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Media Release

Basel, 22 December 2005

Statement - In response to paper by de Jong et al., published in the NEJM, 22 December 2005

Oseltamivir and Resistance in the New England Journal of Medicine (NEJM)

  • rapid and consistent drop in virus level confirmed in surviving patients
  • two cases of resistance in patients with regular treatment regimen reported
  • further evaluation needed on higher dosage, longer treatment and combination therapies
  • NEJM confirms importance of Tamiflu as a treatment option and that stockpiling should be part of pandemic-preparedness plans
  • Maximal benefit achieved with earliest treatment – rapid access to Tamiflu highly beneficial both for seasonal influenza and also for pandemic influenza

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.

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Tamiflu was shown to be active against the H5N1 virus in these cases, as demonstrated by the dramatic impact of the drug on patients’ virus levels.

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.

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 Resistance mutations of the H5N1 virus were detectable in these patients at the end of treatment with Tamiflu,

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 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.

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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.

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One of the contributing authors to the NEJM paper, Professor Peiris, Chief of Virology, Department of Microbiology, Queen Mary hospital, Hong Kong, stated: “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.”

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.

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

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 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.

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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.

Implications for pandemic stockpiling
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.

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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.

Notes to Editors
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.

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 There have been 138 cases of avian influenza reported to date.

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 Of these, 71 patients have died.

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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.

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.


References
1  De Jong, Thanh TT, Khanh TH et al. Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection. NEJM, 2005: 353;25-30
2  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
3  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
4  Roberts, N.: Treatment of influenza with neuraminidase inhibitors virological implications. Philos. Trans. R. Soc. Lond B. Biol. Sci. (2001) 356: 1895-1897
5  Kiso, M. et al. Resistant influenza viruses in children treated with oseltamivir descriptive study. Lancet (2004) 364; 759-765
6  Oxford, J. Oseltamivir in the management of influenza. Expert Opin. Pharmacother. (2005) 6(14), 2493-500
7  NISN Statement on antiviral resistance in influenza viruses. Weekly Epidemiological Record (2004); 33, 308-308
8 Beigel et al. Avian Influenza (H5N1) Infection in Humans. NEJM, 2005: 353; 1374-85
9  http://www.who.int/csr/disease/avian_influenza/country/en/