Treatment-Emergent Influenza Virus Polymerase Acidic Substitutions Independent of Those at I38 Associated With Reduced Baloxavir Susceptibility and Virus Rebound in Trials of Baloxavir Marboxil. (7th April 2020)

• Record Type: Journal Article
• Authors: Ince, William L; Smith, Fraser B; O'Rear, Julian J; Thomson, Michael
• Is Part Of: Journal of infectious diseases. Volume 222:Number 6(2020)
• Page Start: 957
• Page End: 961
• Publication Date: 2020-04-07
• Subjects: antiviral -- baloxavir marboxil -- influenza virus -- resistance; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jiaa164
• Languages: English
• ISSNs: 0022-1899

Abstract

Abstract: Influenza viruses harboring treatment-emergent I38F/M/N/T substitutions in the polymerase acidic (PA) endonuclease exhibited reduced susceptibility to baloxavir and were associated with virus rebound and variable clinical response in clinical trials. US regulatory review of registrational trial data also identified treatment-emergent PA substitutions E23K in A/H1N1 viruses and E23G/K, A37T, and E199G in A/H3N2 viruses, which conferred reduced susceptibility to baloxavir, although to a lesser degree than I38F/M/N/T substitutions, and were associated with virus rebound. Although these non-I38 substitutions emerged less frequently than substitutions at I38, they represent alternate pathways to baloxavir virologic resistance and should be monitored accordingly. Abstract : In clinical trials of baloxavir marboxil, treatment-emergent PA substitutions E23G/K, A37T, and E199G conferred reduced susceptibility to baloxavir and were associated with virus rebound. These non-I38 substitutions represent alternate pathways to baloxavir virologic resistance.