The current standard of care for hepatitis C virus (HCV) infection – combination therapy with pegylated interferon and ribavirin – elicits sustained responses in only ∼50% of the patients treated. No alternatives exist for patients who do not respond to combination therapy. Addition of ribavirin substantially improves response rates to interferon and lowers relapse rates following the cessation of therapy, suggesting that increasing ribavirin exposure may further improve treatment response. A key limitation, however, is the toxic side-effect of ribavirin, hemolytic anemia, which often necessitates a reduction of ribavirin dosage and compromises treatment response. Maximizing treatment response thus requires striking a balance between the antiviral and hemolytic activities of ribavirin. Current models of viral kinetics describe the enhancement of treatment response due to ribavirin. Ribavirin-induced anemia, however, remains poorly understood and precludes rational optimization of combination therapy. Here, we develop a new mathematical model of the population dynamics of erythrocytes that quantitatively describes ribavirin-induced anemia in HCV patients. Based on the assumption that ribavirin accumulation decreases erythrocyte lifespan in a dose-dependent manner, model predictions capture several independent experimental observations of the accumulation of ribavirin in erythrocytes and the resulting decline of hemoglobin in HCV patients undergoing combination therapy, estimate the reduced erythrocyte lifespan during therapy, and describe inter-patient variations in the severity of ribavirin-induced anemia. Further, model predictions estimate the threshold ribavirin exposure beyond which anemia becomes intolerable and suggest guidelines for the usage of growth hormones, such as erythropoietin, that stimulate erythrocyte production and avert the reduction of ribavirin dosage, thereby improving treatment response. Our model thus facilitates, in conjunction with models of viral kinetics, the rational identification of treatment protocols that maximize treatment response while curtailing side effects.

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Our formula for D(opt) presents an avenue for personalizing ribavirin dosage. By keeping anaemia tolerable, the predicted optimal dosage may improve adherence, reduce the need for drug monitoring, and increase response rates. Response rates may be increased further by the higher dosages recommended for patients with ITPA deficiency.

Complete understanding of the mechanisms regulating the proliferation and differentiation that takes place during human immune CD8 + T cell responses is still lacking. Human clinical data is usually limited to blood cell counts, yet the initiation of these responses occurs in the draining lymph nodes; antigen-specific effector and memory CD8 + T cells generated in the lymph nodes migrate to those tissues where they are required. We use approximate Bayesian computation with deterministic mathematical models of CD8 + T cell populations (naive, central memory, effector memory and effector) and yellow fever virus vaccine data to infer the dynamics of these CD8 + T cell populations in three spatial compartments: draining lymph nodes, circulation and skin. We have made use of the literature to obtain rates of division and death for human CD8 + T cell population subsets and thymic export rates. Under the decreasing potential hypothesis for differentiation during an immune response, we find that, as the number of T cell clonotypes driven to an immune response increases, there is a reduction in the number of divisions required to differentiate from a naive to an effector CD8 + T cell, supporting the "division of labour" hypothesis observed in murine studies. We have also considered the reverse differentiation scenario, the increasing potential hypothesis. The decreasing potential model is better supported by the yellow fever virus vaccine data.

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