Polymorphisms in Plasmodium falciparum Chloroquine Resistance Transporter and Multidrug Resistance 1 Genes: Parasite Risk Factors that Affect Treatment Outcomes for P-falciparum Malaria after Artemether-Lumefantrine and Artesunate-Amodiaquine

被引：204

作者：

Venkatesan, Meera ^{[1
,2
]}

Gadalla, Nahla B. ^{[3
,4
]}

Stepniewska, Kasia ^{[5
]}

Dahal, Prabin ^{[5
]}

Nsanzabana, Christian ^{[5
]}

Moriera, Clarissa ^{[5
]}

Price, Ric N. ^{[5
,6
,7
]}

Martensson, Andreas ^{[8
,9
]}

Rosenthal, Philip J. ^{[10
]}

Dorsey, Grant ^{[10
]}

Sutherland, Colin J. ^{[11
]}

Guerin, Philippe ^{[5
]}

Davis, Timothy M. E. ^{[12
]}

Menard, Didier ^{[13
]}

Adam, Ishag ^{[14
]}

Ademowo, George ^{[15
]}

Arze, Cesar ^{[16
]}

Baliraine, Frederick N. ^{[17
]}

Berens-Riha, Nicole ^{[18
]}

Bjorkman, Anders ^{[8
]}

Borrmann, Steffen ^{[19
,20
]}

Checchi, Francesco ^{[21
]}

Desai, Meghna ^{[22
]}

Dhorda, Mehul ^{[23
,24
]}

Djimde, Abdoulaye A. ^{[25
]}

El-Sayed, Badria B. ^{[26
]}

Eshetu, Teferi ^{[27
]}

Eyase, Frederick ^{[28
]}

Falade, Catherine ^{[29
]}

Faucher, Jean-Francois ^{[30
,31
]}

Froberg, Gabrielle ^{[8
]}

Grivoyannis, Anastasia ^{[32
]}

Hamour, Sally ^{[33
]}

Houze, Sandrine ^{[34
,35
,36
]}

Johnson, Jacob ^{[37
]}

Kamugisha, Erasmus ^{[38
]}

Kariuki, Simon ^{[39
]}

Kiechel, Jean-Rene ^{[40
]}

Kironde, Fred ^{[41
,42
]}

Kofoed, Poul-Erik ^{[43
,44
]}

LeBras, Jacques ^{[34
,35
,36
]}

Malmberg, Maja ^{[8
]}

Mwai, Leah ^{[19
]}

Ngasala, Billy ^{[45
]}

Nosten, Francois ^{[46
,47
]}

Nsobya, Samuel L. ^{[48
]}

Nzila, Alexis ^{[19
]}

Oguike, Mary ^{[11
]}

Otienoburu, Sabina Dahlstrom ^{[49
]}

Ogutu, Bernhards ^{[28
]}

机构：

[1] Univ Maryland, Sch Med, WorldWide Antimalarial Resistance Network Mol Mod, Baltimore, MD 21201 USA

[2] Univ Maryland, Sch Med, Howard Hughes Med Inst, Ctr Vaccine Dev, Baltimore, MD 21201 USA

[3] NIAID, NIH, Bethesda, MD 20892 USA

[4] Res Inst Trop Med, Dept Epidemiol, Khartoum, Sudan

[5] Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, World Wide Antimalarial Resistance Network, Oxford, England

[6] Menzies Sch Hlth Res, Global Hlth Div, Darwin, NT, Australia

[7] Charles Darwin Univ, Darwin, NT 0909, Australia

[8] Dept Med Solna, Infect Dis Unit, Stockholm, Sweden

[9] Karolinska Inst, Global Hlth, Dept Publ Hlth Sci, Stockholm, Sweden

[10] Univ Calif San Francisco, Dept Med, San Francisco, CA USA

[11] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Immunol & Infect, London WC1, England

[12] Univ Western Australia, Fremantle Hosp, Sch Med & Pharmacol, Nedlands, WA 6009, Australia

[13] Inst Pasteur Cambodge, Malaria Mol Epidemiol Unit, Phnom Penh, Cambodia

[14] Univ Khartoum, Fac Med, Khartoum, Sudan

[15] Univ Ibadan, Coll Med, Inst Adv Med Res & Training, Ibadan, Nigeria

[16] Univ Maryland, Sch Med, Module & Inst Genome Sci, WorldWide Antimalarial Resistance Network Mol, Baltimore, MD 21201 USA

[17] LeTourneau Univ, Dept Biol, Longview, TX USA

[18] Univ Munich, Dept Infect Dis & Trop Med, Munich, Germany

[19] Wellcome Trust Res Programme, Kenya Med Res Inst, Kilifi, Kenya

[20] Univ Magdeburg, Sch Med, Dept Microbiol, D-39106 Magdeburg, Germany

[21] Save Children, Paris, France

[22] Ctr Dis Control & Prevent, Ctr Global Hlth, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA

[23] Univ Maryland, Sch Med, WorldWide Antimalarial Resistance Network Mol Mod, Baltimore, MD 21201 USA

[24] Epictr Uganda Res Base, Mbarara, Uganda

[25] Univ Sci Techn & Technol Bamako, Fac Pharm, Malaria Res & Training Ctr, Bamako, Mali

[26] Res Inst Trop Med, Dept Epidemiol, Khartoum, Sudan

[27] Jimma Univ, Med Parasitol Unit, Dept Med, Lab Sci & Pathol, Jimma, Ethiopia

[28] US Army, Res Unit Kenya Walter Reed, Kenya Med Res Inst Project, Kisumu, Kenya

[29] Univ Ibadan, Dept Pharmacol & Therapeut, Ibadan, Nigeria

[30] Univ Med Ctr, Dept Infect Dis, Besancon, France

[31] Inst Rech Dev, Paris, France

[32] Univ Washington, Dept Med, Div Emergency Med, Seattle, WA USA

[33] UCL, Ctr Nephrol, Royal Free Hosp, London, England

[34] Hop Xavier Bichat, AP HP, Malaria Natl Reference Ctr, Parasitol Lab, Paris, France

[35] Mere & Enfant Face Infect Trop, Inst Rech Dev, Paris, France

[36] Univ Paris 05, Sorbonne Paris Cite, PRES, Fac Pharm, Paris, France

[37] US Army, Med Res Unit Kenya, Nairobi, Kenya

[38] Catholic Univ Hlth & Allied Sci Bugando, Mwanza, Tanzania

[39] Ctrs Dis Control & Prevent, Kenya Med Res Inst, Malaria Branch, Kisumu, Kenya

[40] Drugs Neglected Dis Initiat, Geneva, Switzerland

[41] Makerere Univ, Coll Hlth Sci, Kampala, Uganda

[42] St Augustine Int Univ, Kampala, Uganda

[43] INDEPTH Network, Projecto Saude Bandim, Bissau, Guinea Bissau

[44] Kolding Cty Hosp, Dept Pediat, Kolding, Denmark

[45] Muhimbili Univ Hlth & Allied Sci, Dept Parasitol, Dar Es Salaam, Tanzania

[46] Univ Oxford, Nuffield Dept Med, Ctr Trop Med, Oxford, England

[47] Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Shoklo Malaria Res Unit, Bangkok, Thailand

[48] Makerere Univ, Coll Hlth Sci, Sch Biomed Sci, Dept Pathol, Kampala, Uganda

[49] Hop Bichat Claude Bernard, Inst Med & Epidemiol Appliquee, Worldwide Antimalarial Resistance Network, F-75877 Paris 18, France

[50] Ctr Muraz, Inst Rech Sci Sante, Bobo Dioulasso, Burkina Faso

来源：

AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE | 2014年 / 91卷 / 04期

关键词：

PLUS SULFADOXINE-PYRIMETHAMINE; PFMDR1 COPY NUMBER; UNCOMPLICATED MALARIA; IN-VIVO; DRUG-RESISTANCE; PLASMODIUM-FALCIPARUM-PFMDR1; ALLELES; DIHYDROARTEMISININ-PIPERAQUINE; COMBINATION THERAPIES; TYROSINE-86; ALLELE; TANZANIAN CHILDREN;

D O I：

10.4269/ajtmh.14-0031

中图分类号：

R1 [预防医学、卫生学];

学科分类号：

100235 [预防医学];

摘要：

Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001) were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.

引用

页码：833 / 843

页数：11

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