title: Impact of different oseltamivir regimens on treating influenza A virus infection and resistance emergence: insights from a modelling study.
abstract: Several studies have proven oseltamivir to be efficient in reducing influenza viral titer and symptom intensity. However, the usefulness of oseltamivir can be compromised by the emergence and spread of drug-resistant virus. The selective pressure exerted by different oseltamivir therapy regimens have received little attention. Combining models of drug pharmacokinetics, pharmacodynamics, viral kinetics and symptom dynamics, we explored the efficacy of oseltamivir in reducing both symptoms (symptom efficacy) and viral load (virological efficacy). We simulated samples of 1000 subjects using previously estimated between-subject variability in viral and symptom dynamic parameters to describe the observed heterogeneity in a patient population. We simulated random mutations conferring resistance to oseltamivir. We explored the effect of therapy initiation time, dose, intake frequency and therapy duration on influenza infection, illness dynamics, and emergence of viral resistance. Symptom and virological efficacies were strongly associated with therapy initiation time. The proportion of subjects shedding resistant virus was 27-fold higher when prophylaxis was initiated during the incubation period compared with no treatment. It fell to below 1% when treatment was initiated after symptom onset for twice-a-day intakes. Lower doses and prophylaxis regimens led to lower efficacies and increased risk of resistance emergence. We conclude that prophylaxis initiated during the incubation period is the main factor leading to resistance emergence.
authors.affiliation: INSERM, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France; Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Canini
authors.affiliation: Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Conway
authors.affiliation: Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Perelson
authors.affiliation: INSERM, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Saint Antoine, Paris, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Carrat
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects / Q000302:isolation & purification*; D007251:Influenza, Human / Q000188:drug therapy* / Q000821:virology; D008962:Models, Theoretical; D053139:Oseltamivir / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000998:Antiviral Agents; D053139:Oseltamivir
references.citation: PLoS Comput Biol. 2007 Dec;3(12):e240
references.pmid: 18069885
references.citation: Eur J Clin Pharmacol. 2003 Sep;59(5-6):411-5
references.pmid: 12910331
references.citation: Pediatr Infect Dis J. 2012 May;31(5):527-9
references.pmid: 22209917
references.citation: Lancet Infect Dis. 2014 Feb;14(2):88-9
references.pmid: 24268592
references.citation: Antimicrob Agents Chemother. 2008 Sep;52(9):3284-92
references.pmid: 18625765
references.citation: Lancet Infect Dis. 2009 Sep;9(9):537-45
references.pmid: 19665930
references.citation: J Virol. 2010 Jul;84(13):6687-98
references.pmid: 20410284
references.citation: JAMA. 2000 Feb 23;283(8):1016-24
references.pmid: 10697061
references.citation: JAMA. 1999 Oct 6;282(13):1240-6
references.pmid: 10517426
references.citation: J Infect Dis. 2013 Apr 15;207(8):1281-5
references.pmid: 23382573
references.citation: J Virol. 2009 Jul;83(14):7151-65
references.pmid: 19439465
references.citation: J Theor Biol. 1994 Apr 21;167(4):323-60
references.pmid: 7516024
references.citation: Antimicrob Agents Chemother. 2006 Jul;50(7):2395-402
references.pmid: 16801417
references.citation: BMJ. 2009 Dec 08;339:b5106
references.pmid: 19995812
references.citation: Antimicrob Agents Chemother. 2009 Mar;53(3):945-52
references.pmid: 19104028
references.citation: N Engl J Med. 2010 Jun 10;362(23):2175-2184
references.pmid: 20558368
references.citation: PLoS Comput Biol. 2011 Feb 03;7(2):e1001058
references.pmid: 21304934
references.citation: J Clin Pharmacol. 2008 Aug;48(8):935-47
references.pmid: 18524996
references.citation: J Virol. 2013 Jan;87(2):1193-9
references.pmid: 23152521
references.citation: Clin Pharmacol Ther. 2009 Sep;86(3):241-3
references.pmid: 19707215
references.citation: J Virol. 2014 Feb;88(3):1652-8
references.pmid: 24257597
references.citation: J Theor Biol. 2007 May 7;246(1):70-86
references.pmid: 17266989
references.citation: Antimicrob Agents Chemother. 2001 Dec;45(12):3403-8
references.pmid: 11709315
references.citation: Pediatr Infect Dis J. 2001 Feb;20(2):127-33
references.pmid: 11224828
references.citation: Lancet Infect Dis. 2014 Feb;14(2):109-18
references.pmid: 24268590
references.citation: J Chem Phys. 2006 Oct 14;125(14):144107
references.pmid: 17042579
references.citation: J Infect Dis. 2013 Feb 15;207(4):553-63
references.pmid: 23204175
references.citation: Emerg Infect Dis. 2011 Apr;17(4):653-60; quiz 765
references.pmid: 21470455
references.citation: Clin Infect Dis. 2012 Nov;55(9):1198-204
references.pmid: 22843781
references.citation: PLoS Pathog. 2013;9(5):e1003354
references.pmid: 23671418
references.citation: J Med Virol. 2007 Oct;79(10):1577-86
references.pmid: 17705169
references.citation: Vaccine. 2003 May 1;21(16):1796-800
references.pmid: 12686097
references.citation: J R Soc Interface. 2010 Jan 6;7(42):35-47
references.pmid: 19474085
references.citation: J Antimicrob Chemother. 2003 Jan;51(1):123-9
references.pmid: 12493796
references.citation: J Infect Dis. 2011 Mar 15;203(6):838-46
references.pmid: 21343149
references.citation: Lancet. 2000 Mar 4;355(9206):827-35
references.pmid: 10711940
references.citation: Philos Trans R Soc Lond B Biol Sci. 2001 Dec 29;356(1416):1877-84
references.pmid: 11779387
references.citation: J Virol. 2010 Aug;84(16):8042-50
references.pmid: 20519385
references.citation: J Virol. 2011 Mar;85(6):2764-70
references.pmid: 21191031
references.citation: PLoS Pathog. 2011 Dec;7(12):e1002431
references.pmid: 22174688
references.citation: Clin Infect Dis. 2013 May;56(9):1197-205
references.pmid: 23307766
references.citation: J Virol. 2006 Aug;80(15):7590-9
references.pmid: 16840338
references.citation: Lancet. 2004 Aug 28-Sep 3;364(9436):759-65
references.pmid: 15337401
references.citation: J Infect Dis. 2001 Feb 15;183(4):523-31
references.pmid: 11170976
references.citation: Lancet. 2000 May 27;355(9218):1845-50
references.pmid: 10866439
references.citation: J Theor Biol. 2005 Jan 21;232(2):223-34
references.pmid: 15530492
references.citation: N Engl J Med. 1997 Sep 25;337(13):874-80
references.pmid: 9302301
references.citation: Wkly Epidemiol Rec. 2009 Feb 5;85(6):37-40
references.pmid: 20151493