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 5 33%) without sacrificing a single SVR among 475 successes (specificity 5 100%). 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;56:567-575) C ombination therapy with peginterferon alfa/ ribavirin (P/R) has been the standard approach to the management of chronic hepatitis C virus (HCV) infections for the last decade. Sustained virological response (SVR) rates of 54% to 56% were achieved in the pivotal trials of Abbreviations: HCV, hepatitis C virus; LLD, lower limit of detection; LLQ, lower limit of quantification; P/R, pegintron alfa/ribavirin; RESPOND-2, Retreatment With HCV Serine Protease Inhibitor Boceprevir and Pegintron/Rebetol 2; SPRINT-2, Serine Protease Inhibitor Therapy 2; SVR, sustained virological response.From the

Importance of virological response in the early stage of telaprevir-based triple therapy for hepatitis C

“…To avoid unproductive expenditures and side effects, attempts have been made to establish response-guided treatment regimens that include early termination rules for unproductive DAA therapy [5,18] . It has been suggested that patients who have a rapid decline in their viral level can be treated with a shorter treatment duration, while preserving the high rate of SVR, and that treatment can be discontinued earlier for patients who are unlikely to respond the treatment.…”

Distribution of Hepatitis C Virus Genotypes in the South Marmara Region

“…Kronik HCV enfeksiyonu tedavisinde pegile-interferon ve ribavirin en yaygın kullanılan ilaçlar olup, tedaviye, direk antiviral etkili yeni ilaçlar da ilave edilmiştir. Direkt etkili antiviral ilaçlar HCV genomundaki NS3/4A serin proteaz bölgesi üzerine inhibitör etki göster-mektedir [5][6][7]. HCV genotip 1 ve 4 genotip 2 ve 3'e oranla interferon tedavisine daha az yanıt vermektedir.…”

“…HCV genotip 1 olan hastalarda telaprevir ve boceprevir ile tedavi şansı artmaktadır. HCV genotipi 1 olan olgularda kronik aktif hepatit ve siroz gelişim riski diğer genotiplere oranla daha yüksek bulunmuştur [4,[6][7][8][9]. HCV genotiplerinin bilinmesi epidemiyolojik verilerin belirlenmesi açısından da önemlidir.…”

“…HCV tedavisinde pegile interferon ve ribavirin tedavisindeki başarının genotip 1' de yeterince etkili olmaması nedeniyle tedaviye direk antiviral etkili olan yeni geliştirilen ilaçlardan boceprevir ve telaprevir dahil edilmiş-tir. Ancak genotip 1 hastalarda virolojik yanıt geleneksel tedaviye oranla daha başarılı olsa da yine de hastaların yaklaşık % 20' sinde tedaviye yanıt alınamamaktadır [6,7,18,19]. Ülkemizde yapılmış olan çalışmalara bakıldığında en sık görülen genotipin 1 olduğu ancak bunu takip eden genotiplerin bölge-sel farklılıklar gösterdiği gözlenmiştir.…”

The Cobas AmpliPrep/Cobas TaqMan HCV Test, Version 2.0, Real-Time PCR Assay Accurately Quantifies Hepatitis C Virus Genotype 4 RNA

“…Futility rules have been established in order to prevent unnecessary exposure to the protease inhibitor and to avoid adverse events, the emergence of viral resistance, and useless costs. They are defined by an HCV RNA level of Ͼ1,000 international units (IU)/ml at week 4 or 12 or detectable at week 24 for telaprevir or by an HCV RNA level of Ն100 IU/ml at week 12 or detectable at week 24 for boceprevir (3,8,9).…”