First phase viral kinetic parameters as predictors of treatment response and their influence on the second phase viral decline.

Abstract

It has recently been shown that upon initiation of interferon (IFN) treatment there is a biphasic decline in hepatitis C virus (HCV) RNA levels. In preliminary results, the rate of second phase viral decline has been shown to be an excellent predictor of treatment response. In this analysis, we determined whether the first phase viral kinetic parameters affected the rate of second phase viral decline. We also assessed whether first phase viral kinetic parameters could be used to predict treatment response within 24 h of initiating treatment. This study is a retrospective analysis of two completed studies from which detailed kinetic data were obtained in patients infected with genotype 1 HCV. In both studies, viral levels were measured frequently over the first 24 h, allowing the determination of IFNs effectiveness in blocking viral production and the viral load at the end of the first phase (v1). The second phase decline slope was calculated by log-linear regression on measurements of serum HCV RNA during days 2, 7 and 14. In study one, sustained viral response (SVR) rates were obtained, allowing the determination of the first phase's predictive power for SVR. Logistic regression and fisher exact tests were used to analyse data. In study one, no patient achieved SVR without an IFN effectiveness greater than 98% and a V1 less than 250 000 copies/mL. When V1 and IFN effectiveness were combined to predict SVR, a negative predictive value= 100%, positive predictive value=71% and accuracy of 95% was obtained after only 24 h of IFN treatment. Both studies illustrated strong correlations for both IFN effectiveness and V1 with the rate of 2nd phase slope (P < 0.001). V1 also correlated significantly with a calculation of infected cell loss (delta), which is a major determinant of the second phase viral decline. These results suggest that early viral kinetics may predict lack of response after only 24 h of treatment initiation and indicate a strong link between the degree of viral load reduction during the first phase, and the subsequent 2nd phase decline slope. This might be explained by a viral dynamics model assuming a jump-start of the immune response when viral loads are reduced below a threshold, subsequently giving rise to a faster 2nd phase decline slope.