
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Affiliation(s)
- Sanhua Wei
- Department of Clinical Laboratory and Research Center, Tangdu Hospital, The Fourth Military Medical University, No. 569 Xinsi Road, Xi'an, Shaanxi 710038, China
| | - Yingfeng Lei
- Department of Microbiology, The Fourth Military Medical University, No. 17 West Road, Xi'an, Shaanxi 710032, China
| | - Jie Yang
- Department of Nephrology, Tangdu Hospital, The Fourth Military Medical University, No. 569 Xinsi Road, Xi'an, Shaanxi 710038, China
| | - Xiaoyan Wang
- Department of Clinical Laboratory and Research Center, Tangdu Hospital, The Fourth Military Medical University, No. 569 Xinsi Road, Xi'an, Shaanxi 710038, China
| | - Fang Shu
- Department of Clinical Laboratory, Xi'an Third Hospital, No. 10 Eastern Section of The Third FengCheng Rd., WeiYang District, Xi'an, Shaanxi 710018, China
| | - Xin Wei
- Department of Infectious Disease, Tangdu Hospital, The Fourth Military Medical University, No. 569 Xinsi Road, Xi'an, Shaanxi 710038, China
| | - Fang Lin
- Department of Clinical Laboratory and Research Center, Tangdu Hospital, The Fourth Military Medical University, No. 569 Xinsi Road, Xi'an, Shaanxi 710038, China
| | - Bin Li
- Department of Clinical Laboratory and Research Center, Tangdu Hospital, The Fourth Military Medical University, No. 569 Xinsi Road, Xi'an, Shaanxi 710038, China
| | - Ying Cui
- Department of Clinical Laboratory and Research Center, Tangdu Hospital, The Fourth Military Medical University, No. 569 Xinsi Road, Xi'an, Shaanxi 710038, China
| | - Hai Zhang
- Laboratory Animal Research Center, The Fourth Military Medical University, No. 17 West Road, Xi'an, Shaanxi 710032, China.
| | - Sanhua Wei
- Department of Clinical Laboratory and Research Center, Tangdu Hospital, The Fourth Military Medical University, No. 569 Xinsi Road, Xi'an, Shaanxi 710038, China.
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16
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Kjellin M, Wesslén T, Löfblad E, Lennerstrand J, Lannergård A. The effect of the first-generation HCV-protease inhibitors boceprevir and telaprevir and the relation to baseline NS3 resistance mutations in genotype 1: experience from a small Swedish cohort. Ups J Med Sci 2018; 123. [PMID: 29536805 PMCID: PMC5901468 DOI: 10.1080/03009734.2018.1441928] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The clinical experience with protease-inhibitor (PI) triple regimen appears disappointing regarding effect, side effects, high work load, and costs. This real-world study evaluates baseline and emerging resistance-associated substitutions (RASs) and their significance for treatment outcome. METHOD Thirty-six genotype 1a/b patients treated according to Swedish recommendations during 2011-2013 with triple therapy including pegylated interferon and ribavirin in combination with a protease-inhibitor, either boceprevir (BOC) or telaprevir (TVR), were retrospectively evaluated. Frozen serum samples from the patients were tested for resistance with pan-genotypic population sequencing. RESULTS Overall, 56% (20/36) of the patients achieved sustained viral response (SVR). The SVR was comparable between BOC (64%; 9/14) and TVR (50%; 11/22) (p = 0.07), and the IL28B type non-CC (48%; 12/25) and CC (46%; 6/13) (p = 0.77). The SVR was higher in patients without cirrhosis (89.5%; 17/19) (p < 0.0005), in treatment-naïve patients (70%; 14/20) (p = 0.02), and those with low viral load (<800,000 IU/mL) (66.7%; 8/12) (p < 0.0002), compared to those with cirrhosis (17.6%; 3/17), treatment-experienced (37.5%; 6/16), and high viral load (>800,000 IU/mL) (50%; 12/24). CONCLUSION PI triple regimes were highly effective in treatment-naïve patients without cirrhosis, but in this real-world cohort an inferior effect was evident in cirrhotic and treatment-experienced patients. Although tested on a limited sample, the baseline resistance testing seems to have no impact on prediction of therapy outcome. The reason could be that the baseline RASs T54S and V55A have relatively low resistance towards BOC and TVR. Emerging RASs, mainly R155K, with known high resistance to BOC and TVR were frequently found in non-responders.
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Affiliation(s)
- Midori Kjellin
- Section of Clinical Microbiology, Department of Medical Sciences, Uppsala University Hospital, Sweden
| | - Terése Wesslén
- Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, Sweden
| | - Erik Löfblad
- Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, Sweden
| | - Johan Lennerstrand
- Section of Clinical Microbiology, Department of Medical Sciences, Uppsala University Hospital, Sweden
| | - Anders Lannergård
- Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, Sweden
- CONTACT Anders Lannergård Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, S 751 85 Uppsala, Sweden
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17
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Kanda T, Nirei K, Matsumoto N, Higuchi T, Nakamura H, Yamagami H, Matsuoka S, Moriyama M. Retreatment of patients with treatment failure of direct-acting antivirals: Focus on hepatitis C virus genotype 1b. World J Gastroenterol 2017; 23:8120-8127. [PMID: 29290649 PMCID: PMC5739919 DOI: 10.3748/wjg.v23.i46.8120] [Citation(s) in RCA: 5] [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: 10/12/2017] [Revised: 11/10/2017] [Accepted: 11/27/2017] [Indexed: 02/06/2023] Open
Abstract
The recent development of direct-acting antiviral agents (DAAs) against hepatitis C virus (HCV) infection could lead to higher sustained virological response (SVR) rates, with shorter treatment durations and fewer adverse events compared with regimens that include interferon. However, a relatively small proportion of patients cannot achieve SVR in the first treatment, including DAAs with or without peginterferon and/or ribavirin. Although retreatment with a combination of DAAs should be conducted for these patients, it is more difficult to achieve SVR when retreating these patients because of resistance-associated substitutions (RASs) or treatment-emergent substitutions. In Japan, HCV genotype 1b (GT1b) is founded in 70% of HCV-infected individuals. In this minireview, we summarize the retreatment regimens and their SVR rates for HCV GT1b. It is important to avoid drugs that target the regions targeted by initial drugs, but next-generation combinations of DAAs, such as sofosbuvir/velpatasvir/voxilaprevir for 12 wk or glecaprevir/pibrentasvir for 12 wk, are proposed to be potential solution for the HCV GT1b-infected patients with treatment failure, mainly on a basis of targeting distinctive regions. Clinicians should follow the new information and resources for DAAs and select the proper combination of DAAs for the retreatment of HCV GT1b-infected patients with treatment failure.
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Affiliation(s)
- Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Kazushige Nirei
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Naoki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Teruhisa Higuchi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hitomi Nakamura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hiroaki Yamagami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Shunichi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
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18
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Hirano J, Okamoto T, Sugiyama Y, Suzuki T, Kusakabe S, Tokunaga M, Fukuhara T, Sasai M, Tougan T, Matsunaga Y, Yamashita K, Sakai Y, Yamamoto M, Horii T, Standley DM, Moriishi K, Moriya K, Koike K, Matsuura Y. Characterization of SPP inhibitors suppressing propagation of HCV and protozoa. Proc Natl Acad Sci U S A 2017; 114:E10782-E10791. [PMID: 29187532 PMCID: PMC5740650 DOI: 10.1073/pnas.1712484114] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Signal peptide peptidase (SPP) is an intramembrane aspartic protease involved in the maturation of the core protein of hepatitis C virus (HCV). The processing of HCV core protein by SPP has been reported to be critical for the propagation and pathogenesis of HCV. Here we examined the inhibitory activity of inhibitors for γ-secretase, another intramembrane cleaving protease, against SPP, and our findings revealed that the dibenzoazepine-type structure in the γ-secretase inhibitors is critical for the inhibition of SPP. The spatial distribution showed that the γ-secretase inhibitor compound YO-01027 with the dibenzoazepine structure exhibits potent inhibiting activity against SPP in vitro and in vivo through the interaction of Val223 in SPP. Treatment with this SPP inhibitor suppressed the maturation of core proteins of all HCV genotypes without the emergence of drug-resistant viruses, in contrast to the treatment with direct-acting antivirals. YO-01027 also efficiently inhibited the propagation of protozoa such as Plasmodium falciparum and Toxoplasma gondii These data suggest that SPP is an ideal target for the development of therapeutics not only against chronic hepatitis C but also against protozoiasis.
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Affiliation(s)
- Junki Hirano
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
| | - Toru Okamoto
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan;
| | - Yukari Sugiyama
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
| | - Tatsuya Suzuki
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
| | - Shinji Kusakabe
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
| | - Makoto Tokunaga
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
| | - Takasuke Fukuhara
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
| | - Miwa Sasai
- Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
| | - Takahiro Tougan
- Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
| | - Yasue Matsunaga
- Planning and Promotion Office for University-Industry Collaboration, Osaka University, Osaka 565-0871, Japan
| | | | - Yusuke Sakai
- Department of Veterinary Pathology, Yamaguchi University, Yamaguchi 753-0841, Japan
| | - Masahiro Yamamoto
- Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
| | - Toshihiro Horii
- Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
| | - Daron M Standley
- Department of Genome Informatics, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
| | - Kohji Moriishi
- Department of Microbiology, Faculty of Medicine, University of Yamanashi, Yamanashi 400-8510, Japan
| | - Kyoji Moriya
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan
| | - Yoshiharu Matsuura
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan;
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19
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Predictors of early discontinuation of interferon-free direct antiviral agents in patients with hepatitis C virus and advanced liver fibrosis: results of a real-life cohort. Eur J Gastroenterol Hepatol 2017; 29:1149-1154. [PMID: 28800033 DOI: 10.1097/meg.0000000000000944] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
AIM The aim of this study was to determine risk factors for premature treatment discontinuation among patients with hepatitis C and advanced fibrosis with advanced fibrosis treated with interferon (IFN)-free direct antiviral agents (DAA)-based therapy. PATIENTS AND METHODS We included all patients with chronic hepatitis C virus infection and advanced liver fibrosis in whom treatment was initiated with IFN-free DAA therapy at a university hospital from December 2015 through June 2016. We prospectively collected data from medical records using standardized questionnaires and evaluated them using Epi Info 7.1.2.0. The primary outcome was treatment interruption and associated factors. RESULTS In total, 214 patients were included in this study; 180 patients were treated with sofosbuvir (SOF)+daclatasvir±ribavirin (RBV), 31 received SOF+simeprevir±RBV, and three were treated with SOF+RBV. Treatment discontinuation rate was 8.9% (19 patients) and cirrhotic decompensation was the main reason [8 (42.1%)]. Among patients with Child B or C cirrhosis (31), 10 (32.2%) prematurely interrupted treatment. The risk factors for treatment discontinuation in univariate analysis were older age (P=0.0252), higher comorbidity index (P=0.0078), higher model for end-stage liver disease (P<0.0001), higher fibrosis index based on the 4 factores (P=0.0122), and lower hemoglobin (P=0.0185) at baseline. Multivariate analysis showed that older age (odds ratio: 1.1, 95% confidence interval: 1.02-1.19) and higher model for end-stage liver disease (odds ratio: 1.27, 95% confidence interval: 1.03-1.56) were associated with premature treatment interruption. CONCLUSION Older age and advanced liver disease were related to treatment interruption. Identification of risk factors associated with treatment discontinuation is important to recognize patients who should be followed up closely during treatment, ando those whom possibly may not benefit from immediate DAA treatment or should be followed up closely during treatment.
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20
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Jakobsen JC, Nielsen EE, Feinberg J, Katakam KK, Fobian K, Hauser G, Poropat G, Djurisic S, Weiss KH, Bjelakovic M, Bjelakovic G, Klingenberg SL, Liu JP, Nikolova D, Koretz RL, Gluud C. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev 2017; 9:CD012143. [PMID: 28922704 PMCID: PMC6484376 DOI: 10.1002/14651858.cd012143.pub3] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs), e.g. sofosbuvir, are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). Sustained virological response (SVR) is used by investigators and regulatory agencies as a surrogate outcome for morbidity and mortality, based solely on observational evidence. However, there have been no randomised trials that have validated that usage. OBJECTIVES To assess the benefits and harms of DAAs in people with chronic HCV. SEARCH METHODS We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016. SELECTION CRITERIA Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and health-related quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and SVR. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. We evaluated the overall quality of the evidence, using GRADE. MAIN RESULTS We included a total of 138 trials randomising a total of 25,232 participants. The trials were generally short-term trials and designed primarily to assess the effect of treatment on SVR. The trials evaluated 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered DAAs that were discontinued or withdrawn from the market. Study populations were treatment-naive in 95 trials, had been exposed to treatment in 17 trials, and comprised both treatment-naive and treatment-experienced individuals in 24 trials. The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.We could not reliably determine the effect of DAAs on the market or under development on our primary outcome of hepatitis C-related morbidity or all-cause mortality. There were no data on hepatitis C-related morbidity and only limited data on mortality from 11 trials (DAA 15/2377 (0.63%) versus control 1/617 (0.16%); OR 3.72, 95% CI 0.53 to 26.18, very low-quality evidence). We did not perform Trial Sequential Analysis on this outcome.There is very low quality evidence that DAAs on the market or under development do not influence serious adverse events (DAA 5.2% versus control 5.6%; OR 0.93, 95% CI 0.75 to 1.15 , 15,817 participants, 43 trials). The Trial Sequential Analysis showed that there was sufficient information to rule out that DAAs reduce the relative risk of a serious adverse event by 20% when compared with placebo. The only DAA that showed a lower risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, the meta-analysis result showed no evidence of a difference.DAAs on the market or under development may reduce the risk of no SVR from 54.1% in untreated people to 23.8% in people treated with DAA (RR 0.44, 95% CI 0.37 to 0.52, 6886 participants, 32 trials, low quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).There was insufficient evidence from trials on withdrawn or discontinued DAAs to determine their effect on hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79; 5 trials, very low-quality evidence). However, these DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73; 29 trials, very low-quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). AUTHORS' CONCLUSIONS The evidence for our main outcomes of interest come from short-term trials, and we are unable to determine the effect of long-term treatment with DAAs. The rates of hepatitis C morbidity and mortality observed in the trials are relatively low and we are uncertain as to how DAAs affect this outcome. Overall, there is very low quality evidence that DAAs on the market or under development do not influence serious adverse events. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs may reduce the number of people with detectable virus in their blood, but we do not have sufficient evidence from randomised trials that enables us to understand how SVR affects long-term clinical outcomes. SVR is still an outcome that needs proper validation in randomised clinical trials.
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Affiliation(s)
- Janus C Jakobsen
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
- Holbaek HospitalDepartment of CardiologyHolbaekDenmark4300
| | - Emil Eik Nielsen
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Joshua Feinberg
- Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812Blegdamsvej 9CopenhagenDenmark2100
| | - Kiran Kumar Katakam
- Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812Blegdamsvej 9CopenhagenDenmark2100
| | - Kristina Fobian
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Goran Hauser
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Goran Poropat
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Snezana Djurisic
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagenDenmark
| | - Karl Heinz Weiss
- Heidelberg University HospitalInternal Medicine IV: Gastroenterology, Infectious Diseases, ToxicologyIm Neuenheimer Feld 410HeidelbergGermanyD‐69120
| | - Milica Bjelakovic
- University of NisMedical FacultyBoulevard Dr Zorana Djindjica 81NisSerbia18000
| | - Goran Bjelakovic
- Medical Faculty, University of NisDepartment of Internal MedicineZorana Djindjica 81NisSerbia18000
| | - Sarah Louise Klingenberg
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
| | - Jian Ping Liu
- Beijing University of Chinese MedicineCentre for Evidence‐Based Chinese Medicine11 Bei San Huan Dong Lu, Chaoyang DistrictBeijingChina100029
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
| | | | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenSjællandDenmarkDK‐2100
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Jakobsen JC, Nielsen EE, Feinberg J, Katakam KK, Fobian K, Hauser G, Poropat G, Djurisic S, Weiss KH, Bjelakovic M, Bjelakovic G, Klingenberg SL, Liu JP, Nikolova D, Koretz RL, Gluud C. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev 2017; 9:CD012143. [PMID: 28922704 PMCID: PMC6484383 DOI: 10.1002/14651858.cd012143.pub2] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs), e.g. sofosbuvir, are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). Sustained virological response (SVR) is used by investigators and regulatory agencies as a surrogate outcome for morbidity and mortality, based solely on observational evidence. However, there have been no randomised trials that have validated that usage. OBJECTIVES To assess the benefits and harms of DAAs in people with chronic HCV. SEARCH METHODS We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016. SELECTION CRITERIA Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and health-related quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and SVR. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. We evaluated the overall quality of the evidence, using GRADE. MAIN RESULTS We included a total of 138 trials randomising a total of 25,232 participants. The trials were generally short-term trials and designed primarily to assess the effect of treatment on SVR. The trials evaluated 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered DAAs that were discontinued or withdrawn from the market. Study populations were treatment-naive in 95 trials, had been exposed to treatment in 17 trials, and comprised both treatment-naive and treatment-experienced individuals in 24 trials. The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.We could not reliably determine the effect of DAAs on the market or under development on our primary outcome of hepatitis C-related morbidity or all-cause mortality. There were no data on hepatitis C-related morbidity and only limited data on mortality from 11 trials (DAA 15/2377 (0.63%) versus control 1/617 (0.16%); OR 3.72, 95% CI 0.53 to 26.18, very low-quality evidence). We did not perform Trial Sequential Analysis on this outcome.There is very low quality evidence that DAAs on the market or under development do not influence serious adverse events (DAA 5.2% versus control 5.6%; OR 0.93, 95% CI 0.75 to 1.15 , 15,817 participants, 43 trials). The Trial Sequential Analysis showed that there was sufficient information to rule out that DAAs reduce the relative risk of a serious adverse event by 20% when compared with placebo. The only DAA that showed a lower risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, the meta-analysis result showed no evidence of a difference.DAAs on the market or under development may reduce the risk of no SVR from 54.1% in untreated people to 23.8% in people treated with DAA (RR 0.44, 95% CI 0.37 to 0.52, 6886 participants, 32 trials, low quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).There was insufficient evidence from trials on withdrawn or discontinued DAAs to determine their effect on hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79; 5 trials, very low-quality evidence). However, these DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73; 29 trials, very low-quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). AUTHORS' CONCLUSIONS The evidence for our main outcomes of interest come from short-term trials, and we are unable to determine the effect of long-term treatment with DAAs. The rates of hepatitis C morbidity and mortality observed in the trials are relatively low and we are uncertain as to how DAAs affect this outcome. Overall, there is very low quality evidence that DAAs on the market or under development do not influence serious adverse events. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs may reduce the number of people with detectable virus in their blood, but we do not have sufficient evidence from randomised trials that enables us to understand how SVR affects long-term clinical outcomes. SVR is still an outcome that needs proper validation in randomised clinical trials.
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Affiliation(s)
| | - Emil Eik Nielsen
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Joshua Feinberg
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Kiran Kumar Katakam
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalBlegdamsvej 9CopenhagenDenmark2100
| | - Kristina Fobian
- Department 7812, Rigshospitalet, Copenhagen University HospitalCopenhagen Trial Unit, Centre for Clinical Intervention ResearchBlegdamsvej 9CopenhagenDenmark2100
| | - Goran Hauser
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Goran Poropat
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51 000
| | - Snezana Djurisic
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalBlegdamsvej 9CopenhagenDenmark2100
| | - Karl Heinz Weiss
- Heidelberg University HospitalInternal Medicine IV: Gastroenterology, Infectious Diseases, ToxicologyIm Neuenheimer Feld 410HeidelbergGermanyD‐69120
| | - Milica Bjelakovic
- University of NisMedical FacultyBoulevard Dr Zorana Djindjica 81NisSerbia18000
| | - Goran Bjelakovic
- Medical Faculty, University of NisDepartment of Internal MedicineZorana Djindjica 81NisSerbia18000
| | - Sarah Louise Klingenberg
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Jian Ping Liu
- Beijing University of Chinese MedicineCentre for Evidence‐Based Chinese Medicine11 Bei San Huan Dong Lu, Chaoyang DistrictBeijingChina100029
| | - Dimitrinka Nikolova
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | | | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
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Turnes J, Domínguez-Hernández R, Casado MÁ. Análisis coste-efectividad de dos estrategias de tratamiento para la hepatitis C crónica: antes y después del acceso a los agentes antivirales de acción directa en España. GASTROENTEROLOGIA Y HEPATOLOGIA 2017. [DOI: 10.1016/j.gastrohep.2017.05.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Hsieh MH, Yeh ML, Su TH, Liu TW, Huang CF, Huang CI, Wang SC, Huang JF, Dai CY, Kao JH, Chuang WL, Chen PJ, Liu CJ, Yu ML. Boceprevir-based triple therapy to rescue HCV genotype 1/HBV dually infected patients refractory to peginterferon plus ribavirin combination therapy in Taiwan. J Formos Med Assoc 2017; 117:497-504. [PMID: 28694000 DOI: 10.1016/j.jfma.2017.06.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Revised: 06/11/2017] [Accepted: 06/15/2017] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND/PURPOSE The role of directly-acting antivirals (DAA)-containing regimens in the treatment of patients dually-infected with hepatitis C virus (HCV) and hepatitis B virus (HBV) remains unclear. The pilot study aimed to explore the safety and efficacy of a protease inhibitor, boceprevir, in combination with peginterferon/ribavirin for HCV genotype 1 (HCV-1)/HBV dually-infected patients refractory to prior peginterferon/ribavirin. METHODS Twelve peginterferon-experienced patients dually-infected with HCV-1/HBV were assigned to receive boceprevir 800 mg, twice a day, plus peginterferon-α 2b 1.5 μg/kg/week and ribavirin 800-1400 mg/day for 36 or 48 weeks. The primary endpoint was HCV sustained virological response (SVR, HCV RNA undetectable 24 weeks after end-of-treatment). RESULTS Five patients terminated treatment early due to adverse events (one at week 4, one at week 46), virological failures (one non-response and one breakthrough), and patient request (n = 1). Eight patients achieved HCV SVR (66.7% in full-analysis set and 72.7% in modified intention-to-treat population). The HCV SVR rate was 71.4% (5/7) in prior relapsers, 60.0% (3/5) in prior null responder; 75% in non-cirrhotic and 50% in cirrhotic patients. All four patients of prior non-cirrhotic relapsers received 36-week regimen and achieved HCV SVR. There was no HBV-related hepatic flare. All patients experienced at least one adverse event. Two had serious adverse events. CONCLUSION Boceprevir plus peginterferon/ribavirin is effective in the treatment of HCV-1/HBV dually infected patients' refractory to prior peginterferon/ribavirin combination therapy.
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Affiliation(s)
- Meng-Hsuan Hsieh
- Health Management Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Medicine, Graduate Institute of Clinical Medicine, College of Medicine, Lipid Science and Aging Research Center, Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- School of Medicine, Graduate Institute of Clinical Medicine, College of Medicine, Lipid Science and Aging Research Center, Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Tung-Hung Su
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Ta-Wei Liu
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chuang-Feng Huang
- School of Medicine, Graduate Institute of Clinical Medicine, College of Medicine, Lipid Science and Aging Research Center, Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ching-I Huang
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Shu-Chi Wang
- Health Management Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Medicine, Graduate Institute of Clinical Medicine, College of Medicine, Lipid Science and Aging Research Center, Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- School of Medicine, Graduate Institute of Clinical Medicine, College of Medicine, Lipid Science and Aging Research Center, Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Health Management Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Medicine, Graduate Institute of Clinical Medicine, College of Medicine, Lipid Science and Aging Research Center, Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Wan-Long Chuang
- School of Medicine, Graduate Institute of Clinical Medicine, College of Medicine, Lipid Science and Aging Research Center, Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
| | - Ming-Lung Yu
- School of Medicine, Graduate Institute of Clinical Medicine, College of Medicine, Lipid Science and Aging Research Center, Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan; Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
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Morishita N, Hiramatsu N, Oze T, Urabe A, Tahata Y, Yamada R, Yakushijin T, Hosui A, Iio S, Yamada A, Hagiwara H, Mita E, Yamada Y, Ito T, Inada M, Katayama K, Yabuuchi I, Imai Y, Hikita H, Sakamori R, Yoshida Y, Tatsumi T, Hayashi N, Takehara T. Ultra-deep sequencing analysis of resistance-associated variants during retreatment with simeprevir-based triple therapy after failure of telaprevir-based triple therapy in patients with genotype 1 hepatitis C virus infection. Hepatol Res 2017; 47:773-782. [PMID: 27593967 DOI: 10.1111/hepr.12817] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 07/15/2016] [Accepted: 08/31/2016] [Indexed: 01/13/2023]
Abstract
AIM Simeprevir (SMV)-based triple therapy is an effective retreatment option following failure of telaprevir (TVR)-based triple therapy. However, it is unclear whether the persistence of resistance-associated variants (RAVs) induced by TVR-based therapy may reduce the treatment effect of SMV-based therapy. METHODS The factors associated with the treatment effect, including RAVs in the NS3 region, were examined in 21 patients with genotype 1b HCV infection who were treated with SMV-based therapy after failure of TVR-based therapy. Ultra-deep sequencing was carried out to detect RAVs. RESULTS With the exception of one patient who discontinued treatment owing to adverse events, the sustained virologic response (SVR) rate was 50% (10/20). Ultra-deep sequencing at the start of SMV-based therapy revealed that TVR-resistant variants were detected in six patients (29%), and no variants were observed at position 168. Cross-resistance between TVR and SMV with low frequency was detected in only one patient, and this patient achieved SVR. Higher SVRs for SMV-based therapy were attained in patients who discontinued treatment owing to the adverse effects of prior TVR-based therapy (discontinuation 100% vs. non-discontinuation 29%, P = 0.005), and patients who relapsed following prior pegylated interferon plus ribavirin therapy (relapse 100% vs. non-response 20%, P = 0.007). CONCLUSIONS In this study, ultra-deep sequencing analysis revealed that TVR and/or SMV-resistant variants may have no influence on the effect of SMV-based therapy after failure of TVR-based therapy. Patients who discontinued treatment owing to adverse effects of TVR-based therapy and relapsers to previous pegylated interferon/ribavirin therapy would be good candidates for retreatment with SMV-based therapy.
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Affiliation(s)
- Naoki Morishita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Naoki Hiramatsu
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tsugiko Oze
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ayako Urabe
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yuki Tahata
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ryoko Yamada
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Takayuki Yakushijin
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | | | - Sadaharu Iio
- Higashiosaka City General Hospital, Higashiosaka, Japan
| | | | | | - Eiji Mita
- National Hospital Organization Osaka National Hospital, Osaka, Japan
| | | | - Toshifumi Ito
- Japan Community Health Care Organization Osaka Hospital, Osaka, Japan
| | | | - Kazuhiro Katayama
- Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
| | - Iwao Yabuuchi
- National Hospital Organization Minami Wakayama Medical Center, Tanabe, Japan
| | | | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yuichi Yoshida
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | | | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
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Gane EJ, DeJesus E, Janczewska E, George J, Diago M, Da Silva MH, Reesink H, Nikitin I, Hinrichsen H, Bourgeois S, Ferenci P, Shukla U, Kalmeijer R, Lenz O, Fevery B, Corbett C, Beumont M, Jessner W. Simeprevir with peginterferon α-2a/ribavirin for chronic hepatitis C virus genotype 1 infection in treatment-experienced patients: an open-label, rollover study. BMC Infect Dis 2017; 17:389. [PMID: 28577353 PMCID: PMC5457573 DOI: 10.1186/s12879-017-2444-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 05/07/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND This Phase 3, open-label, rollover study (NCT01323244) investigated the efficacy and safety of simeprevir plus peginterferon α-2a (PegIFNα-2a) and ribavirin (RBV) in a well-characterized population of HCV genotype 1 (GT1)-infected treatment-experienced patients. METHODS Patients who had failed PegIFNα/RBV treatment in the placebo arm of a previous Phase 2/3 simeprevir study (Phase 2/3 group, n = 125), or had been exposed to HCV direct-acting antivirals (simeprevir or other) for up to 14 days in a selected Phase 1 study (Phase 1 group, n = 16), were eligible. Phase 2/3 group patients were classified according to prior relapse, breakthrough, or non-response (null response, partial response, non-classifiable non-response) to PegIFNα/RBV. Eight patients in the Phase 1 group received short-term (≤14 days) simeprevir. Treatment comprised simeprevir 150 mg once daily (QD) plus PegIFNα-2a/RBV for 12 weeks followed by PegIFNα-2a/RBV for 12 or 36 weeks (using response-guided therapy [RGT] to determine total treatment duration in Phase 2/3 prior relapsers or breakthrough) or 36 weeks fixed (Phase 2/3 group non-responders and Phase 1 group). The primary endpoint was sustained virologic response 12 weeks after planned end of treatment (SVR12). RESULTS Phase 2/3 group: SVR12 rate was 69.6% (87/125) overall; 92.7% (51/55), 60.0% (6/10), 64.3% (18/28), and 36.7% (11/30) in patients with prior relapse, viral breakthrough, partial response, or null response, respectively. SVR12 rates were similar for patients with HCV GT1a (66.0% [33/50]) and GT1b infection (72.0% [54/75]) and among HCV GT1a-infected patients with/without a baseline Q80K polymorphism (66.7% [8/12] and 65.8% [25/38], respectively). The majority of RGT-eligible patients (prior viral relapse or breakthrough) met RGT criteria (89.2% [58/65]); of these, 89.7% (52/58) achieved SVR12. Overall, 16.0% (20/125) of patients experienced on-treatment failure and 14.4% (18/125) experienced post-treatment failure (15 relapses, 3 missing data). Phase 1 group (simeprevir-naïve and -experienced patients combined): SVR12 rate was 37.5% (6/16). Safety and tolerability findings were comparable to those of the feeder studies. CONCLUSIONS The majority of RGT-eligible patients met criteria for shortening treatment to 24 weeks in total. Simeprevir 150 mg QD with PegIFNα-2a/RBV led to a high SVR rate among prior relapsers with HCV GT1 infection. No new safety signals were noted. TRIAL REGISTRATION NCT01323244 . (date of registration: March 24, 2011).
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Affiliation(s)
- Edward J. Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
| | | | - Ewa Janczewska
- Outpatients Clinic for Hepatology, ID Clinic, Myslowice, Poland
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, New South Wales, Australia
| | | | | | - Henk Reesink
- Academic Medical Center, Amsterdam, The Netherlands
| | - Igor Nikitin
- Institution of Russian Academy of Sciences Central Clinical Hospital, Moscow, Russia
| | | | | | - Peter Ferenci
- Allgemeines Krankenhaus der Stadt Wien, Universitätsklinik für Innere Medizin III, Wien, Austria
| | - Umesh Shukla
- Janssen Research & Development, LLC, Titusville, NJ USA
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Abdelhafez TH, Bader El Din NG, Tabll AA, Mashaly MM, Dawood RM, Yassin NA, El-Awady MK. Mice Antibody Response to Conserved Nonadjuvanted Multiple Antigenic Peptides Derived from E1/E2 Regions of Hepatitis C Virus. Viral Immunol 2017; 30:359-365. [PMID: 28402196 DOI: 10.1089/vim.2016.0123] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Synthetic peptides are one of the hepatitis C virus (HCV)-specific small molecules that have antiviral activity and represent a target for HCV vaccine. This study aims to determine the lowest concentration of adjuvanted and non-adjuvanted (multiple antigenic peptide [MAP]) form of three conserved HCV envelope peptides that can induce murine immunogenic responses and evaluate the neutralization capacities of the generated antibodies (Abs) against HCV in cultured Huh7.5 cells. In this study, three HCV synthetic peptides, E1 peptide (a.a 315-323) and E2 peptides (a.a 412-419 and a.a 516-531) were synthesized. Female Balb/c mice were immunized with different concentration of either adjuvanted linear peptides or nonadjuvanted MAP peptides to determine the lowest dose that generates Ab responses enough to confer viral neutralization in vitro. The humoral responses targeting these peptides in immunized mice sera were measured by enzyme-linked immunosorbent assay (ELISA). Viral neutralization capacities of the generated mice Abs were assessed using Huh7.5 cells infected with the HCVcc infectious system (J6/JFH-1). The results of this study showed that the MAPs induce higher Ab titers than adjuvanted linear peptides after 4 weeks of immunization (p = 0.003). The viral neutralization experiments showed that the immunized mice sera contain anti E1/E2 Abs that blocked HCVcc (J6/JFH-1) entry into Huh7.5 cells. In conclusion, the three HCV envelope MAP peptides are more immunogenic and produce higher neutralizing Abs than linear peptides; therefore, they can be essential components for HCV vaccine.
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Affiliation(s)
- Tawfeek H Abdelhafez
- 1 Department of Microbial Biotechnology, National Research Center , Dokki, Giza, Egypt
| | - Noha G Bader El Din
- 1 Department of Microbial Biotechnology, National Research Center , Dokki, Giza, Egypt
| | - Ashraf A Tabll
- 1 Department of Microbial Biotechnology, National Research Center , Dokki, Giza, Egypt
| | - Mohammad M Mashaly
- 2 Department of Chemistry, Faculty of Science, Damietta University , Damietta, Egypt
| | - Reham M Dawood
- 1 Department of Microbial Biotechnology, National Research Center , Dokki, Giza, Egypt
| | - Nemat A Yassin
- 3 Department of Pharmacology, National Research Center , Dokki, Giza, Egypt
| | - Mostafa K El-Awady
- 1 Department of Microbial Biotechnology, National Research Center , Dokki, Giza, Egypt
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Yan Z, Wang Y. Viral and host factors associated with outcomes of hepatitis C virus infection (Review). Mol Med Rep 2017; 15:2909-2924. [PMID: 28339063 DOI: 10.3892/mmr.2017.6351] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 02/13/2017] [Indexed: 11/05/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a major health issue globally. Owing to the progress made in host genetics and HCV molecular virology, emerging data have suggested that the natural course and treatment response in patients with HCV infection are largely determined by complex host‑viral interactions. HCV genotype is the most important viral factor predicting the response to pegylated interferon‑α plus ribavirin therapy. The subtype of HCV genotype 1 is the key viral factor that predicts the efficacy of direct‑acting antiviral therapy. HCV genome heterogeneity and baseline viral load are additionally associated with the treatment response. Multiple host genetic variants localized in genes associated with the immune response have been identified as predictors of spontaneous disease course and therapy outcome in chronic HCV. However, most findings from candidate gene association studies have not been proven universal for all investigated populations and independent studies. Previous findings in independent large genome wide association studies confirmed that interferon‑λ3 gene polymorphisms are associated with spontaneous clearance and treatment responsiveness. A polymorphism of the inosine triphosphatase gene has been identified as a protective factor against ribavirin‑induced anemia and dose reductions. Another genetic variant in the patatin‑like phospholipase domain containing 3 genes is associated with hepatic steatosis and fibrosis in patients with HCV. The present review focused on the identified viral and host factors associated with outcomes of patients with HCV, and assessed the involvement of viral and host genetics in the natural history and treatment outcomes of HCV infection. This will provide novel ideas concerning personalized prevention and individualized clinical management.
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Affiliation(s)
- Zehui Yan
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Shapingba, Chongqing 400038, P.R. China
| | - Yuming Wang
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Shapingba, Chongqing 400038, P.R. China
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Predictors of Early Discontinuation of Pegylated Interferon for Reasons Other Than Lack of Efficacy in United States Veterans With Chronic Hepatitis C. Gastroenterol Nurs 2017; 38:417-28. [PMID: 26626031 DOI: 10.1097/sga.0000000000000214] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
During the dual-therapy era, many patients with chronic hepatitis C discontinued therapy for reasons other than lack of efficacy (non-LOE). We determined whether selected patient characteristics predicted non-LOE discontinuation using national databases of U.S. veterans with Genotypes 1-4. We identified U.S. veterans in the Veterans Health Administration system in 2004-2009 who had hepatitis C-confirming RNA laboratory results and initiated therapy with pegylated interferon and ribavirin. We used a rule to classify patients who discontinued pegylated interferon early, based on pharmacy refill and viral response data. Multivariate Cox regression was used to identify predictors of non-LOE discontinuation. Of 321,238 patients with a hepatitis C International Classification of Diseases, Ninth Revision, code, 15,297 (4.8%) met all inclusion criteria. Non-LOE discontinuers comprised 30.3% of patients. For Genotypes 1-4, the predictors (adjusted hazard ratio) of greatest magnitude were comorbidities of myocardial infarction/congestive heart failure (1.36), renal disease (1.34), and platelets 100/mm or more (1.38). For Genotypes 2 and 3, predictors of greatest magnitude were Black race (1.30), myocardial infarction/congestive heart failure (1.84), albumin 3.5 mg/dl or more (1.65), sleep aid use (1.32), and poor persistence with antidepressants (1.31) and antihypertensive agents (1.37). Our study suggests that many host factors may have contributed to non-LOE dual-therapy discontinuation in veterans and may possibly predict non-LOE discontinuation in triple therapy.
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Hayes CN, Imamura M, Chayama K. The practical management of chronic hepatitis C infection in Japan - dual therapy of daclatasvir + asunaprevir. Expert Rev Gastroenterol Hepatol 2017; 11:103-113. [PMID: 27936974 DOI: 10.1080/17474124.2017.1270205] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Without treatment, many of the 200 million people worldwide with chronic hepatitis C virus (HCV) infection will develop cirrhosis or liver cancer. Japan was the first nation to approve an interferon-free therapy for HCV, and sustained viral response (SVR) rates >90% have been achieved with asunaprevir, a protease inhibitor, plus daclatasvir, an inhibitor of the non-structural 5A (NS5A) protein. Areas covered: This review provides an overview of the results from both clinical trials and real world experience with asunaprevir and daclatasvir therapy focused primarily on Japan. A literature search using the keywords 'asunaprevir,' 'daclatasvir,' 'interferon-free therapy,' and 'direct-acting antiviral drugs' was initially used to select relevant literature for inclusion in the review. Expert commentary: While not approved in the United States, dual therapy with asunaprevir plus daclatasvir has already been successfully used in Japan and throughout East Asia to treat many thousands of patients. Pre-existing or treatment-emergent NS5A-Y93 or -L31 resistance-associated variants (RAVs) may lead to viral breakthrough, and alternative therapies should be considered for these patients, but patients who harbor NS5A RAVs only at low frequency are likely to achieve SVR. The therapy has also been shown to be safe and effective with renal dysfunction or liver cirrhosis.
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Affiliation(s)
- C Nelson Hayes
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Minami-ku , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan
| | - Michio Imamura
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Minami-ku , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan
| | - Kazuaki Chayama
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Minami-ku , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan.,c Laboratory for Digestive Diseases , Center for Genomic Medicine, RIKEN , Hiroshima , Japan
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Feld JJ, Jacobson IM, Sulkowski MS, Poordad F, Tatsch F, Pawlotsky J. Ribavirin revisited in the era of direct-acting antiviral therapy for hepatitis C virus infection. Liver Int 2017; 37:5-18. [PMID: 27473533 PMCID: PMC5216450 DOI: 10.1111/liv.13212] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 07/26/2016] [Indexed: 12/11/2022]
Abstract
Over the past two decades, ribavirin has been an integral component of treatment for hepatitis C virus (HCV) infection, where it has been shown to improve the efficacy of (pegylated) interferon. However, because of treatment-limiting side effects and its additive toxicity with interferon, the search for interferon- and ribavirin-free regimens has been underway. The recent approvals of all-oral direct acting antivirals (DAAs) have revolutionized the HCV therapeutic landscape, and initially it was expected that the role of ribavirin with DAA regimens would be eliminated. On the contrary, what we have witnessed is that ribavirin retains an important role in the optimal treatment of some subgroups of patients, particularly those that historically have been considered the most difficult to cure. Fortunately, it has also been recognized that the safety profile of ribavirin is improved when co-administered with all-oral DAA combinations in the absence of interferon. Despite the antiviral mechanism of action of ribavirin being poorly understood, we now have a range of novel insights into the potential role of ribavirin in all-oral DAA HCV treatment and greater insight into the antiviral mechanism by which it continues to provide clinical benefit for defined patient groups.
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Affiliation(s)
- Jordan J. Feld
- Toronto Centre for Liver DiseaseToronto General HospitalTorontoONCanada
| | | | | | - Fred Poordad
- Texas Liver InstituteUniversity of Texas Health Science CenterSan AntonioTXUSA
| | | | - Jean‐Michel Pawlotsky
- Department of VirologyNational Reference Center for Viral Hepatitis B, C and DeltaHôpital Henri MondorUniversité Paris‐EstCréteilFrance
- INSERM U955CréteilFrance
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31
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Suda KJ, Halbur DJ, Hunkler RJ, Matusiak LM, Schumock GT. Spending on Hepatitis C Antivirals in the United States, 2009-2015. Pharmacotherapy 2016; 37:65-70. [DOI: 10.1002/phar.1865] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2016] [Revised: 08/24/2016] [Accepted: 09/28/2016] [Indexed: 12/19/2022]
Affiliation(s)
- Katie J. Suda
- Department of Veterans Affairs; Center of Innovation for Complex Chronic Healthcare; Edward Hines, Jr. VA Hospital Chicago Illinois
- Department of Pharmacy Systems, Outcomes and Policy; University of Illinois at Chicago; Chicago Illinois
| | - Drew J. Halbur
- Department of Pharmacy Practice; University of Illinois at Chicago; Chicago Illinois
| | | | | | - Glen T. Schumock
- Department of Pharmacy Systems, Outcomes and Policy; University of Illinois at Chicago; Chicago Illinois
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32
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Yamagiwa Y, Asano M, Kawasaki Y, Korenaga M, Murata K, Kanto T, Mizokami M, Masaki N. Pretreatment serum levels of interferon-gamma-inducible protein-10 are associated with virologic response to telaprevir-based therapy. Cytokine 2016; 88:29-36. [PMID: 27541605 DOI: 10.1016/j.cyto.2016.07.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Revised: 07/03/2016] [Accepted: 07/05/2016] [Indexed: 01/16/2023]
Abstract
AIM Telaprevir (TVR) remarkably improves the efficacy of interferon treatment for chronic hepatitis C. Interleukin-28B (IL28B) genotype and interferon-gamma-inducible protein-10 (IP-10) level predict virologic response to peg-interferon (Peg-IFN)/ribavirin (RBV) therapy. We aimed to investigate the usefulness of pretreatment serum IP-10 levels and IL28B genotyping in predicting sustained virologic response (SVR) to TVR-based triple therapy. METHODS In this multi-center study, patients infected with hepatitis C virus genotype 1 with high viral load (⩾5.0logIU/mL) were treated with TVR for 12weeks and Peg-IFN/RBV for 24weeks in Japan. IL28B genotype, serum IP-10 levels, other clinical parameters, and drug dosages were assessed before treatment. RESULTS We included 121 patients who were treated with TVR for at least 8weeks and Peg-IFN/RBV for 24weeks. The median IP-10 levels were significantly lower in rapid virologic response (RVR) or SVR in the IL28B non-TT genotype group, with no significant difference in the TT genotype group. RVR rates were significantly lower in the group with higher serum IP-10 levels (>450pg/mL). In the non-TT IL28B genotype group, RVR and SVR rates were significantly lower in the group with higher IP-10 levels. SVR rates in the group with lower IP-10 levels (<450pg/mL) increased to 82% for those showing RVR, but reduced to 27% in the group with higher IP-10 levels for those not showing RVR. CONCLUSIONS Determination of serum IP-10 levels before treatment could be useful for predicting favorable virologic response to TVR-based triple therapy, especially in patients with IL28B non-TT genotype.
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Affiliation(s)
- Yoko Yamagiwa
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
| | - Mai Asano
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Youhei Kawasaki
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Shizuoka 422-8526, Japan
| | - Masaaki Korenaga
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Kazumoto Murata
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Tatsuya Kanto
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Masashi Mizokami
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Naohiko Masaki
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
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33
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Tamori A, Yoshida K, Kurai O, Kioka K, Hai H, Kozuka R, Motoyama H, Kawamura E, Hagihara A, Uchida-Kobayashi S, Morikawa H, Enomoto M, Murakami Y, Kawada N. Randomized trial of combined triple therapy comprising two types of peginterferon with simeprevir in patients with hepatitis C virus genotype 1b. Hepatol Res 2016; 46:1311-1320. [PMID: 26932745 DOI: 10.1111/hepr.12689] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2015] [Revised: 02/16/2016] [Accepted: 02/29/2016] [Indexed: 02/08/2023]
Abstract
UNLABELLED Simeprevir (SMV) is a potent, macrocyclic hepatitis C virus (HCV) non-structural 3/4 A protease inhibitor. This prospective study compared the efficacy and safety of SMV in combination with peginterferon α2a + ribavirin (P2aR) and with peginterferon α2b + ribavirin (P2bR) in Japanese patients with HCV genotype 1b infection. METHODS Hepatitis C virus genotype 1b patients were randomly assigned to receive SMV (100 mg QD) with P2aR for 12 weeks, then P2aR alone for 12 or 36 weeks; or SMV (100 mg QD) with P2bR for 12 weeks, then P2bR alone for 12 or 36 weeks. The primary endpoint was a sustained virologic response 24 weeks after completing treatment (SVR24). RESULTS In total, 151 patients were randomly assigned to the P2aR (n = 76) or P2bR group (n = 75). Six patients dropped out. Sustained virologic response 24 weeks after completing treatment was achieved in 55 (75.3%) of 73 P2aR patients and 55 (76.4%) of 72 P2bR patients. There was no difference in the rate of SVR24 between the two groups (P = 0.88). No differences in the proportion of patients who became HCV RNA-negative were detected between the P2aR and P2bR groups. The two groups had comparable numbers of adverse events, which led to the discontinuation of treatment in 9.6% and 8.3% of participants in the P2aR and P2bR groups, respectively. CONCLUSION Peginterferon α2a or α2b in combination with SMV + ribavirin therapy showed identical antiviral effects in patients with chronic hepatitis C. Also, the incidence of adverse events was identical for both regimens.
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Affiliation(s)
- Akihiro Tamori
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kanako Yoshida
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Osamu Kurai
- Department of Gastroenterology, Osaka City Juso Hospital, Osaka, Japan
| | - Kiyohide Kioka
- Department of Hepatology, Osaka City General Hospital, Osaka, Japan
| | - Hoang Hai
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Ritsuzo Kozuka
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hiroyuki Motoyama
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Etsushi Kawamura
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Atsushi Hagihara
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | | | - Hiroyasu Morikawa
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masaru Enomoto
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yoshiki Murakami
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
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Carrier P, Essig M, Debette-Gratien M, Sautereau D, Rousseau A, Marquet P, Jacques J, Loustaud-Ratti V. Anti-hepatitis C virus drugs and kidney. World J Hepatol 2016; 8:1343-1353. [PMID: 27917261 PMCID: PMC5114471 DOI: 10.4254/wjh.v8.i32.1343] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Revised: 07/08/2016] [Accepted: 09/18/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) mainly targets the liver but can also induce extrahepatic manifestations. The kidney may be impacted via an immune mediated mechanism or a cytopathic effect. HCV patients are clearly at a greater risk of chronic kidney disease (CKD) than uninfected patients are, and the presence of CKD increases mortality. Interferon-based therapies and ribavirin are difficult to manage and are poorly effective in end-stage renal disease and hemodialysis. These patients should be given priority treatment with new direct anti-viral agents (DAAs) while avoiding peginterferon and ribavirin. The first results were convincing. To aid in the correct use of these drugs in patients with renal insufficiency, their pharmacokinetic properties and potential renal toxicity must be known. The renal toxicity of these new drugs was not a safety signal in clinical trials, and the drugs are generally efficient in these frail populations. These drugs are usually well tolerated, but recent cohort studies have demonstrated that these new regimens may be associated with renal side effects, especially when using sofosbuvir combinations. HCV, renal diseases and comorbidities are intimately linked. The close monitoring of renal function is required, particularly for at-risk patients (transplanted, HIV-coinfected, CKD, hypertensive or diabetic patients). New DAA regimens, which will soon be approved, will probably change the landscape.
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35
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Gray E, Norris S, Schmitz S, O'Leary A. Do disparities between populations in randomized controlled trials and the real world lead to differences in outcomes? J Comp Eff Res 2016; 6:65-82. [PMID: 27854129 DOI: 10.2217/cer-2016-0042] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To conduct a systematic review investigating reasons for the disparity between the efficacy and effectiveness rates reported in randomized controlled trials (RCTs) and observational studies of direct-acting antiviral treatment regimens licensed for use in genotype1 hepatitis C virus-infected individuals. METHODS This systematic review was conducted in accordance with the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses group. RESULTS Statistically significant (p < 0.05) differences in the baseline demographics and sustained virological response rates were observed between RCT and observational studies. CONCLUSION In order for outcomes from RCTs to be generalizable to the real world, greater consideration needs to be taken to include patient populations that are more representative of those awaiting treatment in the clinical setting.
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Affiliation(s)
- Emma Gray
- School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Suzanne Norris
- School of Medicine, Trinity College Dublin, Dublin, Ireland.,Departmentof Hepatology, St James' Hospital, Dublin, Ireland
| | - Susanne Schmitz
- HealthEconomics & Evidence Synthesis Research Unit, Department of PopulationHealth, Luxembourg Health Institute, Luxembourg
| | - Aisling O'Leary
- Schoolof Pharmacy, Royal College of Surgeons of Ireland, Dublin, Ireland.,NationalCentre for Pharmacoeconomics, St James' Hospital, Dublin, Ireland
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36
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Hamada Y, Kiso Y. New directions for protease inhibitors directed drug discovery. Biopolymers 2016; 106:563-79. [PMID: 26584340 PMCID: PMC7161749 DOI: 10.1002/bip.22780] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 10/25/2015] [Accepted: 11/02/2015] [Indexed: 12/29/2022]
Abstract
Proteases play crucial roles in various biological processes, and their activities are essential for all living organisms-from viruses to humans. Since their functions are closely associated with many pathogenic mechanisms, their inhibitors or activators are important molecular targets for developing treatments for various diseases. Here, we describe drugs/drug candidates that target proteases, such as malarial plasmepsins, β-secretase, virus proteases, and dipeptidyl peptidase-4. Previously, we reported inhibitors of aspartic proteases, such as renin, human immunodeficiency virus type 1 protease, human T-lymphotropic virus type I protease, plasmepsins, and β-secretase, as drug candidates for hypertension, adult T-cell leukaemia, human T-lymphotropic virus type I-associated myelopathy, malaria, and Alzheimer's disease. Our inhibitors are also described in this review article as examples of drugs that target proteases. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 563-579, 2016.
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Affiliation(s)
- Yoshio Hamada
- Medicinal Chemistry LaboratoryKobe Pharmaceutical University, MotoyamakitaHigashinada‐kuKobe658‐8558Japan
| | - Yoshiaki Kiso
- Laboratory of Peptide Science, Nagahama Institute of Bio‐Science and TechnologyTamura‐choNagahama526‐0829Japan
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37
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Holmström M, Nangarhari A, Öhman J, Duberg AS, Majeed A, Aleman S. Long-term liver-related morbidity and mortality related to chronic hepatitis C virus infection in Swedish patients with inherited bleeding disorders. Haemophilia 2016; 22:e494-e501. [PMID: 27704656 DOI: 10.1111/hae.13020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/18/2016] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Hepatitis C virus (HCV) infection is common in patients with inherited bleeding disorders treated with clotting factor concentrates prior to the introduction of viral inactivation of these products. The long-term consequences of hepatitis C infection in Swedish patients are not fully understood. AIM To examine the impact of HCV infection on liver-related morbidity and mortality in Swedish patients with inherited bleeding disorders. METHODS We retrospectively collected data on 183 patients with inherited bleeding disorders infected with HCV who attended the Coagulation Unit at Karolinska University Hospital, Sweden. Data regarding end-stage liver disease (ESLD), defined as presence of ascites, encephalopathy, variceal bleeding, hepatocellular carcinoma or liver-related death, were collected from the patient records and the national registers. RESULTS The median follow-up time was 35.9 years (IQR 29.0-41.2). A total of 41% had achieved sustained virological response (SVR) after treatment. In total, 14.2% developed ESLD at the median age of 52.6 years (IQR 46.5-64.7). Nineteen (35.8%) of all deaths were due to liver-related causes. Co-infection with human immunodeficiency virus (HIV), older age at time of infection and severe form of bleeding disorder was associated with higher risk of developing ESLD, while SVR was a strong protective factor. CONCLUSIONS This study demonstrated that liver-related morbidity and mortality was significant in patients with bleeding disorders and HCV infection in Sweden. Patients with HCV-infection should be candidates for treatment with the new highly effective antiviral drugs, since SVR proved to be a strong protective factor.
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Affiliation(s)
- M Holmström
- Coagulation Unit, Department of Medicine Solna, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden
| | - A Nangarhari
- Department of Infectious Diseases, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden
| | - J Öhman
- Karolinska Institutet at Karolinska Hospital, Stockholm, Sweden
| | - A-S Duberg
- Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - A Majeed
- Coagulation Unit, Department of Medicine Solna, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden.,Department of Infectious Diseases, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden
| | - S Aleman
- Department of Infectious Diseases, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden
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Suzuki M, Ishikawa T, Sakuma A, Abe S, Abe H, Koyama F, Nakano T, Ueki A, Noguchi H, Hasegawa E, Yamagata S, Kobayashi M, Ohashi K, Hirosawa H, Fukazawa T, Maruyama Y, Yoshida T. Evaluation of the health-related quality of life using the 36-item short form health survey in patients with chronic hepatitis C receiving pegylated interferon/ribavirin/telaprevir triple treatment. Exp Ther Med 2016; 12:3353-3358. [PMID: 27882162 DOI: 10.3892/etm.2016.3785] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 08/11/2016] [Indexed: 02/06/2023] Open
Abstract
The rate of sustained virologic response (SVR) has increased in patients with chronic hepatitis C (CHC; genotype 1) since triple treatment with pegylated interferon (PEG-IFN), ribavirin (RBV) and telaprevir (TVR) was included in Japanese health insurance. However, side effects such as high-grade anemia and skin disorders means it is important to investigate the extent to which quality of life (QOL) is maintained during treatment. The impact on health-related (HR) QOL, as a result of TVR-based triple treatment was investigated long-term (48 weeks) in 34 patients (18 men, 16 women) following TVR-based triple treatment, using the 36-item short form health survey (SF-36). While scores for physical health were significantly lower during treatment, an improvement was seen in patients who showed complete response to treatment from 12 weeks following treatment (P<0.05). HRQOL improved significantly following completion of TVR-based triple treatment in these complete-responders, with higher scores compared with those prior to treatment. Anemia and skin symptoms appeared frequently during treatment and scores for physical health dropped. Particular care needs to be taken in regards to the management of side effects during TVR treatment. Further evaluations using the SF-36 may help in controlling doses to achieve SVR.
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Affiliation(s)
- Mitsuyuki Suzuki
- Department of Pharmacology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan; Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Toru Ishikawa
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan; Department of Gastroenterology and Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Ai Sakuma
- Department of Pharmacology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Satoshi Abe
- Department of Gastroenterology and Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Hiroko Abe
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan; Department of Nursing, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Fujiko Koyama
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan; Department of Nursing, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Tomomi Nakano
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan; Department of Nursing, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Aya Ueki
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan; Department of Nursing, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Hirohito Noguchi
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan; Department of Nursing, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Erina Hasegawa
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan; Department of Nursing, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Shiori Yamagata
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan; Department of Nursing, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Miki Kobayashi
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan; Department of Nursing, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Kazutaka Ohashi
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan; Department of Nursing, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Hiroshi Hirosawa
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan; Department of Clinical Engineering, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Takako Fukazawa
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan; Department of Nutrition, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Yuka Maruyama
- Education Team of Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan; Administration Bureau of Medical Affairs Section, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
| | - Toshiaki Yoshida
- Department of Gastroenterology and Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Niigata 950-1104, Japan
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Akuta N, Kobayashi M, Suzuki F, Sezaki H, Fujiyama S, Kawamura Y, Hosaka T, Kobayashi M, Saitoh S, Suzuki Y, Arase Y, Ikeda K, Kumada H. Liver Fibrosis and Body Mass Index Predict Hepatocarcinogenesis following Eradication of Hepatitis C Virus RNA by Direct-Acting Antivirals. Oncology 2016; 91:341-347. [DOI: 10.1159/000450551] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 08/28/2016] [Indexed: 01/14/2023]
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Rutter K, Etschmaier A, Ferlitsch M, Maieron A, Hametner S, Horvatits T, Paternostro R, Salzl P, Reiberger T, Peck-Radosavljevic M, Quehenberger P, Hofer H, Trauner M, Ferenci P, Ferlitsch A. von Willebrand factor antigen (vWF-Ag): A non-invasive predictor of treatment response and serious adverse events in HCV patients with interferon triple therapy. Dig Liver Dis 2016; 48:1194-9. [PMID: 27476467 DOI: 10.1016/j.dld.2016.06.033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 05/26/2016] [Accepted: 06/28/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Treatment of chronic hepatitis C virus (HCV) infection was revolutionized within the last years. Interferon free antiviral regimens are not accessible without limitations. Combination of peginterferon/ribavirin with first generation direct acting antivirals is less effective and associated with serious adverse events. AIM We have shown that vWF-Ag is associated with portal hypertension and treatment response to PEG/RBV and we evaluated if vWF-Ag is a predictive marker for treatment response and safety in patients with triple therapy. METHODS 222 HCV-GT 1 patients and DAA based triple therapy were included in this retrospective, multicenter study. RESULTS Median vWF-Ag levels were 167.0% [IQR: 124.0-210.0%]. Significantly higher levels were seen in patients without SVR; median 190% [IQR: 146.0-259.5%] versus SVR: 142.5% [IQR: 114.3-196.8%], p<0.001. Furthermore levels of vWF-Ag were identified as independent predictor of non SVR; (OR: 1.009; 95%CI: 1.016-1.3, p=0.005). In patients with cirrhosis elevated vWF-Ag levels were associated with increased incidence of SAEs (OR: 1.016; 95%CI: 1.004-1.028; p=0.007). Best cut off for prediction of SAEs was vWF-Ag>281.5% with a sensitivity of 78% and a specificity of 90%. CONCLUSION Baseline vWF-Ag levels predict outcome of DAA based treatment in HCV-1 patients and identify patients with a risk of SAEs. Therefore vWF-Ag may be an additional marker for selecting patients for interferon free therapeutic regimens.
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Affiliation(s)
- Karoline Rutter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria; Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alexandra Etschmaier
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Monika Ferlitsch
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | | | | | - Thomas Horvatits
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria; Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Rafael Paternostro
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Petra Salzl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Markus Peck-Radosavljevic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Peter Quehenberger
- Department of Laboratory Medicine, Medical University of Vienna, Austria
| | - Harald Hofer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Peter Ferenci
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Arnulf Ferlitsch
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
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Bose M, Mullick R, Das S, Das S, Karande AA. Combination of neutralizing monoclonal antibodies against Hepatitis C virus E2 protein effectively blocks virus infection. Virus Res 2016; 224:46-57. [PMID: 27574733 DOI: 10.1016/j.virusres.2016.08.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 08/23/2016] [Accepted: 08/25/2016] [Indexed: 01/17/2023]
Abstract
Hepatitis C virus (HCV) represents a major global health threat. The envelope glycoproteins, E1-E2 of HCV play an important role in infection by binding to hepatocyte surface receptors leading to viral entry. Several regions on the E1-E2 are conserved for maintaining structural stability, despite the high mutation rate of HCV. Identification of antigenic determinants in these domains would aid in the development of anti-virals. The present study was aimed to delineate neutralizing epitopes by generating monoclonal antibodies (mAbs) to envelope proteins that can block virus binding and entry. Using HCV-like particles (HCV-LPs) corresponding to genotype 3a (prevalent in India), we obtained three mAbs specific for the E2 protein that significantly inhibited virus binding to hepatoma cells. Using overlapping protein fragments and peptides of the E2 protein, the epitopes corresponding to the mAbs were delineated. MAbs H6D3 and A10F2 recognise sequential linear epitopes, whereas, mAb E3D8 recognises a discontinuous epitope. The epitope of mAb E3D8 overlaps with the CD81 receptor-binding site and that of mAb A10F2 with the hypervariable region 2 of the E2 protein. The epitopes corresponding to these mAbs are distinct and unique. A combination of these antibodies significantly inhibited HCV binding and entry in both HCV pseudoparticle (in vitro) and HCV cell culture (ex vivo) system compared to the mAbs alone (P<0.0001). In conclusion, our findings support the potential of employing a cocktail of neutralizing mAbs in the management of HCV infection.
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Affiliation(s)
- Mihika Bose
- Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India
| | - Ranajoy Mullick
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560 012, India
| | - Soma Das
- Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India
| | - Saumitra Das
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560 012, India
| | - Anjali A Karande
- Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
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Walker A, Kaiser R, Bartenschlager R, Timm J. Genotypic resistance testing of HCV - is there a clinical need? GMS INFECTIOUS DISEASES 2016; 4:Doc05. [PMID: 30671319 PMCID: PMC6301723 DOI: 10.3205/id000023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Persistent infections with the hepatitis C virus (HCV) pose a profound global public health burden. In the past 5 years treatment of chronic hepatitis C has dramatically changed. Novel direct-acting antivirals (DAAs) specifically inhibiting viral enzymes or factors that are essential for the viral replication cycle have been developed and licensed for hepatitis C therapy. These novel drugs target the viral NS3/4A protease, the NS5B RNA-dependent RNA-polymerase or the replication factor NS5A. Combinations of DAAs against these targets are highly efficacious achieving virus elimination in the majority of treated patients. In countries where affordable, this rapid clinical development virtually replaced earlier interferon (IFN)-α based therapy that had been in use as standard of care for the last 25 years. With the approval of DAAs for the treatment of chronic hepatitis C the question emerged whether resistance-associated substitutions (RASs) might be of clinical relevance. Here, we discuss the available evidence for the possible benefit of resistance genotyping prior to therapy to optimize treatment of chronic hepatitis C.
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Affiliation(s)
- Andreas Walker
- Institute for Virology, Heinrich-Heine-University, University Hospital, Düsseldorf, Germany
| | - Rolf Kaiser
- Institute of Virology, University of Cologne, Cologne, Germany
| | - Ralf Bartenschlager
- Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.,German Center for Infection Research, Heidelberg University, Heidelberg, Germany
| | - Jörg Timm
- Institute for Virology, Heinrich-Heine-University, University Hospital, Düsseldorf, Germany
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Pecoraro V, Cariani E, Villa E, Trenti T. Optimisation of triple therapy for patients with chronic hepatitis C: a systematic review. Eur J Clin Invest 2016; 46:737-48. [PMID: 27376688 DOI: 10.1111/eci.12656] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Accepted: 02/11/2016] [Indexed: 12/15/2022]
Abstract
BACKGROUND Triple therapy with Pegylated-Interferon α (PEG-IFNα)/Ribavirin (RBV) and Boceprevir (Boc) or Telaprevir (Tel) significantly improved sustained virological response (SVR) rates for patients with genotype 1 HCV infection compared to PEG-IFNα/RBV alone (dual therapy). However, less is known about factors associated with rates of SVR and of adverse events (AEs). MATERIAL AND METHODS The aim of this systematic review was to evaluate the evidence regarding the factors affecting response and rate of AEs associated with triple therapy. We performed systematic electronic searches in Medline, Embase, Scopus and Central as well as a list of reference literature. We included randomised controlled trials examining triple therapy compared with dual therapy and reporting data according to patients features and about AEs. Odds ratios (OR) were pooled using either fixed or random effect model, as appropriate. RESULTS We included data from 14 studies. Treatment with triple therapy increased SVR rate compared to dual therapy especially in patients previously treated with PEG-IFNα/RBV and with increased pretreatment alanine aminotransferase (ALT) levels. Higher rate of serious AEs and treatment discontinuation due to AEs was also observed particularly in treatment-experienced patients. CONCLUSIONS The present study shows how improved results of triple therapy are mainly observed in some patients' subsets and are accompanied by increased risk of AEs compared to dual therapy. These results might be useful for optimising treatment of chronic hepatitis C when IFN-free regimens are unavailable.
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Affiliation(s)
- Valentina Pecoraro
- Clinical Pathology - Toxicology, Ospedale Civile Sant'Agostino Estense, Modena, Italy
| | - Elisabetta Cariani
- Clinical Pathology - Toxicology, Ospedale Civile Sant'Agostino Estense, Modena, Italy
| | - Erica Villa
- Division of Gastroenterology, AOU Modena, Modena, Italy
| | - Tommaso Trenti
- Clinical Pathology - Toxicology, Ospedale Civile Sant'Agostino Estense, Modena, Italy
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Ho SB, Dollarhide A, Thorisdottir H, Michelsen J, Perry C, Kravetz D, Herrin A, Carlson L, Hadley S, Montoya D, Robinson S, Sanchez C, Enrique E, Groessl E. A Primary Care-based Collaborative Hepatitis C Clinic: Clinical Structure and Virologic Outcomes with Direct Acting Antiviral Therapy. ACTA ACUST UNITED AC 2016. [DOI: 10.2174/1874220301603010070] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Background:
Currently 4 million persons in the US have active hepatitis C virus (HCV) infection and most have never successfully completed antiviral treatment. Newer therapies herald potential for wider uptake and acceptance of treatment, but the number of hepatology specialists is limited and newer models are needed to increase access to care. The aim of this study is to describe a collaborative primary care-based clinic for HCV treatment.
Methods:
Retrospective analysis of a collaborative primary care clinic developed for the evaluation and treatment of patients with chronic hepatitis C at one VA medical center. A half-day clinic was organized with 4 primary care MDs, 2 hepatologists, 2 nurse practitioners, and a co-located psychiatrist, pharmacist and nurse case manager. Clinic productivity and outcomes related to the number of patients who initiated and completed treatment with direct acting antivirals (DAA) and pegylated interferon and ribavirin were evaluated.
Results:
In this 18 month period, the clinic had 1890 confirmed HCV registry patients and 1690 clinic visits. 74 HCV genotype 1 patients initiated DAA therapy. Primary care providers treated 47 patients (32% cirrhotic) and hepatologists treated 27 patients (48% cirrhotic). Final SVR rate was 54.6% (39.2% cirrhotics vs. 65.2% noncirrhotics). SVR rates were higher in patients with primary care providers (61.7%) vs. hepatologists (44.4%). Despite numerous adverse events, early treatment termination for adverse events occurred in 5.3% vs. 21.3% for virologic non-response. Multivariate analysis revealed no significant differences between primary care and hepatology for SVR and treatment discontinuations.
Conclusion:
This clinic demonstrated effectiveness and safety with DAA therapy. This illustrates potential for a primary care based collaborative clinic, which will be crucial for expanding access to effective HCV care.
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Miotto N, Mendes LC, Zanaga LP, Goncales ESL, Lazarini MSK, Pedro MN, Goncales FL, Stucchi RSB, Vigani AG. Predictors of early treatment discontinuation and severe anemia in a Brazilian cohort of hepatitis C patients treated with first-generation protease inhibitors. Braz J Med Biol Res 2016; 49:S0100-879X2016000700702. [PMID: 27356107 PMCID: PMC4926529 DOI: 10.1590/1414-431x20165300] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 03/24/2016] [Indexed: 12/14/2022] Open
Abstract
The aim of this study was to determine risk factors for adverse events (AE)-related treatment discontinuation and severe anemia among patients with chronic hepatitis C virus (HCV) genotype 1 infection, treated with first-generation protease inhibitor (PI)-based therapy. We included all patients who initiated treatment with PI-based therapy at a Brazilian university hospital between November 2013 and December 2014. We prospectively collected data from medical records using standardized questionnaires and used Epi Info 6.0 for analysis. Severe anemia was defined as hemoglobin ≤8.5 mg/dL. We included 203 patients: 132 treated with telaprevir (TVR) and 71 treated with boceprevir (BOC). AE-related treatment discontinuation rate was 19.2% and anemia was the main reason (38.5%). Risk factors for treatment discontinuation were higher comorbidity index (OR=1.85, CI=1.05-3.25) for BOC, and higher bilirubin count (OR=1.02, CI=1.01-1.04) and lower BMI (OR=0.98, CI=0.96-0.99) for TVR. Severe anemia occurred in 35 (17.2%) patients. Risk factors for this outcome were lower estimated glomerular filtration rate (eGFR; OR=0.95, CI=0.91-0.98) for patients treated with TVR, and higher comorbidity index (OR=2.21, CI=1.04-4.67) and ribavirin dosage (OR=0.84, CI=0.72-0.99) for those treated with BOC. Fifty-five (57.3%) patients treated with TVR and 15 (27.3%) patients treated with BOC achieved sustained virological response (SVR). Among patients who received TVR and interrupted treatment due to AE (n=19), only 26.3% (n=5) achieved SVR (P=0.003). Higher number of comorbidities, lower eGFR and advanced liver disease are associated with severe anemia and early treatment cessation, which may compromise SVR achievement.
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Affiliation(s)
- N Miotto
- Divisão de Moléstias Infecciosas, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
| | - L C Mendes
- Divisão de Moléstias Infecciosas, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
| | - L P Zanaga
- Divisão de Moléstias Infecciosas, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
| | - E S L Goncales
- Divisão de Moléstias Infecciosas, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
| | - M S K Lazarini
- Divisão de Moléstias Infecciosas, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
| | - M N Pedro
- Divisão de Moléstias Infecciosas, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
| | - F L Goncales
- Divisão de Moléstias Infecciosas, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
| | - R S B Stucchi
- Divisão de Moléstias Infecciosas, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
| | - A G Vigani
- Divisão de Moléstias Infecciosas, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
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Lam JT, Salazar L. New combination antiviral for the treatment of hepatitis C. Am J Health Syst Pharm 2016; 73:1042-50. [PMID: 27217519 DOI: 10.2146/ajhp150163] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
PURPOSE The pharmacology, pharmacokinetics, clinical efficacy, and safety of Viekira, as well as its place in hepatitis C virus (HCV) therapy, are reviewed. SUMMARY Ombitasvir 25 mg-paritaprevir 150 mg-ritonavir 100 mg plus dasabuvir 250 mg (Viekira) is approved in the United States as a combination direct-acting antiviral agent for treatment-naive or treatment-experienced patients with HCV genotype 1 infection, including those with compensated cirrhosis. It is the first coformulated direct-acting antiviral that targets different stages of the virus's life cycle. Viekira is administered as an oral, interferon-free regimen. Phase III clinical trials demonstrated that Viekira administered with or without ribavirin can achieve sustained virological response rates of ≥90%. These results are notable because they show that high virological cure rates can be achieved without peginterferon and ribavirin. Viekira is also effective for special patient populations, such as individuals coinfected with HIV, liver transplant recipients, and those with advanced renal disease. The most frequently reported adverse effects among patients associated with Viekira without ribavirin were nausea, pruritus, and insomnia. During clinical trials, the most common adverse effects among patients receiving Viekira with ribavirin were fatigue, nausea, pruritus, insomnia, and weakness. CONCLUSION Viekira, the first coformulated direct-acting antiviral that targets different stages of the HCV life cycle, is an interferon-free treatment for HCV genotype 1 infection. It is associated with a virological cure rate of ≥90% and treatment durations of 12 and 24 weeks. Viekira is also effective and safe for patients who have undergone liver transplantation, are coinfected with HIV, or have advanced kidney disease.
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Affiliation(s)
- Jerika T Lam
- Department of Pharmacy Practice, Chapman University School of Pharmacy, Irvine, CA.
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Two-Year Follow-Up Analysis of Telaprevir-Based Antiviral Triple Therapy for HCV Recurrence in Genotype 1 Infected Liver Graft Recipients as a First Step towards Modern HCV Therapy. HEPATITIS RESEARCH AND TREATMENT 2016; 2016:8325467. [PMID: 27195149 PMCID: PMC4852367 DOI: 10.1155/2016/8325467] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 03/08/2016] [Indexed: 12/15/2022]
Abstract
Objective. The introduction of protease inhibitors telaprevir and boceprevir in 2011 had extended the antiviral treatment options especially in genotype 1 infected hepatitis C relapsers and nonresponders to interferon/ribavirin therapy. The aim of this study was to analyze the long-term treatment efficiency of telaprevir-based triple therapy for patients with hepatitis C reinfection after orthotopic liver transplantation. Patients and Methods. We included 12 patients with histologically confirmed graft fibrosis due to hepatitis C reinfection. The treatment duration was scheduled as 12 weeks of telaprevir-based antiviral triple therapy followed by 36 weeks of dual therapy with pegylated interferon/ribavirin. The patients were followed up for two years after the end of triple therapy. Results. Of the 12 patients, 6 (50%) completed the full 48 weeks of antiviral treatment. An end of treatment response and a sustained virological response 52 weeks after the end of the antiviral treatment course were achieved in 8/12 (67%) and 7/12 (58%) patients, respectively. Conclusion. Telaprevir-based triple therapy was shown to be a long-term effective but complex treatment option for individual patients with hepatitis C graft. With the recent improvements in hepatitis C therapy options telaprevir may not be recommended as a standard therapy for this indication anymore.
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Kwo PY, Badshah MB. Treatment of HCV in Patients who Failed First-Generation PI Therapy: a Review of Current Literature. Curr Gastroenterol Rep 2016; 17:462. [PMID: 26342813 DOI: 10.1007/s11894-015-0462-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The addition of the first direct-acting antiviral agents, the NS3 protease inhibitors boceprevir or telaprevir, to peg interferon and ribavirin was a major advance in the treatment of genotype 1 hepatitis C individuals with sustained virological response (SVR) rates of 63-75 %. Those who did not achieve SVR had high rates of resistance-associated variants against NS3 protease domain. Retreatment options for those who have failed first-generation protease inhibitors generally are guided by retreatment with direct-acting antiviral agents from other classes. Phase 2 and phase 3 data have demonstrated that retreatment with 12-24 weeks of a NS5B inhibitor (sofosbuvir) in combination with a NS5a inhibitor (daclatasvir or ledipasvir) with or without ribavirin can achieve SVR at high rates comparable to treatment-naive individuals.
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Affiliation(s)
- Paul Y Kwo
- Department of Medicine, Division of Gastroenterology/Hepatology, Indiana University School of Medicine, 975 W. Walnut, IB 327, Indianapolis, IN, 46202-5121, USA,
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Lorcy S, Gaudy-Marqueste C, Botta D, Portal I, Quiles N, Oulies V, Mancini J, Grob JJ, Richard MA. [Cutaneous adverse events of telaprevir/peginterferon/ribavirin therapy for chronic hepatitis C: A multicenter prospective cohort study]. Ann Dermatol Venereol 2016; 143:336-46. [PMID: 27161648 DOI: 10.1016/j.annder.2016.02.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Revised: 01/25/2016] [Accepted: 02/10/2016] [Indexed: 01/14/2023]
Abstract
BACKGROUND Telaprevir, sale of which was suspended, has been approved in combination with pegylated interferon and ribavirin (triple therapy) in the treatment of chronic hepatitis C virus (HCV). Skin eruptions and isolated cases of severe cutaneous adverse reactions (SCAR) have been reported. AIMS Our aim was to assess the incidence of skin eruption and the clinical characteristics of mucocutaneous adverse events (AE), and to identify potential risk factors for telaprevir-associated skin eruption. PATIENTS AND METHODS A prospective observational multicenter follow-up cohort study with monthly controls by a dermatologist and additional examinations in case of any undercurrent AE. RESULTS Among the 48 enrolled patients, the incidence of skin eruption was 58.4%, consisting mainly of maculopapular and eczematous lesions and only one case of SCAR. Telaprevir was discontinued in 6% of patients due to severe rash, whereas peginterferon and ribavirin were continued. The median time to onset of rash following telaprevir initiation was 25 days (range: 3-79 days). The rash was preceded by skin dryness and associated with pruritus in 100% and 90% of patients, respectively. Of those presenting with skin eruption, 37.5% also complained of conjunctival or oral lesions, or of anorectal symptoms. Neither a past history of dermatological conditions nor sociodemographic or viral status was predictive factor for skin rash. CONCLUSIONS Telaprevir-related dermatitis has a high incidence but is mostly of mild intensity. In most cases, tri-therapy was continued under close dermatological follow-up allowing rapid detection of rare instances of severe drug eruptions. Ribavirin and Interferon were thus continued even in the event of diffuse eruptions, enabling confirmation of the causative role of telaprevir in these eruptions.
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Affiliation(s)
- S Lorcy
- Inserm CRO2, UMR 911, service de dermatologie et de cancérologie cutanée, hôpital de la Timone, Aix-Marseille université, AP-HM, 264, rue Saint-Pierre, 13385 Marseille cedex 5, France
| | - C Gaudy-Marqueste
- Inserm CRO2, UMR 911, service de dermatologie et de cancérologie cutanée, hôpital de la Timone, Aix-Marseille université, AP-HM, 264, rue Saint-Pierre, 13385 Marseille cedex 5, France.
| | - D Botta
- Service d'hépato-gastroentérologie, hôpital Conception, Aix-Marseille université, AP-HM, 147, boulevard Baille, 13005 Marseille, France
| | - I Portal
- Service d'hépato-gastroentérologie, hôpital Conception, Aix-Marseille université, AP-HM, 147, boulevard Baille, 13005 Marseille, France
| | - N Quiles
- Service de dermatologie, hôpital Saint-Joseph, 26, boulevard de Louvain, 13285 Marseille, France
| | - V Oulies
- Service d'hépato-gastroentérologie, hôpital Saint-Joseph, 26, boulevard de Louvain, 13285 Marseille, France
| | - J Mancini
- Inserm, IRD, SESSTIM, service de santé publique et d'information médicale, hôpital de la Timone, Aix-Marseille université, AP-HM, 13385 Marseille, France
| | - J-J Grob
- Inserm CRO2, UMR 911, service de dermatologie et de cancérologie cutanée, hôpital de la Timone, Aix-Marseille université, AP-HM, 264, rue Saint-Pierre, 13385 Marseille cedex 5, France
| | - M-A Richard
- Inserm CRO2, UMR 911, service de dermatologie et de cancérologie cutanée, hôpital de la Timone, Aix-Marseille université, AP-HM, 264, rue Saint-Pierre, 13385 Marseille cedex 5, France
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Matsui K, Kamijo-Ikemori A, Sugaya T, Ikeda H, Okuse C, Shibagaki Y, Yasuda T, Kimura K. Does elevation of serum creatinine in patients with chronic hepatitis C under therapy of telaprevir mean renal impairment? Nephrology (Carlton) 2016; 20:843-8. [PMID: 25998031 DOI: 10.1111/nep.12517] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/17/2015] [Indexed: 12/21/2022]
Abstract
AIM Treatment with telaprevir (TVR) entails adverse side-effects including anaemia and elevation of serum creatinine (SCr) level. Our purpose was to evaluate the effects of treatment with TVR on renal function in adults with chronic hepatitis C. METHODS Thirteen adult patients with HCV genotype 1b who were scheduled to be treated with TVR, pegylated interferon (PEG IFN), and ribavirin (RBV) were prospectively followed. Patients were divided into two groups: (i) patients with an increase in SCr during the treatment (n = 8), and (ii) patients without an increase in SCr (n = 5). Urine and serum parameters were evaluated. RESULTS Although there was no difference in SCr level between the two groups before HCV therapy, the SCr level was persistently high in the patients in the increase-in-SCr group during the triple therapy. The SCr level returned to the pre-treatment level after cessation of TVR. There were no differences in urinary L-FABP, NAG, serum cystatin C level and eGFRcys throughout the study between the two groups. The serum cystatin C level at pre-treatment tended to be higher in the increase-in-SCr group. Urinary L-FABP and NAG levels in these groups remained within normal limits during treatment. We found that the increase in SCr was not associated with the degree of renal impairment. The increase in SCr may have been induced as a result of a decrease in creatinine secretion from proximal tubules via inhibition of transporters of creatinine induced by TVR. CONCLUSION Elevation of SCr levels with TVR therapy may not suggest renal impairment.
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Affiliation(s)
- Katsuomi Matsui
- Department of Nephrology and Hypertension, Internal Medicine, St. Marianna University School of Medicine, Miyamae-Ku, Kanagawa, Japan
| | - Atsuko Kamijo-Ikemori
- Department of Nephrology and Hypertension, Internal Medicine, St. Marianna University School of Medicine, Miyamae-Ku, Kanagawa, Japan.,Department of Anatomy, St. Marianna University School of Medicine, Miyamae-Ku, Kanagawa, Japan
| | - Takeshi Sugaya
- Department of Nephrology and Hypertension, Internal Medicine, St. Marianna University School of Medicine, Miyamae-Ku, Kanagawa, Japan
| | - Hiroki Ikeda
- Department of Gastroenterology and Hepatology, Internal Medicine, St. Marianna University School of Medicine, Miyamae-Ku, Kanagawa, Japan
| | - Chiaki Okuse
- Department of Gastroenterology and Hepatology, Internal Medicine, St. Marianna University School of Medicine, Miyamae-Ku, Kanagawa, Japan
| | - Yugo Shibagaki
- Department of Nephrology and Hypertension, Internal Medicine, St. Marianna University School of Medicine, Miyamae-Ku, Kanagawa, Japan
| | - Takashi Yasuda
- Department of Nephrology and Hypertension, Internal Medicine, St. Marianna University School of Medicine, Miyamae-Ku, Kanagawa, Japan
| | - Kenjiro Kimura
- Department of Nephrology and Hypertension, Internal Medicine, St. Marianna University School of Medicine, Miyamae-Ku, Kanagawa, Japan
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