Modelling hepatitis C virus kinetics: The relationship between the infected cell loss rate and the final slope of viral decay

Abstract

Background: Patients infected with hepatitis C virus (HCV) who respond to treatment with interferon-α plus ribavirin exhibit biphasic or triphasic viral load decreases. While the rapid first phase is indicative of the effectiveness of therapy in blocking viral production (ε), the slope of the final phase (λ), that is, the second phase in biphasic decreases and the third phase in triphasic decreases, depends on the infected cell loss rate (δ). In standard models, λ is approximately εδ when the viral clearance rate c>>δ, as has been previously estimated. Methods: The relationship among ε, δ, λ and the baseline fraction of HCV-infected hepatocytes (π) was investigated in a model that included proliferation of hepatocytes. Results: We found that λ was not proportional to ε, but rather obeyed a complex relationship that could lead to dramatic increases in estimates of δ as ε increased. In particular, when ε<99%, λ moderately underestimated δ in patients with a small π whereas δ might be up to 10-fold larger than λ in patients with a large π. Interestingly, when ε>99%, δ-λ regardless of π. Conclusions: Our results indicated that in patients undergoing therapy who achieved a 2 log10 reduction in viral load (ε<99%), previously estimated δ values might represent only a minimal estimate of the infected cell loss rate. Moreover, combining interferon-α with new antiviral agents to achieve ε>99% should allow for a more accurate estimate of δ in HCV RNA kinetic studies. This might be important when using viral kinetics to estimate the effect of the immune response on viral elimination and the attainment of sustained virological response.