Session Title: Category 5g. VIRAL HEPATITIS: g. HEPATITIS C - CLINICAL (THERAPY)
Presentation Date: Apr 15, 2010
ASSOCIATION OF HOST PHARMACODYNAMIC EFFECTS AND VIROLOGIC RESPONSE TO PEGINTERFERON ALFA-2A/RIBAVIRIN IN PATIENTS WITH CHRONIC HEPATITIS C
R.T. Chung1, A. Di Bisceglie2*, F.F. Poordad3, T. Hassanein4, X. Zhou5, E. Lentz6, A. Prabhakar6, F.M. Hamzeh6
1Massachusetts General Hospital, Boston, MA, 2Saint Louis University School of Medicine, St. Louis, MO, 3Cedars Sinai Medical Center, Los Angeles, 4University of California San Diego, San Diego, CA, 5RTI Health Solutions, Research Triangle Park, NC, 6Genentech, South San Francisco, CA, USA. *email@example.com
Objective: Patients receiving HCV treatment frequently experience cytopenias and weight loss.
Aim: We sought to assess pharmacodynamic effects of peginterferon alfa-2a/ribavirin (PEG/RBV) by evaluating the relationship between change in hematologic parameters, body weight, and virologic response.
Methods: Genotype 1/4 HCV patients receiving 24 or 48 weeks of PEG/RBV combination therapy were pooled from 2 registration trials and 2 Phase IV trials involving predominantly Latinos or African-Americans. Maximum decreases in hemoglobin (Hb), neutrophils, platelets, and weight were assessed by virologic response status (SVR, relapse, breakthrough, and nonresponder) and by race/ethnicity.
Results: Of 1778 HCV genotype 1,4,5, or 6 patients analyzed, the majority were male, non-Hispanic Caucasians, with baseline HCV RNA >800,000, and ALT ≤3 x ULN. Mean baseline BMI was 27.5 kg/m2.
[Adjusted* Mean Maximum Decreases from Baseline]
|Viral Response and Race/Ethnic Groups ||Neutrophils in 109/L, Mean (SE) ||Platelets in 109/L, Mean (SE) ||Hb in g/dL, Mean (SE) ||% Weight change from baseline (SE) |
|SVR ||2.58 (0.06)† ||87.13 (1.94)† ||3.82 (0.06) ||6.18 (0.17) |
|Relapse ||2.49 (0.07)† ||91.66 (2.30)† ||3.97 (0.07) ||6.58 (0.22) |
|Breakthrough ||2.45 (0.10)† ||91.30 (3.49)† ||3.97 (0.11) ||7.10 (0.34)† |
|Nonresponder‡ ||2.12 (0.07) ||79.16 (2.38) ||3.82 (0.08) ||5.96 (0.23) |
|Black ||1.81 (0.11)¶ ||75.57 (3.98)¶ ||3.75 (0.13) ||7.50 (0.39)¶ |
|Hispanic Caucasian ||2.54 (0.08) ||88.64 (2.77) ||4.17 (0.09)¶ ||6.34 (0.26) |
|Other race ||1.92 (0.14)¶ ||72.96 (4.72)¶ ||3.77 (0.15) ||6.23 (0.47) |
|Non-Hispanic Caucasian ||2.49 (0.04) ||88.00 (1.49) ||3.82 (0.04) ||6.20 (0.12) |
|* Least squares means adjusted for cirrhosis and drug exposure (total exposure for PEG/RBV; total exposure per kg for RBV) †P<0.05 vs. nonresponders. ‡Never achieved HCV RNA undetectability. ¶P<0.05 vs. non-Hispanic Caucasians. |
Maximum decreases from baseline in hematologic variables and weight were associated with virologic response. Patients achieving undetectability experienced greater declines than non-responders. After adjusting for drug exposure, only decreases in neutrophils and platelets were associated with virologic response. Compared with non-Hispanic Caucasians, Black patients had significantly smaller decreases in neutrophils and platelets but greater declines in weight, while Hispanic Caucasians had greater decreases in Hb.
Conclusions: Maximum decreases from baseline in hematologic variables and weight were associated with virologic response. After adjusting for drug exposure, only decreases in neutrophils and platelets were associated with virologic response, suggesting that anemia and weight loss are more sensitive to total drug exposure. Taken together, these data suggest that the myelosuppressive pharmacodynamic effect of PEG/RBV reflects maximal induction of the host antiviral state.