# 8354
Last January, we looked at a Eurosurveillance journal reports (see Community Cluster Of Antiviral Resistant pH1N1 in Japan) that detailed a recent (between November and December 2013) cluster of resistant pH1N1 (with the H275Y mutation) in Sapporo, Japan. Six genetically similar viruses were detected, although none of the patients had known contact with each other, which suggests a resistant strain may be starting to spread in that region.
The most common cause of Neuraminidase Inhibitor (NAI) antiviral drugs (like oseltamivir aka Tamiflu ®) is the H275Y mutation - where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at the neuraminidase position 275 (Note: some scientists use 'N2 numbering' (H274Y)).
Up until 2006 we only saw a smattering of oseltamivir resistant seasonal H1N1 cases, almost always attributed to `spontaneous mutations’ within a patient already receiving the drug. While of concern to the patient being treated, it appeared to be poorly transmissible, and less than 1% of cases exhibited resistance.
But in 2008 the profile of antiviral resistant seasonal flu changed, and by the spring roughly 25% of European samples tested showed the H275Y mutation (see Increased Tamiflu Resistance In Seasonal Influenza).
By the end of 2008, nearly all of the samples tested in the United States were resistant to oseltamivir and the CDC was forced to issue major new guidance for the use of antivirals (see CIDRAP article With H1N1 resistance, CDC changes advice on flu drugs).
One benefit of the arrival of the H1N1 pandemic strain the following spring was that it effectively removed this resistant strain from circulation. Despite some scattered clusters of resistance reported in Asia and Australia (see NEJM: Oseltamivir Resistant H1N1 in Australia), nearly 99% of the pH1N1 viruses tested around the globe have remained sensitive to NA inhibiting drugs.
The latest FluView report (week 8) indicated that of 3733 viruses tested this flu season in the United States, only 28 (0.8%) showed signs of NA Inhibitor resistance.
Today, Hong Kong’s CHP has a report in their Communicable Diseases Watch (CDW) that indicates a slightly higher (but still < 2%) incidence rate of Oseltamivir resistance detected over the past several years, but reassuring finds that the overwhelming majority of viruses tested still remain sensitive to the drug, and reports no signs of community transmission.
Human Infections with Oseltamivir-resistant Influenza A(H1N1)pdm09 Virus in Hong Kong
Reported by Dr Henry YH Mou, Medical and Health Officer, Respiratory Disease Office, Surveillance and
Epidemiology Branch, CHP.
(EXCERPT)From May 2009 to February 2014, more than 2,700 influenza A(H1N1)pdm09 viruses were tested for oseltamivir resistance in Hong Kong. Among them, a total of 46 reports (<2% of tested samples) of oseltamivir-resistant influenza A(H1N1)pdm09 virus were detected. The cases affected 26 males and 20 females with a male to female ratio of 1.3:1. Their ages ranged from 5 months to 85 years (median: 16 years). Most of them (87%) were known to acquire the infection locally. No epidemiological linkage was identified among the cases. The annual number of cases detected ranged from 1 to 17 during the period between 2009 and 2013. The monthly number of cases ranged from 0 to 6.
Fifteen cases (33%) had known exposure to a full course of oseltamivir before the collection of specimens. Among the 44 cases with information available, 26 cases (59%) enjoyed good past health. The remaining 18 cases had one or more underlying medical conditions such as hypertension, diabetes, chronic lung diseases, malignant conditions, etc. There was one fatal case affecting a 52 years old female who had multiple chronic medical conditions including hypertension, diabetes and depression. It was also noted that five cases were known to have conditions that resulted in immunosuppressed or immunocompromised state. Viral replication may persist in such patients for prolonged periods of time despite antiviral treatment and this can create a favourable environment for selection of drug-resistant strain.
Molecular tests showed the presence of nucleotide mutation resulting in H275Y amino acid substitution in the neuraminidase protein (N1) of all the oseltamivir-resistant viruses isolated. All were found to be sensitive to another neuraminidase inhibitor zanamivir.
So far, the vast majority of influenza A(H1N1)pdm09 viruses tested in Hong Kong remained sensitive to oseltamivir. Cases of oseltamivir-resistant viruses were sporadic and infrequently found and there is no evidence of onward transmission of oseltamivir-resistant influenza A(H1N1)pdm09 viruses in Hong Kong. Zanamivir remains a treatment option in patients with severe or deteriorating illness caused by oseltamivir-resistant virus. The CHP will continue to monitor the global and local situation of oseltamivir-resistant influenza viruses and remain vigilant for any further changes in influenza viruses that may have public health significance.
While surveillance for antiviral resistance continues to be reassuring, scientists remember the remarkable speed by which seasonal influenza went from being almost 100% sensitive to being nearly 100% resistant.
So, as the report says, continued vigilance is required.
