A summary of amino acid substitutions in the influenza polymerase acidic (PA) protein that have been associated with reduced susceptibility to baloxavir is given in the following table. 

The amino acid substitution I38T in the PA protein is considered clinically relevant due to its frequency of occurrence and the availability of clinical data suggesting reduced treatment efficacy. Other substitutions at residue 38 (e.g., I38M), as well as substitutions at other conserved residues in PA, have been observed less frequently following exposure to baloxavir. Their clinical significance is not clear at this time. PA substitutions affecting baloxavir susceptibility have rarely been found in viruses not exposed to this drug. It is best to screen for PA substitutions associated with reduced baloxavir susceptibility by sequencing the full-length PA gene using Sanger or Next Generation Sequencing (NGS, deep sequencing). Viruses carrying any PA substitutions listed should be forwarded to one of the WHO Collaborating Centres for Reference and Research on Influenza (WHO CC) for further analysis, including phenotypic testing.

The approximate fold increases in baloxavir EC50 (equating to reductions in susceptibility) of PA-substituted viruses relative to wild-type viruses or (sub)type specific median EC50 are given in the table. Published data are derived from various cell culture-based assays (e.g., plaque reduction). The approximate fold increases in EC50 serve as a guide only.