Weiping Deng

Hepatitis C Virus Treatment-Related Anemia Is Associated With Higher Sustained Virologic Response Rate

BACKGROUND & AIMS Hepatitis C virus (HCV) treatment is frequently complicated by anemia from ribavirin (RBV)-related hemolysis and peginterferon-alfa (PEG-IFN)-related bone marrow suppression. We investigated the relationships among treatment outcomes, anemia, and their management with RBV dose reduction and/or erythropoiesis-stimulating agents (ESAs). METHODS We analyzed data from a trial conducted at 118 United States academic and community centers in treatment-naïve patients with HCV genotype 1. Patients were treated for as many as 48 weeks with 1 of 3 PEG-IFN/RBV regimens. ESAs were permitted for anemic patients (hemoglobin [Hb] <10 g/dL) after RBV dose reduction. Sustained virologic responses (SVR) were assessed based on decreases in Hb, anemia, and ESA use. RESULTS While patients received treatment, 3023 had their Hb levels measured at least once. An SVR was associated with the magnitude of Hb decrease: >3 g/dL, 43.7%; ≤3 g/dL, 29.9% (P < .001). Anemia occurred in 865 patients (28.6%); 449 of these (51.9%) used ESAs. In patients with early-onset anemia (≤ 8 weeks of treatment), ESAs were associated with higher SVR rate (45.0% vs 25.9%; P < .001) and reduced discontinuation of treatment because of adverse events (12.6% vs 30.1%, P < .001). ESAs did not affect SVR or discontinuation rates among patients with late-stage anemia. CONCLUSIONS Among HCV genotype 1-infected patients treated with PEG-IFN/RBV, anemia was associated with higher rates of SVR. The effect of ESAs varied by time to anemia; patients with early-onset anemia had higher rates of SVR with ESA use, whereas no effect was observed in those with late-onset anemia. Prospective trials are needed to assess the role of ESAs in HCV treatment.

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

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)

11 SUSTAINED VIROLOGIC RESPONSE (SVR) IN PRIOR PEGINTERFERON/RIBAVIRIN (PR) TREATMENT FAILURES AFTER RETREATMENT WITH BOCEPREVIR (BOC)-+-PR: THE PROVIDE STUDY INTERIM RESULTS

1University Henri Poincare of Nancy, Vandoeuvre-les-Nancy, France; 2South Florida Center of Gastroenterology, Wellington, FL; 3Northwestern Feinberg School of Medicine, Chicago, IL; 4Henry Ford Hospital, Detroit, MI; 5Alamo Medical Research, San Antonio, TX; 6University of British Columbia and Vancouver General Hospital, Vancouver, BC, Canada; 7Liver Specialists of Texas, Houston, TX; 8Virginia Commonwealth University School of Medicine, Richmond, VA; 9Mt. Vernon Endoscopy Center, Alexandria, VA; 10Weill Cornell Medical College, New York, NY; 11Universite Denis Diderot-Paris, Paris; 12Hopital Beaujon, Clichy, France; 13Duke University School of Medicine, Durham, NC; 14Cedars-Sinai Medical Center, Los Angeles, CA; 15Merck Sharp & Dohme Corp, Whitehouse Station, NJ; 16Baylor College of Medicine, Houston, TX

Boceprevir for chronic HCV genotype 1 infection in patients with prior treatment failure to peginterferon/ribavirin, including prior null response

BACKGROUND & AIMS Boceprevir with peginterferon/ribavirin (BOC/PR) leads to significantly higher sustained virological response (SVR) rates in patients with chronic hepatitis C and partial response or relapse after prior treatment with peginterferon/ribavirin. We studied the efficacy of BOC/PR in patients with prior treatment failure, including those with a null response (<2-log10 decline in HCV RNA), to peginterferon/ribavirin. METHODS Patients in the control arms of boceprevir Phase 2/3 studies who did not achieve SVR were re-treated with BOC/PR for up to 44 weeks. Patients enrolling >2 weeks after end-of-treatment in the prior study received PR for 4 weeks before adding boceprevir. RESULTS Of 168 patients enrolled, four discontinued from the PR lead-in and 164 received BOC/PR. Baseline viral load was >800,000 IU/ml in 77% of patients; 62% had HCV genotype 1a, and 10% were cirrhotic. In the ITT analysis (all 168 patients), SVR was achieved in 20 (38%) of 52 patients with prior null response, 57 (67%) of 85 with prior partial response, and 27 (93%) of 29 with prior relapse. In the mITT analysis (164 BOC/PR-treated patients), SVR rates were 41% (20/49), 67% (57/85), and 96% (27/28), respectively. SVR was achieved by 48% of patients with <1-log10 decline in HCV-RNA after lead-in and 76% of those with ⩾ 1-log10 decline or undetectable HCV-RNA after lead-in. The most common adverse events were anemia (49%), fatigue (48%), and dysgeusia (35%); 8% of patients discontinued due to adverse events. CONCLUSIONS Re-treatment with BOC/PR improved SVR rates in all patient subgroups, including those with prior null response.

Safety and efficacy of boceprevir/peginterferon/ribavirin for HCV G1 compensated cirrhotics: meta-analysis of 5 trials.

BACKGROUND & AIMS HCV-infected cirrhotics may urgently need therapy but are often under-represented in clinical trials resulting in limited data to guide their management. We performed a meta-analysis of well-compensated cirrhotic patients from five Phase 3 trials. METHODS Patients received P/R (peginterferon/ribavirin; 4 weeks) followed by BOC (boceprevir)/P/R or P/R for 24, 32, or 44 weeks. Sustained virologic response (SVR) rates were calculated by Metavir score. Multivariate logistic regression (MLR) models identified baseline and on-treatment predictors of SVR. Safety was evaluated by adverse-event (AE) reporting and laboratory monitoring. RESULTS Pooled meta-estimates for SVR rates (95% confidence interval) in 212 F4 (cirrhotic) patients were 55% (43, 66) with BOC/P/R vs.17% (0, 41) with P/R. MLR identified 4 predictors of SVR in F3/F4 patients: undetectable HCV-RNA at treatment week (TW) 8; ⩾ 1 log10 decline in HCV-RNA from baseline at TW4; male; and baseline HCV-RNA ⩽ 800,000 IU/ml. SVR rate was 89% (65/73) in F4 patients who were HCV-RNA undetectable at TW8. No F3 (0/5) or F4 (0/17) patients with <3 log10 decline and detectable HCV-RNA at TW8 achieved SVR. Anemia and diarrhea occurred more frequently in cirrhotic than non-cirrhotic patients. Serious AEs, discontinuations due to an AE, interventions to manage anemia, infections, and thrombocytopenia occurred more frequently in cirrhotics with BOC/P/R than P/R. Potential hepatic decompensation and/or sepsis were identified in 2 P/R and 3 BOC/P/R recipients. CONCLUSIONS BOC/P/R appears to have a generally favorable benefit-risk profile in compensated cirrhotic patients. SVR rates were particularly high in cirrhotic patients with undetectable HCV-RNA at TW8.

Adherence to assigned dosing regimen and sustained virological response among chronic hepatitis C genotype 1 patients treated with boceprevir plus peginterferon alfa‐2b/ribavirin

Adherence to therapeutic regimens affects the efficacy of peginterferon alfa (P) and ribavirin (R) therapy in patients with chronic hepatitis C virus genotype 1.