Molnupiravir is effective against hepatitis E virus infection in an animal model

  • Hepatol Commun. 2026 Apr 13;10(5):e0944. doi: 10.1097/HC9.0000000000000944.
Shusheng Wu  1 ,  Nicholas Foo-Siong Chew  1 ,  Xiaodan Ma  1 ,  Jianwen Situ  1 ,  Estie Hon-Kiu Shun  2 ,  Can Li  1 ,  Jonathan Daniel Ip  1 ,  Siu-Fung Stanley Ho  1 ,  Anna Jinxia Zhang  1 ,  James Yiu-Hung Tsoi  1 ,  Wan-Mui Chan  1 ,  Weihui Ma  1 ,  Yonghao Liang  1 ,  Weiwei Mao  1 ,  Karina Wing Yee Chen  1 ,  Feifei Yin  3 ,  Kelvin Kai-Wang To  1  2 ,  Shuofeng Yuan  1  2 ,  Jasper Fuk-Woo Chan  1  2  3 ,  Longchao Zhu  4 ,  Yaowei Huang  5  6 ,  Siddharth Sridhar  1  7
Affiliations
  • 1. State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
  • 2. Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong Special Administrative Region, China.
  • 3. Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Key Laboratory of Tropical Translational Medicine, Ministry of Education, Hainan Medical University, Haikou, Hainan, China.
  • 4. School of Life and Health Technology, Dongguan University of Technology, Dongguan, China.
  • 5. State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, China.
  • 6. Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
  • 7. Pandemic Research Alliance, The University of Hong Kong, Hong Kong Special Administrative Region, China.
PMID: 41974041 DOI: 10.1097/HC9.0000000000000944
Abstract

Background: There are few treatment options for patients with chronic hepatitis E unresponsive to ribavirin. Drug repurposing is required to identify new treatments. Molnupiravir, a nucleoside analogue, is approved for the treatment of coronavirus disease 2019 (COVID-19). This study evaluated the activity of molnupiravir against hepatitis E virus (HEV) in Cell Culture and animal models.

Methods: Cytotoxicity and Antiviral efficacy of molnupiravir, ribavirin, and sofosbuvir were investigated using infectious cDNA clones and wild-type HEV isolates in PLC/PRF/5 cells and primary rat hepatocytes. Immunosuppressed rats were infected with HEV and treated with molnupiravir and ribavirin. The effectiveness of molnupiravir in clearing HEV in serum, feces, and liver tissue was compared with that of untreated and ribavirin-treated Animals. Mutations arising in virus populations during treatment were assessed using next-generation Sequencing.

Results: The Antiviral effect of molnupiravir was comparable to that of ribavirin and superior to that of sofosbuvir against HEV strains in vitro, with decreased HEV RNA in supernatant (p<0.05) and cytoplasmic viral protein expression. No additive effect with sofosbuvir was observed. Rats (n=14 per group) treated with 400 mg/kg/d molnupiravir cleared viremia within 4 weeks of treatment, and 9/14 of these Animals also cleared viral shedding in stool. Mean viremia and fecal viral loads were reduced compared with untreated and ribavirin-treated Animals (p≤0.005). Partial effectiveness was apparent at the lower 250 mg/kg/d molnupiravir dose. Molnupiravir-treated rats had improved liver histology compared with control Animals. Frequent transition mutations were observed in HEV from molnupiravir-treated Animals.

Conclusions: Molnupiravir limits HEV Infection in Cell Culture and animal models. Molnupiravir could be an alternative for ribavirin-refractory chronic hepatitis E.

Keywords
N-hydroxycytidine; chronic hepatitis E; molnupiravir; ribavirin; transplant.
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