Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: Double blind randomised controlled trial

Endang Rahayu Sedyaningsih, Moh Suhud Malik, Vivi Setiawaty, Trihono Trihono, Erlina Burhan, Tjandra Yoga Aditama, Prijanti Z. Soepandi, Lia G. Partakusuma, Agung P. Sutiyoso, Ika Priatni, Hadi Jusuf, Emmy Hermiyanti Pranggono, Arto Yuwono Soeroto, Djatnika Setiabudi, Dadang Hudaya Somasetia, Sri Sudarwati, Tini T. Maskoen, Yovita Hartantri, Ida Parwati, Sardikin GiriputroDewi Murniati, Sondang Maryutka Sirait, Tony Soetanto, Sri Sulastri, Rismali Agus, Adria Rusli, Sila Wiweka, Steve Wignall, Kevin Baird, Iko Safika, Chariya Sangsajja, Weerawat Manosuthi, Patama Sutha, Chareon Chuchottaworn, Piamlarp Sansayunh, Kittima Bangpattanasiri, Walter R.J. Taylor, Kasia Stepniewska, Caroline Fukuda, Niklas Lindegardh, Nicholas White, Nick Day, Tawee Chotpitayasunondh, Piyarat Suntarattiwong, Umaporn Chantbuddhiwet, Supichaya Netsawang, Kulkanya Chokephaibulkit, Nirun Vanprapar, Wasana Prasitsuebsai, Orasri Wittawatmongkol, Thanomsak Anekthananon, Winai Ratanasuwan, Yong Rongrungruang, Pilaipan Puthavathana, Paul A. Tambyah, Yee Sin Leo, Dale Fisher, Louis Chai, Lawrence Lee, Raymond Lin, Ngo Ngoc Quang Minh, Truong Huu Khanh, Le Phan Kim Thoa, Le Anh Tuan, Tran Thi My Dung, Lam Thi Thuy Ha, Le Minh Qui, Le Quoc Thinh, Nguyen Ngoc Tu Anh, Tran Anh Tuan, Trinh Hong Nhien, Bui Pham Phuong, Phan Tu Qui, Tieu Chau Thy, Bui Xuan Vu, Le Binh Bao Tinh, Dang Thi Thanh, Vo Phuong Khanh, Do Chau Viet, Tran Thi Thuy, Vo Quoc Bao, Le Nguyen Nhat Trung, Ho Thi Kim Thoa, Tran Thi Ngoc Anh, Tran Thi Thu Loan, Tran Quynh Huong, Nguyen Thi Hanh Le, Ho Lu Viet, Ha Manh Tuan, Nguyen Thi Thanh Ha, Nguyen Van Vinh Chau, Nguyen Thanh Truong, Le Thi Thu Thao, Nguyen Thanh Phong, Pham Tran Dieu Hien, Pham Thi Hai Men, Cao Thi Tam, Tran Vinh Diet, Nguyen Van Hao, Nguyen Van Kinh, Nguyen Duc Hien, Nguyen Hong Ha, Hoang Van Tuyet, Nguyen Ngoc Phuc, Nguyen Quoc Thai, Luong Quoc Chinh, Nguyen Trung Cap, Vu Dinh Phu, Tran Thi Hai Ninh, Nguyen Vu Trung, Nguyen Thanh Liem, Bui Vu Huy, Luong Thi San, Phan Huu Phuc, Ho Anh Tuan, Cao Viet Tung, Doan Thi Mai Thanh, Le Xuan Ngoc, Pham Viet Hung, Dau Viet Hung, Pham Thu Hien, John Beigel, Michael Polis, Elizabeth Higgs, Nghiem My Ngoc, Tran Thuy Ngan, Nguyen Thi Tham, Duong Thi Tam, Nguyen Thi Thuy Chinh BKrong, Le Thi Tam Uyen, Vu Thi Ty Hang, Tran Tan Thanh, Juliet E. Bryant, Do Quang Ha, Vo Minh Hien, Lam An Nguyet, Le Nguyen Truc Nhu, Huynh Duy Khuong, Elaine Stockwell, Laura Merson, Jeremy J. Farrar, Frederick Hayden, Tran Tinh Hien, Annette Fox, Menno D. De Jong, Peter Horby, Heiman L. Wertheim, H. Rogier Van Doorn

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Objective: To investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza. Design: Double blind randomised trial. Setting: Thirteen hospitals in Indonesia, Singapore, Thailand, and Vietnam. Participants: Patients aged ≥1 year admitted to hospital with confirmed severe influenza. Interventions: Oral oseltamivir at double dose (150 mg twice a day/paediatric equivalent) versus standard dose (75 mg twice a day/paediatric equivalent). Main outcome measure: Viral status according to reverse transcriptase polymerase chain reaction (RT-PCR) for influenza RNA in nasal and throat swabs on day five. Results: Of 326 patients (including 246 (75.5%) children aged <15), 165 and 161 were randomised to double or standard dose oseltamivir, respectively. Of these, 260 (79.8%) were infected with influenza virus A (133 (40.8%) with A/H3N2, 72 (22.1%) with A/H1N1-pdm09, 38 (11.7%) with seasonal A/H1N1, 17 (5.2%) with A/H5N1) and 53 (16.2%) with influenza virus B. A further 3.9% (13) were false positive by rapid antigen test (negative by RT-PCR and no rise in convalescent haemagglutination inhibition titers). Similar proportions of patients were negative for RT-PCR on day five of treatment: 115/159 (72.3%, 95% confidence interval 64.9% to 78.7%) double dose recipients versus 105/154 (68.2%, 60.5% to 75.0%) standard dose recipients; difference 4.2% (-5.9 to 14.2); P=0.42. No differences were found in clearance of virus in subgroup analyses by virus type/subtype, age, and duration of illness before randomisation. Mortality was similar: 12/165 (7.3%, 4.2% to 12.3%) in double dose recipients versus 9/161 (5.6%, 3.0% to 10.3%) in standard dose recipients. No differences were found between double and standard dose arms in median days on supplemental oxygen (3 (interquartile range 2-5) v 3.5 (2-7)), in intensive care (4.5 (3-6) v 5 (2-11), and on mechanical ventilation (2.5 (1-16) v 8 (1-16)), respectively. No important differences in tolerability were found. Conclusions: There were no virological or clinical advantages with double dose oseltamivir compared with standard dose in patients with severe influenza admitted to hospital. Registration: Clinical Trials NCT00298233.

Original languageEnglish
Article numberf3039
JournalBMJ (Online)
Issue number7911
Publication statusPublished - 8 Jun 2013


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