Our data showed that both ‘oseltamivir-resistant’ (H275Y) and ‘oseltamivir-susceptible’ seasonal A(H1N1) caused severe and fatal diseases among hospitalized adults. Failure to receive antiviral or an antiviral agent to which the virus was susceptible was associated with adverse clinical outcomes. It is important for clinicians to consider the issue of antiviral resistance while managing severe influenza infections. Real-time surveillance data are essential.
Our findings are consistent with the reports on ambulatory patients which showed that symptoms and complication rates of ‘oseltamivir-resistant’ and ‘oseltamivir-susceptible’ seasonal A(H1N1) influenza are generally comparable.2,7,10 We add that among hospitalized adults, the major clinical outcomes including length-of-stay, ICU admission, and mortality rates are also similar.11 Notably, we found that the ‘oseltamivir-resistant’ seasonal A(H1N1) virus had predominantly affected the older, compromised individuals, an observation consistently reported across geographic regions.2,7,11 The nasopharyngeal viral loads were also shown to be lower in such patients, although the difference was considered rather small (<1 ‘log’). These findings remain to be explained, as in cell culture and ferret models this recent H275Y mutant virus does not appear to have impaired replicative capacity and viral fitness.4,5 Whether host factors (e.g., innate/adaptive immunity) have played a role in naturally occurring human infections is uncertain. We were unable to analyze the impact of influenza vaccination because of incomplete data; however, the vaccination rate in our hospital cohort, and Hong Kong in general, had been shown to be very low (<20%).9,12 Importantly, our data indicated that the ‘oseltamivir-resistant’ strain is capable of causing severe and even fatal diseases, and in such patients, failure to receive an effective antiviral treatment may lead to adverse outcomes.9,13 In Hong Kong, zanamivir- or amantadine-containing regimen for the ‘oseltamivir-resistant’ strain was not being considered regularly until late January 2009, when widespread circulation of the virus had already occurred; before the A/H1N1pdm09 pandemic, only about half of the hospitalized influenza patients were treated with antivirals. We acknowledge that our study is limited by a small sample size, but our data do provide support to the use of a susceptible antiviral regimen to treat severe influenza and highlight the importance of real-time surveillance data on antiviral resistance to assist patient care. Managing severe influenza in the context of oseltamivir-resistance is challenging because: (i) resistance testing result is usually not available at time of treatment initiation and most rapid diagnostic assays do not even differentiate H1 and H3 subtypes; (ii) there are pharmacologic limitations with inhalational zanamivir (e.g., lack of systemic availability); (iii) adamantane susceptibility is variable across H1N1 virus clades, its resistance barrier is low and efficacy uncertain; and (iv) there may be cross-resistance to other neuraminidase inhibitors (e.g., with peramivir).14 As such, continuous surveillance and timely recommendations to clinicians, development of newer tools for rapid detection of antiviral resistance, and clinical trials on newer antiviral agents including the use of combination therapies are urgently required to prepare for the possible emergence and sustained transmission of this and other drug-resistant influenza virus (e.g. oseltamivir-resistant A(H1N1)pdm09 virus which is currently resistant to adamantanes).15,16