Perhaps related to this is the similarly counterintuitive finding that the good-response IL28B genotype is associated with higher HCV viral load at baseline, whereas high viral load is generally predictive of poor treatment outcomes. It has been demonstrated through simulation studies that this relationship may be explained by a kind of selection bias, in which patients with both low baseline viral load and the good-response IL28B genotype are particularly likely to spontaneously resolve HCV infection, so that patients carrying the good-response genotype that progress to chronic infection (i.e., those ascertained in chronic HCV

cohorts) are more likely to carry high viral loads, compared to poor-response IL28B genotypes.35 Whether this Apitolisib ic50 indeed occurs has yet to be determined and will require prospective study of HCV viral kinetics as well as immune and liver-specific responses in infected patients from the acute phase through establishment of chronic infection. Such studies will be crucial to our understanding of the effect of IL28B genotype on both spontaneous and treatment-induced clearance of HCV and may shed light on the relevance of hepatic ISG expression and peripheral

IFN-λ production to HCV clearance. Examination BAY 73-4506 of the relationship between IL28B genotype and early viral kinetics may shed some light on the possible mechanisms for the genetic association; however, studies to date have shown mixed results. Several reports36-39 have suggested that the mafosfamide protective IL28B genotype is associated with a steeper first-phase decline (i.e., decrease in viral titer over the first several days of treatment), with a generally weaker effect on the second-phase decline (i.e., 2-28 days after treatment initiation), suggesting, per Neumann et

al.,40 that the major mode of IL28B action may be on the clearance of free virus. Consistent with this, a study of Taiwanese chronic HCV patients employing a constrained version of the Neumann model suggested that the primary effect of IL28B genotype may be on the viral clearance rate41; however, others have suggested that the assumptions underlying this constrained model may be unrealistic and may complicate the interpretation.42 In contrast, a study employing a smaller sample size, but a denser sampling scheme in the initial phase, suggested that the primary IL28B effect may be on the death rate of infected hepatocytes (δ), though there was a trend toward an association between IL28B genotype and first-phase decline as well.43 A better understanding of the precise relationship between IL28B genotype and viral kinetics will require more detailed, well-powered prospective studies. There is some evidence in favor of an interplay between IL28B and natural killer (NK) cell activity in HCV responses.