Refinement of stopping rules during treatment of hepatitis C genotype 1 infection with boceprevir and peginterferon/ribavirin

Authors


  • Potential conflict of interest: The Serine Protease Inhibitor Therapy 2 study (ClinicalTrials.gov identifier NCT00705432) and the Retreatment With HCV Serine Protease Inhibitor Boceprevir and Pegintron/Rebetol 2 study (ClinicalTrials.gov identifier NCT00708500) were funded by Schering-Plough/Merck. The trials were designed, managed, and analyzed by employees of the sponsor in conjunction with external academic investigators. Every coauthor of this article had full access to all pertinent data upon request. A penultimate version of this article was reviewed by the sponsor. Each coauthor approved an essentially final version of this article. The opinions expressed in this report represent the consensus of the authors and do not necessarily reflect the formal positions of Merck or the other institutions listed as investigator affiliations. Present and former employees of Merck may own stock or stock options in the company. All academic authors have been investigators for Schering-Plough/Merck. In addition, Ira M. Jacobson has received research support from Schering-Plough/Merck, Tibotec, Roche/Genentech, Pharmasset, Anadys, Boehringer-Ingelheim, Novartis, Gilead, Vertex, GlobeImmune, Idenix, Abbott, Zymogenetics, and Human Genome Sciences and has served as a consultant and/or speaker for Bristol-Myers Squibb, Novartis, Gilead, Schering-Plough/Merck, Pfizer, Vertex, GlobeImmune, Human Genome Sciences, Boehringer-Ingelheim, Pharmasset, Zymogenetics, Tibotec, Abbott, Roche/Genentech, Anadys, and Sanofi-Aventis. Patrick Marcellin has received grant support from Abbott, Bristol-Myers Squibb, Boehringer-Ingelheim, Echosens, Gilead, Janssen-Tibotec, Schering-Plough/Merck, Novartis, Roche, Pfizer, Pharmasset, GlaxoSmithKline and Vertex and has served as a consultant and/or speaker for Abbott, Bristol-Myers Squibb, Gilead, Janssen-Tibotec, Schering-Plough/Merck, Novartis, Roche, Pharmasset, and Vertex. Stefan Zeuzem has served as a consultant and/or speaker for Abbott, Achillion, Bristol-Myers Squibb, Boehringer-Ingelheim, Gilead, iTherX, Janssen-Cilag, Schering-Plough/Merck, Novartis, Roche, Santaris, Taussen-Tibotec, and Vertex. Mark S. Sulkowski has been a consultant for Schering-Plough/Merck, Abbott, Anadys, Boehringer Ingelheim Pharmaceuticals, Gilead, Pfizer, Human Genome Sciences, Roche, Taussen-Tibotec, and Vertex and has received grant support from Schering-Plough/Merck, Abbott, Boehringer Ingelheim Pharmaceuticals, Gilead, Bristol-Myers Squibb, Roche, Vertex, Tibotec, and Pharmasset. Rafael Esteban has served as a consultant and/or speaker for Schering-Plough/Merck. Fred Poordad has received research grants from Schering-Plough/Merck, Vertex, Genentech, Bristol-Myers Squibb, Gilead, Pfizer, Abbott, Tibotec, Idenix and Pharmasset, is a member of the speaker's bureau for Genentech and Gilead, and is an advisor/consultant for Schering-Plough/Merck, Vertex, Gilead, Genentech, and Abbott. Savino Bruno has served as a consultant and/or speaker for Schering-Plough/Merck, Bristol-Myers Squibb, and Roche. Jean-Pierre Bronowicki has served as a consultant and/or speaker for Schering-Plough/Merck, Roche, Gilead, Bristol-Myers-Squibb, Janssen, Boehringer-Ingelheim, Novartis, and Bayer and has received payments from Roche for expenses incurred by meeting attendance.

  • Navdeep Boparai is currently affiliated with Bristol-Myers Squibb (Hopewell, NJ); Keith M. Gottesdiener is currently affiliated with Rhythm Pharmaceuticals (Boston, MA); and Clifford A. Brass is currently affiliated with Novartis (Summit, NJ).

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. Conclusion: 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. (HEPATOLOGY 2012)

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