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BMJ. 2013 May 30;346:f3039. doi: 10.1136/bmj.f3039.

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.

Collaborators (148)

Sedyaningsih ER, Malik MS, Setiawaty V, Trihono T, Burhan E, Aditama TY, Soepandi PZ, Partakusuma LG, Sutiyoso AP, Priatni I, Bandung RS, Jusuf H, Pranggono EH, Soeroto AY, Setiabudi D, Somasetia DH, Sudarwati S, Maskoen TT, Hartantri Y, Parwati I, Giriputro S, Murniati D, Sirait SM, Soetanto T, Sulastri S, Agus R, Rusli A, Wiweka S, Wignall S, Baird K, Safika I, Sangsajja C, Manosuthi W, Sutha P, Chuchottaworn C, Sansayunh P, Bangpattanasiri K, Taylor WR, Stepniewska K, Fukuda C, Lindegardh N, White N, Day N, Chotpitayasunondh T, Suntarattiwong P, Chantbuddhiwet U, Netsawang S, Chokephaibulkit K, Vanprapar N, Prasitsuebsai W, Wittawatmongkol O, Anekthananon T, Ratanasuwan W, Rongrungruang Y, Puthavathana P, Tambyah PA, Leo YS, Fisher D, Chai L, Lee L, Lin R, Minh NN, Khanh TH, Thoa le PK, Tuan le A, Thi TM, Ha LT, Qui le M, Thinh le Q, Anh NN, Tuan TA, Nhien TH, Phuong BP, Qui PT, Thy TC, Vu BX, Tinh le BB, Thanh DT, Khanh VP, Viet do C, Thuy TT, Bao VQ, Trung le NN, Thoa HT, Anh TT, Loan TT, Huong TQ, Le NT, Viet HL, Tuan HM, Ha NV, Truong NT, Thao le TT, Phong NT, Hien PT, Men PT, Tam CT, Diet TV, Qui PT, Van Hao N, Van Kinh N, Hien ND, Ha NH, Van Tuyet H, Phuc NN, Thai NQ, Chinh LQ, Cap NT, Phu VD, Ninh TT, Trung NV, Liem NT, Huy BV, San LT, Phuc PH, Tuan HA, Tung CV, Thanh DT, Ngoc le X, Hung PV, Hung DV, Hien PT, Beigel J, Polis M, Higgs E, Ngan TT, Tham Nt, Tam DT, BKrong NT, Uyen le TT, Hang Vt, Thanh TT, Bryant JE, Ha do Q, Hien VM, Nguyet LA, Nhu le NT, Khuong HD, Stockwell E, Merson L, Farrar JJ, Hayden F, Hien TT, Fox A, de Jong MD, Horby P, Wertheim HL, van Doorn HR.

Abstract

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.

PMID:
23723457
PMCID:
PMC3668094
[Indexed for MEDLINE]
Free PMC Article
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