Correspondence

Oseltamivir Resistance in Influenza A (H5N1) Infection

N Engl J Med 2006; 354:1423-1424March 30, 2006

Article

To the Editor:

De Jong et al. (Dec. 22 issue)1 report resistance to oseltamivir in two of three recent deaths from influenza A (H5N1) virus infection and recommend investigation into new antiviral drugs for use either alone or in combination with oseltamivir. Zanamivir is another licensed neuraminidase inhibitor. Studies with nebulized and intravenous preparations suggest that zanamivir has good safety and efficacy, even in patients with underlying respiratory disease.2-4 The H274Y mutation that confers resistance to oseltamivir inpatients with H5N1 infection does not confer cross-resistance to zanamivir, a phenomenon attributable to differences in binding properties.5 A treatment regimen combining these two neuraminidase inhibitors would be expected to reduce the opportunity for the selection of resistant mutants, in a manner akin to the use of dual nucleoside analogues in antiretroviral therapy.

Ravindra K. Gupta, M.P.H., M.R.C.P.
Jonathan S. Nguyen-Van-Tam, M.B.E., D.M.
Health Protection Agency, London NW9 5HT, United Kingdom

5 References

1. 1

   de Jong MD, Thanh TT, Khanh TH, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med 2005;353:2667-2672
   Full Text | Web of Science | Medline

2. 2

   Ison MG, Gnann JW Jr, Nagy-Agren S, et al. Safety and efficacy of nebulized zanamivir in hospitalized patients with serious influenza. Antivir Ther 2003;8:183-190
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   Hayden FG, Osterhaus AD, Treanor JJ, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections. N Engl J Med 1997;337:874-880
   Full Text | Web of Science | Medline

4. 4

   Calfee DP, Peng AW, Cass LM, Lobo M, Hayden FG. Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection. Antimicrob Agents Chemother 1999;43:1616-1620
   Web of Science | Medline

5. 5

   Moscona A. Oseltamivir resistance -- disabling our influenza defenses. N Engl J Med 2005;353:2633-2636
   Full Text | Web of Science | Medline

Author/Editor Response

Zanamivir is an attractive antiviral drug for combined treatment of influenza A (H5N1) because of nonoverlapping resistance patterns in this drug and oseltamivir. However, the licensed preparation of zanamivir may be less appealing since it is administered by inhalation, which provides drugs predominantly to the upper respiratory tract. Since human infection with current strains of influenza H5N1 can be associated with disseminated infection and replication in the lower respiratory tract and extrapulmonary sites,1-3 combined treatment with nebulized zanamivir and oral oseltamivir would be likely to result in monotherapy in the lower respiratory tract and nonrespiratory sites. Although it would be important to evaluate the effects of combined treatment with zanamivir in influenza H5N1, the route of administration will need to be carefully considered.

Menno D. de Jong, M.D., Ph.D.
Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam
mddejong@hcm.vnn.vn

Tran Tinh Hien, M.D., Ph.D.
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam

Jeremy Farrar, D.Phil., F.R.C.P.
Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam

3 References

1. 1

   de Jong MD, Van Cam B, Qui PT, et al. Fatal avian influenza A (H5N1) in a child presenting with diarrhea followed by coma. N Engl J Med 2005;352:686-691
   Full Text | Web of Science | Medline

2. 2

   Uiprasertkul M, Puthavathana P, Sangsiriwut K, et al. Influenza A H5N1 replication sites in humans. Emerg Infect Dis 2005;11:1036-1041
   Web of Science | Medline

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   The Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5. Avian influenza A (H5N1) infection in humans. N Engl J Med 2005;353:1374-1385
   Full Text | Web of Science | Medline

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