Center for the Study of Hepatitis C, Weill Cornell Medical College, New York, NY, USA. email@example.com.
Boceprevir with peginterferon/ribavirin significantly improves SVR rates over peginterferon/ribavirin alone in patients with chronic HCV-genotype 1 infection, but treatment failure remains a significant problem. We sought to develop stopping rules for patients destined to fail boceprevir-based combination therapy from the Phase 3 trial databases in order to minimize drug toxicity, resistance, and costs in the face of ultimate futility.
Exploratory post-hoc analyses using SPRINT-2 (treatment-naïve) and RESPOND-2 (prior treatment-experienced) were undertaken to determine if 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 a HCV RNA cut-off of ≥100 IU/mL would have discontinued therapy in 65 of 195 failures (sensitivity 33%) without sacrificing a single SVR out of 475 successes (specificity 100%). Viral variants emerged after Week 12 in 36 (73%) of 49 evaluable patients who would have discontinued at Week 12 using a ≥100 IU/mL rule. In RESPOND-2, 5 of 6 patients with Week-12 HCV-RNA levels between LLD (9.3 IU/mL) and LLQ (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.
Although a stopping rule of detectable HCV-RNA at Week 12 would forfeit some SVR cases, Week-12 HCV-RNA levels ≥100 IU/mL almost universally predicted failure to achieve SVR in both treatment-naïve and treatment-experienced patients. In boceprevir recipients, the combination of stopping rules of HCV-RNA ≥100 IU/mL at Week 12 and detectable at Week 24 maximized early discontinuation of futile therapy while minimizing premature treatment discontinuation.