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Testing For H1N1 Suspended In Many Areas: Is Tamiflu Resistance Being Underreported?

Strain-specific testing for 2009 H1N1 influenza (swine flu) has been suspended in many areas due to the high prevalence of this pandemic strain in the human population.

Public health officials report that widespread confirmatory testing is superfluous and not cost-effective: Testing can be omitted, they say, in the majority of patients who present with flu-like symptoms because 2009 H1N1 is now the most common bug around.

Unfortunately, influenza is a very adaptable virus—some would call it “sloppy,” due to the promiscuous and random nature of its genetic acquisitions. It freely shares information with other viruses that cohabit the same infected cell; its genome shifts, drifts, and recombines faster than virologists can keep up with it.

It is influenza’s propensity for rapid genetic transformation that makes vaccine development so difficult: An immunization that appeared to be a good viral match in midsummer is suddenly rendered ineffectual as new strains emerge in the fall.

Virology Basics: The Structure of Influenza A (H1N1)

Influenza A viruses all share a common structure:
  1. A viral envelope, composed of lipoproteins and glycoproteins (including the variable “H” and “N” antigens)
  2. A viral genome, consisting of eight single, highly-segmented RNA strands that contain the codes for eleven proteins needed for construction and function of a mature virus
Structure and Function Elegantly Combine
  • The manufacture of all viral proteins takes place in the hijacked nucleus of an infected cell
  • The segmented nature of influenza’s RNA allows for free exchange of entire genes between different viruses, as well as the frequent breaking and random recombining of genetic segments
  • Polymorphisms (“many forms”) exist within the population of influenza viruses; these may be due to differences in entire gene segments or to point mutations within a single gene
  • Most polymorphisms are the result of random mutation and confer no evolutionary benefit to the virus, but some allow the virus to survive and replicate more efficiently in certain environments (higher temperatures, different species, etc.)
  • Specific polymorphisms may derive survival benefits under certain environmental pressures (the development of bacterial resistance to antibiotics is a classic example of one polymorphism conferring an advantage over another due to a selective force that eliminates only the susceptible bacteria)

Emerging Tamiflu (Oseltamivir) Resistance in Novel H1N1

As of March 2009, analyses of viruses circulating in the United States revealed that 98% of the “garden-variety” flu (a different H1N1 strain) was resistant to Tamiflu, a drug commonly used to treat influenza. Scientists were puzzled by the near-universal resistance of influenza to Tamiflu, and public health experts who had stockpiled the drug in preparation for a pandemic of highly-lethal H5N1 (avian flu) were understandably concerned.

Further investigation revealed that the development of Tamiflu resistance was probably not due to the overuse of the drug, but arose instead as the result of a spontaneous mutation in the viral genome. More ominous, however, was the finding that the new mutation not only conferred resistance to oseltamivir; it seemed to increase the virus’ ability to infect people. (Dharan N, et al. Infections with oseltamivir-resistant influenza A (H1N1) virus in the United States. JAMA. 2009;301[10]:1034-41)

Enter 2009 H1N1…

On June 30, 2009, a case of Tamiflu-resistant influenza A/H1N1 (pandemic “swine flu”) was reported in Denmark.

On August 15 the World Health Organization reported Tamiflu-resistant cases in patients from Hunan, China and Singapore (where H5N1 remains endemic).

On August 22 the Centers for Disease Control and Prevention reported that six cases of Tamiflu-resistant 2009 influenza A/H1N1 had been detected in the United States.

Unfortunately, only about 1,000 samples had been tested for Tamiflu resistance in the U.S. Nearly 9,000 people with swine flu had already been hospitalized here by that time, and an untold number of infected individuals remained at home, effectively excluded from the database.

Henry Niman, PhD, of Recombinomics, Inc., reports an increasing detection rate for the H274Y polymorphism that confers Tamiflu resistance in 2009 pandemic flu. He agrees that this polymorphism—apparently the result of a random mutation—has been present in the viral genome for some time, and he summarizes reports of resistant cases in Seattle, California, Texas, and North Carolina.

In other words, all across America, drug-resistant strains of pandemic H1N1 influenza are emerging; due to limited surveillance, public health officials probably aren’t cognizant of the full breadth of the problem and there may be more surprises from this ever-changing organism that are flying just beneath the radar.

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