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

Ira M. Jacobson, Patrick Marcellin, Stefan Zeuzem, Mark S. Sulkowski, Rafael Esteban, Fred Poordad, Savino Bruno, Margaret H. Burroughs, Lisa D. Pedicone, Navdeep Boparai, Weiping Deng, Mark J. Dinubile, Keith M. Gottesdiener, Clifford A. Brass, Janice K. Albrecht, Jean Pierre Bronowicki

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)567-575
Number of pages9
JournalHepatology
Volume56
Issue number2
DOIs
StatePublished - Aug 1 2012

ASJC Scopus subject areas

  • Hepatology

Fingerprint Dive into the research topics of 'Refinement of stopping rules during treatment of hepatitis C genotype 1 infection with boceprevir and peginterferon/ribavirin'. Together they form a unique fingerprint.

  • Cite this

    Jacobson, I. M., Marcellin, P., Zeuzem, S., Sulkowski, M. S., Esteban, R., Poordad, F., Bruno, S., Burroughs, M. H., Pedicone, L. D., Boparai, N., Deng, W., Dinubile, M. J., Gottesdiener, K. M., Brass, C. A., Albrecht, J. K., & Bronowicki, J. P. (2012). Refinement of stopping rules during treatment of hepatitis C genotype 1 infection with boceprevir and peginterferon/ribavirin. Hepatology, 56(2), 567-575. https://doi.org/10.1002/hep.25865