Emergence of oseltamivir-resistant influenza A/H3N2 virus with altered hemagglutination pattern in a hematopoietic stem cell transplant recipient

Background: Persistent influenza virus replication during antiviral therapy in patients undergoing hematopoietic stem cell transplantation (HSCT) could promote the emergence of antiviral drug resistance. Objectives: To follow the viral genotypic and drug susceptibility changes in a patient who developed progressive influenza A/H3N2 pneumonia despite oseltamivir therapy after haploidentical HSCT. Study design: Direct genotypic analysis of the neuraminidase (NA) and hemagglutinin (HA) genes in successive bronchoalveolar lavage specimens was employed in combination with hemagglutination and NA enzymatic activity assays of the corresponding viral isolates. Results: The emergence of NA oseltamivir-resistance mutation R292K was detected by 12 days of oseltamivir treatment with 44,286-fold increase in oseltamivir IC₅₀. Resurgence of wild type viral population was identified by 7 days after cessation of oseltamivir. Sequential HA mutations R228S and A138S were identified and associated with a shift in the HA receptor binding pattern reflected by loss of the ability to agglutinate chicken erythrocytes. Conclusions: These rapid evolutionary changes warrant close virologic monitoring of immunocompromised patients treated for influenza infection, and raise concern about the efficacy of mono-drug therapy for influenza-associated disease in HSCT recipients.