title: Benefits of using multiple first-line therapies against malaria.
abstract: Despite the availability of many drugs and therapies to treat malaria, many countries' national policies recommend using a single first-line therapy for most clinical malaria cases. To assess whether this is the best strategy for the population as a whole, we designed an evolutionary-epidemiological modeling framework for malaria and compared the benefits of different treatment strategies in the context of resistance evolution. Our results show that the population-wide use of multiple first-line therapies (MFT) against malaria yields a better clinical outcome than using a single therapy or a cycling strategy where therapies are rotated, either on a fixed cycling schedule or when resistance levels or treatment failure become too high. MFT strategies also delay the emergence and slow the fixation of resistant strains (phenotypes), and they allow a larger fraction of the population to be treated without trading off future treatment of cases that may be untreatable because of high resistance levels. Earlier papers have noted that cycling strategies have the disadvantage of creating a less temporally variable environment than MFT strategies, making resistance evolution easier for the parasite. Here, we illustrate a second feature of parasite ecology that impairs the performance of cycling policies, namely, that cycling policies degrade the mean fitness of the parasite population more quickly than MFT policies, making it easier for new resistant types to invade and spread. The clinical benefits of using multiple first-line therapies against malaria suggest that MFT policies should play a key role in malaria elimination and control programs.
authors.affiliation: Resources for the Future, Washington, DC 20036, USA. mboni@oucru.org
authors.forename: Maciej F
authors.initials: MF
authors.lastname: Boni
authors.forename: David L
authors.initials: DL
authors.lastname: Smith
authors.forename: Ramanan
authors.initials: R
authors.lastname: Laxminarayan
mesh_terms: D000962:Antimalarials / Q000627:therapeutic use*; D003198:Computer Simulation; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000453:epidemiology*; D008954:Models, Biological; D013997:Time Factors
chemical_list: D000962:Antimalarials
references.citation: Drug Resist Updat. 2005 Feb-Apr;8(1-2):43-50
references.pmid: 15939341
references.citation: Am J Trop Med Hyg. 1994 Aug;51(2):123-37
references.pmid: 8074247
references.citation: Drug Resist Updat. 1998;1(6):389-96
references.pmid: 17092820
references.citation: Nature. 2005 Nov 24;438(7067):492-5
references.pmid: 16306991
references.citation: Clin Microbiol Rev. 2004 Jan;17(1):235-54
references.pmid: 14726463
references.citation: Proc Biol Sci. 1997 Jan 22;264(1378):61-7
references.pmid: 9061961
references.citation: Acta Trop. 2005 Jun;94(3):230-40
references.pmid: 15878154
references.citation: Pharmacol Rev. 2005 Mar;57(1):117-45
references.pmid: 15734729
references.citation: Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13285-90
references.pmid: 15308772
references.citation: Science. 2008 Apr 18;320(5874):330-4
references.pmid: 18420924
references.citation: Parasitology. 2006 May;132(Pt 5):615-24
references.pmid: 16426485
references.citation: Parassitologia. 1999 Sep;41(1-3):241-6
references.pmid: 10697862
references.citation: Trends Parasitol. 2003 Feb;19(2):70-3
references.pmid: 12586474
references.citation: Trans R Soc Trop Med Hyg. 1992 Jul-Aug;86(4):355-8
references.pmid: 1359683
references.citation: Trans R Soc Trop Med Hyg. 1991 May-Jun;85(3):349-55
references.pmid: 1683034
references.citation: Adv Parasitol. 2002;52:235-64
references.pmid: 12521262
references.citation: Am J Trop Med Hyg. 2005 Feb;72(2):163-73
references.pmid: 15741553
references.citation: Parasitol Today. 1993 May;9(5):168-74
references.pmid: 15463746
references.citation: Parasitol Today. 2000 Aug;16(8):340-7
references.pmid: 10900482
references.citation: Trop Med Int Health. 2000 Nov;5(11):755-64
references.pmid: 11123822
references.citation: Drug Resist Updat. 1998 Mar;1(1):3-9
references.pmid: 17092790
references.citation: Trans R Soc Trop Med Hyg. 1998 Mar-Apr;92(2):188-95
references.pmid: 9764331
references.citation: Lancet. 1999 Jun 5;353(9168):1965-7
references.pmid: 10371589
references.citation: J Health Econ. 2002 Jul;21(4):709-18
references.pmid: 12146599
references.citation: Parasitology. 1997 Aug;115 ( Pt 2):133-41
references.pmid: 10190169
references.citation: Proc Biol Sci. 2003 Mar 7;270(1514):545-54
references.pmid: 12641911
references.citation: Malar J. 2008 Apr 25;7:67
references.pmid: 18439283
references.citation: J Natl Malar Soc. 1951 Dec;10(4):327-36
references.pmid: 14908561
references.citation: Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12106-11
references.pmid: 9342370
references.citation: Acta Trop. 2005 Jun;94(3):207-17
references.pmid: 15894181
references.citation: Evolution. 2005 Mar;59(3):477-91
references.pmid: 15856691
references.citation: Bull World Health Organ. 1960;22:669-83
references.pmid: 13846510
references.citation: Trans R Soc Trop Med Hyg. 1986;80(6):889-92
references.pmid: 3603638
references.citation: J Clin Invest. 2004 Apr;113(8):1084-92
references.pmid: 15085184
references.citation: Philos Trans R Soc Lond B Biol Sci. 2002 Apr 29;357(1420):505-19
references.pmid: 12028788
references.citation: Malar J. 2007 May 29;6:72
references.pmid: 17535417