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Low incidence of HCV reinfection: Exposure, testing frequency, or protective immunity?

We read with interest the report wherein Grebely and colleagues found lower incidence of HCV reinfection following natural HCV clearance than incidence of initial HCV infection within a Vancouver, Canada, community-based cohort.1 These findings are given as evidence of protective immunity provided by prior HCV infection. However, the comparison of initial HCV infection and HCV reinfection incidence has several inherent methodological difficulties, particularly when conducted retrospectively. First, demographic and behavioral characteristics generally differ among the denominator populations: uninfected individuals for initial HCV infection and previously infected individuals with viral clearance for HCV reinfection. The latter group is often older and may have reduced risk behavior after HCV diagnosis. Adjustment for baseline characteristics as performed by Grebely et al. reduces but does not remove this concern. Second, longitudinal reporting of injection risk behavior may not be available to cover the at-risk study period. Third, the HCV testing interval is generally heterogeneous and may be relatively broad. Variability in testing interval is a minor issue for determination of incidence of initial HCV infection, because long-lasting seroconversion to anti-HCV antibody following infection supports detection of all new cases. However, an incident case of HCV reinfection requires detection of new HCV viremia, which is dependent on the proportion of cases with persistent viremia, duration of viremia in clearance cases and interval of HCV RNA testing. A previous study of HCV reinfection demonstrated that HCV viremia in the setting of HCV reinfection was at a lower level, generally transient, and shorter in duration compared to initial HCV viremia.2 The duration of HCV viremia among individuals with natural HCV clearance following initial HCV infection is generally less than 12 weeks.3 Thus, a testing interval for HCV RNA longer than 12 weeks in an HCV reinfection cohort where a majority of new viremic cases could be expected to clear viremia may miss many HCV reinfection cases. Studies of HCV reinfection from community-based and primary care–based cohorts in Baltimore,2 Vancouver,1 and Sydney4 are outlined in Table 1. In contrast to the findings in Vancouver and Baltimore, we found no evidence for lower incidence of HCV reinfection compared to initial infection. Key features of our study were a young aged cohort, with the same median age in both uninfected and previously infected subgroups, high rate of frequent (daily) injection drug use, and a relatively short interval for HCV RNA testing. An evaluation of the HCV RNA testing interval within the Vancouver study, including a comparison among HCV reinfection cases and noncases in the previously infected group, may provide some explanation for the apparent lower incidence of HCV reinfection. A relatively long testing interval (greater than 6 months) would suggest than many HCV reinfection cases may have been undetected. The absence of persistent HCV viremia following HCV reinfection may reflect partial protective immunity, but alternatively could relate to the same host factors that influenced viral clearance following initial HCV infection.5,6 As suggested by Grebely et al., prospective studies of HCV clearance, reinfection, and potential protective immunity are crucial to advance the understanding of early HCV immunopathogenesis.