Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: the special case of molnupiravir

Abstract

This review considers antiviral nucleoside analog (NA) drugs, including ribavirin, favipiravir, and molnupiravir, which induce genome error catastrophe in SARS‐CoV or SARS‐CoV‐2 via lethal mutagenesis as a mode of action. In vitro data indicate that molnupiravir may be 100 times more potent as an antiviral agent than ribavirin or favipiravir. Molnupiravir has recently demonstrated efficacy in a phase 3 clinical trial. Because of its anticipated global use, its relative potency, and the reported in vitro “host” cell mutagenicity of its active principle, β‐d‐N4‐hydroxycytidine, we have reviewed the development of molnupiravir and its genotoxicity safety evaluation, as well as the genotoxicity profiles of three congeners, that is, ribavirin, favipiravir, and 5‐(2‐chloroethyl)‐2′‐deoxyuridine. We consider the potential genetic risks of molnupiravir on the basis of all available information and focus on the need for additional human genotoxicity data and follow‐up in patients treated with molnupiravir and similar drugs. Such human data are especially relevant for antiviral NAs that have the potential of permanently modifying the genomes of treated patients and/or causing human teratogenicity or embryotoxicity. We conclude that the results of preclinical genotoxicity studies and phase 1 human clinical safety, tolerability, and pharmacokinetics are critical components of drug safety assessments and sentinels of unanticipated adverse health effects. We provide our rationale for performing more thorough genotoxicity testing prior to and within phase 1 clinical trials, including human PIG‐A and error corrected next generation sequencing (duplex sequencing) studies in DNA and mitochondrial DNA of patients treated with antiviral NAs that induce genome error catastrophe via lethal mutagenesis.

DNA damage in peripheral blood lymphocytes of severely ill COVID-19 patients in relation to inflammatory markers and parameters of hemostasis

“…This is in line with the available literature data about genotoxic effects of certain medications like erythromycin and/or lincomycin [ 55 ], metronidazole and dimetridazole [ 56 ], and glucocorticoid receptor agonists [ 57 ]. Likewice, our results correspond to previously conducted studies related to genotoxic potential of oral anticoagulant [ 58 ] and antiviral [ 59 ] therapy. The last one indicated that the antiviral nucleoside analog drugs could induce genome error catastrophe in SARS-CoV-2 via lethal mutagenesis.…”

First-generation oral antivirals against SARS-CoV-2

“…Finally, pharmacovigilance for new antivirals is of upmost importance to address long-term safety concerns. The antiviral mechanism of molnupiravir is lethal mutagenesis; therefore, the mutagenic potential in human cells must be carefully monitored [ [26] , [27] , [28] ]. In their assessment report on molnupiravir, the European Medicines Agency concluded that lack of genotoxic potential cannot be definitively excluded, although the genotoxic risk could be considered justifiable in the context of the clinical benefit [ 29 ].…”

Molnupiravir Does Not Induce Mutagenesis in Host Lung Cells during SARS-CoV-2 Treatment

“… 10 Nevertheless, the conclusion that “MOV is not considered to pose an increased risk of genotoxicity in clinical use” 10 has been questioned by other researchers owing to lack of details on protocol used and assay sensitivity. 24 , 25 While NHC (MOV’s active metabolite) showed positive mutagenesis in Zhou et al 5 in vitro HPRT genotoxicity assay, the cells were cultured in the presence of NHC for 32 days in contrast to the typical 5 days of MOV treatment in animal studies 2 and clinical trials. 12 , 13 , 26 Interestingly, cells exposed to 1 minute of UV light showed higher (~1.3-fold to ~4.4-fold) inferred mutation effect compared to NHC’s highest effect in the HPRT genotoxicity assay.…”