gms | German Medical Science

Introduction: Although impacting hundreds of thousands of people in Western nations each year, hepatitis E virus (HEV) is an under-reported health problem [1]. HEV usually is a self-limiting disease, but especially immunocompromised individuals are at risk to develop a chronic course of infection, with rapid progression to fibrosis, cirrhosis or even the development of liver failure. Janus kinase (JAK) inhibitors are a novel drug class for the treatment of autoimmune inflammatory rheumatic disease (AIRD). As JAKs play a key role in innate immunity, viral infections and reactivation are frequently reported during JAK inhibitor treatment in AIRD patients [2].

To characterize the influence of JAK inhibitors on HEV replication ex vivo and assess the risk for the development of symptomatic HEV infection during JAK Inhibitor therapy in vivo.

Methods: To determine the effect of JAK inhibitors on HEV replication we performed infection experiments with primary human hepatocytes (PHH) followed by immunofluorescence analysis and RNAseq. To evaluate the risk of HEV infection during JAK Inhibitor therapy, we monitored HEV RNA and HEV IgG/IgM of 140 AIRD patients, receiving JAK inhibitors. Moreover, we conducted a retrospective analysis of liver enzymes of patients which were anti-HEV IgG/IgM positive.

Results: Transcriptomic analysis of PHH revealed an upregulation of innate immunity components during HEV infection. This induction was perturbed in the presence of a JAK inhibitor, concomitant with strong elevation of HEV RNA levels. In line, infection experiments displayed an up to 50-fold increase of progeny virus production during JAK inhibitor treatment indicating that JAK signaling is critical to control HEV infection. Monitoring of seroprevalence identified 17 patients which were anti-HEV IgG and/or IgM positive, while no patient hat detectable HEV RNA levels. Five patients had detectable anti-HEV IgM levels suggesting a recent HEV infection. Three of 17 had a period with elevated liver enzymes (f.e. GGT> 200 U/L) during time of retrospective analysis (ranging from 10 to 23 months).

Conclusion: Obtained ex vivo data suggest that JAK inhibition facilitates HEV life cycle progression. Considering that JAK inhibitors are routinely applied for the treatment of AIRD, these patients may be at higher risk for a symptomatic course and outcome of HEV infection. In addition to established protocols, screening for HEV seroprevalence and HEV RNA should be considered prior starting JAK inhibitor treatment and in case of elevated liver enzymes during JAK inhibitor therapy.