Viruses Resistant to Oseltamivir or Baloxavir: What Do the Data Reveal About Resistance?

Three classes of antiviral drugs are approved for the treatment or prophylaxis of influenza: the M2 inhibitors (amantadine and rimantadine), the neuraminidase inhibitors (oseltamivir, peramivir, zanamivir, and laninamivir), and the polymerase inhibitors (favipiravir and baloxavir). These antiviral drugs are fully effective against drug-susceptible viruses but work less well or not at all against drug-resistant viruses. The clinical significance of antiviral drug-resistant viruses is influenced by many factors including their frequency of emergence, genetic stability, pathogenicity, transmissibility, and replication fitness. The emergence and global spread of M2 inhibitor-resistant viruses and oseltamivir-resistant viruses occurred in the early 2000s. Recently, human-to-human transmission of baloxavir-resistant viruses has been observed. These resistant viruses are genetically stable, show similar or higher pathogenicity, transmissibility, and replication fitness compared with their susceptible counterparts, and exhibit highly reduced antiviral susceptibility. The clinical efficacy of oseltamivir and baloxavir is limited in patients infected with these resistant viruses compared with those infected with wild-type viruses, indicating that antiviral-resistant viruses can lead to clinical resistance to antiviral drugs.