The assumption of a gradual increase

The assumption of a gradual increase CP-690550 in antiviral effectiveness that explains

the initially slow decrease in viral load still needs to be validated, even though it is supported by the observation that the active forms of mericitabine in vitro take ∼48 hours to accumulate to steady-state triphosphate levels.13 It is noteworthy that RBV, which needs to be phosphorylated to its monophosphate, diphosphate, and triphosphate analogues, when given as monotherapy also induces a monophasic viral decline consistent with the variable effectivenss assumption.29 Second, our model does not distinguish between the cytidine and the uridine triphosphates, which could have slightly different potencies Cytoskeletal Signaling inhibitor and are expected to accumulate at different rates. Third, it is hard to precisely estimate ε1, ε2, and δ, because they have overlapping effects on the viral load decline. At least one additional sampling measurement between days 1 and 4 would be necessary to estimate more precisely the initial antiviral effectiveness, ε1. However, the fact that the CE and the VE models provided very similar estimates of ε and δ (Tables 1 and 2) is an indication that these parameters were precisely estimated, and consequently that infected cell loss/death

may be playing a minor role in the overall viral load decline. Lastly, for the sake of parameter identifiability, the target cell level was assumed constant throughout the study period. The kinetics of HCV crotamiton RNA rebound after the end of treatment may be affected by the increased availability of target cells,30 and hence our estimates of the rate at which antiviral effectiveness decays after the end of treatment may not be as reliable

as we would wish. Recent developments in viral dynamic modeling have emphasized the interplay between the kinetics of intracellular viral RNA and the extracellular viral kinetics measured by serum levels of HCV RNA.31 Within the context of such models it has been shown that the initial rate of decline of serum HCV RNA is proportional to the ability of drug to block the late stages of virion production (i.e., assembly/secretion).32 If a drug does not block virion assembly/secretion, there may be release of preformed virions during the first phase of viral decline that masks the intrinsic plasma HCV clearance rate.32 Thus the slow initial viral decline observed with mericitabine may reflect the fact that blocking NS5B has only a minimal effect on blocking virus assembly/secretion into the circulation. However, even if a minimal effect in blocking virus assembly/secretion is taken into account using a model that incorporates intracellular events,32 a gradual decrease in the virus production rate, as in the VE model, is still required to fit the data (not shown).

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