Increase in the prevalence of mutations associated with sulfadoxine-pyrimethamine resistance in Plasmodium falciparum isolates collected from early to late pregnancy in Nanoro, Burkina Faso

Esmée Ruizendaal, Marc C Tahita, Ronald B Geskus, Inge Versteeg, Susana Scott, Umberto d'Alessandro, Palpouguini Lompo, Karim Derra, Maminata Traore-Coulibaly, Menno D de Jong, Henk D F H Schallig, Halidou Tinto, Petra F Mens, Esmée Ruizendaal, Marc C Tahita, Ronald B Geskus, Inge Versteeg, Susana Scott, Umberto d'Alessandro, Palpouguini Lompo, Karim Derra, Maminata Traore-Coulibaly, Menno D de Jong, Henk D F H Schallig, Halidou Tinto, Petra F Mens

Abstract

Background: Pregnant women are a high-risk group for Plasmodium falciparum infections, which may result in maternal anaemia and low birth weight newborns, among other adverse birth outcomes. Intermittent preventive treatment with sulfadoxine-pyrimethamine during pregnancy (IPTp-SP) is widely implemented to prevent these negative effects of malaria. However, resistance against SP by P. falciparum may decrease efficacy of IPTp-SP. Combinations of point mutations in the dhps (codons A437, K540) and dhfr genes (codons N51, C59, S108) of P. falciparum are associated with SP resistance. In this study the prevalence of SP resistance mutations was determined among P. falciparum found in pregnant women and the general population (GP) from Nanoro, Burkina Faso and the association of IPTp-SP dosing and other variables with mutations was studied.

Methods: Blood spots on filter papers were collected from pregnant women at their first antenatal care visit (ANC booking) and at delivery, from an ongoing trial and from the GP in a cross-sectional survey. The dhps and dhfr genes were amplified by nested PCR and products were sequenced to identify mutations conferring resistance (ANC booking, n = 400; delivery, n = 223; GP, n = 400). Prevalence was estimated with generalized estimating equations and for multivariate analyses mixed effects logistic regression was used.

Results: The prevalence of the triple dhfr mutation was high, and significantly higher in the GP and at delivery than at ANC booking, but it did not affect birth weight. Furthermore, quintuple mutations (triple dhfr and double dhps mutations) were found for the first time in Burkina Faso. IPTp-SP did not significantly affect the occurrence of any of the mutations, but high transmission season was associated with increased mutation prevalence in delivery samples. It is unclear why the prevalence of mutations was higher in the GP than in pregnant women at ANC booking.

Conclusion: The high number of mutants and the presence of quintuple mutants in Burkina Faso confirm concerns about the efficacy of IPTp-SP in the near future. Other drug combinations to tackle malaria in pregnancy should, therefore, be explored. An increase in mutation prevalence due to IPTp-SP dosing could not be confirmed.

Keywords: Mutations; Plasmodium falciparum; Pregnancy; Resistance; Sulfadoxine–pyrimethamine.

Figures

Fig. 1
Fig. 1
Flowchart of the longitudinal survey of SP resistance mutations in pregnant women
Fig. 2
Fig. 2
Flowchart of the cross-sectional survey of SP resistance mutations in the general population
Fig. 3
Fig. 3
Prevalence of mutant, mixed and wild type alleles in ANC, delivery and GP samples

References

    1. WHO . World Malaria report 2015. Geneva: World Health Organization; 2015.
    1. Adu B, Cherif MK, Bosomprah S, Diarra A, Arthur FKN, Dickson EK, et al. Antibody levels against GLURP R2, MSP1 block 2 hybrid and AS202.11 and the risk of malaria in children living in hyperendemic (Burkina Faso) and hypo-endemic (Ghana) areas. Malar J. 2016;15:123. doi: 10.1186/s12936-016-1146-4.
    1. Ryg-Cornejo V, Ly A, Hansen DS. Immunological processes underlying the slow acquisition of humoral immunity to malaria. Parasitology. 2016;143:199–207. doi: 10.1017/S0031182015001705.
    1. Fried M, Duffy PE. Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta. Science. 1996;272:1502–1504. doi: 10.1126/science.272.5267.1502.
    1. Rogerson SJ, Hviid L, Duffy PE, Leke RFG, Taylor DW. Malaria in pregnancy: pathogenesis and immunity. Lancet Infect Dis. 2007;7:105–117. doi: 10.1016/S1473-3099(07)70022-1.
    1. Maubert B, Fievet N, Tami G, Cot M, Boudin C, Deloron P. Development of antibodies against chondroitin sulfate A-adherent Plasmodium falciparum in pregnant women. Infect Immun. 1999;67:5367–5371.
    1. Fried M, Nosten F, Brockman A, Brabin B, Duffy PE. Maternal antibodies block malaria. Nature. 1998;20:851–852. doi: 10.1038/27570.
    1. Duffy PE, Fried M. Antibodies that inhibit Plasmodium falciparum adhesion to chondroitin sulfate a are associated with increased birth weight and the gestational age of newborns. Infect Immun. 2003;71:6620–6623. doi: 10.1128/IAI.71.11.6620-6623.2003.
    1. Desai M, ter Kuile FO, Nosten F, McGready R, Asamoa K, Brabin B, et al. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis. 2007;7:93–104. doi: 10.1016/S1473-3099(07)70021-X.
    1. Guyatt HL, Snow RW. Impact of malaria during pregnancy on low birth weight in sub-Saharan Africa. Clin Microbiol Rev. 2004;17:760. doi: 10.1128/CMR.17.4.760-769.2004.
    1. World Health Organization . Policy brief for the implementation of intermittent preventive treatment of malaria in pregnancy using sulfadoxine–pyrimethamine (IPTp-SP) Geneva: World Health Organization; 2013.
    1. WHO . A Strategic framework for malaria prevention and control during pregnancy in the African Region. Brazzaville: World Health Organization Regional Office for Africa; 2004.
    1. Karunajeewa HA, Salman S, Mueller I, Baiwog F, Gomorrai S, Law I, et al. Pharmacokinetic properties of sulfadoxine–pyrimethamine in pregnant women. Antimicrob Agents Chemother. 2009;53:4368–4376. doi: 10.1128/AAC.00335-09.
    1. Naidoo I, Roper C. Drug resistance maps to guide intermittent preventive treatment of malaria in African infants. Parasitology. 2011;138:1469–1479. doi: 10.1017/S0031182011000746.
    1. Geiger C, Compaore G, Coulibaly B, Sie A, Dittmer M, Sanchez C, et al. Substantial increase in mutations in the genes pfdhfr and pfdhps puts sulphadoxine-pyrimethamine-based intermittent preventive treatment for malaria at risk in Burkina Faso. Trop Med Int Health. 2014;19:690–697. doi: 10.1111/tmi.12305.
    1. Harrington WE, Mutabingwa TK, Muehlenbachs A, Sorensen B, Bolla MC, Fried M, et al. Competitive facilitation of drug-resistant Plasmodium falciparum malaria parasites in pregnant women who receive preventive treatment. Proc Natl Acad Sci USA. 2009;106:9027–9032. doi: 10.1073/pnas.0901415106.
    1. Harrington WE, Morrison R, Fried M, Duffy PE. Intermittent preventive treatment in pregnant women is associated with increased risk of severe malaria in their offspring. PLoS ONE. 2013;8:e56183. doi: 10.1371/journal.pone.0056183.
    1. Desai M, Gutman J, Taylor SM, Wiegand RE, Khairallah C, Kayentao K, et al. Impact of sulfadoxine–pyrimethamine resistance on effectiveness of intermittent preventive therapy for malaria in pregnancy at clearing infections and preventing low birth weight. Clin Infect Dis. 2016;62:323–333. doi: 10.1093/cid/civ881.
    1. Happi CT, Gbotosho GO, Folarin OA, Akinboye DO, Yusuf BO, Ebong OO, et al. Polymorphisms in Plasmodium falciparum dhfr and dhps genes and age related in vivo sulfadoxine–pyrimethamine resistance in malaria-infected patients from Nigeria. Acta Trop. 2005;95:183–193. doi: 10.1016/j.actatropica.2005.06.015.
    1. Gansané A, Nébié I, Soulama I, Tiono A, Diarra A, Konaté AT, et al. Les raison d’un changement de médicaments de première intention pour le traitement du paludisme simple au Burkina Faso en 2005. Bull Soc Path Exot. 2009;102:31–35. doi: 10.3185/pathexo3235.
    1. Bertin G, Briand V, Bonaventure D, Carrieu A, Massougbodji A, Cot M, et al. Molecular markers of resistance to sulphadoxine-pyrimethamine during intermittent preventive treatment of pregnant women in Benin. Malar J. 2011;10:196. doi: 10.1186/1475-2875-10-196.
    1. Coulibaly SO, Kayentao K, Taylor S, Guirou EA, Khairallah C, Guindo N, et al. Parasite clearance following treatment with sulphadoxine-pyrimethamine for intermittent preventive treatment in Burkina-Faso and Mali: 42-day in vivo follow-up study. Malar J. 2014;13:41. doi: 10.1186/1475-2875-13-41.
    1. Tahita MC, Tinto H, Erhart A, Kazienga A, Fitzhenry R, VanOvermeir C, et al. Prevalence of the dhfr and dhps Mutations among pregnant women in rural Burkina Faso five years after the introduction of intermittent preventive treatment with sulfadoxine–pyrimethamine. PLoS ONE. 2015;10:e0137440. doi: 10.1371/journal.pone.0137440.
    1. Scott S, Mens PF, Tinto H, Nahum A, Ruizendaal E, Pagnoni F, et al. Community-based scheduled screening and treatment of malaria in pregnancy for improved maternal and infant health in The Gambia, Burkina Faso and Benin: study protocol for a randomized controlled trial. Trials. 2014;15:340. doi: 10.1186/1745-6215-15-340.
    1. Kattenberg JH, Tahita CM, Versteeg IJ, Tinto H, Traoré-Coulibaly M, Schallig HDFH, et al. Antigen persistence of rapid diagnostic tests in pregnant women in Nanoro, Burkina Faso, and the implications for the diagnosis of malaria in pregnancy. Trop Med Int Health. 2012;17:550–557. doi: 10.1111/j.1365-3156.2012.02975.x.
    1. Hermsen CC, Telgt DS, Linders EH, van de Locht LA, Eling WM, Mensink EJ, et al. Detection of Plasmodium falciparum malaria parasites in vivo by real-time quantitative PCR. Mol Biochem Parasitol. 2001;118:247–251. doi: 10.1016/S0166-6851(01)00379-6.
    1. Wang CW, Hermsen CC, Sauerwein RW, Arnot DE, Theander TG, Lavstsen T. The Plasmodium falciparum var gene transcription strategy at the onset of blood stage infection in a human volunteer. Parasitol Int. 2009;58:478–480. doi: 10.1016/j.parint.2009.07.004.
    1. Duraisingh MT, Curtis J, Warhurst DC. Plasmodium falciparum: detection of polymorphisms in the dihydrofolate reductase and dihydropteroate synthetase genes by PCR and restriction digestion. Exp Parasitol. 1998;89:1–8. doi: 10.1006/expr.1998.4274.
    1. Diallo DA, Sutherland C, Nebié I, Konaté AT, Ord R, Pota H, et al. Sustained use of insecticide-treated curtains is not associated with greater circulation of drug-resistant malaria parasites, or with higher risk of treatment failure among children with uncomplicated malaria in Burkina Faso. Am J Trop Med Hyg. 2007;76:237–244.
    1. Bouyou-Akotet MK, Mawili-Mboumba DP, Tchantchou T, Kombila M. High prevalence of sulfadoxine/pyrimethamine-resistant alleles of Plasmodium falciparum isolates in pregnant women at the time of introduction of intermittent preventive treatment with sulfadoxine/pyrimethamine in Gabon. J Antimicrob Chemother. 2010;65:438–441. doi: 10.1093/jac/dkp467.
    1. Mockenhaupt FP, Bedu-Addo G, Eggelte TA, Hommerich L, Holmberg V, von Oertzen C, et al. Rapid increase in the prevalence of sulfadoxine–pyrimethamine resistance among Plasmodium falciparum isolated from pregnant women in Ghana. J Infect Dis. 2008;198:1545–1549. doi: 10.1086/592455.
    1. Moussiliou A, De Tove YS-S, Doritchamou J, Luty AJF, Massougbodji A, Alifrangis M, et al. High rates of parasite recrudescence following intermittent preventive treatment with sulphadoxine–pyrimethamine during pregnancy in Benin. Malar J. 2013;12:195. doi: 10.1186/1475-2875-12-195.
    1. Chauvin P, Menard S, Iriart X, Nsango SE, Tchioffo MT, Abate L, et al. Prevalence of Plasmodium falciparum parasites resistant to sulfadoxine/pyrimethamine in pregnant women in Yaounde, Cameroon: emergence of highly resistant pfdhfr/pfdhps alleles. J Antimicrob Chemother. 2015;70:2566–2571. doi: 10.1093/jac/dkv160.
    1. Menéndez C, Serra-Casas E, Scahill MD, Sanz S, Nhabomba A, Bardají A, et al. HIV and placental infection modulate the appearance of drug-resistant Plasmodium falciparum in pregnant women who receive intermittent preventive treatment. Clin Infect Dis. 2011;52:41–48. doi: 10.1093/cid/ciq049.
    1. Asih PBS, Rogers WO, Susanti AI, Rahmat A, Rozi IE, Kusumaningtyas MA, et al. Seasonal distribution of anti-malarial drug resistance alleles on the island of Sumba, Indonesia. Malar J. 2009;8:222. doi: 10.1186/1475-2875-8-222.
    1. Bushman M, Morton L, Duah N, Quashie N, Abuaku B, Koram KA, et al. Within-host competition and drug resistance in the human malaria parasite Plasmodium falciparum. Proc R Soc Lond B. 2016;283:20183038. doi: 10.1098/rspb.2015.3038.
    1. Wargo AR, Huijben S, de Roode JC, Shepherd J, Read AF. Competitive release and facilitation of drug-resistant parasites after therapeutic chemotherapy in a rodent malaria model. Proc Natl Acad Sci USA. 2007;104:19914–19919. doi: 10.1073/pnas.0707766104.
    1. Råberg L, de Roode JC, Bell AS, Stamou P, Gray D, Read AF. The role of immune-mediated apparent competition in genetically diverse malaria infections. Am Nat. 2006;168:41–53.
    1. Agomo CO, Oyibo WA, Sutherland C, Hallet R, Oguike M. Assessment of markers of antimalarial drug resistance in Plasmodium falciparum isolates from pregnant women in Lagos, Nigeria. PLoS ONE. 2016;11:e0146908. doi: 10.1371/journal.pone.0146908.
    1. Iwalokun BA, Iwalokun SO, Adebodun V, Balogun M. Carriage of mutant dihydrofolate reductase and dihydropteroate synthase genes among Plasmodium falciparum isolates recovered from pregnant women with asymptomatic infection in Lagos, Nigeria. Med Princ Pract. 2015;24:436–443. doi: 10.1159/000430987.
    1. Khalil IF, Rønn AM, Alifrangis M, Gabar HA, Jelinek T, Satti GMH, et al. Response of Plasmodium falciparum to cotrimoxazole therapy: relationship with plasma drug concentrations and dihydrofolate reductase and dihydropteroate synthase genotypes. Am J Trop Med Hyg. 2005;73:174–177.
    1. Mockenhaupt FP, May J, Eggelte TA, Thies FL, Ademowo OG, Bienzle U, et al. Short report: high prevalence and imbalanced age distribution of the Plasmodium falciparum dihydrofolate reductase gene Asn108 mutation in an area of low pyrimethamine usage in Nigeria. Am J Trop Med Hyg. 1999;61:375–377.
    1. Raman J, Little F, Roper C, Kleinschmidt I, Cassam Y, Maharaj R, et al. Five years of large-scale dhfr and dhps mutation surveillance following the phased implementation of artesunate plus sulfadoxine-pyrimethamine in Maputo Province, Southern Mozambique. Am J Trop Med Hyg. 2010;82:788–794. doi: 10.4269/ajtmh.2010.09-0401.
    1. McCollum AM, Schneider KA, Griffing SM, Zhou Z, Kariuki S, Ter-Kuile F, et al. Differences in selective pressure on dhps and dhfr drug resistant mutations in western Kenya. Malar J. 2012;11:77. doi: 10.1186/1475-2875-11-77.
    1. Minja DTR, Schmiegelow C, Mmbando B, Boström S, Oesterholt M, Magistrado P, et al. Plasmodium falciparum mutant haplotype infection during pregnancy associated with reduced birthweight, Tanzania. Emerg Infect Dis. 2013;19:1446–1454. doi: 10.3201/eid1909.130133.
    1. Gutman J, Kalilani L, Taylor S, Zhou Z, Wiegand RE, Thwai KL, et al. The A581G mutation in the gene encoding Plasmodium falciparum dihydropteroate synthetase reduces the effectiveness of sulfadoxine–pyrimethamine preventive therapy in Malawian pregnant women. J Infect Dis. 2015;211:1997–2005. doi: 10.1093/infdis/jiu836.
    1. Chico RM, Cano J, Ariti C, Collier TJ, Chandramohan D, Roper C, et al. Influence of malaria transmission intensity and the 581G mutation on the efficacy of intermittent preventive treatment in pregnancy: systematic review and meta-analysis. Trop Med Int Health. 2015;20:1621–1633. doi: 10.1111/tmi.12595.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever