Mericitabine and Either Boceprevir or Telaprevir in Combination with Peginterferon Alfa-2a plus Ribavirin for Patients with chronic Hepatitis C Genotype 1 Infection and Prior Null Response: The Randomized DYNAMO 1 and DYNAMO 2 Studies.

Most patients with chronic hepatitis C virus (HCV) genotype 1 infection who have had a pre- vious null response ( < 2-log 10 reduction in HCV RNA by treatment week 12) to peginter- feron/ribavirin (PegIFN/RBV) do not achieve a sustained virological response (SVR) when re-treated with a first-generation HCV protease inhibitor (PI) administered in combination with PegIFN/RBV. We studied the incremental benefits associated with adding mericitabine (nucleoside analog inhibitor of HCV polymerase) to PI plus PegIFN alfa-2a/RBV-based therapy in two double-blind randomized multicenter phase 2 trials (with boceprevir in DYNAMO 1, and with telaprevir in DYNAMO 2). The primary endpoint in both trials was SVR, defined as HCV RNA < 25 IU/mL 12 weeks after the end of treatment (SVR12). Over- all, the addition of mericitabine to PI plus PegIFN alfa-2a/RBV therapy resulted in SVR12 rates of 60 - 70% in DYNAMO 1 and of 71 - 96% in DYNAMO 2. SVR12 rates were similar in patients infected with HCV genotype 1a and 1b in both trials. The placebo control arms in both studies were stopped because of high rates of virological failure. Numerically lower relapse rates were associated with longer treatment with mericitabine (24 versus 12 weeks), telaprevir-containing regimens, and regimens that included 48 weeks of PegIFN alfa-2a/RBV therapy. No mericitabine resistance mutations were identified in any patient in either trial. The addition of mericitabine did not add to the safety burden associated with either telaprevir or boceprevir-based regimens. These studies demonstrate increased SVR rates and reduced relapse rates in difficult-to-treat patients when a nucleoside polymerase inhibitor with intermediate antiviral potency is added to regimens containing a first-genera- tion PI

A Reference High-Pressure CO2 Adsorption Isotherm for Ammonium ZSM-5 Zeolite: Results of an Interlaboratory Study

© 2018, The Author(s). This paper reports the results of an international interlaboratory study led by the National Institute of Standards and Technology (NIST) on the measurement of high-pressure surface excess carbon dioxide adsorption isotherms on NIST Reference Material RM 8852 (ammonium ZSM-5 zeolite), at 293.15 K (20 °C) from 1 kPa up to 4.5 MPa. Eleven laboratories participated in this exercise and, for the first time, high-pressure adsorption reference data are reported using a reference material. An empirical reference equation nex=d(1+exp[(-ln(P)+a)/b])c, [nex-surface excess uptake (mmol/g), P-equilibrium pressure (MPa), a = −6.22, b = 1.97, c = 4.73, and d = 3.87] along with the 95% uncertainty interval (Uk = 2 = 0.075 mmol/g) were determined for the reference isotherm using a Bayesian, Markov Chain Monte Carlo method. Together, this zeolitic reference material and the associated adsorption data provide a means for laboratories to test and validate high-pressure adsorption equipment and measurements. Recommendations are provided for measuring reliable high-pressure adsorption isotherms using this material, including activation procedures, data processing methods to determine surface excess uptake, and the appropriate equation of state to be used

Mericitabine and Either Boceprevir or Telaprevir in Combination with Peginterferon Alfa-2a plus Ribavirin for Patients with chronic Hepatitis C Genotype 1 Infection and Prior Null Response: The Randomized DYNAMO 1 and DYNAMO 2 Studies.

Most patients with chronic hepatitis C virus (HCV) genotype 1 infection who have had a pre- vious null response ( < 2-log 10 reduction in HCV RNA by treatment week 12) to peginter- feron/ribavirin (PegIFN/RBV) do not achieve a sustained virological response (SVR) when re-treated with a first-generation HCV protease inhibitor (PI) administered in combination with PegIFN/RBV. We studied the incremental benefits associated with adding mericitabine (nucleoside analog inhibitor of HCV polymerase) to PI plus PegIFN alfa-2a/RBV-based therapy in two double-blind randomized multicenter phase 2 trials (with boceprevir in DYNAMO 1, and with telaprevir in DYNAMO 2). The primary endpoint in both trials was SVR, defined as HCV RNA < 25 IU/mL 12 weeks after the end of treatment (SVR12). Over- all, the addition of mericitabine to PI plus PegIFN alfa-2a/RBV therapy resulted in SVR12 rates of 60 - 70% in DYNAMO 1 and of 71 - 96% in DYNAMO 2. SVR12 rates were similar in patients infected with HCV genotype 1a and 1b in both trials. The placebo control arms in both studies were stopped because of high rates of virological failure. Numerically lower relapse rates were associated with longer treatment with mericitabine (24 versus 12 weeks), telaprevir-containing regimens, and regimens that included 48 weeks of PegIFN alfa-2a/RBV therapy. No mericitabine resistance mutations were identified in any patient in either trial. The addition of mericitabine did not add to the safety burden associated with either telaprevir or boceprevir-based regimens. These studies demonstrate increased SVR rates and reduced relapse rates in difficult-to-treat patients when a nucleoside polymerase inhibitor with intermediate antiviral potency is added to regimens containing a first-genera- tion PI

Induction pegylated interferon Alfa-2a and high dose ribavirin do not increase SVR in heavy patients with HCV genotype 1 and high viral loads

Background & Aims Patients infected with hepatitis C virus (HCV) genotype 1, body weight <85 kg, and high baseline viral load respond poorly to standard doses of pegylated interferon (peginterferon) and ribavirin. We evaluated intensified therapy with peginterferon alfa-2a plus ribavirin. Methods This double-blind randomized trial included HCV genotype 1-infected outpatients from hepatology clinics with body weight <85 kg and HCV RNA titer <400,000 IU/mL. Patients were randomized to 180 μg/wk peginterferon alfa-2a for 48 weeks plus 1200 mg/day ribavirin (standard of care) (group A, n = 191) or 1400/1600 mg/day ribavirin (group B, n = 189). Additional groups included 360 μg/wk peginterferon alfa-2a for 12 weeks then 180 μg/wk peginterferon alfa-2a for 36 weeks plus 1200 mg/day ribavirin (group C, n = 382) or 1400/1600 mg/day ribavirin (group D, n = 383). Follow-up lasted 24 weeks after treatment. Results Sustained virologic response rates (HCV RNA level <15 IU/mL at end of follow-up) in groups A, B, C, and D were 38%, 43%, 44%, and 41%, respectively. There were no significant differences among the 4 groups or between pooled peginterferon alfa-2a regimens (A + B vs C + D: odds ratio [OR], 1.08; 95% confidence interval [CI], 0.831.39; P = .584) or pooled ribavirin regimens (A + C vs B + D: OR, 1.00; 95% CI, 0.791.28; P = .974). Conclusions In patients infected with HCV genotype 1 who are difficult to treat (high viral load, body weight <85 kg), a 12-week induction regimen of peginterferon alfa-2a and/or higher-dose ribavirin is not more effective than the standard regimen. © 2010 AGA Institute

Patient disposition in DYNAMO 1.

<p>BOC, boceprevir; MCB, mericitabine; P/R, peginterferon alfa-2a + ribavirin.</p

Study designs of DYNAMO 1 (a) and DYNAMO 2 (b).

<p>BOC, boceprevir 800 mg TID (at recommended intervals of 7–9 hours); MCB, mericitabine 1000 mg BID; P/R, peginterferon alfa-2a 180 μg once/week + ribavirin 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg); PBO, placebo; TVR, telaprevir 750 mg TID (at recommended intervals of 7–9 hours). Control Arms C in DYNAMO 1 and D in DYNAMO 2 were closed due to futility while the studies were ongoing (27 July 2012 in DYNAMO 1 and 10 July 2012 in DYNAMO 2), after which patients in these groups were given the option to receive mericitabine for a maximum duration of 24 weeks. MCB was added to the regimen for 5 patients in Arm C in DYNAMO 1 and to the regimen for 9 patients in Arm D in DYNAMO 2 at various time points and for various durations.</p

SVR12 rates by treatment arm in the overall populations and by HCV genotype and presence/absence of bridging fibrosis or cirrhosis in DYNAMO 1 (a) and DYNAMO 2 (b).

<p>BOC, boceprevir; MCB, mericitabine; P/R, peginterferon alfa-2a + ribavirin; TVR, telaprevir.</p