15, 16, 24, 26, 27 In one study of individuals with chronic HCV and paired liver biopsies, serum IP-10 levels at the time of liver biopsy were predictive of the development of fibrosis 3-5 years later.24 Further research is required to understand whether higher IP-10 levels early during HCV infection are predictive of subsequent fibrosis progression. After adjusting for IL28B genotype, lower HCV RNA levels (<4 log IU/mL) among those HCV RNA-positive

at acute HCV detection was independently associated with spontaneous clearance. This is consistent with analyses demonstrating that lower HCV RNA levels are associated with spontaneous HCV clearance.30 While it has been demonstrated in a well-characterized cohort of injecting drug users followed monthly after infection that initially high HCV-RNA level (first month FK228 datasheet of infection) is predictive of spontaneous clearance, HCV RNA levels were lower in the period 1-3 months following infection among those with spontaneous clearance.31 In the current study, the majority of HCV RNA positive individuals with acute HCV had a duration of infection >1 RNA Synthesis inhibitor month and the early peak HCV RNA was likely missed. This probably explains the heterogeneity in the results

observed between studies. However, the longer estimated duration of infection among those with acute infection is consistent with individuals identified in the clinical setting. As such, low HCV RNA levels could be used to predict those with an increased likelihood of spontaneous clearance and therapy could potentially be deferred in this group. This study has some limitations. Three cohorts of individuals with acute HCV acquired mainly through injection drug use were combined and there were some differences between cohorts.

Potential unmeasured confounding factors may have influenced the observed results of the study. Also, measurement of the cleaved and uncleaved fractions of IP-10 requires storage of plasma in specialized tubes to avoid postcollection cleavage. Unfortunately, the samples used in this study were not stored to allow for measurement of cleaved IP-10, so this could not be evaluated. Finally, although an association between IP-10 levels and clearance was identified, the mechanisms underlying this remain unclear. In a large cohort of these patients with acute HCV, high IP-10 levels at acute HCV detection were associated with reduced spontaneous clearance independent of IL28B genotype, and therefore may serve as a useful tool to prioritize patients for early antiviral therapy. Author Contributions: G.J.D., G.V.M., M.H., and J.M.K. designed the original ATAHC study and wrote the protocol. J.Gr., J.J.F., T.A., G.V.M., G.J.D., J.B., N.H.S., and A.R.L. designed the IP-10 substudy. J.Gr., J.J.F., and G.J.D. drafted the primary statistical analysis plan, which was reviewed by G.V.M., A.R.L., J.B., and N.H.S. T.A., J.Ge., and I.S. coordinated IP-10 testing and IL28B genetic sequencing. J.J.