title: On-treatment HCV RNA as a predictor of sustained virological response in HCV genotype 3-infected patients treated with daclatasvir and sofosbuvir.
abstract: Many currently available direct-acting antiviral (DAA) regimens are less effective against HCV genotype 3 than against other HCV genotypes. The all-oral, pangenotypic DAA combination of daclatasvir (NS5A inhibitor) + sofosbuvir (nucleotide NS5B inhibitor) was studied in genotype 3-infected treatment-naive and -experienced patients (ALLY-3) who achieved rates of sustained virological response at post-treatment Week 12 (SVR12) of 90 and 86% respectively. In this analysis, we assessed whether on-treatment responses to daclatasvir + sofosbuvir in genotype 3-infected patients could predict treatment outcome.
  
  
  
  In ALLY-3, treatment-naive and -experienced patients, with or without cirrhosis, were treated with daclatasvir + sofosbuvir for 12 weeks. HCV RNA kinetics and categorical virological responses on treatment were assessed. The proportions of responders and nonresponders by study week, and time to first undetectable HCV RNA, were analysed for utility in predicting treatment outcome.
  
  
  
  Overall, HCV RNA levels declined rapidly during Week 1 of treatment in both treatment-naive and -experienced cohorts. Although patients with cirrhosis had a slower initial virological response as measured by the proportion of patients with HCV RNA below the lower limit of quantification at Week 1, responses converged thereafter. Positive and negative predictive values calculated for on-treatment responses were generally comparable with the overall SVR12 rate and were therefore limited indicators of outcome. SVR12 rates were not impacted by time to first undetectable HCV RNA.
  
  
  
  On-treatment responses are not useful predictors of ultimate virological response to the daclatasvir + sofosbuvir regimen.
authors.affiliation: Swedish Medical Center, Seattle, WA, USA. kris.kowdley@swedish.org.
authors.forename: Kris V
authors.initials: KV
authors.lastname: Kowdley
authors.affiliation: University of Florida, Gainesville, FL, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Nelson
authors.affiliation: Quest Clinical Research, San Francisco, CA, USA.
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Lalezari
authors.affiliation: Clinical Research Centers of America, LLC, Murray, UT, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Box
authors.affiliation: Atlanta Gastroenterology Associates, Atlanta, GA, USA.
authors.forename: Norman
authors.initials: N
authors.lastname: Gitlin
authors.affiliation: Digestive Health Specialists, Winston-Salem, NC, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Poleynard
authors.affiliation: University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Mordechai
authors.initials: M
authors.lastname: Rabinovitz
authors.affiliation: Digestive Disease Associates, Baltimore, MD, USA.
authors.forename: Natarajan
authors.initials: N
authors.lastname: Ravendhran
authors.affiliation: Gastrointestinal Specialists of Georgia, Marietta, GA, USA.
authors.forename: Aasim M
authors.initials: AM
authors.lastname: Sheikh
authors.affiliation: Virginia Mason Medical Center, Seattle, WA, USA.
authors.forename: Asma
authors.initials: A
authors.lastname: Siddique
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ, USA.
authors.forename: Rafia
authors.initials: R
authors.lastname: Bhore
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Noviello
authors.affiliation: Bristol-Myers Squibb Research and Development, Wallingford, CT, USA.
authors.forename: Khurram
authors.initials: K
authors.lastname: Rana
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002219:Carbamates; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D008103:Liver Cirrhosis / Q000097:blood / Q000209:etiology; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D012367:RNA, Viral / Q000097:blood; D000069474:Sofosbuvir / Q000008:administration & dosage* / Q000009:adverse effects; D000072230:Sustained Virologic Response; D013997:Time Factors; D014481:United States; D014633:Valine / Q000031:analogs & derivatives; D019562:Viral Load; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; D012367:RNA, Viral; D014633:Valine; C549273:daclatasvir; D000069474:Sofosbuvir
keywords: HCV therapy; NS5A inhibitor; NS5B inhibitor; direct-acting antiviral; response-guided therapy