By Stan Deresinski, MD, FACP, FIDSA
Clinical Professor of Medicine, Stanford University
SYNOPSIS: Prevalent SARS-CoV-2 variants are persistently resistant to therapeutic and prophylactic monoclonal antibodies but remain susceptible to nirmatrelvir/ritonavir, remdesivir, and molnupiravir.
SOURCES: Imai M, Ito M, Kiso M, et al. Efficacy of antiviral agents against omicron subvariants BQ.1.1 and XBB. N Engl J Med 2023;388:89-91.
Takashita E, Yamayoshi S, Halfmann P, et al. In vitro efficacy of antiviral agents against omicron subvariant BA.4.6. N Engl J Med 2022;387:2094-2097.
Takashita et al examined the susceptibility of two omicron BA.4.6 isolates to available antiviral drugs and monoclonal antibodies using a live-virus 50% focus reduction neutralization test (FRNT). The isolates were susceptible to bebtelovimab and imdevimab, but they were resistant to other monoclonal antibodies: casirivimab, sotrovimab, and tixagevimab and cilgavimab (the last are the two components of Evusheld). The isolates retained susceptibility to remdesivir, nirmatrelvir, and molnupiravir.
Imai et al used the same assay to evaluate susceptibility of two additional variants — BQ.1.1 and XBB — and found them to be resistant to imdevimab/casirivimab (REGEN-COV), tixagevimab/cilgavimab (Evusheld), sotrovimab, and bebtelovimab. However, they were susceptible to remdesivir, molnupiravir, and nirmatrelvir.
COMMENTARY
The success of SARS-CoV-2 omicron variants has been remarkable. BA.4.6, BQ.1.1, and XBB all carry several mutations affecting the spike protein, which has been the target of monoclonal antibodies used for therapy and for prophylaxis. One mutation common to all three is R346T, which can be used as a marker for potential resistance to current commercial monoclonals.
Recognition of increasing prevalence of resistant subvariants has led to the removal of the only therapeutic monoclonal, bebtelovimab, from the market. The most recent National Institutes of Health guideline (updated Dec. 28, 2022) acknowledges the increasing prevalence of resistance to Evusheld in all regions of the United States, but it goes on to indicate that in the absence of an alternative option for pre-exposure prophylaxis, they continue to recommend its use in eligible individuals. They further state the decision to administer Evusheld “should be based on the regional prevalence of the resistant subvariants,1 the individual patient’s risks, the available resources, and logistics.”2 At the Stanford laboratory, the prevalence of virus with the resistance-associated R346T mutation has reached 54%, and we had already discontinued the use of Evusheld in anticipation of a proportion exceeding 50%.
Thus, we now have no effective monoclonal antibodies for either therapy or pre-exposure prophylaxis. Fortunately, the available therapeutic small molecules, remdesivir, nirmatrelvir (marketed together with ritonavir as Paxlovid), and molnupiravir retain in vitro activity.
REFERENCES
1. Centers for Disease Control and Prevention. COVID data tracker. Monitoring variant proportions.
2. National Institutes of Health. COVID-19 treatment guidelines. Antiviral agents, including antibody products. Last updated Dec. 28, 2022.
Prevalent SARS-CoV-2 variants are persistently resistant to therapeutic and prophylactic monoclonal antibodies but remain susceptible to nirmatrelvir/ritonavir, remdesivir, and molnupiravir.
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