Low frequency of resistance to Tamiflu confirmed

May 10 2007

New data published by the World Health Organisation (WHO) has confirmed a low frequency of resistance to Tamiflu (oseltamivir) over 3 influenza seasons (2003:2006).

The information, published by the Neuraminidase Inhibitor Susceptibility Network in the WHO's Weekly Epidemiological Record, has shown that resistance of around 0.3% to oseltamivir was seen during the influenza seasons in which there had been substantial Tamiflu use in Japan (35 million patients), the highest use in any market. This level of resistance is extremely low compared to rates of 65% seen in Japan with another antiviral, amantadine2.

"These results confirm that the potential for the development of resistance to Tamiflu is very low, even when used extensively in the management of seasonal influenza," commented Dr. David Reddy, Pandemic Task Force Leader, Roche. "This provides reassurance to the scientific community that since the introduction of Tamiflu in 1999, the levels of resistance have remained similar to those seen in the clinical development programme. Roche and the NISN continue to maintain high vigilance to keep on top of the evolving virus. "

As with any antiviral medication, there is a theoretical risk that a virus may emerge with decreased sensitivity to a drug. The Neuraminidase Inhibitor Susceptibility Network undertook screening for susceptibility to oseltamivir of influenza viruses randomly submitted to the national WHO Collaborating Centre for Reference and Research on Influenza and other Respiratory Diseases in Tokyo, Japan. Influenza virus isolates collected were tested by neuraminidase inhibition assay (IC50 or sequence analysis) to detect mutations associated with drug-resistance.

Results were as follows:

Influenza Season in Japan No of Influenza A isolates tested Resistance No of Influenza B isolates tested Resistance

• 2003/2004 1180 3 (0.3%) 171 0
• 2004/2005 618 0 252 1(0.4%)
• 2005/2006 429 4 (0.9%) 163 0
• Total 2227 7 (0.32%) 586 1 (0.17%)

These preliminary findings indicate that a low frequency of oseltamivir resistance was present in community isolates during influenza seasons in which there had been substantial oseltamivir use in Japan. Low frequencies of oseltamivir resistance in influenza A viruses (<0.5%) were also detected in isolates collected through the WHO Global Influenza Surveillance Network during the first 3 years (1999-2002) after the introduction of the neuraminidase inhibitors into clinical use.

The possible development of anti-viral resistance is of concern for pandemic planning and preparedness. However, to date, there have only been three documented cases of Tamiflu resistance to avian influenza H5N1. 3,4 In one case, the prophylactic dose (75 mg daily) rather than the treatment dose (75 mg twice daily) was given to a patient already exhibiting clinical symptoms, thus under-dosing the patient and increasing the risk of resistance.3 Once the twice daily treatment dose was provided, the patient recovered from her illness. Again this resistant virus was shown to cause less severe infection and was less capable of transmission. In the other two cases, the recommended dose and duration of oseltamivir was followed.4 However, while one patient received treatment on the second day of illness, the other patient started treatment late, on the sixth day of illness. Two further possible cases of resistance of H5N1 to Tamiflu in Egypt have been identified and are currently under investigation.

Recently, the World Health Organization (WHO) reconfirmed the need for world governments to be vigilant in their plans to protect against a potential pandemic outbreak. WHO also reconfirmed that stockpiling antivirals - in particular oseltamivir- in advance is presently the only way to ensure that sufficient supplies are available in the event of a pandemic. Roche has been working closely with WHO and national governments to ensure governments are aware of the importance of stockpiling antivirals in the event of a pandemic situation. Roche has received and fulfilled pandemic orders for Tamiflu from more than 80 countries worldwide. The magnitude of these orders varies with some countries, France, Finland, Iceland, Ireland, Luxembourg, Netherlands, New Zealand, Norway, Switzerland and UK stockpiling or intending to stockpile adequate quantities of Tamiflu to cover 20-40% of their population. Roche has also donated 5.125 million courses of Tamiflu treatment to the WHO for international rapid response and regional response to a pandemic influenza strain.

Influenza, commonly called the flu, is a serious disease and annual outbreaks and epidemics are caused by influenza A and B viruses. Influenza is a highly contagious viral illness and is characterised by a sudden onset of debilitating clinical symptoms which affect the entire body. Up to 500 million people are infected by influenza and up to 500,000 deaths are attributed to influenza each year. Influenza complications occur in all patient groups and include bronchitis, sinusitis, otitis media, and pneumonia.

Tamiflu is designed to be active against all clinically relevant influenza viruses and works by blocking the action of the neuraminidase (NA) enzyme on the surface of the virus. When neuraminidase is inhibited, the virus is not able to spread to and infect other cells in the body.

It is licensed for the treatment and prophylaxis of influenza in children aged one year and above and in adults.