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      Current therapy for chronic hepatitis C: The role of direct-acting antivirals

      a , , b , ∗∗

      Antiviral Research

      Published by Elsevier B.V.

      Direct-acting antivirals, NS3/4A drugs, NS5A drugs, NS5B drugs, BID, twice a day, CDC, Centers for Disease Control and Prevention, DAA, direct-acting antiviral, EC50, half maximal effective concentration, FDA, U S Food and Drug Administration, GT, genotype, HBV, hepatitis B virus, HCC, hepatocellular carcinoma, HCV, hepatitis C virus, HIV, human immunodeficiency virus, IC50, half maximal inhibitory concentration, PegIFNα, pegylated interferon alfa, QD, once a day, RBV, ribavirin, SVR12, sustained virologic response after the treatment for 12 weeks, SVR24, sustained virologic response after the treatment for 24 weeks, TID, three times a day, WHO, World Health Organization

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          Abstract

          One of the most exciting developments in antiviral research has been the discovery of the direct-acting antivirals (DAAs) that effectively cure chronic hepatitis C virus (HCV) infections. Based on more than 100 clinical trials and real-world studies, we provide a comprehensive overview of FDA-approved therapies and newly discovered anti-HCV agents with a special focus on drug efficacy, mechanisms of action, and safety. We show that HCV drug development has advanced in multiple aspects: (i) interferon-based regimens were replaced by interferon-free regimens; (ii) genotype-specific drugs evolved to drugs for all HCV genotypes; (iii) therapies based upon multiple pills per day were simplified to a single pill per day; (iv) drug potency increased from moderate (∼60%) to high (>90%) levels of sustained virologic responses; (v) treatment durations were shortened from 48 to 12 or 8 weeks; and (vi) therapies could be administered orally regardless of prior treatment history and cirrhotic status. However, despite these remarkable achievements made in HCV drug discovery, challenges remain in the management of difficult-to-treat patients.

          Highlights

          • HCV genotype-specific drugs evolve to pan-genotypic drugs.
          • Drug potency increases from moderate (∼60%) to high (>90%) levels of sustained virologic response.
          • Treatment durations are shortened from a 48-week to 12-week or 8-week period.
          • HCV therapies based upon multiple pills per day are simplified to a single pill per day.
          • HCV therapies are administered orally regardless of prior treatment history and cirrhotic status.

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          Most cited references 272

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          Boceprevir for untreated chronic HCV genotype 1 infection.

          Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies. We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately. A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively. The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.).
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            Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome.

            A random-primed complementary DNA library was constructed from plasma containing the uncharacterized non-A, non-B hepatitis (NANBH) agent and screened with serum from a patient diagnosed with NANBH. A complementary DNA clone was isolated that was shown to encode an antigen associated specifically with NANBH infections. This clone is not derived from host DNA but from an RNA molecule present in NANBH infections that consists of at least 10,000 nucleotides and that is positive-stranded with respect to the encoded NANBH antigen. These data indicate that this clone is derived from the genome of the NANBH agent and are consistent with the agent being similar to the togaviridae or flaviviridae. This molecular approach should be of great value in the isolation and characterization of other unidentified infectious agents.
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              Is Open Access

              EASL Recommendations on Treatment of Hepatitis C 2015.

              (2015)
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                Author and article information

                Contributors
                Journal
                Antiviral Res
                Antiviral Res
                Antiviral Research
                Published by Elsevier B.V.
                0166-3542
                1872-9096
                24 February 2017
                June 2017
                24 February 2017
                : 142
                : 83-122
                Affiliations
                [a ]Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
                [b ]KU Leuven – University of Leuven, Rega Institute for Medical Research, Department of Microbiology and Immunology, Minderbroedersstraat 10, Leuven, 3000, Belgium
                Author notes
                []Corresponding author. liguangdi.research@ 123456gmail.com
                [∗∗ ]Corresponding author. erik.declercq@ 123456kuleuven.be
                Article
                S0166-3542(16)30752-5
                10.1016/j.antiviral.2017.02.014
                7172984
                28238877
                © 2017 Published by Elsevier B.V.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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