Global 
Deutschland 
Italia Liver and Bile
Gastroenterology. 2025;168(4):769-783.e12
A pangenotypic hepatitis E virus replication inhibitor with high potency in a rat infection model
Background and aims: Hepatitis E virus (HEV) constitutes a substantial public health burden with ~20 million human infections annually, including 3.3 million symptomatic cases. Appropriate treatment options for, in particular, HEV-infected immunocompromised patients and pregnant women are lacking, underscoring the urgent need for potent and safe antiviral drugs.
Methods: HEV subgenomic replicon systems were used to screen a small library of preselected nucleoside analogues, originally developed in a hepatitis C virus (HCV) antiviral program. Antiviral activity of the selected hit on HEV infection was evaluated in a variety of cell culture systems, and the efficacy of the compound was assessed in the athymic nude rat HEV infection model.
Results: Compound JNJ-9117 exerts pangenotype antiviral activity against HEV in different cell types as well as in primary human hepatocytes. A high level of conservation is observed between 3 crucial motifs in the catalytic domain of the HCV and HEV polymerases. This suggests a mechanism of action that is identical to that of the molecule against HCV, whereby the 5’-triphosphate of JNJ-9117 acts as a chain terminator during viral RNA synthesis. JNJ-9117 has a favorable pharmacokinetic and safety profile in rats and results in a pronounced antiviral effect in a chronic rat HEV infection model, both in a prophylactic and therapeutic setting. The combination of JNJ-9117 and ribavirin (each at an intentionally selected suboptimal/inactive dose) was highly effective in infected rats in lowering the viral RNA load in liver and feces to (almost) undetectable levels.
Conclusions: JNJ-9117 has a profile that holds promise for the treatment of life-threatening hepatitis E virus infections in humans. Phase I studies with JNJ-9117 have been initiated in healthy human volunteers.
DOI: 10.1053/j.gastro.2024.10.043
Prof. Dr. Tobias Böttler
Head of Gerok Liver Center, University Medical Center Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany
A pangenotypic nucleoside analogue as a new therapeutic approach for HEV infection
Hepatitis E virus (HEV) infections are usually asymptomatic and self-limiting in healthy individuals. However, in immunosuppressed individuals—such as organ transplant recipients or patients with hematological diseases—HEV can progress to a chronic infection. The underlying mechanism of viral persistence in these patients is an insufficient development of the HEV-specific immune response. Clinically, chronic HEV infection is associated with rapid progression of chronic liver disease, with the development of liver fibrosis and ultimately liver cirrhosis, as well as related complications. To date, the treatment of chronic HEV infection has relied heavily on two approaches. First, reduction of immunosuppression is recommended to restore HEV-specific immunity, which facilitates immune-mediated viral clearance. However, due to the risk of graft rejections when reducing immunosuppression, this therapeutic option is often underutilized. Second, treatment with ribavirin has shown efficacy in several case studies, but does not lead to viral clearance in all individuals. In addition to hemolytic anemia, the use of ribavirin also carries the risk of developing resistance mutations, which can further limit its effectiveness. The development of new and effective treatment options is therefore urgently needed to treat chronic HEV infection more effectively.
This study by Zhang et al. offers new hope in this area. JNJ-9117, a nucleoside analogue originally developed as part of an antiviral program targeting hepatitis C, has demonstrated pangenotypic antiviral activity against HEV in both cell culture models and primary human hepatocytes. Its mechanism of action involves chain termination during viral RNA synthesis. In preclinical models, particularly in a rat model, treatment with JNJ-9117 led to a significant reduction in HEV viral loads. Remarkably, the combination of JNJ-9117 with ribavirin produced synergistic antiviral effects, achieving maximal viral suppression even at suboptimal doses. This synergy has the potential to increase treatment efficacy and prevent the development of resistance mutations. Phase 1 clinical trials are currently underway to evaluate the safety of this compound in humans. Beyond these concrete, promising results, it is certainly welcome that new substances for the treatment of chronic HEV infection are being actively developed and tested in order to close the gaps that still exist in the treatment of HEV infections.