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HCV Reinfection: is there protective effect following natural HCV clearance?
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Hepatology
May 2007
Low incidence of HCV reinfection: Exposure, testing frequency, or protective immunity?
Gregory J. Dore, Joanne Micallef
National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Darlinghurst, NSW, Australia
Potential conflict of interest: Nothing to report.
Letter
Low Incidence of HCV Reinfection: Exposure, Testing Frequency, or Protective Immunity?
To the Editor:
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 Sydney[4] 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.
Gregory J. Dore, Joanne Micallef
National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Darlinghurst, NSW, Australia
Reply:
We thank Drs. Dore and Micallef for their comments on our manuscript discussing the lower risk of HCV reinfection among previously infected injection drug users (IDUs).[1] We acknowledge that there are a number of limitations associated with our retrospective study design. They also suggest that the population at risk of reinfection is older and that they may have reduced risk behavior for HCV acquisition, perhaps as a result of their previous diagnosis. Although older, they were using illicit drugs more often than subjects previously uninfected with HCV, suggesting that the risk of HCV acquisition remained high. We acknowledge that with our retrospective design, we were not able to delineate the specific nature of risks associated with drug use (including injection equipment sharing) that would more accurately define HCV transmission risks. However, the extent of the protection we observed makes us confident that there was a protective effect, although measuring the magnitude of this effect would require more reliable risk behavior data and more systematic HCV RNA testing. This relates to their concern regarding the HCV testing frequency. It is indeed possible that we missed some cases of transient reinfection, because our median interval between HCV RNA tests was 15.6 months as compared to just 5 months in the study of Micallef et al.[2]
Irrespective of these limitations, as mentioned by Dore and Micallef, the absence of chronic reinfection over a long duration of follow-up (5.2 years) in this large study indicates that some IDUs may be protected from HCV reinfection either through reduced risk behaviors for acquisition, host factors responsible for the resolution of primary viremia, or a partial protective immunity leading to enhanced clearance after reinfection. In chimpanzees reinfected with HCV, there is rapid control of viral replication, short-lived viremia, and universal spontaneous resolution of secondary infection.[3] Additionally, in humans and chimpanzees, reinfection generally leads to an attenuated course of infection, with the level and duration of viremia markedly reduced.[4-7] This being said, our data are quite reassuring in that chronic reinfection seems much less frequent in this population.
We are quite intrigued that Dore and Micallef report no protective effect of prior HCV infection in a younger population with more frequent injection drug use.[2] It should be pointed out, however, that only 18 individuals at risk of reinfection were evaluated and that the risk of HCV infection in the previously uninfected group was twice that reported by Mehta[8] and ourselves,[1] suggesting that the protective effect of prior infection may be lower in higher risk subjects. Taken together, these data suggest that the magnitude of protection against reinfection (as well as its specific mechanism) may differ between populations. Future prospective studies are needed to evaluate the natural history of HCV reinfection in IDUs and should include a detailed assessment of risk behaviors and more frequent and systematic HCV RNA testing. This type of information is necessary to better understand the immunopathogenesis and natural history of HCV in IDUs, thereby helping to define public health HCV control measures and treatment recommendations.
Jason Grebely 1, Brian Conway 1, Jesse D. Raffa 2, Calvin Lai 4, Mel Krajden 5, Mark W. Tyndall 3 4
1Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada
2Department of Statistics, University of British Columbia, Vancouver, BC, Canada
3Department of Medicine, University of British Columbia, Vancouver, BC, Canada
4British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada
5British Columbia Centre for Disease Control, Vancouver, BC, Canada
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