• Potential conflict of interest: Nothing to report.


We thank Kamar et al. for their interest in our article. We have to stress that the primary aim of our study was to address basic principles of immune control in hepatitis E virus (HEV) infection and, possibly, to generate additional hypotheses. As in any other study describing, for the first time, an association between a disease condition and a distinct function of immune cells, potential clinical implications obviously need to be confirmed in independent studies. We would therefore be happy to support any other group in testing HEV-specific T-cell responses.

Ribavirin, a cheap and easy-to-apply drug, is fortunately effective in most (but not all!) patients with persistent HEV infection. However, ribavirin treatment is not always uncomplicated, because side effects and comorbidities may prevent optimal dosing of ribavirin in single patients. Among several other—maybe more important—findings, one potential novel hypothesis that emerged from our study was that antiviral therapy may be delayed in patients with detectable HEV-specific T-cell responses. The association between strength, frequency, and quality (i.e., interferon-gamma versus interleukin-10) of T-cell responses and HEV RNA status is striking and should be self-explanatory. We are surprised that Kamar et al. 1 neglect the importance of the included control groups in this type of study. Of note, all but 3 HEV RNA-negative transplant patients had acquired HEV after transplantation and thus cleared HEV spontaneously and developed HEV-specific T-cell responses. On the contrary, a correlation between the level of HEV viremia and strength of T-cell responses could not be established because immune responses were very weak or absent in this group.

Similar to hepatitis C, we currently do not know the detailed mode of action how ribavirin suppresses HEV replication. Modulation of immune responses could potentially contribute to the clearance of HEV infection. It might indeed be interesting to study, in more detail, the temporal relationship between ribavirin therapy and the evolution of HEV-specific T-cell responses, which was unfortunately not possible here because of limitations in sample availability.

We are just in the beginning of understanding potential interactions between HEV and the host's immune system. This topic is of particular interest, because HEV did not evolve as a virus leading to prolonged, or even persisting, infections. The key observations of our study were that we describe, for the first time, the weakness of HEV-specific T-cell responses in chronic hepatitis E, whereas strong, multispecific responses can be observed in resolved patients. The finding that the blocking of certain costimulatory pathways can restore some levels of HEV-specific immunity has implications for understanding immunological mechanisms of chronicity. We invite our colleagues in Toulouse to address similar research questions in their cohort of individuals with chronic HEV infection. However, because the number of chronic hepatitis E patients is still limited, only collaborative projects across centers will be able to answer many of the above-discussed issues.

Pothakamuri Venkata Suneetha Ph.D.*, Sven Pischke M.D.*, Heiner Wedemeyer M.D.*, * Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.