Clinical Pearls & Morning Reports
Additional effective antiviral agents are needed for the treatment and prevention of influenza virus infections. Two classes of agents, M2 ion-channel inhibitors and neuraminidase inhibitors, are widely available. However, circulating influenza viruses are now largely resistant to M2 ion-channel inhibitors, and the emergence of antiviral resistance to neuraminidase inhibitors remains a threat. Hayden et al. recently reported the results of phase 2 and 3 randomized, controlled trials that evaluated single-dose baloxavir treatment in otherwise healthy persons with acute influenza. Read the latest NEJM Original Article here.
Q: What is baloxavir?
A: Baloxavir marboxil is the small molecule prodrug of the selective polymerase acidic protein (PA) inhibitor S-033447 that has shown nanomolar antiviral activity against influenza A and B viruses in vitro, including strains resistant to current antiviral agents. In murine models of seasonal influenza and avian influenza A(H5N1) or A(H7N9), orally administered baloxavir was associated with rapid reductions in pulmonary viral loads and decreased mortality. In an ascending single-dose study involving healthy volunteers, baloxavir was administered up to the highest dose tested (80 mg) without evident safety concerns, and it showed linear pharmacokinetic characteristics and a long plasma elimination half-life (range, 49 to 91 hours).
Q: Describe the influenza virus polymerase complex.
A: The influenza virus polymerase complex has received considerable attention as a target for developing antiviral agents. The polymerase heterotrimer is composed of three protein subunits (polymerase basic protein 1 [PB1], polymerase basic protein 2 [PB2], and polymerase acidic protein [PA]) that are highly conserved and essential for efficient viral replication. The PB2 subunit binds to the cap of host cellular pre–messenger RNA, which is subsequently cleaved by the cap-dependent endonuclease in the PA subunit. This “cap-snatching” process provides an RNA primer for transcription of viral messenger RNA by the RNA-dependent RNA polymerase function of PB1.
A: In the phase 3 trial by Hayden et al., the median time to alleviation of symptoms was shorter in the baloxavir group than in the placebo group in both the intention-to-treat infected population (53.7 hours vs. 80.2 hours, P<0.001) and intention-to-treat population (65.4 hours vs. 88.6 hours, P<0.001). More rapid alleviation of symptoms with baloxavir than with placebo was evident by day 2. A shorter time to alleviation of symptoms with baloxavir than with placebo was observed in both adolescents and adults. The median time to alleviation of symptoms was similar in the baloxavir group (53.5 hours) and the oseltamivir group (53.8 hours). Baloxavir was associated with significantly more rapid declines in infectious viral load than placebo or oseltamivir. It is unclear why the time to alleviation of symptoms was similar in the baloxavir group and the oseltamivir group even though baloxavir showed greater antiviral activity. Adverse events that were considered to be related to the trial regimen were more common in oseltamivir recipients (8.4%) than in baloxavir recipients (4.4%, P=0.009) or placebo recipients (3.9%).
A: All influenza-specific antiviral agents lead to the emergence of resistant variants. Specific amino acid substitutions in the active endonuclease site (I38T/F) reduce susceptibility to baloxavir by a factor of 11 to 57 for representative influenza A viruses in cell culture. In the trials by Hayden et al., the emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial, respectively.