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      Newer direct-acting antivirals for hepatitis C virus infection: Perspectives for India

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          Abstract

          Approximately three per cent of the world's population (170-200 million people) is chronically infected with hepatitis C virus (HCV) and almost 500,000 people die each year (mostly in lower middle-income countries) from complications secondary to HCV infection. In India, HCV infection imposes a considerable burden of mortality, morbidity and healthcare costs. In the last two decades, the treatment of HCV has evolved from interferon (IFN)-based therapies with or without ribavirin (RBV) to pegylated-IFN (PEG-IFN) and RBV-based therapies that were better tolerated by patients. However, the introduction of oral drugs, which specifically target virus-specific proteins, has now revolutionized the treatment of chronic HCV. These agents are known as direct-acting antivirals (DAAs). These drugs have resulted in very high HCV cure rates even with reduced treatment duration and an excellent tolerability by the patients compared to PEG-IFN- and RBV-based therapies. In India, sofosbuvir (SOF), one of the most effective DAAs, has been made available at a compassionate price; thus only those DAA-based management strategies, which contain SOF are adopted in India. Here, we review different DAAs and their possible roles in different genotypes and stages of liver disease, stressing upon the role of SOF. An attempt has also been made to devise strategies using SOF for the most prevalent genotypes in our country (genotypes 3 and 1) and cirrhosis.

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          Most cited references29

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          Diagnosis, management, and treatment of hepatitis C: an update.

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            Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.

            A sustained virological response (SVR) rate of 41% has been achieved with interferon alfa-2b plus ribavirin therapy of chronic hepatitis C. In this randomised trial, peginterferon alfa-2b plus ribavirin was compared with interferon alfa-2b plus ribavirin. 1530 patients with chronic hepatitis C were assigned interferon alfa-2b (3 MU subcutaneously three times per week) plus ribavirin 1000-1200 mg/day orally, peginterferon alfa-2b 1.5 microg/kg each week plus 800 mg/day ribavirin, or peginterferon alfa-2b 1.5 microg/kg per week for 4 weeks then 0.5 microg/kg per week plus ribavirin 1000-1200 mg/day for 48 weeks. The primary endpoint was the SVR rate (undetectable hepatitis C virus [HCV] RNA in serum at 24-week follow-up). Analyses were based on patients who received at least one dose of study medication. The SVR rate was significantly higher (p=0.01 for both comparisons) in the higher-dose peginterferon group (274/511 [54%]) than in the lower-dose peginterferon (244/514 [47%]) or interferon (235/505 [47%]) groups. Among patients with HCV genotype 1 infection, the corresponding SVR rates were 42% (145/348), 34% (118/349), and 33% (114/343). The rate for patients with genotype 2 and 3 infections was about 80% for all treatment groups. Secondary analyses identified bodyweight as an important predictor of SVR, prompting comparison of the interferon regimens after adjusting ribavirin for bodyweight (mg/kg). Side-effect profiles were similar between the treatment groups. In patients with chronic hepatitis C, the most effective therapy is the combination of peginterferon alfa-2b 1.5 microg/kg per week plus ribavirin. The benefit is mostly achieved in patients with HCV genotype 1 infections.
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              Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis.

              High rates of sustained virologic response were observed among patients with hepatitis C virus (HCV) infection who received 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor ledipasvir. This study examined 8 weeks of treatment with this regimen. In this phase 3, open-label study, we randomly assigned 647 previously untreated patients with HCV genotype 1 infection without cirrhosis to receive ledipasvir and sofosbuvir (ledipasvir-sofosbuvir) for 8 weeks, ledipasvir-sofosbuvir plus ribavirin for 8 weeks, or ledipasvir-sofosbuvir for 12 weeks. The primary end point was sustained virologic response at 12 weeks after the end of therapy. The rate of sustained virologic response was 94% (95% confidence interval [CI], 90 to 97) with 8 weeks of ledipasvir-sofosbuvir, 93% (95% CI, 89 to 96) with 8 weeks of ledipasvir-sofosbuvir plus ribavirin, and 95% (95% CI, 92 to 98) with 12 weeks of ledipasvir-sofosbuvir. As compared with the rate of sustained virologic response in the group that received 8 weeks of ledipasvir-sofosbuvir, the rate in the 12-week group was 1 percentage point higher (97.5% CI, -4 to 6) and the rate in the group that received 8 weeks of ledipasvir-sofosbuvir with ribavirin was 1 percentage point lower (95% CI, -6 to 4); these results indicated noninferiority of the 8-week ledipasvir-sofosbuvir regimen, on the basis of a noninferiority margin of 12 percentage points. Adverse events were more common in the group that received ribavirin than in the other two groups. No patient who received 8 weeks of only ledipasvir-sofosbuvir discontinued treatment owing to adverse events. Ledipasvir-sofosbuvir for 8 weeks was associated with a high rate of sustained virologic response among previously untreated patients with HCV genotype 1 infection without cirrhosis. No additional benefit was associated with the inclusion of ribavirin in the regimen or with extension of the duration of treatment to 12 weeks. (Funded by Gilead Sciences; ION-3 ClinicalTrials.gov number, NCT01851330.).
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                Author and article information

                Journal
                Indian J Med Res
                Indian J. Med. Res
                IJMR
                The Indian Journal of Medical Research
                Medknow Publications & Media Pvt Ltd (India )
                0971-5916
                July 2017
                : 146
                : 1
                : 23-33
                Affiliations
                [1] Institute of Liver, Gastroenterology, & Pancreatico-Biliary Sciences, Sir Ganga Ram Hospital, New Delhi, India
                Author notes
                Reprint requests: Dr. Anil Arora, Institute of Liver, Gastroenterology, & Pancreatico-Biliary Sciences, Ganga Ram Institute for Postgraduate Medical Education & Research, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi 110 060, India e-mail: dranilarora50@ 123456gmail.com
                Article
                IJMR-146-23
                10.4103/ijmr.IJMR_679_15
                5719604
                29168457
                d92295cd-bfd3-4306-b256-6605d655f6cc
                Copyright: © 2017 Indian Journal of Medical Research

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

                History
                : 09 February 2016
                Categories
                Review Article

                Medicine
                antiviral therapy,chronic hepatitis,cirrhosis,direct-acting antivirals,hepatitis c virus,hepatocellular carcinoma,sofosbuvir

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