Sunday, May 26, 2013

The Taiwan H7N9 Patient & Antiviral Resistance


Photo Credit – Wikipedia




# 7322


The good news - that Taiwan’s first and only H7N9 patient was released from the hospital earlier this week - is tempered somewhat by reports that his viral infection proved at least partially resistant to our first line antiviral drug; oseltamivir.


Two reports.  First this one from a week ago, before he was released.


H7N9 case has drug- and non-resistant strains

Sunday, May 19, 2013
The China Post/Asia News Network

TAIPEI, Taiwan - The only H7N9 patient so far in Taiwan was carrying two strains of the same virus, with one being drug resistant and the other not, making it tricky to treat to him, doctors said.


Huang Li-min, a doctor from National Taiwan University Hospital (NTUH), explained that it was possible the avian flu virus was not drug resistant when the patient was first infected, but mutated later to become resistant to Tamiflu.

(Continue . . . )


And this one today, where Taiwan media is reporting:


Drug-resistant H7N9 strains to change treatment: researcher

2013/05/26 17:46:26

Taipei, May 26 (CNA) The discovery that some H7N9 bird flu virus strains have developed drug resistance will affect the strategies for dealing with future cases, a researcher said Saturday.


Some H7N9 strains found in a Taiwanese businessmen who became the first and only confirmed case outside China in late April after returning from there, were resistant to Tamiflu, a drug used to prevent and treat flu, said Shih Shin-ru, director of Chang Gung University's Research Center for Emerging Viral Infections.

(continue . . . )



We’ll have to await the publication of this researcher’s results to learn the whole story, but for now it appears that this patient’s recovery was delayed because his infection did not respond satisfactorily to Tamiflu.


While it is possible this patient was infected by an already resistant strain, It is not uncommon for a small percentage of patients who are treated with antivirals to spontaneously generate resistant strains of the virus. 


Essentially, when the drug inhibits the replication of susceptible strains – any viable resistant mutations that arise are given an opportunity to proliferate.


A good example of this phenomenon is described in an October, 2010 EID Journal article called:


Emergence of Oseltamivir-Resistant Pandemic (H1N1) 2009 Virus within 48 Hours

Masafumi Inoue, Timothy Barkham, Yee-Sin Leo, Kwai-Peng Chan, Angela Chow, Christopher W. Wong, Raphael Tze-Chuen Lee, Sebastian Maurer-Stroh, Raymond Lin, and Cui Lin


An oseltamivir-resistant influenza A pandemic (H1N1) 2009 virus evolved and emerged from zero to 52% of detectable virus within 48 hours of a patient’s exposure to oseltamivir. Phylogenetic analysis and data gathered by pyrosequencing and cloning directly on clinical samples suggest that the mutant emerged de novo.


While this can be bad news for the patient, most of these spontaneous mutations have been poorly transmissible, meaning they haven’t been able to spread widely in the community.


The CDC, in their H7N9 FAQ has this to say about antiviral treatment options for this emerging virus.


Are there medicines to treat illness associated with this virus?

CDC recommends oseltamivir (Tamiflu®) and zanamivir (Relenza®) for treatment of H7N9. Most of the H7N9 viruses that have been studied are likely susceptible (sensitive) to the two influenza antiviral drugs that are used to treat seasonal flu. Those drugs are oseltamivir (Tamiflu®) and zanamivir (Relenza®) (neuraminidase inhibitors). Like seasonal influenza viruses, avian A(H7N9) viruses are resistant to the influenza antiviral drugs known as the adamantanes.


It’s important to note that influenza viruses may acquire genetic changes which can make one or more influenza antiviral drugs less effective. This happens with seasonal influenza viruses and could happen with H7N9 viruses found in China. As new H7N9 virus isolates are received, CDC will conduct ongoing testing to determine the susceptibility of other H7N9 viruses to existing antiviral drugs. More information about antiviral resistance is available at Influenza Antiviral Drug Resistance: Questions & Answers.



Of course, we have seen flu strains develop antiviral resistance and - over time - manage to spread widely. 


By 2006 we had only seen a small number of oseltamivir (Tamiflu ®) resistant seasonal H1N1 cases, and they were almost always attributed to `spontaneous mutations’ within a patient receiving the drug. 


During the 2006-2007 flu season, laboratories reported no resistant strains in Europe or Japan, and they were found in fewer than 1% of samples from the United States.


This resistance was caused by a mutation called H275Y, where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at the neuraminidase position 275.


(Note: some scientists use 'N2 numbering' (H274Y) and some use 'N1 numbering' (H275Y))


The following year, during the 2007-2008 flu season, oseltamivir resistant viruses suddenly took off, and by the spring of 2008 roughly 25% of European samples tested showed the H275Y mutation (see Increased Tamiflu Resistance In Seasonal Influenza).   


By the end of the year, resistant seasonal H1N1 has become dominant around the world.


And had the old seasonal H1N1 virus not been replaced by the pandemic H1N1 virus in the spring of 2009 – which was (and still is) overwhelmingly sensitive to oseltamivir – our pharmacological options for treating seasonal flu today would be greatly impaired.


Since 2009 we’ve seen sporadic cases of antiviral resistance show up in the new H1N1 virus, but only rarely (see NEJM: Oseltamivir Resistant H1N1 in Australia) have we seen clusters that suggest limited community spread.


But we know that pharmacological victories over viruses and bacteria have always been fleeting at best.


Pathogens – given enough time – have demonstrated a keen ability to evade each new generation of drugs we throw at them. 


A reminder that in our ongoing battle against infectious diseases, that nature always bats last.

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