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Treatment of Hepatitis C:  A Systematic Review

Anita Kohli, MD, MS1,2; Ashton Shaffer, BA3; Amy Sherman, MD3; Shyam Kottilil, MD, PHD3
[+] Author Affiliations
1Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland
2Critical Care Medicine Department, Clinical Research Center, National Institutes of Health, Bethesda, Maryland
3Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
JAMA. 2014;312(6):631-640. doi:10.1001/jama.2014.7085.
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Published online

Importance  Hepatitis C virus (HCV) infects more than 185 million individuals worldwide. Twenty percent of patients chronically infected with HCV progress to cirrhosis. New, simpler therapeutics using direct-acting antivirals that target various stages of the HCV life cycle are in development to eradicate HCV without concomitant interferon.

Objectives  To summarize published evidence on safety, efficacy (measured by a sustained virologic response [SVR], which is the treatment goal of undetectable plasma HCV RNA 12 or 24 weeks after therapy completion), and tolerability of current US Food and Drug Administration–approved interferon-based regimens and oral interferon-free regimens used for treating HCV infection and coinfection with human immunodeficiency virus (HIV) and HCV; to provide treatment recommendations for specialists and generalists based on published evidence.

Evidence Review  A literature search of Web of Science, Scopus, Embase, Agricola, Cochrane Library, Cinahl Plus, ClinicalTrials.gov, Conference Papers Index, Gideon, PsycINFO, Google Scholar, and Oaister was conducted from January 1, 2009, to May 30, 2014. Publications describing phase 2, 3, and 4 studies evaluating the treatment of HCV were included. Forty-one studies involving 19 063 adult patients were included. Strength of clinical data and subsequent HCV treatment recommendations were graded according to the Oxford Centre for Evidence-Based Medicine.

Findings  Patients infected with HCV genotype 1 represent 60% to 75% of HCV infections in the United States. Hepatitis C virus genotype 1 is more difficult to cure than genotype 2 or genotype 3. Patients with HCV genotype 1 should receive treatment with sofosbuvir + pegylated interferon + ribavirin because of the shorter duration of therapy and high rates of SVR (89%-90%). Simeprevir + pegylated interferon + ribavirin is an alternative for patients with HCV genotype 1 (SVR, 79%-86%). Patients with HCV genotypes 2 and 3, representing 20% to 29% of US HCV infections, should receive therapy with sofosbuvir + ribavirin alone (SVR for genotype 2, 12 weeks’ duration: 82%-93%; SVR for genotype 3, 24 weeks’ duration, 80%-95%). Patients with HIV-HCV coinfection and patients with compensated cirrhosis (ie, cirrhosis but preserved synthetic liver function) should receive the same treatment as HCV-monoinfected patients.

Conclusions and Relevance  New, short-duration, simpler therapies result in high SVR rates for HCV-infected patients. In conjunction with increased screening for HCV as suggested by recent Centers for Disease Control and Prevention guidelines, availability of new therapies may lead to the treatment of many more people with chronic HCV infection.

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Figure.
Steps in the Hepatitis C Virus Life Cycle Targeted by Directly Acting Antiviral Agents

Directly acting antiviral agents (DAAs; shown in cyan) disrupt hepatitis C virus (HCV) replication by targeting critical enzymatic steps in the HCV life cycle. Antiviral drug treatment with a DAA combined with ribavirin with or without pegylated interferon, depending on HCV genotype (see Table 4), increases suppression of HCV replication compared with interferon and ribavirin alone, leading to improved sustained virologic response rates. The illustration is schematic; structures are not to scale. Question marks indicate that mechanism of action is uncertain. Abbreviations: E, envelope glycoprotein; NS, nonstructural protein; + and −, positive and negative HCV RNA strands.

aNot approved by the US Food and Drug Administration.

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