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{\pard\sa900\fs50\f0\i Media Release\par}
{\pard\f0\li0\ri0\sa360\sl360\fs22 Basel, 22 December 2005\line \line {\b Statement 
- In response to paper 
by de Jong et al., published in the NEJM, 22 December 2005} \line \line {\b Oseltamivir 
and Resistance in the New England Journal of Medicine (NEJM)} \par}{\pard\f0\li440\ri0\sl360\fs22 - rapid 
and consistent drop in virus level confirmed in surviving patients\par}{\pard\f0\li440\ri0\sl360\fs22 - two 
cases 
of resistance in patients with regular treatment regimen reported\par}{\pard\f0\li440\ri0\sl360\fs22 - further 
evaluation 
needed on higher dosage, longer treatment and combination therapies\par}{\pard\f0\li440\ri0\sl360\fs22 - NEJM 
confirms importance 
of Tamiflu as a treatment option and that stockpiling should be part of pandemic-preparedness plans\par}{\pard\f0\li440\ri0\sl360\fs22 - Maximal 
benefit achieved with earliest treatment \u8211? rapid access to Tamiflu highly beneficial both for 
seasonal influenza and also for pandemic influenza\par}\line {\pard\f0\li0\ri0\sa360\sl360\fs22 The 
results of the NEJM paper show that all patients infected with the current circulating strain of the 
H5N1 virus who received treatment with Tamiflu and survived had a rapid and consistent drop in viral 
load (amount of virus circulating in the body) upon initiation of treatment, demonstrating a link between 
a decrease in viral load and survival.{\super {\pard\f0\li0\ri0\sa360\sl360\fs18 1\par}}  
Tamiflu was shown to be active against the H5N1 virus in these 
cases, as demonstrated by the dramatic impact of the drug on patients\u8217? virus levels. \line \line Two 
patients described in the NEJM paper developed resistance to the current H5N1 virus, following treatment 
with the approved seasonal dose and duration of treatment with Tamiflu, and subsequently died from their 
condition.{\super {\pard\f0\li0\ri0\sa360\sl360\fs18 1\par}}  Resistance mutations of the 
H5N1 virus were detectable in these patients at the end 
of treatment with Tamiflu,{\super {\pard\f0\li0\ri0\sa360\sl360\fs18 1\par}}  though the 
viral mutation isolated in those patients is known to be less 
infective and less transmissible than the wild type virus when present in other subtypes of influenza 
viruses.{\super {\pard\f0\li0\ri0\sa360\sl360\fs18 1\par}}  \line \line The 
paper suggests that the use of higher doses of Tamiflu, 
longer durations of therapy or combination therapies may be needed for the treatment of patients infected 
with the H5N1 virus.{\super {\pard\f0\li0\ri0\sa360\sl360\fs18 1\par}}  \line \line One 
of the contributing authors to the NEJM paper, 
Professor Peiris, Chief of Virology, Department of Microbiology, Queen Mary hospital, Hong Kong, stated: 
\u8220?Oseltamivir is an important part of our defenses against avian flu H5N1. However, no single drug is 
likely to be the panacea for all our problems in this regard. We are confronting a new disease and we 
are still learning how to use our therapeutic and preventive options, including oseltamivir, to best 
effect.\u8221?\line \line The current circulating H5N1 virus is extremely virulent, meaning 
it very rapidly induces a severe infection in humans, which results in deaths in an extremely high proportion 
of those infected. Any emerging pandemic strain may be different to the current H5N1 virus, as the H5N1 
strain will need to acquire the ability to transmit from humans to humans to become a human pandemic 
strain and experts believe it may be less virulent in this form. \line \line Tamiflu 
is designed to be active against all clinically relevant influenza viruses, including the H5N1 virus, 
and has been shown to be effective against the H5N1 virus in the laboratory, in animals infected with 
the H5N1 strain taken from humans{\super {\pard\f0\li0\ri0\sa360\sl360\fs18 2\par}}  The 
potential exists for an influenza virus to emerge with 
decreased sensitivity to any antiviral treatment, and Roche has both internal and external mechanisms 
in place to monitor for emerging reports of resistance. The vast majority of data, collected from thousands 
of patients worldwide who were treated with Tamiflu (oseltamivir phosphate) for seasonal influenza, 
indicate that incidence of resistant viruses is rare.{\super {\pard\f0\li0\ri0\sa360\sl360\fs18 3,4,5\par}} \line \line Since 
human clinical trials have not yet been conducted with the H5N1 avian flu strain, case reports such 
as those cited in the NEJM article are helpful in the ongoing study of this severe disease and viral 
resistance. Roche agrees that other treatment regimens for the H5N1 virus need to be explored, including 
higher dose and/or longer duration of treatment with Tamiflu, or a combination of antiviral agents. 
Safety data exists to support the use of a higher dose of Tamiflu. To this end, Roche is collaborating 
with the National Institutes of Health (NIH) and the World Health Organisation (WHO), who are undertaking 
clinical research to assess the efficacy of a higher dose of Tamiflu in the treatment of severe influenza 
including the H5N1 virus. \line \line {\b Implications for pandemic stockpiling} \line According 
to the Neuraminidase Inhibitor Susceptibility Network (NISN), the clinical and epidemiological implications 
of possible antiviral resistance in future pandemic influenza viruses are incompletely understood. However, 
neuraminidase inhibitors such as Tamiflu should be effective for both prevention and treatment for such 
viruses, and concerns about antiviral resistance, particularly to NA inhibitors, should not dissuade 
countries from developing adequate antiviral stockpiles for pandemic response.{\super {\pard\f0\li0\ri0\sa360\sl360\fs18 6\par}}  
\line \line The 
currently approved dose and duration of Tamiflu therefore remains the minimum required for the treatment 
of pandemic influenza. However when a pandemic strain emerges, it will be vital to test the susceptibility 
of the pandemic strain to Tamiflu to determine the optimal dose and duration for treatment. Roche will 
continue to work with external experts to find the best solution in the fight against a potential pandemic, 
to ascertain the optimal dose and duration of Tamiflu for the treatment of a pandemic influenza strain 
and to explore potential combinations with additional therapies for the treatment of the severe H5N1 
virus.\line \line {\b Notes to Editors} \line The clinical 
features of H5N1 
illness in humans are variable, with fever, shortness of breath, gastroenteritis, and pulmonary complications. 
The H5N1 virus has been detected in lung, blood, cerebro-spinal fluid and faeces indicating systemic 
infection.{\super {\pard\f0\li0\ri0\sa360\sl360\fs18 7\par}}  There have been 138 cases 
of avian influenza reported to date.{\super {\pard\f0\li0\ri0\sa360\sl360\fs18 8\par}}  
Of these, 71 patients 
have died.{\super {\pard\f0\li0\ri0\sa360\sl360\fs18 8\par}}  \line \line There 
are documented cases of good responses to Tamiflu 
as well as cases where the drug has not saved patients. In nearly all of these cases, patients were 
administered Tamiflu too late, making it difficult to assess whether the current approved dose and duration 
of treatment with Tamiflu is effective in treating the H5N1 strain. The frequency of resistance emergence 
during Tamiflu treatment of the H5N1 virus has not been determined, as little sampling has been performed 
in the patients infected to date. \line \line Experts underscore that antiviral 
stockpiles should be considered one of a number of measures of national pandemic preparedness consistent 
with the national priorities of each country.\line \line \line {\pard\f0\li0\ri0\sa360\sl360\fs18 References\line 1 
\u160?De Jong, 
Thanh TT, Khanh TH et al. Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection. NEJM, 
2005: 353;25-30\line 2 \u160?Ives, J. et al. The H274Y mutation in the influenza A/H1N1 neuraminidase 
active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro 
and in vivo. Antiviral Research 2002: 55; 307-317\line 3 \u160?Yen et al.Virulence May Determine 
the Necessary Duration and Dosage of Oseltamivir Treatment for Highly Pathogenic A/Vietnam/1203/04 Influenza 
Virus in Mice. JID 2005:192 (15 August): 665-672\line 4 \u160?Roberts, N.: Treatment of influenza 
with neuraminidase inhibitors virological implications. Philos. Trans. R. Soc. Lond B. Biol. Sci. (2001) 
356: 1895-1897\line 5 \u160?Kiso, M. et al. Resistant influenza viruses in children treated 
with 
oseltamivir descriptive study. Lancet (2004) 364; 759-765\line 6 \u160?Oxford, J. Oseltamivir 
in 
the management of influenza. Expert Opin. Pharmacother. (2005) 6(14), 2493-500\line 7 \u160?NISN 
Statement on antiviral resistance in influenza viruses. Weekly Epidemiological Record (2004); 33, 308-308\line 8 
 
Beigel et al. Avian Influenza (H5N1) Infection in Humans. NEJM, 2005: 353; 1374-85\line 9 
\u160?http://www.who.int/csr/disease/avian_influenza/country/en/\par}\par}
{\pard \par}
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{\pard\sb180\f1\fs22 Corporate Communications\line Roche Group Media Relations \par}
{\pard\sb180\f1\fs22 Tel. +41 61 688 88 88\line Fax +41 61 688 27 75\line www.roche.com \par}
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