scholarly journals Simeprevir-Based Triple Therapy with Reduced Doses of Pegylated Interferon α-2a Plus Ribavirin for Interferon Ineligible Patients with Genotype 1b Hepatitis C Virus

Gut and Liver ◽  
2017 ◽  
Vol 11 (4) ◽  
pp. 551-558 ◽  
Author(s):  
Hideyuki Tamai ◽  
Yoshiyuki Ida ◽  
Akira Kawashima ◽  
Naoki Shingaki ◽  
Ryo Shimizu ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Triple Therapy ◽  
Pegylated Interferon ◽  
Interferon Α ◽  
Genotype 1B

scholarly journals Using Pharmacokinetic and Viral Kinetic Modeling To Estimate the Antiviral Effectiveness of Telaprevir, Boceprevir, and Pegylated Interferon during Triple Therapy in Treatment-Experienced Hepatitis C Virus-Infected Cirrhotic Patients

2014 ◽  
Vol 58 (9) ◽  
pp. 5332-5341 ◽  
Author(s):  
Cédric Laouénan ◽  
Patrick Marcellin ◽  
Martine Lapalus ◽  
Feryel Khelifa-Mouri ◽  
Nathalie Boyer ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Triple Therapy ◽  
Pegylated Interferon ◽  
Hcv Rna ◽  
Second Phase ◽  
Compensated Cirrhosis ◽  
Viral Kinetic ◽  
Significant Difference ◽  
Infected Cells

ABSTRACTTriple therapy combining a protease inhibitor (PI) (telaprevir or boceprevir), pegylated interferon (PEG-IFN), and ribavirin (RBV) has dramatically increased the chance of eradicating hepatitis C virus (HCV). However, the efficacy of this treatment remains suboptimal in cirrhotic treatment-experienced patients. Here, we aimed to better understand the origin of this impaired response by estimating the antiviral effectiveness of each drug. Fifteen HCV genotype 1-infected patients with compensated cirrhosis, who were nonresponders to prior PEG-IFN/RBV therapy, were enrolled in a nonrandomized study. HCV RNA and concentrations of PIs, PEG-IFN, and RBV were frequently assessed in the first 12 weeks of treatment and were analyzed using a pharmacokinetic/viral kinetic model. The two PIs achieved similar levels of molar concentrations (P= 0.5), but there was a significant difference in the 50% effective concentrations (EC50) (P= 0.008), leading to greater effectiveness for telaprevir than for boceprevir in blocking viral production (99.8% versus 99.0%, respectively,P= 0.002). In all patients, the antiviral effectiveness of PEG-IFN was modest (43.4%), and there was no significant contribution of RBV exposure to the total antiviral effectiveness. The second phase of viral decline, which is attributed to the loss rate of infected cells, was slow (0.19 day−1) and was higher in patients who subsequently eradicated HCV (P= 0.03). The two PIs achieved high levels of antiviral effectiveness. However, the suboptimal antiviral effectiveness of PEG-IFN/RBV and the low loss of infected cells suggest that a longer treatment duration might be needed in cirrhotic treatment-experienced patients and that a future IFN-free regimen may be particularly beneficial in these patients.

scholarly journals Naturally Occurring Resistance-Associated Variants of Hepatitis C Virus Protease Inhibitors in Poor Responders to Pegylated Interferon-Ribavirin

2015 ◽  
Vol 53 (7) ◽  
pp. 2195-2202 ◽  
Author(s):  
Sylvie Larrat ◽  
Sophie Vallet ◽  
Sandra David-Tchouda ◽  
Alban Caporossi ◽  
Jennifer Margier ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Viral Load ◽  
Hepatitis C ◽  
Triple Therapy ◽  
Pegylated Interferon ◽  
Poor Responders ◽  
Obvious Effect ◽  
Treatment Naïve ◽  
Detection Of Mutations ◽  
The Impact

The pretherapeutic presence of protease inhibitor (PI) resistance-associated variants (RAVs) has not been shown to be predictive of triple-therapy outcomes in treatment-naive patients. However, they may influence the outcome in patients with less effective pegylated interferon (pegIFN)-ribavirin (RBV) backbones. Using hepatitis C virus (HCV) population sequence analysis, we retrospectively investigated the prevalence of baseline nonstructural 3 (NS3) RAVs in a multicenter cohort of poor IFN-RBV responders (i.e., prior null responders or patients with a viral load decrease of <1 log IU/ml during the pegIFN-RBV lead-in phase). The impact of the presence of these RAVs on the outcome of triple therapy was studied. Among 282 patients, the prevalances (95% confidence intervals) of baseline RAVs ranged from 5.7% (3.3% to 9.0%) to 22.0% (17.3% to 27.3%), depending to the algorithm used. Among mutations conferring a >3-fold shift in 50% inhibitory concentration (IC50) for telaprevir or boceprevir, T54S was the most frequently detected mutation (3.9%), followed by A156T, R155K (0.7%), V36M, and V55A (0.35%). Mutations were more frequently found in patients infected with genotype 1a (7.5 to 23.6%) than 1b (3.3 to 19.8%) (P= 0.03). No other sociodemographic or viroclinical characteristic was significantly associated with a higher prevalence of RAVs. No obvious effect of baseline RAVs on viral load was observed. In this cohort of poor responders to IFN-RBV, no link was found with a sustained virological response to triple therapy, regardless of the algorithm used for the detection of mutations. Based on a cross-study comparison, baseline RAVs are not more frequent in poor IFN-RBV responders than in treatment-naive patients and, even in these difficult-to-treat patients, this study demonstrates no impact on treatment outcome, arguing against resistance analysis prior to treatment.

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