# An experimental evaluation of drug-induced mutational meltdown as an antiviral treatment strategy

## TL;DR

This study tests a new antiviral drug that increases the mutation rate of influenza A virus, leading to population extinction at high doses.

## Contribution

The study provides the first evidence that influenza A virus populations can adapt to low concentrations of favipiravir but undergo extinction at high concentrations.

## Key findings

- Viral populations adapted to low concentrations of favipiravir over time.
- High concentrations of favipiravir caused population extinction through mutational meltdown.
- Whole genome polymorphism data was analyzed across fifteen time points to track adaptation and extinction.

## Abstract

The rapid evolution of drug resistance remains a critical public health concern. The treatment of influenza A virus (IAV) has proven particularly challenging, due to the ability of the virus to develop resistance against current antivirals and vaccines. Here we evaluate a novel antiviral drug therapy, favipiravir, for which the mechanism of action in IAV involves an interaction with the viral RNA-dependent RNA polymerase resulting in an effective increase in the viral mutation rate. We utilized an experimental evolution framework, combined with novel population genetic method development for inference from time-sampled data, in order to evaluate the effectiveness of favipiravir against IAV. Evaluating whole genome polymorphism data across fifteen time points under multiple drug concentrations and in controls, we present the first evidence for the ability of viral populations to effectively adapt to low concentrations of favipiravir. In contrast, under high concentrations, we observe population extinction, indicative of mutational meltdown. We discuss the observed dynamics with respect to the evolutionary forces at play and emphasize the utility of evolutionary theory to inform drug development.