Sustained response to interferon-ribavirin combination therapy predicted by a model of hepatitis C virus dynamics using both HCV RNA and alanine aminotransferase

Abstract

Background and aims: Standard models simulate the dynamics of hepatitis C virus (HCV) infection using HCV RNA kinetics and show a correlation between the clearance of infected hepatocytes and response to interferon. However, they are unable to predict whether the response will be maintained. The aim of our work was to identify criteria by which sustained responses may be predicted and defined. Methods: In our model the clearance rate of infected cells is a function of their number and the baseline rate is computed by the alanine aminotransferase (ALT) kinetics during the first month of therapy. We simulated the variations of viral and infected cell loads in 31 consecutive patients treated with IFN-α2b 3-5 MU every other day, with or without ribavirin, for 6 or 12 months depending on HCV genotype. Results: At baseline the computed (in 28 of 31 cases) percentage of infected cells was lower in seven sustained responders (mean: 11.7%, range: 1-24.6%) than in 14 transient responders (mean: 28.2%, range: 7.4-75.5%) and in seven non-responders (mean: 41%, range: 8.8-86%) (P=0.036). At the end of therapy the computed infected cell number was <100 cells/ml of extracellular fluid in all sustained responders (mean: 18.4, range: 1.7-48), in three transient responders (mean: 3500, range: 1.52-17 500) and in none non-responders (mean: 28 500, range: 1200-96 000] (P=0.003). Overall of 10 patients with less than 100 infected cells/ml at the end of therapy seven (six had combination therapy) showed sustained response. All three relapsers received interferon monotherapy. Conclusion: The analysis of infected cells dynamics using the new model might be useful to tailor treatment duration in patients with combination therapy.