Epidemiological and clinical characteristics of persistent hepatitis E due to rat hepatitis E virus and genotype 4 hepatitis E virus

Abstract

Background: Hepatitis E virus (HEV) can cause persistent infections in immunocompromised persons. Chronic HEV infections described in the literature are usually due to genotype 3 HEV, which belongs to Orthohepevirus species A. However, the predominant HEV genotype in East Asia is genotype 4 (HEV-4). In addition, we have recently shown that rat hepatitis E (Orthohepevirus species C) is capable of infecting humans. Rat hepatitis E (HEV-C) is a highly divergent rodent virus sharing less than 60% genetic homology with HEV genotypes within species A. HEV-C1 infection is missed by most HEV diagnostic methods. We have previously shown that genotype 4 HEV and HEV-C can also cause persistent hepatitis in immunocompromised persons, but the characteristics of HEV infection in this population are uncertain. The aim of this study is to compare the epidemiological and clinical characteristics of persistent HEV-4 and HEV-C infections. Methods: This study was conducted in Hong Kong where routine HEV genotyping surveillance and diagnostic testing for HEV-C is performed. We retrieved data of hepatitis E patients from January 1, 2017 to December 31, 2019. Out of 95 eligible patients with genotyping data, we identified 70 HEV-4 and 11 HEV-C infected patients with available data. Clinical history was reviewed to identify patients with persistent HEV-4 and HEV-C infection, defined as HEV viremia for more than 3 months. Response to reduction in immunosuppression or ribavirin therapy was assessed in treated individuals. Results: The mean age of HEV-4 patients was 57.5 while that of HEV-C patients was 64 (p = 0.301). 6/11 (54.5%) HEV-C infections occurred in transplant recipients or HIV-infected persons compared to 6/70 (8.6%) HEV-4 infections (p < 0.005). Persistent infection occurred in 7/11 (63.6%) HEV-C infected patients, including one apparently immunocompetent elderly woman. All 6 HEV-4 infected transplant recipients progressed to persistent infection. None of the individuals with persistent HEV-4 or HEV-C infection spontaneously cleared viremia despite reduction of immunosuppression. Of 5 HEV-4 and 2 HEV-C infected persons receiving ribavirin, 4 had sustained virological response, while 3 were non-responders. Mortality among persistently infected individuals was 3/13 (23%), but was not directly attributable to HEV. Conclusion: Rat hepatitis E (HEV-C) and HEV genotype 4 are emerging variants capable of causing persistent hepatitis E in immunocompromised persons. HEV-C, in particular, appears to preferentially infect immunocompromised individuals who are predisposed to progress to persistent infection. Worryingly, these infections are associated with high rates of progression to persistence despite reduction of immunosuppression. Ribavirin refractory disease is not infrequent. Further research on clinical characteristics and ribavirin responsiveness of HEV-4 and HEV-C infections in immunocompromised persons is required.