Mutagenic Effects of Ribavirin on Hepatitis E Virus—Viral Extinction versus Selection of Fitness-Enhancing Mutations

Abstract

Hepatitis E virus (HEV), an important agent of viral hepatitis worldwide, can cause severe courses of infection in pregnant women and immunosuppressed patients. To date, HEV infections can only be treated with ribavirin (RBV). Major drawbacks of this therapy are that RBV is not approved for administration to pregnant women and that the virus can acquire mutations, which render the intra-host population less sensitive or even resistant to RBV. One of the proposed modes of action of RBV is a direct mutagenic effect on viral genomes, inducing mismatches and subsequent nucleotide substitutions. These transition events can drive the already error-prone viral replication beyond an error threshold, causing viral population extinction. In contrast, the expanded heterogeneous viral population can facilitate selection of mutant viruses with enhanced replication fitness. Emergence of these mutant viruses can lead to therapeutic failure. Consequently, the onset of RBV treatment in chronically HEV-infected individuals can result in two divergent outcomes: viral extinction versus selection of fitness-enhanced viruses. Following an overview of RNA viruses treated with RBV in clinics and a summary of the different antiviral modes of action of this drug, we focus on the mutagenic effect of RBV on HEV intrahost populations, and how HEV is able to overcome lethal mutagenesis.

Hepatitis E virus replication and interferon responses in human placental cells

“…Ribavirin (RBV) remains the treatment of choice in chronic infections and can be considered in fulminant cases 11, 12, 13. However, RBV administration should be carefully considered because of possible side effects,11 in particular anemia and treatment failure due to the selection of viral mutants with increased replication fitness 14, 15, 16. Of note, RBV is also contraindicated in pregnant individuals.…”

Hepatitis E: Diagnostic and Therapeutic Challenges

“…The drug (RBV) pressure in chronic patients may thus result in virus eradication as well as selection of replication competent quasi-species [25].…”

Updates in Hepatitis E virus (HEV) field; lessons learned from human liver chimeric mice

“…Besides, RBV has several other antiviral mechanisms such as inhibition of a cellular inosine monophosphate dehydrogenase (IMPDH), inhibition of viral replication, inhibition of capping, influence on interferon‐stimulated genes (ISGs) and immune clearance effect. However, a sustained virologic response was not achieved in about 38% of treated patients or relapse was recorded during therapy because of the emergence of mutant strains . Pegylated interferon alpha (PEG‐IFN‐α) can also be used for the treatment of HEV infection, but this therapy is not efficient in all settings and it causes severe side effects.…”