Impact of Safety-Related Dose Reductions or Discontinuations on Sustained Virologic Response in HCV-Infected Patients: Results from the GUARD-C Cohort.

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced ≥1 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with ≥1 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not ≥5. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin.This study was sponsored by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Support for third-party writing assistance for this manuscript, furnished by Blair Jarvis MSc, ELS, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland

Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

Background: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. Methods: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. Results: SVR24 rates were 46.1 % (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1,2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655. Conclusions: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginter-feron alfa-2a/ribavirin

The cyclophilin inhibitor Debio 025 combined with peg-IFN2a significantly reduces viral load in treatment na&#239;ve hepatitis C patients

The anti-hepatitis C virus (HCV) effect and safety of 3 different oral doses of Debio 025 in combination with peginterferon alpha 2a (peg-IFN&#945;2a) 180 &#61549;g/week was investigated in a multicenter, randomized, double-blind, placebo-controlled escalating dose-ranging phase IIa study in treatment na\uefve chronic HCV patients. Doses of 200, 600, and 1000 mg/day of Debio 25 in combination with peg-IFN&#945;2a 180 &#61549;g/week for 4 weeks were compared to monotherapy with either Debio 025 1000 mg/day or peg-IFN&#945;2a 180 &#61549;g/week. In the treatment groups combining peg-IFN&#945;2a and the 2 higher Debio 025 doses (600 mg and 1000 mg), mean log10 HCV RNA levels after 4 weeks of treatment decreased by \u2013 5.07 \ub1 1.73 and \u2013 5.09 \ub1 1.91 log10 IU/mL, respectively. Mean reduction of HCV RNA levels in the peg-IFN&#945;2a and Debio 025 1000 mg monotherapy groups was respectively \u2013 3.56 \ub1 2.37 and \u2013 2.87 \ub1 2.28 log10 IU/mL. In patients with genotype 1 and 4, response to the 600 and 1000 mg combination treatments showed a continuous decay in viral load; HCV RNA reductions, which were significantly different (Holm-Bonferroni adjusted p-values &lt; 0.02) from either monotherapy group, reached \u2013 4.61 \ub1 1.88 and \u2013 4.75 \ub1 2.19 log10 IU/mL at week 4, respectively. Adverse events were comparable between treatment groups apart from a higher incidence of neutropenia associated with peg-IFN&#945;2a and an increased incidence of isolated hyperbilirubinemia at the highest dose of Debio 025 (1000 mg/day). Conclusion: Results confirm that Debio 025 has a potent activity against the 4 most prevalent HCV genotypes and an additive effect on HCV RNA reduction at the dose of 600 and 1000 mg/day when combined with peg-IFN&#61537;2a in patients with genotype 1 and 4

Efficacy and safety of increasing doses of the cyclophilin inhibitor Debio 025 in combination with pegylated Interferon alpha-2a in treatment naïve mono-infected HCV patients.

WITHOUT ABSTRAC

The cyclophilin inhibitor Debio 025 combined with PEG IFN\u3b12a significantly reduces viral load in treatment-naive hepatitis C patients.

The anti-hepatitis C virus (HCV) effect and safety of three different oral doses of the cyclophilin inhibitor Debio 025 in combination with pegylated interferon-alpha2a (PEG IFN-alpha2a) were investigated in a multicenter, randomized, double-blind, placebo-controlled escalating dose-ranging phase II study in treatment-na\uefve patients with chronic hepatitis C. Doses of 200, 600, and 1,000 mg/day Debio 025 in combination with PEG IFN-alpha2a 180 microg/week for 4 weeks were compared with monotherapy with either 1,000 mg/day Debio 025 or 180 microg/week PEG IFN-alpha2a. In patients with genotypes 1 and 4, the 600- and 1,000-mg combination treatments induced a continuous decay in viral load that reached -4.61 +/- 1.88 and -4.75 +/- 2.19 log(10) IU/mL at week 4, respectively. In patients with genotypes 2 and 3, HCV RNA levels at week 4 were reduced by -5.91 +/- 1.11 and -5.89 +/- 0.43 log(10) IU/mL, respectively, with the same treatment regimens. Adverse events were comparable between treatment groups apart from a higher incidence of neutropenia associated with PEG IFN-alpha2a and an increased incidence of isolated hyperbilirubinemia at the highest dose of Debio 025 (1,000 mg/day). Conclusion: These results confirm that Debio 025 has a potent activity and an additive effect on HCV RNA reduction in genotype 1 and 4 patients at 600 and 1,000 mg/day when combined with PEG IFN-alpha2a

Efficacy and safety of increasing doses of the cyclophilin inhibitor Debio 025 in combination with pegylated Interferon alpha-2a in treatment naïve mono-infected HCV patients. 43rd Annual Meeting of the European Association for the Study of the Liver (EASL). Milano,Italia, 23-27 Aprile, 2008.

not applicabl