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PLoS Med. Efficacy of Oseltamivir-Zanamivir Combination Compared to Each Monotherapy for Seasonal Influenza: A Randomized Placebo-Controlled Trial
Efficacy of Oseltamivir-Zanamivir Combination Compared to Each Monotherapy for Seasonal Influenza: A Randomized Placebo-Controlled Trial (PLoS, abstract, edited)
[Source: PLoS, full text: <cite cite="http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000362?utm_so urce=feedburner&utm_medium=feed&utm_campaign=Feed% 3A+plosmedicine%2FNewArticles+%28Ambra+-+Medicine+New+Articles%29">PLoS Medicine: Efficacy of Oseltamivir-Zanamivir Combination Compared to Each Monotherapy for Seasonal Influenza: A Randomized Placebo-Controlled Trial</cite>. Abstract, edited.]
Efficacy of Oseltamivir-Zanamivir Combination Compared to Each Monotherapy for Seasonal Influenza: A Randomized Placebo-Controlled Trial
Xavier Duval 1,2,3, Sylvie van der Werf 4,5,6, Thierry Blanchon 7,8, Anne Mosnier 9, Maude Bouscambert-Duchamp 10,11, Annick Tibi 12,13, Vincent Enouf 4, C?cile Charlois-Ou 14, Corine Vincent 2,3,15, Laurent Andreoletti 16,17, Florence Tubach 2,3,18, Bruno Lina 10,11, France Mentr? 2,3,15, Catherine Leport 14,19*, and the Bivir Study Group?
1 Inserm CIC 007, APHP, H?pital Bichat, Paris, France,
2 Inserm U738, Paris, France,
3 Universit? Paris Diderot, Paris 7, UFR de M?decine, site Bichat, Paris, France,
4 Institut Pasteur, Centre National de R?f?rence des virus influenzae (R?gion-Nord), Unit? de G?n?tique Mol?culaire des Virus ? ARN, Paris, France,
5 CNRS URA3015, Paris, France,
6 Universit? Paris Diderot, Paris 7, UFR Sciences du Vivant, Paris, France,
7 Inserm UPMC UMR-S 707, Facult? de m?decine Pierre et Marie Curie, Paris, France,
8 Universit? Pierre et Marie Curie, Paris 6, UFR de M?decine, U707, Paris, France,
9 R?seau des Groupes R?gionaux d'Observation de la Grippe (GROG), Coordination nationale, Paris, France,
10 Hospices Civils de Lyon, Centre National de R?f?rence des virus influenzae (R?gion-Sud), GHE, Bron, France,
11 Universit? Lyon 1, VirPatH, CNRS FRE 3011, Lyon, France,
12 APHP- Agence G?n?rale des Equipements et Produits de Sant?, Unit? Essais Cliniques, Paris, France,
13 Universit? Paris Descartes, Paris 5, Facult? de Pharmacie, Paris, France,
14 Universit? Paris Diderot, Paris 7, UFR de M?decine, site Bichat, Laboratoire de Recherche en Pathologie Infectieuse, Paris, France,
15 APHP, H?pital Bichat, Unit? de Biostatistiques, Paris, France,
16 H?pital Robert Debr?, Unit? de Virologie m?dicale, Reims, France,
17 Unit? de Virologie M?dicale et Mol?culaire Facult? de M?decine Universit? Champagne-Ardenne IFR53/EA-4303, Reims, France,
18 APHP H?pital Bichat, D?partement d'Epid?miologie, Biostatistiques et Recherche Clinique, Paris, France,
19 APHP, Unit? de Coordination des Risques Epid?miques et Biologiques, Paris, France
Abstract
Background
Neuraminidase inhibitors are thought to be efficacious in reducing the time to alleviation of symptoms in outpatients with seasonal influenza. The objective of this study was to compare the short-term virological efficacy of oseltamivir-zanamivir combination versus each monotherapy plus placebo.
Methods and Findings
We conducted a randomized placebo-controlled trial with 145 general practitioners throughout France during the 2008?2009 seasonal influenza epidemic. Patients, general practitioners, and outcome assessors were all blinded to treatment assignment. Adult outpatients presenting influenza-like illness for less than 36 hours and a positive influenza A rapid test diagnosis were randomized to oseltamivir 75 mg orally twice daily plus zanamivir 10 mg by inhalation twice daily (OZ), oseltamivir plus inhaled placebo (O), or zanamivir plus oral placebo (Z). Treatment efficacy was assessed virologically according to the proportion of patients with nasal influenza reverse transcription (RT)-PCR below 200 copies genome equivalent (cgeq)/?l at day 2 (primary outcome), and clinically to the time to alleviation of symptoms until day 14. Overall 541 patients (of the 900 planned) were included (OZ, n = 192; O, n = 176; Z, n = 173), 49% male, mean age 39 years. In the intention- to-treat analysis conducted in the 447 patients with RT-PCR-confirmed influenza A, 46%, 59%, and 34% in OZ (n = 157), O (n = 141), and Z (n = 149) arms had RT-PCR<200 cgeq/?l (−13.0%, 95% confidence interval [CI] −23.1 to −2.9, p = 0.025; +12.3%, 95% CI 2.39?22.2, p = 0.028 for OZ/O and OZ/Z comparisons). Mean day 0 to day 2 viral load decrease was 2.14, 2.49, and 1.68 log10 cgeq/?l (p = 0.060, p = 0.016 for OZ/O and OZ/Z). Median time to alleviation of symptoms was 4.0, 3.0, and 4.0 days (+1.0, 95% CI 0.0?4.0, p = 0.018; +0.0, 95% CI −3.0 to 3.0, p = 0.960 for OZ/O and OZ/Z). Four severe adverse events were observed. Nausea and/or vomiting tended to be more frequent in the combination arm (OZ, n = 13; O, n = 4; and Z, n = 5 patients, respectively).
Conclusions
In adults with seasonal influenza A mainly H3N2 virus infection, the oseltamivir-zanamivir combination appeared less effective than oseltamivir monotherapy, and not significantly more effective than zanamivir monotherapy. Despite the theoretical potential for the reduction of the emergence of antiviral resistance, the lower effectiveness of this combination calls for caution in its use in clinical practice.
Trial registration
www.ClinicalTrials.gov NCT00799760
Citation: Duval X, van der Werf S, Blanchon T, Mosnier A, Bouscambert-Duchamp M, et al. (2010) Efficacy of Oseltamivir-Zanamivir Combination Compared to Each Monotherapy for Seasonal Influenza: A Randomized Placebo-Controlled Trial. PLoS Med 7(11): e1000362. doi:10.1371/journal.pmed.1000362
Academic Editor: Benjamin J. Cowling, The University of Hong Kong, Hong Kong
Received: April 29, 2010; Accepted: September 22, 2010; Published: November 2, 2010
Copyright: ? 2010 Duval et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by a research grant from the French Ministry of Health. The sponsor was: D?partement ? la Recherche Clinique et au Developpement, Assistance Publique ? Hopitaux de Paris (Programme hospitalier de recherche clinique, AOM 06060 and AOM 08209). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: XD has had a conference invitation from GSK and lecture fees from Roche and Gilead. AM has membership in the ministry of health advisory board on influenza; involvement in some epidemiological studies partially or fully granted by Roche and GSK, and travel grants from Roche for participation in scientific meetings. SVDW has had a conference invitation from GSK; research grant from GSK on unrelated subject; joined patent from institution with GSK on unrelated subject; travel grants for meetings from GSK; contribution to clinical trial financed by Roche; member of the advisory committee on influenza of the French ministry of health; is a member of ESWI; is a member of the scientific committee of the GEIG; and is vice-president of the GROG network. FM received fees from Roche, preclinical pharmacokinetic department, for a course on MONOLIX in December 2008. BL has had paid consultancy and board membership (Roche, GSK, Novartis, BioCryst, MedImmune), has had research grants from Roche and Sanofi-Pasteur, and had received travel grants and honoraria for speaking or participation at meetings (Roche, Sanofi-Pasteur).
Abbreviations: cgeq, copies genome equivalent; CI, confidence interval; IQR, interquartile range; ITT, intention to treat; NIC, National Influenza Centre; O, oseltamivir; OZ, oseltamivir-zanamivir combination; RT, reverse transcription; SD, standard deviation; Z, zanamivir
* E-mail: catherine.leport@univ-paris-diderot.fr
? Membership of the BIVIR Study Group is provided in the Acknowledgments.
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Efficacy of Oseltamivir-Zanamivir Combination Compared to Each Monotherapy for Seasonal Influenza: A Randomized Placebo-Controlled Trial
Xavier Duval 1,2,3, Sylvie van der Werf 4,5,6, Thierry Blanchon 7,8, Anne Mosnier 9, Maude Bouscambert-Duchamp 10,11, Annick Tibi 12,13, Vincent Enouf 4, C?cile Charlois-Ou 14, Corine Vincent 2,3,15, Laurent Andreoletti 16,17, Florence Tubach 2,3,18, Bruno Lina 10,11, France Mentr? 2,3,15, Catherine Leport 14,19*, and the Bivir Study Group?
1 Inserm CIC 007, APHP, H?pital Bichat, Paris, France,
2 Inserm U738, Paris, France,
3 Universit? Paris Diderot, Paris 7, UFR de M?decine, site Bichat, Paris, France,
4 Institut Pasteur, Centre National de R?f?rence des virus influenzae (R?gion-Nord), Unit? de G?n?tique Mol?culaire des Virus ? ARN, Paris, France,
5 CNRS URA3015, Paris, France,
6 Universit? Paris Diderot, Paris 7, UFR Sciences du Vivant, Paris, France,
7 Inserm UPMC UMR-S 707, Facult? de m?decine Pierre et Marie Curie, Paris, France,
8 Universit? Pierre et Marie Curie, Paris 6, UFR de M?decine, U707, Paris, France,
9 R?seau des Groupes R?gionaux d'Observation de la Grippe (GROG), Coordination nationale, Paris, France,
10 Hospices Civils de Lyon, Centre National de R?f?rence des virus influenzae (R?gion-Sud), GHE, Bron, France,
11 Universit? Lyon 1, VirPatH, CNRS FRE 3011, Lyon, France,
12 APHP- Agence G?n?rale des Equipements et Produits de Sant?, Unit? Essais Cliniques, Paris, France,
13 Universit? Paris Descartes, Paris 5, Facult? de Pharmacie, Paris, France,
14 Universit? Paris Diderot, Paris 7, UFR de M?decine, site Bichat, Laboratoire de Recherche en Pathologie Infectieuse, Paris, France,
15 APHP, H?pital Bichat, Unit? de Biostatistiques, Paris, France,
16 H?pital Robert Debr?, Unit? de Virologie m?dicale, Reims, France,
17 Unit? de Virologie M?dicale et Mol?culaire Facult? de M?decine Universit? Champagne-Ardenne IFR53/EA-4303, Reims, France,
18 APHP H?pital Bichat, D?partement d'Epid?miologie, Biostatistiques et Recherche Clinique, Paris, France,
19 APHP, Unit? de Coordination des Risques Epid?miques et Biologiques, Paris, France
Abstract
Background
Neuraminidase inhibitors are thought to be efficacious in reducing the time to alleviation of symptoms in outpatients with seasonal influenza. The objective of this study was to compare the short-term virological efficacy of oseltamivir-zanamivir combination versus each monotherapy plus placebo.
Methods and Findings
We conducted a randomized placebo-controlled trial with 145 general practitioners throughout France during the 2008?2009 seasonal influenza epidemic. Patients, general practitioners, and outcome assessors were all blinded to treatment assignment. Adult outpatients presenting influenza-like illness for less than 36 hours and a positive influenza A rapid test diagnosis were randomized to oseltamivir 75 mg orally twice daily plus zanamivir 10 mg by inhalation twice daily (OZ), oseltamivir plus inhaled placebo (O), or zanamivir plus oral placebo (Z). Treatment efficacy was assessed virologically according to the proportion of patients with nasal influenza reverse transcription (RT)-PCR below 200 copies genome equivalent (cgeq)/?l at day 2 (primary outcome), and clinically to the time to alleviation of symptoms until day 14. Overall 541 patients (of the 900 planned) were included (OZ, n = 192; O, n = 176; Z, n = 173), 49% male, mean age 39 years. In the intention- to-treat analysis conducted in the 447 patients with RT-PCR-confirmed influenza A, 46%, 59%, and 34% in OZ (n = 157), O (n = 141), and Z (n = 149) arms had RT-PCR<200 cgeq/?l (−13.0%, 95% confidence interval [CI] −23.1 to −2.9, p = 0.025; +12.3%, 95% CI 2.39?22.2, p = 0.028 for OZ/O and OZ/Z comparisons). Mean day 0 to day 2 viral load decrease was 2.14, 2.49, and 1.68 log10 cgeq/?l (p = 0.060, p = 0.016 for OZ/O and OZ/Z). Median time to alleviation of symptoms was 4.0, 3.0, and 4.0 days (+1.0, 95% CI 0.0?4.0, p = 0.018; +0.0, 95% CI −3.0 to 3.0, p = 0.960 for OZ/O and OZ/Z). Four severe adverse events were observed. Nausea and/or vomiting tended to be more frequent in the combination arm (OZ, n = 13; O, n = 4; and Z, n = 5 patients, respectively).
Conclusions
In adults with seasonal influenza A mainly H3N2 virus infection, the oseltamivir-zanamivir combination appeared less effective than oseltamivir monotherapy, and not significantly more effective than zanamivir monotherapy. Despite the theoretical potential for the reduction of the emergence of antiviral resistance, the lower effectiveness of this combination calls for caution in its use in clinical practice.
Trial registration
www.ClinicalTrials.gov NCT00799760
Citation: Duval X, van der Werf S, Blanchon T, Mosnier A, Bouscambert-Duchamp M, et al. (2010) Efficacy of Oseltamivir-Zanamivir Combination Compared to Each Monotherapy for Seasonal Influenza: A Randomized Placebo-Controlled Trial. PLoS Med 7(11): e1000362. doi:10.1371/journal.pmed.1000362
Academic Editor: Benjamin J. Cowling, The University of Hong Kong, Hong Kong
Received: April 29, 2010; Accepted: September 22, 2010; Published: November 2, 2010
Copyright: ? 2010 Duval et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by a research grant from the French Ministry of Health. The sponsor was: D?partement ? la Recherche Clinique et au Developpement, Assistance Publique ? Hopitaux de Paris (Programme hospitalier de recherche clinique, AOM 06060 and AOM 08209). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: XD has had a conference invitation from GSK and lecture fees from Roche and Gilead. AM has membership in the ministry of health advisory board on influenza; involvement in some epidemiological studies partially or fully granted by Roche and GSK, and travel grants from Roche for participation in scientific meetings. SVDW has had a conference invitation from GSK; research grant from GSK on unrelated subject; joined patent from institution with GSK on unrelated subject; travel grants for meetings from GSK; contribution to clinical trial financed by Roche; member of the advisory committee on influenza of the French ministry of health; is a member of ESWI; is a member of the scientific committee of the GEIG; and is vice-president of the GROG network. FM received fees from Roche, preclinical pharmacokinetic department, for a course on MONOLIX in December 2008. BL has had paid consultancy and board membership (Roche, GSK, Novartis, BioCryst, MedImmune), has had research grants from Roche and Sanofi-Pasteur, and had received travel grants and honoraria for speaking or participation at meetings (Roche, Sanofi-Pasteur).
Abbreviations: cgeq, copies genome equivalent; CI, confidence interval; IQR, interquartile range; ITT, intention to treat; NIC, National Influenza Centre; O, oseltamivir; OZ, oseltamivir-zanamivir combination; RT, reverse transcription; SD, standard deviation; Z, zanamivir
* E-mail: catherine.leport@univ-paris-diderot.fr
? Membership of the BIVIR Study Group is provided in the Acknowledgments.
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