title: Clinical relevance of detectable but not quantifiable hepatitis C virus RNA during boceprevir or telaprevir treatment.
abstract: Boceprevir- and telaprevir-based treatments for chronic hepatitis C virus (HCV) infection use specific response-guided therapy (RGT) guidelines. Eligibility for shortened treatment duration is based on achieving undetectable HCV RNA early during treatment. It is unclear whether a detected HCV RNA level that is below the assay lower limit of quantitation (detectable/BLOQ) is comparable to an undetectable HCV RNA level for RGT decision making. We analyzed data from boceprevir and telaprevir clinical trials to obtain a comprehensive understanding of the frequency and clinical relevance of detectable/BLOQ HCV RNA measurements. In Phase 3 trials P05216 (boceprevir), C216 (telaprevir), and 108 (telaprevir), detectable/BLOQ levels were reported for approximately 10%-20% of all on-treatment HCV RNA measurements. In P05216 and C216, subjects with detectable/BLOQ HCV RNA, on average, had a reduced sustained virologic response (SVR) rate compared with subjects with undetectable HCV RNA at the same on-treatment timepoint. At key RGT timepoints (week 8 for boceprevir, week 4 for telaprevir), subjects with detectable/BLOQ HCV RNA had an approximately 20% lower SVR rate compared with subjects with undetectable HCV RNA, and this difference widened for later on-treatment timepoints. A similar trend was observed for Study 108, but the differences in SVR rates were modest, potentially explained by a higher frequency of reported detectable/BLOQ results. Analyses of Phase 2 boceprevir and telaprevir trials indicated subjects with detectable/BLOQ HCV RNA at RGT timepoints benefited from extended treatment duration.
  
  
  CONCLUSIONS
  During boceprevir- and telaprevir-based treatment, subjects with detectable/BLOQ HCV RNA had a reduced virologic response compared with subjects with undetectable HCV RNA. Eligibility for shortened treatment duration should be based on achieving undetectable HCV RNA (i.e., HCV RNA not detected) at RGT decision timepoints.
authors.affiliation: Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA. Patrick.Harrington@fda.hhs.gov
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Harrington
authors.forename: Wen
authors.initials: W
authors.lastname: Zeng
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Naeger
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003657:Decision Making; D005500:Follow-Up Studies; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000097:blood* / Q000188:drug therapy*; D006801:Humans; D009842:Oligopeptides / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D011392:Proline / Q000031:analogs & derivatives* / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood*; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D009842:Oligopeptides; D012367:RNA, Viral; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline