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Hepatitis D virus infection—Not a vanishing disease in Europe!

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 Mehta8 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.