title: Refinement of stopping rules during treatment of hepatitis C genotype 1 infection with boceprevir and peginterferon/ribavirin.
abstract: In comparison with peginterferon/ribavirin alone, boceprevir with peginterferon/ribavirin significantly improves sustained virological response (SVR) rates in patients with chronic hepatitis C virus (HCV) genotype 1 infections, but treatment failure remains a significant problem. Using phase 3 trial databases, we sought to develop stopping rules for patients destined to fail boceprevir-based combination therapy in order to minimize drug toxicity, resistance, and costs in the face of ultimate futility. Exploratory post hoc analyses using data from the Serine Protease Inhibitor Therapy 2 (SPRINT-2) study (treatment-naive patients) and the Retreatment With HCV Serine Protease Inhibitor Boceprevir and Pegintron/Rebetol 2 (RESPOND-2) study (treatment-experienced patients) were undertaken to determine whether protocol-specified stopping rules (detectable HCV RNA at week 24 for SPRINT-2 and at week 12 for RESPOND-2) could be refined and harmonized. In SPRINT-2, a week 12 rule with an HCV RNA cutoff of ≥ 100 IU/mL would have discontinued therapy in 65 of 195 failures (sensitivity = 33%) without sacrificing a single SVR among 475 successes (specificity = 100%). Viral variants emerged after week 12 in 36 of the 49 evaluable patients (73%) who would have discontinued at week 12 using a ≥ 100 IU/mL stopping rule. In RESPOND-2, five of six patients with week 12 HCV RNA levels between the lower limit of detection (9.3 IU/mL) and the lower limit of quantification (25 IU/mL) who continued therapy despite the protocol-stipulated futility rule achieved SVR; one additional patient with a week 12 HCV RNA level of 148 IU/mL also continued therapy, had undetectable HCV RNA at week 16, and attained SVR.
  
  
  CONCLUSIONS
  Although a stopping rule of detectable HCV RNA at week 12 would have forfeited some SVR cases, week 12 HCV RNA levels ≥ 100 IU/mL almost universally predicted a failure to achieve SVR in both treatment-naive and treatment-experienced patients. In boceprevir recipients, the combination of 2 stopping rules-an HCV RNA level ≥ 100 IU/mL at week 12 and detectable HCV RNA at week 24--maximized the early discontinuation of futile therapy and minimized premature treatment discontinuation.
authors.affiliation: Center for Study of Hepatitis C, Weill Cornell Medical College, New York, NY, USA. imj2001@med.cornell.edu
authors.forename: Ira M
authors.initials: IM
authors.lastname: Jacobson
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sulkowski
authors.forename: Rafael
authors.initials: R
authors.lastname: Esteban
authors.forename: Fred
authors.initials: F
authors.lastname: Poordad
authors.forename: Savino
authors.initials: S
authors.lastname: Bruno
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Burroughs
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Pedicone
authors.forename: Navdeep
authors.initials: N
authors.lastname: Boparai
authors.forename: Weiping
authors.initials: W
authors.lastname: Deng
authors.forename: Mark J
authors.initials: MJ
authors.lastname: DiNubile
authors.forename: Keith M
authors.initials: KM
authors.lastname: Gottesdiener
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Brass
authors.forename: Janice K
authors.initials: JK
authors.lastname: Albrecht
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bronowicki
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects; D017326:Clinical Trials, Phase III as Topic; D016208:Databases, Factual; D016903:Drug Monitoring / Q000379:methods*; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000009:adverse effects; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects; D011392:Proline / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D012367:RNA, Viral / Q000097:blood; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D012189:Retrospective Studies; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects*; D017211:Treatment Failure
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; 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; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a