Molnupiravir in Combination With Nirmatrelvir/Ritonavir: No Cause for Alarm

The rapid identification and clinical development of drugs to treat infection with SARS-CoV-2 are a notable success of the global response to the COVID-19 pandemic. To date, 3 small-molecule antiviral drugs have been approved or granted emergency use authorization by the US Food and Drug Administration for the treatment of COVID-19: remdesivir, nirmatrelvir (coadministered with ritonavir as a pharmacologic enhancer; NMV/r), and molnupiravir (MOV). Each drug interferes with replication of SARS-CoV-2 through a different mechanism of action: remdesivir inhibits the RNA-dependent RNA polymerase via chain termination; nirmatrelvir inhibits the viral 3C-like protease (3CLpro); and MOV, a prodrug of NHC (β-D-N4-hydroxycytidine), is a nonchain terminating cytosine analog, the incorporation of which leads to accumulation of mutations in viral RNA, eventually resulting in replication-defective virus through “error catastrophe” [1]. Although MOV showed only a modest (31%) decrease in the rate of hospitalization or death when compared with placebo in a randomized phase 3 trial conducted in outpatients with symptomatic COVID-19 [2], MOV remains an important option for certain patients because it is orally bioavailable and has no significant drug-drug interactions.

Efforts to improve the clinical benefit of MOV and prevent the reported clinical and/or virologic relapse following treatment with NMV/r [3] have prompted exploration of the combined administration of MOV plus NMV/r. A study in rhesus macaques experimentally infected with the Delta variant of SARS-CoV-2 found that the combination of MOV and NMV/r reduced disease severity as compared with control animals who received the vehicle control [4]. The combined therapy also resulted in significantly lower total lung virus load and reduced lung pathology at necropsy on day 4 postinfection as compared with the vehicle control and MOV-only groups [4].

A concern regarding the use of MOV in combination with NMV/r is the potential for an increased risk of emergent NMV-resistant mutants. At first glance, this concern runs counter to the paradigm that use of antiviral drugs in combination decreases the risk of emerging drug resistance (eg, treatment of HIV with dolutegravir plus lamivudine vs monotherapy with either agent). The mutagenic action of NHC, however, theoretically could generate mutations in 3CLpro that confer NMV resistance. These mutants could in turn be selected by NMV, paradoxically increasing the risk of NMV resistance when this combination is administered.

Zhou et al address this concern in an elegant analysis published in this issue of The Journal of Infectious Diseases [5]. They employed multiplexed Primer ID next-generation sequencing to determine the mutation profiles of SARS-CoV-2 in lung samples obtained at necropsy from macaques in each of the 4 aforementioned groups from the study. This approach allowed the authors to generate single-genome data for 3 regions of the SARS-CoV-2 genome: nsp5 (which encodes 3CLpro), a portion of nsp12 (which encodes RNA-dependent RNA polymerase), and the portion of the S gene that encodes the receptor-binding domain.

The authors found a significantly higher rate of nucleotide substitutions in SARS-CoV-2 RNA from the MOV-treated group as compared with the other groups [5]. Although the MOV + NMV/r group had a higher substitution rate than the NMV/r or vehicle group, it was lower than the MOV group. Moreover, the overall increase in the mutation rate did not result in any mutation hot spots in nsp5. Most important, although treatment with MOV did result in the emergence of the 3CLpro mutations T21L, L50F, A173V, and P252L, which are associated with reduced susceptibility to NMV in vitro [6], there was no apparent selection of these mutations in the combination therapy group [5].

These results are reassuring in terms of the potential for MOV to increase the risk of emergent resistance to SARS-CoV-2 protease inhibitors. The lower substitution rate observed in virus from macaques in the combination arm vs the MOV monotherapy arm may have limited the opportunity for resistance to emerge. The authors note appropriately that their study does not address the question of whether, in cases of persistent SARS-CoV-2 infection, initial treatment with MOV might reduce the efficacy of subsequent treatment with NMV/r due to the increased presence of NMV/r resistance mutations.

Whether treatment of COVID-19 with a combination of NMV/r plus MOV improves clinical outcomes remains to be proven. The study in nonhuman primates on which the current analysis is based was too small to find statistically significant differences between the combination and monotherapy arms [4]. Nevertheless, the results of that study with the encouraging data from the analysis by Zhou et al [5] provide a rationale for proceeding with human clinical trials of this combination in appropriate patient populations.

Notes

Financial support. This work was supported in part by a grant from the National Institute of Allergy and Infectious Diseases (UM1 AI069412).

References

Author notes