Understanding the effect of the HCV polymerase inhibitor mericitabine on early viral kinetics in the phase 2 JUMP-C and PROPEL studies

Abstract

Aims: The aim was to evaluate early viral kinetics in patients receiving mericitabine [hepatitis C virus (HCV) nucleoside polymerase inhibitor] with peginterferon alfa-2a (40KD) and ribavirin in two clinical trials (PROPEL and JUMP-C).

Methods: We examined rapid virological responses (RVRs; week 4 HCV RNA <15 IU ml(-1) ) and complete early virological responses (cEVR; week 12 HCV RNA <15 IU ml(-1) ) in HCV genotype 1/4-infected patients receiving mericitabine (500 or 1000 mg) or placebo twice daily plus peginterferon alfa-2a and ribavirin.

Results: Among IL28B rs12979860 CC genotype patients receiving 500 or 1000 mg mericitabine or placebo, respectively, RVR rates were 64.3% (95% confidence interval: 38.8-83.7%), 95.1% (83.9-98.7%) and 33.3% (20.2-49.7%), and cEVR rates were 100% (78.5-100%), 100% (91.4-100%) and 80.6% (65.0-90.3%). Among non-CC genotype patients, RVR rates were 26.5% (14.6-43.1%), 52.3% (43.0-61.3%) and 5.7% (2.2-13.8%), and cEVR rates were 76.5% (60.0-87.6%), 84.6% (76.6-90.1%) and 28.6% (19.3-40.1%), respectively. In multiple regression analysis, IL28B genotype (P < 0.0001), mericitabine dose (P < 0.0001) and bodyweight (P = 0.0009) were associated with first-phase (α) slope (change in log10 HCV RNA from baseline to week 1).

Conclusions: Mericitabine-containing triple therapy reduces the impact of IL28B genotype on RVR and cEVR compared with peginterferon alfa-2a and ribavirin dual therapy. The IL28B genotype, mericitabine dose and bodyweight are the most important factors associated with the α slope, and there is no evidence of a pharmacokinetic drug-drug interaction between mericitabine and ribavirin.

Keywords: hepatitis C virus polymerase inhibitor; mericitabine; pharmacodynamics; pharmacokinetics; ribavirin.

Figure 1

Study design of PROPEL (A) and JUMP-C (B). The rapid virological response (RVR) was defined as undetectable (<15 IU ml⁻¹; limit of detection) hepatitis C virus (HCV) RNA after week 4 of treatment. Abbreviations: MCB, mericitabine; P/R, peginterferon alfa-2a (40KD) 180 μg week⁻¹ plus ribavirin 1000 mg day⁻¹ (<75 kg) or 1200 mg day ⁻¹ (≥75 kg)

Figure 2

Comparison of α slopes (reductions in HCV RNA by week 1) by mericitabine dose and host IL28B genotype. Numbers at the top of the figure are the number of patients in each category. Horizontal bar, median; filled circle, mean; boxes show interquartile range; vertical dotted line (whiskers) show maximal and minimal values; open circles show outliers

Figure 3

Mean change in serum HCV RNA level from baseline by dose and host IL28B genotype. Vertical bars represent 95% confidence intervals. , CC, merticitabine 500 mg bid (n = 15); , non-CC, merticitabine 500 mg bid (n = 34); , CC, merticitabine 1000 mg bid (n = 42); , non-CC, merticitabine 1000 mg bid (n = 111); , CC, placebo bid (n = 37); , non-CC, placebo bid (n = 71)

Figure 4

Virological response rates at weeks 4 [rapid virological responses (RVR) left] and 12 [complete early virological responses (cEVR) right] according to mericitabine dosage and host IL28B genotype. Vertical lines represent 95% confidence intervals. , mericitabine 500 mg bid plus peginterferon alfa-2a (40KD) and ribavirin; , mericitabine 1000 mg bid plus peginterferon alfa-2a (40KD) and ribavirin; , placebo plus peginterferon alfa-2a (40KD) and ribavirin

Figure 5

Mean plasma concentrations of RO4995855 (A) and ribavirin (B) at steady state in patients who received mericitabine in combination with peginterferon alfa-2a (40KD) and ribavirin in two clinical studies. Data for mericitabine 1000 mg bid monotherapy (A) are from healthy volunteers with normal creatinine clearance who received the drug alone for 5 days. Vertical bars represent standard deviations. , mericitabine 1000 mg bid + peginterferon alfa-2a (40KD) and ribavirin (n = 59); , mericitabine 1000 mg bid monotherapy (n = 10); □, placebo bid + peginterferon alfa-2a (40KD) and ribavirin (n = 35)