Association of host pharmacodynamic effects with virologic response to pegylated interferon alfa-2a/ribavirin in chronic hepatitis C

Abstract

Patients receiving therapy for chronic hepatitis C virus (HCV) infection frequently experience cytopenias and weight loss. We retrospectively assessed the pharmacodynamic effects of pegylated interferon (PEG-IFN) alfa-2a and ribavirin by evaluating the relationship between changes in hematologic parameters, body weight, and virologic response. Patients with HCV genotypes 1, 4, 5, or 6 receiving 24 or 48 weeks of PEG-IFN alfa-2a and ribavirin therapy were pooled from four phase 3/4 trials. Maximum decreases in hemoglobin level, neutrophil count, platelet count, and weight during therapy were assessed according to virologic response category (sustained virologic response [SVR], relapse, breakthrough, and nonresponder) and race/ethnicity. Of 1,778 patients analyzed, more than half were male, non-Hispanic Caucasian, and infected with HCV genotype 1; had a baseline HCV RNA >800,000; and had alanine aminotransferase levels ≤3 × the upper limit of normal. Virologic responders (SVR, relapse, and breakthrough) experienced greater maximum decreases from baseline in hemoglobin level, neutrophil count, platelet count, and weight compared with nonresponders; however, no clear trend was observed between SVR, relapse, and breakthrough. After adjusting for drug exposure and treatment duration, only decreases in neutrophil count remained associated with virologic response. Significantly greater declines in neutrophil (P < 0.0001) and platelet (P < 0.005) count were observed at weeks 4, 12, and 24 of therapy in virologic responders compared with nonresponders. This difference between responders and nonresponders was also observed among racial/ethnic groups, although statistical significance was not consistent across all groups.

Conclusion: This post hoc analysis of HCV patients treated with PEG-IFN alfa-2a and ribavirin shows that maximum decreases from baseline in hematologic parameters and weight loss were associated with virologic response. However, after adjusting for drug exposure and accounting for duration of therapy, only neutropenia was independently associated with virologic response.

Trial registration: ClinicalTrials.gov NCT00087607.

Fig. 1

(A) Mean maximum decreases from baseline in pharmacodynamic parameters by virologic response category. Fig. shows cirrhosis-adjusted least squares means for neutrophils and platelets. For haemoglobin and weight, cirrhosis is not significant and adjustment was not required. Error bars represent upper 95% confidence intervals. NS, not significant; *P < 0.01 versus nonresponders; **P < 0.0001 versus nonresponders.

Fig. 2

Adjusted mean maximum decreases from baseline in pharmacodynamic parameters by virologic response status – A) All patients; B) Treatment completers (patients completing at least 44 weeks of treatment). Fig. shows least squares means adjusted for cirrhosis and drug exposure (total peginterferon and total ribavirin received per kg of weight at baseline) if significant (P < 0.05). Error bars represent upper 95% confidence intervals. NS, not significant; *P < 0.05 versus nonresponders; **P < 0.01 versus nonresponders; ***P < 0.001 versus nonresponders; ****P < 0.0001 versus nonresponders.

Fig. 3

Adjusted mean change in pharmacodynamic parameters from baseline to weeks 4, 12, and 24 for virologic responders and nonresponders. Error bars represent 95% confidence intervals. Figure shows least squares means adjusted for cirrhosis and drug exposure (total peginterferon and total ribavirin received per kg of weight up to the time of measurement) if significant (P < 0.05) at one or more time points. Responders = Patients with SVR, relapse, and breakthroughs. P values are from tests comparing responders and nonresponders. NS, not significant; *P < 0.05; **P < 0.005; ***P < 0.001; ****P < 0.0001.

Fig. 4

Adjusted mean percent decreases from baseline in pharmacodynamic parameters by race/ethnicity. Figure shows least squares means adjusted for cirrhosis and drug exposure (total peginterferon and total ribavirin received per kg of weight at baseline) if significant (P < 0.05). Error bars represent upper 95% confidence intervals. NS, not significant; *P < 0.01 versus non-Latino Caucasians; **P < 0.001 versus non-Latino Caucasians; ***P < 0.0001 versus Non-Latino Caucasians.

Fig. 5

Adjusted mean maximum decrease in pharmacodynamic parameters in virologic responders and nonresponders by race/ethnicity. Error bars represent upper 95% confidence intervals. Figure shows least squares means adjusted for cirrhosis and drug exposure (total peginterferon and total ribavirin received per kg of weight at baseline) if significant (P < 0.05). Patients achieved undetectable HCV RNA levels on treatment (i.e., SVR, breakthrough, and relapse). P values are from tests comparing responders and nonresponders among race/ethnic groups. NS, not significant; *P < 0.05; **P < 0.01; ***P < 0.001.

Fig. 6

Association between hemoglobin decline and SVR rates. Fig. shows predicted percentages of SVR from logistic regression models before and after adjusting for total exposure for peginterferon alfa-2a and total ribavirin exposure per kg. Cirrhosis was adjusted for in both models. P values are from the corresponding tests for odds ratios. Error bars represent upper 95% confidence intervals.