Evolutionary safety of lethal mutagenesis driven by antiviral treatment

• Published in: PLoS biology Vol. 21; no. 8; p. e3002214
• Main Authors: Lobinska, Gabriela, Pilpel, Yitzhak, Nowak, Martin A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.08.2023; Public Library of Science (PLoS)
• Subjects: Adenosine; Antiviral agents; Antiviral Agents - adverse effects; Biology and Life Sciences; Coronaviruses; COVID-19; COVID-19 - genetics; COVID-19 vaccines; Drug resistance; Evolution; Genomes; Humans; Hydroxylamines; Immune clearance; Immune system; Immunology; Immunosuppressive agents; Infections; Load distribution; Mathematical analysis; Medicine and health sciences; Mutagenesis; Mutagenesis - genetics; Mutagens - toxicity; Mutants; Mutation; Mutation rates; Nucleoside analogs; Pandemics; Pathogens; RNA polymerase; Safety; Severe acute respiratory syndrome coronavirus 2; Viral diseases; Viruses; Viruses - genetics
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3002214

Nucleoside analogs are a major class of antiviral drugs. Some act by increasing the viral mutation rate causing lethal mutagenesis of the virus. Their mutagenic capacity, however, may lead to an evolutionary safety concern. We define evolutionary safety as a probabilistic assurance that the treatment will not generate an increased number of mutants. We develop a mathematical framework to estimate the total mutant load produced with and without mutagenic treatment. We predict rates of appearance of such virus mutants as a function of the timing of treatment and the immune competence of patients, employing realistic assumptions about the vulnerability of the viral genome and its potential to generate viable mutants. We focus on the case study of Molnupiravir, which is an FDA-approved treatment against Coronavirus Disease-2019 (COVID-19). We estimate that Molnupiravir is narrowly evolutionarily safe, subject to the current estimate of parameters. Evolutionary safety can be improved by restricting treatment with this drug to individuals with a low immunological clearance rate and, in future, by designing treatments that lead to a greater increase in mutation rate. We report a simple mathematical rule to determine the fold increase in mutation rate required to obtain evolutionary safety that is also applicable to other pathogen-treatment combinations.