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Management of direct-acting antiviral agent failures

  • Maria Buti
    Correspondence
    Corresponding author. Address: Hospital Universitari Vall Hebron, Passeig Vall Hebron, 119-129, 08035 Barcelona, Spain. Tel.: +34 932746559; fax: +34 934274495.
    Affiliations
    Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain

    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
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  • Mar Riveiro-Barciela
    Affiliations
    Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain
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  • Rafael Esteban
    Affiliations
    Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain

    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
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Published:August 20, 2015DOI:https://doi.org/10.1016/j.jhep.2015.08.010

      Summary

      Failure to respond to the approved combinations of multiple direct-acting antiviral agents is relatively low in hepatitis C virus treatment registration studies, with rates of 1% to 7%, depending on the patients’ baseline characteristics. In real life, failure is slightly higher, likely because of lower compliance. Treatment failures are usually related to relapse and less often to on-treatment viral breakthrough. Hepatitis C drug-resistant variants are detected in most patients who do not achieve viral eradication. The risk of developing these variants depends on host- and virus-related factors, the properties of the drugs used, and the treatment strategies applied. Patients who carry resistance-associated variants may not obtain benefits from treatment and are at risk of disease progression and transmission of the variants. Whether hepatitis C resistance-associated variants persist depends on their type: NS3-4A variants often disappear gradually after therapy is stopped, whereas NS5A variants tend to persist for more than 2 years.
      The best way to prevent emergence of resistant variants is to eliminate the virus at the first treatment using highly potent antivirals with genetic barriers to resistance. In patients failing first-generation protease inhibitors, combination therapies with sofosbuvir and NS5 inhibitors have proven effective. Some salvage regimens can be shortened to 12 weeks by addition of ribavirin. The optimal treatment for patients who fail an NS5A inhibitor and those with multidrug-resistant variants remains to be defined, and research efforts should continue to focus on treatment for these patients.

      Abbreviations:

      HCV (hepatitis C virus), DAA (direct-acting antiviral), TPV (telaprevir), BOC (boceprevir), SMV (simeprevir), SOF (sofosbuvir), DSV (dasabuvir), LDV (ledipasvir), DCV (daclatasvir), OBV (ombitasvir), GT (genotype), RBV (ribavirin), PI (protease inhibitor), PTV/r (paritaprevir boosted with ritonavir), SVR (sustained virologic response), P (pegylated interferon), RAV (resistance-associated variant), HIV (human immunodeficiency virus), GZV (grazoprevir), EBV (elbasvir), U.S. (United States), FDA (Food and Drug Administration), EMA (European Medicines Agency)

      Keywords

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