Table 1. Treatment-emergent and other amino acid substitutions in the polymerase acidic protein associated with reduced baloxavir susceptibility in vitro^a.

PA amino acid substitution	EC50 fold changeb
	A(H3N2)	A(H1N1)pdm09c	B	References
E23G	NA	4–5	ND	[3], [4], current study
E23K	6	5	< 3	[3], [4], [5], [7]
E23R	ND	NA	ND	[3]
A36Vd	6	4	< 3	[5]
A37T	8	ND	ND	[3], [4], [5]
I38F	20	11	< 3	[3], [4], [5], [7]
I38M	14	13	8	[3], [4], [5], [14]
	10	ND	ND	current study
I38T	49–57	27	6	[3], [8], [4], [5] [7], [10]
I38L	­ND	8	ND	current study
E119De	5	6	< 3	[5]
E199G	5	ND	ND	[3], [5]

NA: data not available; ND: not detected or tested; PA: polymerase acidic.

^a The Expert Working Group on Antiviral Susceptibility for the World Health Organization Global Influenza Surveillance and Response System has not yet issued guidance regarding a threshold (fold change) for reporting phenotypic test results for baloxavir. Arbitrary threshold (˃ three-fold EC₅₀) was used to list PA amino acid substitutions that confer reduced susceptibility to baloxavir.

^b Fold change calculated by comparing EC₅₀ of test virus to the reference value (e.g. control virus).

^c Reverse genetically engineered Influenza A(H1N1) viruses, A/WSN/33 and A/Puerto Rico/8/34 were also tested.

^d F36V in PA of influenza B virus.

^e E120D in PA of influenza B virus.