14 October 2008

South Africa reports frequent resistance to oseltamivir (Tamiflu) in Influenza A Viruses (H1N1) this winter, similar to Europe last winter

In the upcoming November 2008 issue of the Emerging Infectious Diseases journal posted on the US CDC website (www.cdc.gov) a paper is posted for early publication this month by Besselaar and colleagues from South Africa, and collaborators in the UK, titled “Widespread Oseltamivir Resistance in Influenza A viruses (H1N1), South Africa.

This paper is important because it demonstrates that the southern hemisphere is now seeing the same oseltamivir (Tamiflu) antiviral drug resistance in H1N1 influenza A viruses as was initially reported to variable degrees in European nations beginning last January (2008) in Norway.

So far, this oseltamivir resistance phenomenon remains unexplained, and is almost entirely seen in persons who have NOT taken the drug oseltamivir (Tamiflu). So far, this antiviral resistance to the only oral neuraminidase drug (oseltamivir, Tamiflu) is NOT being seen with H3N1 or H5N1 influenza A viruses.

This winter in South Africa saw the major influenza virus in circulation to be H1N1. Virus isolates were obtained from outpatients in South Africa by throat or nasopharyngeal swab between May and July (winter influenza season in this part of the southern hemisphere).

23/23 (100%) influenza A H1N1 virus isolates from May and June were tested in WHO Influenza Reference Labs in London and Melbourne and found to be “highly resistant to oseltamivir by the NA inhibition enzyme assay, with 50% inhibitory concentration values of 554nM to 1,485 nM”.

45/45 (100%) additional influenza A H1N1 virus isolates from July 2008 were tested by PCR in the National Institute for Communicable Diseases (NICD) in Sandringham, South Africa. They were also found to be resistant to oseltamivir at the 274 mutation site. Sequence analysis confirmed the H274Y mutation that confers oseltamivir resistance and established that the N1gene sequences were closely related to those in Europe at the beginning of 2008.

The authors reasoned that oseltamivir resistant H1N1 viruses had likely spread from Europe to South Africa, and then spread readily within the country. They conclude by noting that such drug-resistant viruses may appear soon in other nations in the southern hemisphere, and that influenza A H3N2 viruses remain susceptible to oseltamivir.

The mechanism whereby such drug-resistant influenza A (H1N1) viruses have developed, and acquired the ability to be transmitted efficiently and in a sustained manner from person-to-person, is important to define. Exposure to oseltamivir has been reported in only a very small fraction of patients with these oseltamivir-resistant viruses.

This resistance issue was mentioned briefly by Dr. Keiji Fukuda in the October 2, 2008 WHO virtual press conference on seasonal flu in the northern hemisphere posted on the WHO influenza website.

Understanding the mechanism of resistance is essential, in part to try to prevent such oseltamivir resistance from developing on the part of other influenza viruses such as influenza A (H3N2) and avian influenza A (H5N1).

In the majority of cases, the only oral anti-influenza drug that avian influenza A (H5N1) is susceptible to is oseltamivir. Hence, it is the primary anti-influenza drug stockpiled by WHO, USA, and multiple other nations for potential use if the H5N1 avian influenza virus changes such that it acquires the ability to spread in a sustained and efficient manner from person-to-person-to person.

Daniel R. Lucey, MD, MPH

EROne Institutes Washington Hospital Center

Adjunct Professor of Microbiology and immunology

Georgetown University Medical Center

Washington D.C.

Website for this posting: www.BePast.org

e-mail: DRL23@Georgetown.edu