title: Management of direct-acting antiviral agent failures.
abstract: 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.
authors: 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. Electronic address: mbuti@vhebron.net.
authors: Maria
authors: M
authors: Buti
authors: Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: Mar
authors: M
authors: Riveiro-Barciela
authors: 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.
authors: Rafael
authors: R
authors: Esteban
mesh_terms: D015081:2-Naphthylamine; D000813:Anilides / Q000008:administration & dosage; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage; D002219:Carbamates / Q000008:administration & dosage; D002986:Clinical Trials as Topic; D003521:Cyclopropanes; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005449:Fluorenes / Q000008:administration & dosage; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007372:Interferons / Q000008:administration & dosage; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000008:administration & dosage; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000008:administration & dosage; D011759:Pyrrolidines; D012254:Ribavirin / Q000008:administration & dosage; D000069616:Simeprevir / Q000008:administration & dosage; D000069474:Sofosbuvir / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D017211:Treatment Failure; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D014542:Uridine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives; D014633:Valine / Q000031:analogs & derivatives
chemical_list: D000813:Anilides; D000998:Antiviral Agents; D001562:Benzimidazoles; D002219:Carbamates; D003521:Cyclopropanes; D005449:Fluorenes; D007093:Imidazoles; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D011759:Pyrrolidines; D013449:Sulfonamides; C000595958:ledipasvir, sofosbuvir drug combination; C586094:ombitasvir; D012254:Ribavirin; D014498:Uracil; D007372:Interferons; D011392:Proline; D000069616:Simeprevir; D015081:2-Naphthylamine; C588260:dasabuvir; D014542:Uridine Monophosphate; D014633:Valine; C549273:daclatasvir; C585405:paritaprevir; D000069474:Sofosbuvir
keywords: Daclatasvir; Direct-acting antivirals; Hepatitis C virus; Interferon; Ledipasvir; Resistance-associated variants; Simeprevir; Sofosbuvir; Treatment