To the Editor: De Jong et al. (Dec. 22 issue)1 report resistanceto oseltamivir in two of three recent deaths from influenzaA (H5N1) virus infection and recommend investigation into newantiviral drugs for use either alone or in combination withoseltamivir. Zanamivir is another licensed neuraminidase inhibitor.Studies with nebulized and intravenous preparations suggestthat zanamivir has good safety and efficacy, even in patientswith underlying respiratory disease.2,3,4 The H274Y mutationthat confers resistance to oseltamivir inpatients with H5N1infection does not confer cross-resistance to zanamivir, a phenomenonattributable to differences in binding properties.5 A treatmentregimen combining these two neuraminidase inhibitors would beexpected to reduce the opportunity for the selection of resistantmutants, in a manner akin to the use of dual nucleoside analoguesin 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
References
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. [Free Full Text]
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. [Medline]
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. [Free Full Text]
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. [Free Full Text]
Moscona A. Oseltamivir resistance -- disabling our influenza defenses. N Engl J Med 2005;353:2633-2636. [Free Full Text]
The authors reply: Zanamivir is an attractive antiviral drugfor combined treatment of influenza A (H5N1) because of nonoverlappingresistance patterns in this drug and oseltamivir. However, thelicensed preparation of zanamivir may be less appealing sinceit is administered by inhalation, which provides drugs predominantlyto the upper respiratory tract. Since human infection with currentstrains of influenza H5N1 can be associated with disseminatedinfection and replication in the lower respiratory tract andextrapulmonary sites,1,2,3 combined treatment with nebulizedzanamivir and oral oseltamivir would be likely to result inmonotherapy in the lower respiratory tract and nonrespiratorysites. Although it would be important to evaluate the effectsof combined treatment with zanamivir in influenza H5N1, theroute 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{at}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
References
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. [Free Full Text]
Uiprasertkul M, Puthavathana P, Sangsiriwut K, et al. Influenza A H5N1 replication sites in humans. Emerg Infect Dis 2005;11:1036-1041. [ISI][Medline]
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. [Free Full Text]
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