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

44 Citations (Scopus)

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
Pages (from-to)567-575
Number of pages9
JournalHepatology
Volume56
Issue number2
DOIs
Publication statusPublished - Aug 2012

Fingerprint

Ribavirin
Hepatitis C
Hepacivirus
Genotype
Infection
RNA
Serine Proteinase Inhibitors
Therapeutics
Medical Futility
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
Drug Costs
Retreatment
Chronic Hepatitis C
Drug-Related Side Effects and Adverse Reactions
Treatment Failure
Drug Resistance
Limit of Detection

ASJC Scopus subject areas

  • Hepatology

Cite this

Jacobson, I. M., Marcellin, P., Zeuzem, S., Sulkowski, M. S., Esteban, R., Poordad, F., ... 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

Refinement of stopping rules during treatment of hepatitis C genotype 1 infection with boceprevir and peginterferon/ribavirin. / Jacobson, Ira M.; Marcellin, Patrick; Zeuzem, Stefan; Sulkowski, Mark S.; Esteban, Rafael; Poordad, Fred; Bruno, Savino; Burroughs, Margaret H.; Pedicone, Lisa D.; Boparai, Navdeep; Deng, Weiping; Dinubile, Mark J.; Gottesdiener, Keith M.; Brass, Clifford A.; Albrecht, Janice K.; Bronowicki, Jean Pierre.

In: Hepatology, Vol. 56, No. 2, 08.2012, p. 567-575.

Research output: Contribution to journalArticle

Jacobson, IM, Marcellin, P, Zeuzem, S, Sulkowski, MS, Esteban, R, Poordad, F, Bruno, S, Burroughs, MH, Pedicone, LD, Boparai, N, Deng, W, Dinubile, MJ, Gottesdiener, KM, Brass, CA, Albrecht, JK & Bronowicki, JP 2012, 'Refinement of stopping rules during treatment of hepatitis C genotype 1 infection with boceprevir and peginterferon/ribavirin', Hepatology, vol. 56, no. 2, pp. 567-575. https://doi.org/10.1002/hep.25865
Jacobson, Ira M. ; Marcellin, Patrick ; Zeuzem, Stefan ; Sulkowski, Mark S. ; Esteban, Rafael ; Poordad, Fred ; Bruno, Savino ; Burroughs, Margaret H. ; Pedicone, Lisa D. ; Boparai, Navdeep ; Deng, Weiping ; Dinubile, Mark J. ; Gottesdiener, Keith M. ; Brass, Clifford A. ; Albrecht, Janice K. ; Bronowicki, Jean Pierre. / Refinement of stopping rules during treatment of hepatitis C genotype 1 infection with boceprevir and peginterferon/ribavirin. In: Hepatology. 2012 ; Vol. 56, No. 2. pp. 567-575.
@article{e46b08685b324f679372f1f9379ad038,
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. 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.",
author = "Jacobson, {Ira M.} and Patrick Marcellin and Stefan Zeuzem and Sulkowski, {Mark S.} and Rafael Esteban and Fred Poordad and Savino Bruno and Burroughs, {Margaret H.} and Pedicone, {Lisa D.} and Navdeep Boparai and Weiping Deng and Dinubile, {Mark J.} and Gottesdiener, {Keith M.} and Brass, {Clifford A.} and Albrecht, {Janice K.} and Bronowicki, {Jean Pierre}",
year = "2012",
month = "8",
doi = "10.1002/hep.25865",
language = "English",
volume = "56",
pages = "567--575",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Inc.",
number = "2",

}

TY - JOUR

T1 - Refinement of stopping rules during treatment of hepatitis C genotype 1 infection with boceprevir and peginterferon/ribavirin

AU - Jacobson, Ira M.

AU - Marcellin, Patrick

AU - Zeuzem, Stefan

AU - Sulkowski, Mark S.

AU - Esteban, Rafael

AU - Poordad, Fred

AU - Bruno, Savino

AU - Burroughs, Margaret H.

AU - Pedicone, Lisa D.

AU - Boparai, Navdeep

AU - Deng, Weiping

AU - Dinubile, Mark J.

AU - Gottesdiener, Keith M.

AU - Brass, Clifford A.

AU - Albrecht, Janice K.

AU - Bronowicki, Jean Pierre

PY - 2012/8

Y1 - 2012/8

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84864354805&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84864354805&partnerID=8YFLogxK

U2 - 10.1002/hep.25865

DO - 10.1002/hep.25865

M3 - Article

VL - 56

SP - 567

EP - 575

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 2

ER -