1.Resistance to mericitabine, a nucleoside analogue inhibitor of HCV RNA-dependent RNA polymerase/PMID 22402762; Antiviral therapy 2012; 17(3):411-23 (Review Article)/Name matches: danoprevir mericitabine; rg7128
Abstract:Mericitabine (RG7128), an orally administered prodrug of PSI-6130, is the most clinically advanced nucleoside analogue inhibitor of the RNA-dependent RNA polymerase (RdRp) of HCV. This review describes what has been learnt so far about the resistance profile of mericitabine. A serine to threonine substitution at position 282 (S282T) of the RdRp that reduces its replication capacity to approximately 15% of wild-type is the only variant that has been consistently generated in serial in vitro passage experiments. To date, no evidence of genotypic resistance to mericitabine has been detected by population or clonal sequence analysis in any baseline or on-treatment samples collected from >600 patients enrolled in Phase I/II trials of mericitabine administered as monotherapy, in combination with pegylated interferon/ribavirin, or in combination with the protease inhibitor, danoprevir, for 14 days in the proof-of-concept study of interferon-free therapy.

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2.Modelling the interaction between danoprevir and mericitabine in the treatment of chronic HCV infection/PMID 26555159; Antiviral therapy 2016; 21(4):297-306/Name matches: danoprevir mericitabine
Abstract:
Background: Modelling HCV RNA decline kinetics under therapy has proven useful for characterizing treatment effectiveness.
Methods: Here we model HCV viral kinetics (VK) in 72 patients given a combination of danoprevir, a protease inhibitor, and mericitabine, a nucleoside polymerase inhibitor, for 14 days in the INFORM-1 trial. A biphasic VK model with time-varying danoprevir and mericitabine effectiveness and Bliss independence for characterizing the interaction between both drugs provided the best fit to the VK data.
Results: The average final antiviral effectiveness of the drug combination varied between 0.998 for 100 mg three times daily of danoprevir and 500 mg twice daily of mericitabine and 0.9998 for 600 mg twice daily of danoprevir and 1,000 mg twice daily of mericitabine. Using the individual parameters estimated from the VK data collected over 2 weeks, we were not able to reproduce the low sustained virological response rates obtained in a more recent study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir for 24 weeks.
Conclusions: This suggests that drug-resistant viruses emerge after 2 weeks of treatment and that longer studies are necessary to provide accurate predictions of longer treatment outcomes.

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3.Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial/PMID 20951424; Lancet (London, England) 2010 Oct; 376(9751):1467-75/Name matches: danoprevir rg7128
Abstract:
Background: Present interferon-based standard of care treatment for chronic hepatitis C virus (HCV) infection is limited by both efficacy and tolerability. We assessed the safety, tolerability, and antiviral activity of an all-oral combination treatment with two experimental anti-HCV drugs-RG7128, a nucleoside polymerase inhibitor; and danoprevir, an NS3/4A protease inhibitor-in patients with chronic HCV infection.
Methods: Patients from six centres in New Zealand and Australia who were chronically infected with HCV genotype 1 received up to 13 days oral combination treatment with RG7128 (500 mg or 1000 mg twice daily) and danoprevir (100 mg or 200 mg every 8 h or 600 mg or 900 mg twice daily) or placebo. Eligible patients were sequentially enrolled into one of seven treatment cohorts and were randomly assigned by interactive voice or web response system to either active treatment or placebo. Patients were separately randomly assigned within each cohort with a block size that reflected the number of patients in the cohort and the ratio of treatment to placebo. The random allocation schedule was computer generated. Dose escalation was started in HCV treatment-naive patients; standard of care treatment-experienced patients, including previous null responders, were enrolled in higher-dose danoprevir cohorts. Investigators, personnel at the study centre, and patients were masked to treatment allocation. However, the pharmacist who prepared the doses, personnel involved in pharmacokinetic sample analyses, statisticians who prepared data summaries, and the clinical pharmacologists who reviewed the data before deciding to initiate dosing in the next cohort were not masked to treatment allocation. The primary outcome was change in HCV RNA concentration from baseline to day 14 in patients who received 13 days of combination treatment. All patients who completed treatment with the study drugs were included in the analyses. This study is registered with ClinicalTrials.gov, NCT00801255.
Findings: 88 patients were randomly assigned to a study drug treatment regimen (n=74 over seven treatment groups; 73 received at least one dose of study drug) or to placebo (n=14, all of whom received at least one dose). The median change in HCV RNA concentration from baseline to day 14 ranged from -3·7 to -5·2 log(10) IU/mL in the cohorts that received 13 days of combination treatment. At the highest combination doses tested (1000 mg RG7128 and 900 mg danoprevir twice daily), the median change in HCV RNA concentration from baseline to day 14 was -5·1 log(10) IU/mL (IQR -5·6 to -4·7) in treatment-naive patients and -4·9 log(10) IU/mL in previous standard of care null responders (-5·2 to -4·5) compared with an increase of 0·1 log(10) IU/mL in the placebo group. The combination of RG7128 and danoprevir was well tolerated with no treatment-related serious or severe adverse events, no grade 3 or 4 changes in laboratory parameters, and no safety-related treatment discontinuations.
Interpretation: This oral combination of a nucleoside analogue polymerase inhibitor and protease inhibitor holds promise as an interferon-free treatment for chronic HCV.