Treatment of influenza with neuraminidase inhibitors: virological implications
1Roche Products Ltd, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AY, UK. noel.roberts@roche.com
Abstract:
Evaluation of the emergence of influenza virus resistance to neuraminidase inhibitors (NAIs) is now demanded following experience with amantadinamines. Preliminary data have indicated that NAI-resistant virus is unlikely to emerge readily in the clinic and this is consistent with the difficulty experienced in selecting resistant virus in vitro. Resistance mutations can occur in both neuraminidase and haemagglutinin genes. The neuraminidase mutations are viral subtype specific and, therefore, clinically relevant subtypes must be employed for in vitro studies if pre-clinical data are to have predictive value. Haemagglutinin mutations generated in vitro are probably both subtype and cell culture system specific and, therefore, may not be predictive of clinical findings. Analysis of influenza-positive samples from NAI-treated patients in the clinical setting must include samples from late treatment time-points (day 4 and later) in order for resistant virus to be detected as in vitro studies and current clinical experience have indicated that resistant virus is slow to emerge and is transient.
Insights
Emergence of influenza virus resistance to neuraminidase inhibitors (NAIs) is unlikely to occur rapidly in clinics. Studies show NAI-resistant influenza strains are slow to emerge and transient, even in vitro.
Area of Science:
- Virology
- Antimicrobial Resistance
Background:
- Influenza virus resistance to antiviral drugs, like amantadine, necessitates evaluating resistance to neuraminidase inhibitors (NAIs).
- Preliminary data suggest NAI-resistant influenza emergence is difficult both in vitro and clinically.
Purpose of the Study:
- To assess the likelihood and characteristics of influenza virus resistance to neuraminidase inhibitors (NAIs).
- To determine the predictive value of in vitro studies for clinical NAI resistance.
- To identify optimal sampling times for detecting NAI-resistant influenza in patients.
Main Methods:
- In vitro selection of resistant influenza virus strains.
- Analysis of resistance mutations in neuraminidase and haemagglutinin genes.
- Examination of clinical samples from NAI-treated patients.
Main Results:
- NAI-resistant influenza virus is difficult to select in vitro.
- Resistance mutations can arise in neuraminidase (subtype-specific) and haemagglutinin (potentially system-specific) genes.
- Late-stage clinical samples (day 4+) are crucial for detecting slow-emerging, transient NAI resistance.
Conclusions:
- Clinically relevant influenza subtypes are essential for predictive in vitro NAI resistance studies.
- In vitro haemagglutinin mutations may not accurately predict clinical resistance.
- Detecting NAI-resistant influenza requires analysis of late-treatment clinical samples due to slow and transient emergence.
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