Basel, March 3 2008

Reports of increased survival in bird flu patients taking Tamiflu

Physicians from countries worst-affected by the deadly bird flu (H5N1 influenza virus) have reported an increased survival rate in patients treated with the oral antiviral Tamiflu (oseltamivir).  These data reinforce the World Health Organization (WHO) advisory that Tamiflu is the only antiviral strongly recommended for the treatment of humans infected with the H5N1 virus.  The physicians’ report was revealed this week at the International Symposium on Respiratory Viral Infections (ISRVI) in Singapore.¹

According to the WHO the H5N1 virus has already killed 234 people in 12 countries.² Tamiflu is the only antiviral reported to have been used against H5N1 in humans outside the laboratory and actually in the field.

In Indonesia, of the total of 119 H5N1 human cases reported, 22 survived - an 18 percent survival rate overall. Of these, 33 patients received no Tamiflu, all of whom died. Tamiflu was administered to 86 patients with a 26 percent survival rate overall. Time from onset of illness to initiation of treatment appeared to influence survival. Of the 2 patients who received Tamiflu within 24 hours of illness onset both survived. 55 percent survived if given the drug within four days (6/11), and 35 percent survived if given Tamiflu within six days (13/37)³. The survival rate of those receiving it later than 6 days after illness onset was 18 percent (9/49)² Recent information on 8 Vietnamese patients infected with H5N1, was also presented. All 8 patients received Tamiflu. However, all 8 patients presented to the hospital later than 5 days after onset of illness. Only 3 of the 8 patients survived reinforcing that treatment benefit is reduced for patients that receive the drug later in the course of illness.^3,4In 2 patients who were unable to take the drug orally due to the severity of their illness physicians administered the drug by nasogatric tube and found it was well absorbed and there was a reduction in H5N1 virus in these patients.

Susceptibility of circulating H5N1 strains to Tamiflu
These clinical findings are supported by new animal data, also presented at ISRVI, which shows that oseltamivir treatment was effective against H5N1 influenza viruses representing different clades/subclades.  However higher doses were required for the more pathogenic H5N1 viruses.⁵

“Multiple factors can affect the susceptibility of antiviral therapy with highly pathogenic H5N1 influenza viruses and it is reassuring that oseltamivir, in mouse models, demonstrates activity even  to the most pathogenic circulating strains,” comments study author Dr. Elena Govorkova, St. Jude Children’s Research Hospital, Memphis, US. “Antiviral drugs are an essential component for the early control of an influenza pandemic.”

Data also confirms the low level of resistance reported to date with Tamiflu to H5N1 avian influenza in the field; there are only five cases of published reports of H5N1 resistance or reduced susceptibility to Tamiflu to date.^6,7,8 Laboratory results have shown 96 percent of H5N1 strains (53 out of 55) tested in the laboratory were sensitive to Tamiflu.⁹

This compares to the around 14 percent  of isolates tested this year of the seasonal influenza A H1N1 virus showing resistance to Tamiflu, reported at the conference.¹⁰ It is important to note that these increased levels of resistance have only been reported spontaneously in this year’s H1N1 (Solomon Islands) seasonal strain, and not an avian strain such as H5N1 and not in patients who have been administered Tamiflu.¹¹

“Currently, we are seeing that Tamiflu has been used as part of the clinical management of patients infected with H5N1 with only isolated cases of resistance being reported,” comments Dr David Reddy, Global Pandemic Task Force Leader at Roche. “This is reassuring for governments that have stockpiled Tamiflu for pandemic use. It is however critical that both Roche and the medical community remain vigilant so that we can understand this mutating virus and be best prepared for defence against a potential pandemic strain.”

Roche has undertaken several research initiatives to study the use of Tamiflu against the evolving H5N1 avian influenza virus, including collaborations with the National Institutes of Health (NIH), the Southeast Asia Influenza Clinical Trials Research Network and other research institutions.

Note to editors:
Difference between a pandemic strain of influenza and seasonal influenza
A pandemic strain of influenza is always of the A variety and is a completely new strain to which there will be no immunity whereas a seasonal strain of influenza is one that has previously been circulating, which may have changed slightly (antigenic drift) and to which a level of immunity exists.

About pandemic influenza
An influenza pandemic occurs when a new strain of influenza A virus appears, against which the human population has no immunity resulting in several, simultaneous epidemics worldwide with enormous numbers of deaths and illness. The most severe influenza pandemics to date include: ‘Spanish flu’ A (H1N1): 1918 caused in excess of 30 million deaths worldwide, ‘Asian flu’ A (H2N2): 1958 caused 1 million deaths worldwide, ‘Hong Kong flu’ A (H3N2): 1968 caused 800,000 deaths worldwide in six weeks. The WHO believes that we are as close to the next pandemic as we have been any time in the past 37 years, with two of the three widely-recognised prerequisites for a human pandemic met to date in the avian influenza outbreak in East Asia. Firstly, a new influenza virus strain has emerged (H5N1), and secondly, the virus has spread to humans. The final barrier will be the transmission of the virus from human to human.

About Tamiflu
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 spread of the virus to other cells in the body is inhibited. It is licensed for the treatment and prophylaxis of influenza in children aged one year and above and in adults. The most frequently reported adverse events in clinical studies were nausea, vomiting, and diarrhea. Tamiflu is available for the treatment of influenza in more than 80 countries worldwide.  
Tamiflu was approved based on studies in seasonal influenza.  The magnitude of effect of Tamiflu in treating and preventing novel strains of influenza (such as those that may be involved in a pandemic or associated with avian flu) cannot be predicted. The WHO has recommended that higher doses and longer duration may be required

Roche and Gilead
Tamiflu was invented by Gilead Sciences and licensed to Roche in 1996. Roche and Gilead partnered on clinical development, with Roche leading efforts to produce, register and bring the product to the markets. Under the terms of the companies’ agreement, amended in November 2005, Gilead participates with Roche in the consideration of sub-licenses for the pandemic supply of Tamiflu in resource-limited countries. To ensure broader access to Tamiflu for all patients in need, Gilead has agreed to waive its right to full royalty payments for product sold under these sub-licenses.

About Roche
Headquartered in Basel, Switzerland, Roche is one of the world’s leading research-focused healthcare groups in the fields of pharmaceuticals and diagnostics. As the world’s biggest biotech company and an innovator of products and services for the early detection, prevention, diagnosis and treatment of diseases, the Group contributes on a broad range of fronts to improving people’s health and quality of life. Roche is the world leader in in-vitro diagnostics and drugs for cancer and transplantation, a market leader in virology and active in other major therapeutic areas such as autoimmune diseases, inflammation, metabolism and central nervous system.

Additional information
- Roche Health Kiosk, Influenza
- About Tamiflu
- About influenza
- WHO: Global influenza programme
- WHO: Avian flu

References
1) Antivirals and therapeutics session, X International symposium on Respiratory Viral infections, Singapore, Sunday 2nd March 2008
2) World Health Organization. Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO. 28 February 2008
http://www.who.int/csr/disease/avian_influenza/country/cases_table_2008_02_28/en/index.html   
3) Sedyaningsih ER. The Indonesian Experience, X International symposium on Respiratory Viral infections, Singapore, Sunday 2nd March 2008
4) Wertheim HFI. The recent Vietnamese Experience, X International symposium on Respiratory Viral infections, Singapore, Sunday 2nd March 2008
5) Govorkova E. Influenza Antivirals in H5N1 Disease, Animal Model, X International symposium on Respiratory Viral infections, Singapore, Sunday 2nd March 2008
6) Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus. Update on Avian Influenza A (H5N1) Virus Infection in Humans. N Engl J Med 358;3
7) de Jong MD, Thanh TT, Khanh TH, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med 2005;353:2667-72
8) Saad MD, Boynton BR, Earhart KC, et al. Detection of oseltamivir resistance mutation N294S in humans with influenza A H5N1. In: Program and abstracts of the Options for the Control of Influenza Conference, Toronto, June 17–23, 2007:228. abstract.
9) Hurt AC. et al. Susceptibility of highly pathogenic (H5N1) avian influenza viruses to the neuraminidase inhibitors and adamantanes. Antiviral Research 73  (2007) 228-231
10) World Health Organization. Influenza A (H1N1) virus resistance to oseltamivir - Last quarter 2007 to 28 February 2008. 28 February 2008.
http://www.who.int/csr/disease/influenza/H1N1ResistanceWeb20080228.pdf
11) World Health Organization. WHO/ECDC frequently asked questions for Oseltamivir Resistance. Last updated 15 February 2008.