1 University of Manitoba, Room 510730 William Avenue, Winnipeg, Canada; 2 Aldershot Health Centre, Aldershot; 6 Roche Global Development, Welwyn, UK; 3 Cardiothoracic Department, Cisanello Hospital, Pisa, Italy; 4 Dossenheim, Germany; 5 Euraxi, Saint Martin dHeres, France; 7 F. Hoffmann-La Roche, Basel, Switzerland
Received 4 January 2002; returned 30 April 2002; revised 3 July 2002; accepted 24 September 2002
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Abstract |
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Keywords: influenza, neuraminidase inhibitors, oseltamivir, treatment
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Introduction |
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There is a need for effective and well-tolerated treatments that can reduce the impact of influenza on the individual and society. Oseltamivir is the oral prodrug of oseltamivir carboxylate, a potent inhibitor of influenza A and B viral neuraminidase. Oseltamivir is well tolerated and effective for the treatment of acute influenza in previously healthy adults.5,6 In influenza-infected patients treated within 36 h of symptom onset, oseltamivir reduced the duration of clinical illness by 30% (P < 0.001), when compared with symptomatic treatment alone.5
The pathogenesis of influenza illness suggests that inhibiting viral replication as early as possible after infection will reduce the duration and intensity of symptoms. In the study of Nicholson et al.,6 patients starting oseltamivir within 24 h of symptom onset had a 37% reduction in illness duration compared with placebo. Studies with the inhaled influenza neuraminidase inhibitor zanamivir have also suggested the additional benefit of earlier treatment.7,8 These findings are consistent with increased treatment benefits that result from early antiviral treatment of other viral diseases.9,10
The IMPACT (IMmediate Possibility to ACcess oseltamivir Treatment) study investigated the relationship between the time to intervention and duration of illness as a primary endpoint, plus other parameters of illness, by treating with oral oseltamivir as early as possible after the onset of influenza symptoms.
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Materials and methods |
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Baseline and day 21 sera were assayed together by measurement of the haemagglutination-inhibition (HAI) antibody or complement fixation test (CFT) antibody. The following antigens were used for the majority of HAI assays: A/Bayern/7/95 (H1N1), A/Sydney/5/97 (H3N2), B/Yamanashi/66/98; the antigens used for CFTs were influenza A and B nucleocapsid.
Temperature and symptom scores were recorded twice daily and a health scale questionnaire was answered daily for 21 days after the start of the study.
The primary endpoint was duration of illness as a function of time to the first treatment dose, calculated from the time of onset of fever (defined as the earliest time that the patient either measured an elevated temperature or felt feverish) in the laboratory-confirmed, influenza virus-infected population. The duration of illness was defined as the time from symptom onset to alleviation of all symptoms. Duration of illness was measured from the onset of fever or when the patient felt feverish until all symptoms were scored as mild or absent and remained so for at least 24 h. Other endpoints included the severity of the influenza illness by measurement of area under the curve of total symptom scores, the times to resolution of fever (assessed as the time to return to an afebrile state, i.e. a temperature of 37.2°C), and return to baseline health and activity scores. Adverse events were recorded up to study day 21 (±4) and graded on a four-point scale (mild, moderate, severe, life threatening).
The study was conducted in accordance with the principles of the Declaration of Helsinki (amended) or with the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The protocols were approved by local or regional ethics committees prior to implementation and all participants gave written informed consent before enrolment.
Analysis of data
To determine the added value of early intervention, the relationship between time to treatment and illness duration from fever onset was analysed. The results were compared descriptively by time-to-treatment groups and also by accelerated failure time (AFT) modelling on the actual data collected.11 The LIFEREG procedure in SAS (version 6.12) was used to perform the AFT analysis, in a Unix environment. Estimates were produced on the natural log scale, but were back-transformed for presentation in all summary tables. The error structure was modelled using the log-normal distribution, and for all best fit models, normal probability plots of the residuals were produced and examined for indications of lack-of-fit.
The median times of illness duration from illness onset are also presented for time-to-treatment groups together with 95% confidence intervals.
KaplanMeier curves of the duration of illness data were constructed for each time-to-treatment group in order to estimate the median duration of illness and associated 95% confidence interval along with other summary statistics.
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Results |
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Discussion |
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This is the first report to describe the mathematical relationship between illness duration and time to effective antiviral intervention. The results based on the observed time-to-treatment group data and those produced by AFT modelling were highly comparable. The time-to-treatment group data consisted of results for all subjects recruited within specified mean 6 or 12 h windows, whereas AFT modelling permitted us to predict the effect of intervention at any time as well as the results of extrapolation to the limits of time studied. The observed effects and the values predicted by AFT modelling were somewhat different even though they were both derived from analysis of the study database.
The absence of a concurrent control group treated with placebo in this study might raise the question of whether the beneficial effects of early initiation of oseltamivir plus symptomatic therapy in persons with influenza illness were due to early initiation of symptomatic therapy alone. This is unlikely given the previous observation in persons with laboratory-confirmed influenza who were treated with the same symptomatic therapy plus placebo,6 in whom no difference was observed in the median duration of illness between those persons treated at <36 h and those in whom therapy was initiated within 24 h of illness onset.
The study confirmed that physicians can accurately diagnose influenza in patients reporting soon after fever onset by use of a clinical case definition and knowledge that influenza virus is circulating within the community. There were no major differences in the sensitivity of the clinical diagnosis between the treatment time windows, and the 67% infection rate was similar to that found in previous placebo-controlled treatment studies with oseltamivir.5,6 The study also confirmed that influenza presents with characteristic sudden identifiable and severe symptom onset,13 only 2/958 patients having presented with mild symptoms in this study. Education of potential volunteers about symptoms of influenza illness made possible self-referral for diagnosis and the implementation of antiviral therapy.
The proportion of individuals with influenza who receive some form of drug treatment is 59%. Antibiotics are the most frequently prescribed drugs (45%), followed by antipyretics/analgesics (22.5%).3 Antibiotics are likely to be prescribed to patients with influenza in all age groups.14,15 Inappropriate antibiotic treatment provides no medical benefit and increases the risk of antibacterial resistance.15 The results of this study confirm that oseltamivir therapy would be more logical than antibiotics for patients with uncomplicated influenza.
Translating the results of this study into clinical practice will be challenging, but, it is argued, clinically important. Strategies to do so must provide early diagnosis and access to oseltamivir therapy without markedly increasing the workload for practitioners in the influenza season. This study has demonstrated that early presentation is possible by public education of influenza symptom characteristics, as approximately two-thirds of those who were infected presented to their general practitioners within 24 h of symptom onset, and a quarter within 12 h. One solution may lie in application of the UK Department of Health guidelines to implement the NICE recommendations for another neuraminidase inhibitor drug, zanamivir.16 Telephone triage and walk-in centres for specific patient groups organized by practice nurses or other health professionals, e.g. community pharmacists, working to a protocol of standard diagnostic questions will help address the issues of overburdened GPs and facilitate timely initiation of treatment.
The overall incidence and pattern of adverse events were similar to those reported in previous studies.5,6 Nausea was significantly reduced by taking the first dose of oseltamivir with food, suggesting that the mechanism of action may be at the local gastric level. The proportion of patients who discontinued drug because of gastrointestinal events was small and similar to previous studies, due to the fact that the majority of these events were of isolated occurrence after the first dose and did not persist with continued dosing.
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Conclusion |
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Acknowledgements |
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Study investigators: Belgium: Didier, Vanret Namur; Frans, Pardinaens Antwerpen; Didier, Giet Liege; Bernard, Clarysse West-Vlaaderen; Jacques, Saintpo Hainaut; Frank, Decoutere Limburg; Rodolphe, Liagre Oost-Vlaanderen; Noel, Provoost Vlaams Brabant; Canada: Dr G. Acyuthan Regina; Dr Marc Afilalo Montreal; Dr Gordon Arbess Toronto; Dr Laurie Breger Montreal; Dr I. Campbell Montreal; Dr David Carswell Harrow; Dr Howard Conter Halifax; Dr Percy Crocker St Johns; Dr Francisco Diaz-Mitoma Ottawa; Dr Anthony DUrzo Toronto; Dr G.W. Hammond Winnipeg; Dr Brian R. Holroyd, Edmonton; Dr Allan Kelley Edmonton; Dr Gerald Lazarenko Calgary; Dr P.H. Orr Winnipeg; Dr Jean-Pascal Ouellet Sherbrooke; Dr Plyush Patel Toronto; Dr Daniel Shu Vancouver; Dr J.N. Simonsen Winnipeg; Dr Guy Stiver Montreal; Dr Sylvie Trottier Quebec City; Dr Paul Whitsitt Oshawa; Denmark: Bente, Klarland Copenhagen; Ronald, Dahl Aarhus; Jacobsen Vig; Laybourn Copenhagen; Schelde Vig; Wilstrup Soro; Pertti, Himanen Turku; Timo, Kaitilia Lappeenranta; Leena, Kiiski Kuopio; Perti, Kivi Tampere; Jamo, Koski Jyvaskylan; Merja, Pitkanen Helsinki; Arto, Strandberg Helsinki; Timo, Veskiari Tampere; France: Dr Alain Campagne Tours; Dr Gilles Grandmottet Besancon; Dr Michael Gregoire Tallard; Dr Dominique Lejay Vieux Conde; Dr Charles Mercier, Henri Montagne; Dr Gerald Mongin Mont Pellier; Dr Simon Musso Eaunes; Dr Francois Spilthooren Evreux; Dr Richard Josse Bordeaux; Dr Bruno Pascal Toulon; Dr Jean-Loup Rey Armees; Dr Jean-Louis Soares Armees; Germany: Dr Flobdorf Duren; Dr Barghoom Dormage; Dr Gessert Rothenburg; Dr Schlauch Lochham; Dr Adler Ludwigshafen; Dr Ludke Freiburg; Iceland: Gunnar, B. Gunnarsson Reykjavik; Vilhjalmur, Ari Arason Hafnarfjordur; Jon, Stiener Jonsson Gardabaer; Ireland: Dr Tom Finnegan Dublin; Dr Brian ODoherty Donaghmeade; Dr Niall Moore Dublin; Dr Liam Lynch Dublin; Dr Philip OConnell Dublin; Dr Alan Byrne Dublin; Dr William Kavanagh Dublin; Dr Tim Gleeson Dublin; Israel: Prof Shai Ashkenzi Petach-Tikva; Dr Efrat Harlev Shoam; Prof Ethan Rubinstein Givataeem; Dr Aya Shelem Hedera; Dr Tessa Shelouche Hedera; Dr Dorit Wolf Natania; Dr Moshe Zlotnik Ashkelon; Dr Bibiana Chazan Tiberia; Dr Nava Gasper Ofakim; Dr David Hassin Hedera; Dr Nir Heilzenrat Kiryat-Gat; Dr Doron Hemoni Hedera; Dr Liora Ben, Nitzan Masika Petach Tikva; Dr Raul Raz Afula; Dr Moshe Torem Afula; Dr Tsvika Weiss Herzelia; Dr Yoran Menda Herzelia; Dr Akram Abdful Ofakim; Dr Bibiana Chazan Tiberia; Dr Gay Nir Afula; Dr Avraham Borer Ofakim; Dr Bat-Sheva Gottersman Kfar-Saba; Dr Yova Helman Natania; Dr Oma Ofir Afula; Prof Fransinsc Schlaeffer Beer-Sheva A; Dr David Gabay Rishon Lezion; Dr Oren Avraham Natania; Dr Cama Sulliman Tiberia; Italy: Prof Pietro Crovari Genova; Netherlands: Dr G.J.M. Van Doesburg Lichtenvoorde; Luiten Den Haag; Dr R.G.G. Groot Arnemuiden; Dr P.H.L. Hofstede Giesbeek; Dr F.B. Naber Heemskerk; Dr J. Veerman Nijverdal; Norway: Sigbjorn, Elle Elverum; Mikkel, Mundal Oslo; Niels-Erik, Landmark Sandvika; Sjur Rod-Larsen Asgardstrand; Pal, Vik Sandvika; Kristian, Furuseth Jessheim; Sigve, Tonstad Oslo; Aage, Bjertnaes Trondheim; Sweden: Dr Stig Cronberg Maimo; Dr Per Forsberg Vaxjo ; Dr Peter Holgersson Karlskrona; Dr Bo Claesson Goteborg; Dr Mikael Mullart Sundsbruk; Dr Eva Gutniak Vaellingsby; Switzerland: Claude, Breitenstien Liestal; Roland, Seitz Margrethen; Urs, Beat Goflin Binningen; Thomas, Aeschbach Lausanne; Eric, Jensen Bern; Blaise, Genfron Lausanne; UK: Hall, Tim Plymouth; Middleton Fowey; Ritchie Peterhead; Haworth Blackpool; Doel Cleveleys; Newby Cambridgeshire; Rogers, D. Edgbaston; Wallace, P. Cheadle; Anderson, D. Bristol; Crawford, A. Winchester; Dove, N. Harrow; Lynch, H. Bolton; Finlay, M. Rochdale; Gilfeather, B. Windsor; Arora, S. B. London; Jones, G. Canterbury; Moseley, D. Sheffield; Muir, W. Nottingham; Quinn, Leslie Glasgow; Richardson, D. Dorset.
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Footnotes |
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Members of the IMPACT Study Group are listed in the Acknowledgements.
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References |
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