[en] Malaria is a major public health problem in the Democratic Republic of Congo. Despite progress achieved over the past decade in the fight against malaria, further efforts have to be done such as in the surveillance and the containment of Plasmodium falciparum resistant strains. We investigated resistance to artemisinin-based combination therapies currently in use in Democratic Republic of Congo by surveying molecular polymorphisms in three genes: pfcrt, pfmdr1 and pfk13 to explore possible emergence of amodiaquine, lumefantrine or artemisinin resistance in Democratic Republic of Congo. This study essentially revealed that resistance to chloroquine is still decreasing while polymorphism related to amodiaquine resistance seems to be not present in Democratic Republic of Congo, that three samples, located in the east of the country, harbor Pfmdr1 amplification and that none of the mutations found in South-East Asia correlated with artemisinine resistance have been found in Democratic Republic of Congo. But new mutations have been identified, especially the M476K, occurred in the same position that the M476I previously identified in the F32-ART strain, strongly resistant to artemisinine. Antimalarial first-line treatments currently in use in Democratic Republic of Congo are not associated with emergence of molecular markers of resistance.
Disciplines :
Laboratory medicine & medical technology
Author, co-author :
Mvumbi Makaba, Dieudonné; University of Kinshasa > Department of basic sciences, school of medecine
Bobanga Lengu, Thierry
Kayembe Ntumba, Jean-Marie; Université de Kinshasa > Internal medecine
Mvumbi Lelo, Georges; Université de Kinshasa > Biochemistry and molecular biology unit
Situakibanza Nani-Tuma, Hippolyte; Université de Kinshasa > Internal medecine- Parasitology and tropical medecine
Benoit-Vical, Françoise; Centre National de la Recherche Scientifique - CNRS, Toulouse, France > Laboratoire de chimie de coordination
Melin, Pierrette ; Université de Liège > Département des sciences biomédicales et précliniques > Bactériologie, mycologie, parasitologie, virologie
De Mol, Patrick ; Université de Liège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Hayette, Marie-Pierre ; Université de Liège > Département des sciences biomédicales et précliniques > Bactériologie, mycologie, parasitologie, virologie
Language :
English
Title :
Molecular surveillance of Plasmodium falciparum resistance to artemisinin-based combination therapies in the Democratic Republic of Congo
Alternative titles :
[en] Surveillance moléculaire de la résistance de Plasmodium falciparum aux associations thérapeutiques à base d'artémisinine
Publication date :
08 June 2017
Journal title :
PLoS ONE
eISSN :
1932-6203
Publisher :
Public Library of Science, San Franscisco, United States - California
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
ARES - Académie de Recherche et d'Enseignement Supérieur
(2015) World Malaria Report, , World Health Organization. Geneva: WHO Press
(2015) Global Technical Strategy for Malaria 2016-2030, , WHO. Geneva, World Health Organization
Bruce-Chwatt, L.J., Black, R.H., Canfield, C.J., Clyde, D.F., Peters, W., Wernsdorfer, W.H., (1986) Chemotherapy of Malaria, , Geneva, World Health Organization
Pradines, B., Dormoire, J., Briolant, S., Bogreau, H., Rogier, C., La résistance aux antipaludiques (2010) Rev Fr Lab, 422, pp. 51-62
(2015) Guidelines for the Treatment of Malaria, , WHO. Third Edition. Geneva, World Health Organization
Murray, C.J., Rosenfeld, L.C., Lim, S.S., Andrews, K.G., Foreman, K.J., Haring, D., Global malaria mortality between 1980 and 2010: A systematic analysis (2012) Lancet, 379, pp. 413-431
Phillips, M., Phillips-Howard, P.A., Economic implications of resistance to antimalarial drugs (1996) Pharmacoeconomics, 10, pp. 225-238. , PMID: 10163571
Talisuna, A.O., Bloland, P., D'Alessandro, U., History, dynamics, and public health importance of malaria parasite resistance (2004) Clinical and Microbiology Reviews, 17, pp. 235-254
Price, R.N., Nosten, F., Drug resistant falciparum malaria: Clinical consequences and strategies for prevention (2001) Drug Resistance Updates, 4, pp. 187-196. , https://doi.org/10.1054/drup.2001.0195, PMID: 11768332
White, N.J., Nosten, F., Looareesuwan, S., Watkins, W.M., Marsh, K., Snow, R.W., Averting a malaria disaster (1999) Lancet, 353, pp. 1965-1967. , PMID: 10371589
(2016) Update on Artemisinin and ACT Resistance, April 2016, , WHO. Geneva, World Health Organization
Plowe, C.V., Roper, C., Barnwell, J.W., Happi, C.T., Joshi, H.H., Mbacham, W., World Antimalarial Resistance Network (WARN) III: Molecular markers for drug resistant malaria (2007) Malar J, 6, p. 121. , https://doi.org/10.1186/1475-2875-6-121, PMID: 17822535
Mvumbi, D.M., Kayembe, N., Situakibanza, N.T., Bobanga, L., Mvumbi, L., De Mol, P., Falciparum malaria molecular drug resistance in the Democratic Republic of Congo: A systematic review (2015) Malar J, 14, p. 354. , https://doi.org/10.1186/s12936-015-0892-z, PMID: 26376639
Djimde, A., Doumbo, O.K., Cortese, J.F., Kayentao, K., Doumbo, S., Diourte, Y., A molecular marker for chloroquine-resistant falciparum malaria (2001) N Engl J Med, 344, pp. 257-263. , https://doi.org/10.1056/NEJM200101253440403, PMID: 11172152
Sa, J.M., Twu, O., Protecting the malaria drug arsenal: Halting the rise and spread of amodiaquine resistance by monitoring the PfCRT SVMNT type (2010) Malar J, 9, p. 374. , https://doi.org/10.1186/1475-2875-9-374, PMID: 21182787
Ariey, F., Witkowski, B., Amaratunga, C., Beghain, J., Langlois, A.C., Khim, N., A molecular marker of artemisinin-resistant Plasmodium falciparum malaria (2014) Nature, 13, pp. 50-55
Chavchich, M., Gerena, L., Peters, J., Chen, N., Cheng, Q., Kyle, D.E., Role of pfmdr1 amplification and expression in induction of resistance to artemisinin derivatives in Plasmodium falciparum (2010) Antimicrob Agents Chemother, 54, pp. 2455-2464. , https://doi.org/10.1128/AAC.00947-09, PMID: 20350946
Lobo, E., De Sousa, B., Rosa, S., Figueiredo, P., Lobo, L., Pateira, S., Prevalence of pfmdr1 alleles associated with artemether-lumefantrine tolerance/resistance in Maputo before and after the implementation of artemisinin-based combination therapy (2014) Malar J, 13, p. 300. , https://doi.org/10.1186/1475-2875-13-300, PMID: 25098280
Preechapornkul, P., Imwong, M., Chotivanich, K., Pongtavornpinyo, W., Dondorp, A.M., Plasmodium falciparum pfmdr1 amplification, mefloquine resistance, and parasite fitness (2009) Antimicrob Agents Chemother, 53, pp. 1509-1515. , https://doi.org/10.1128/AAC.00241-08, PMID: 19164150
Sidhu, A.B., Uhlemann, A.C., Valderramos, S.G., Valderramos, J.C., Krishna, S., Fidock, D.A., Decreasing pfmdr1 copy number in Plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin (2006) J Infect Dis, 194, pp. 528-535. , https://doi.org/10.1086/507115, PMID: 16845638
Lim, P., Alker, A.P., Khim, N., Shah, N.K., Incardona, S., Doung, S., pfmdr1 copy number and arteminisin derivatives combination therapy failure in falciparum malaria in Cambodia (2009) Malar J, 8, p. 11. , https://doi.org/10.1186/1475-2875-8-11, PMID: 19138391
Ngalah, B.S., Ingasia, L.A., Cheruiyot, A.C., Chebon, L.J., Juma, D.W., Muiruri, P., Analysis of major genome loci underlying artemisinin resistance and pfmdr1 copy number in pre- and post-ACTs in western Kenya (2015) Sci Rep, 5, p. 8308. , https://doi.org/10.1038/srep08308, PMID: 25655315
Mvumbi, D.M., Boreux, R., Sacheli, R., Lelo, M., Lengu, B., Nani-Tuma, S., Assessment of pfcrt 72-76 haplotypes eight years after chloroquine withdrawal in Kinshasa. Democratic Republic of Congo (2013) Malar J, 12, p. 459. , https://doi.org/10.1186/1475-2875-12-459, PMID: 24359280
Cnops, L., Jacobs, J., Van Esbroeck, M., Validation of a four-primer real-time PCR as a diagnostic tool for single and mixed Plasmodium infections (2011) ClinMicrobiol Infect, 17, pp. 1101-1107
Copy number estimation of P. falciparum pfmdr1 (2011) Molecular Module, , WWARN
Price, R.N., Uhlemann, A.C., Brockman, A., McGready, R., Ashley, E., Phaipun, L., Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number (2004) Lancet, 364, pp. 438-447. , https://doi.org/10.1016/S0140-6736(04)16767-6, PMID: 15288742
Mvumbi, D.M., Bobanga, L., Melin, P., De Mol, P., Kayembe, N., Situakibanza, N.T., High prevalence of Plasmodium falciparum infection in asymptomatic individuals from the Democratic Republic of Congo (2016) Malar Res Treat, , https://doi.org/10.1155/2016/5405802, PMID: 26942036
Uhlemann, A.C., Ramharter, M., Lell, B., Kremsner, P.G., Krishna, S., Amplification of Plasmodium falciparum multidrug resistance gene 1 in isolates from Gabon (2005) J Infect Dis, 192, pp. 1830-1835. , https://doi.org/10.1086/497337, PMID: 16235185
Gadalla, N.B., Adam, I., Elzaki, S.E., Bashir, S., Mukhtar, I., Oguike, M., Increased pfmdr1 copy number and sequence polymorphisms in Plasmodium falciparum isolates from Sudanese malaria patients treated with artemether-lumefantrine (2011) Antimicrob Agents Chemother, 55, pp. 5408-5411. , https://doi.org/10.1128/AAC.05102-11, PMID: 21896916
Mungthin, M., Khositnithikul, R., Sitthichot, N., Suwandittakul, N., Wattanaveeradej, V., Ward, S.A., Association between the pfmdr1 gene and in vitro artemether and lumefantrine sensitivity in Thai isolates of Plasmodium falciparum (2010) Am J Trop Med Hyg, 83, pp. 1005-1009. , https://doi.org/10.4269/ajtmh.2010.10-0339, PMID: 21036827
Duah, N.O., Matrevi, S.A., De Souza, D.K., Binnah, D.D., Tamakloe, M.M., Opoku, V.S., Increased pfmdr1 gene copy number and the decline in pfcrt and pfmdr1 resistance alleles in Ghanaian Plasmodium falciparumisolates after the change of anti-malarial drug treatment policy (2013) Malar J, 12, p. 377. , https://doi.org/10.1186/1475-2875-12-377, PMID: 24172030
Dokomajilar, C., Nsobya, S.L., Greenhouse, B., Rosenthal, P.J., Dorsey, G., Selection of Plasmodium falciparum pfmdr1 alleles following therapy with artemether-lumefantrine in an area of Uganda where malaria is highly endemic (2006) Antimicrob Agents Chemother, 50, pp. 1893-1895. , https://doi.org/10.1128/AAC.50.5.1893-1895.2006, PMID: 16641472
Mobula, L., Lilley, B., Tshefu, A.K., Rosenthal PJ.Resistance-mediating Polymorphisms in Plasmodium falciparum infections in Kinshasa, Democratic Republic of the Congo (2009) Am J Trop Med Hyg, 80, pp. 555-558. , PMID: 19346374
Ochong, E.O., Van Den Broek, I.V., Keus, K., Nzila, A., Short report: Association between chloroquine and amodiaquine resistance and allelic variation in the Plasmodium falciparum multiple drug resistance 1 gene and the chloroquine resistance transporter gene in isolates from the upper Nile in southern Sudan (2003) Am J Trop Med Hyg, 69, pp. 184-187. , PMID: 13677373
Beshir, K., Sutherland, C.J., Merinopoulos, I., Durrani, N., Leslie, T., Rowland, M., Amodiaquine resistance in Plasmodium falciparum malaria in Afghanistan is associated with the pfcrt SVMNT allele at codons 72 to 76 (2010) Antimicrob Agents Hemother, 54, pp. 3714-3716
Alifrangis, M., Dalgaard, M.B., Lusingu, J.P., Vestergaard, L.S., Staalsoe, T., Jensen, A.T., Occurrence of the Southeast Asian/South American SVMNT haplotype of the chloroquine-resistance transporter gene in Plasmodium falciparum in Tanzania (2006) J Infect Dis, 193, pp. 1738-1741. , https://doi.org/10.1086/504269, PMID: 16703518
Mehlotra, R.K., Mattera, G., Bockarie, M.J., Maguire, J.D., Baird, J.K., Sharma, Y.D., Discordant patterns of genetic variation at two chloroquine resistance loci in worldwide populations of the malaria parasite Plasmodium falciparum (2008) Antimicrob Agents Chemother, 52, pp. 2212-2222. , https://doi.org/10.1128/AAC.00089-08, PMID: 18411325
Gama, B.E., De Carvalho, G.A.P., LutucutaKosi, F.J., De Oliveira, N.K.A., Fortes, F., Plasmodium falciparum isolates from Angola show the SVMNT haplotype in the pfcrt gene (2010) Malar J, 9, p. 174. , https://doi.org/10.1186/1475-2875-9-174, PMID: 20565881
Mekonnen, S.K., Aseffa, A., Berhe, N., Teklehaymanot, T., Clouse, R.M., Gebru, T., Return of chloroquine-sensitive Plasmodium falciparum parasites and emergence of chloroquine-resistant Plasmodium vivax in Ethiopia (2014) Malar J, 13, p. 244. , https://doi.org/10.1186/1475-2875-13-244, PMID: 24964730
Ngassa Mbenda, H.G., Das, A., Occurrence of multiple chloroquine-resistant Pfcrt haplotypes and emergence of the S(agt) VMNT type in Cameroonian Plasmodium falciparum (2014) J Antimicrob Chemother, 69, pp. 400-403. , https://doi.org/10.1093/jac/dkt388, PMID: 24092656
Taylor, S.M., Parobek, C.M., DeConti, D.K., Kayentao, K., Coulibaly, S.O., Greenwood, B.M., Absence of putative artemisinin resistance mutations among Plasmodium falciparum in Sub-Saharan Africa: A molecular epidemiologic study (2015) J Infect Dis, 211, pp. 680-688. , https://doi.org/10.1093/infdis/jiu467, PMID: 25180240
Ménard, D., Khim, N., Beghain, J., Adegnika, A.A., Shafiul-Alam, M., Amodu, O., A Worldwide Map of Plasmodium falciparum K13-Propeller Polymorphisms (2016) N Engl J Med, 374, pp. 2453-2464. , https://doi.org/10.1056/NEJMoa1513137, PMID: 27332904
Wang, Z., Shrestha, S., Li, X., Miao, J., Yuan, L., Cabrera, M., Prevalence of K13-propeller polymorphisms in Plasmodium falciparum from China-Myanmar border in 2007-2012 (2015) Malar J, 14, p. 168
Torrentino-Madamet, M., Collet, L., Lepère, J., Benoit, N., Amalvict, R., Ménard, D., K13-propeller polymorphisms in Plasmodium falciparum isolates from patients in Mayotte in 2013 and 2014 (2015) Antimicrob Agents Chemother, 59, pp. 7878-7881. , https://doi.org/10.1128/AAC.01251-15, 409 PMID: 26416865
Witkowski, B., Lelièvre, J., Barragán, M.J.L., Laurent, V., Su, X., Berry, A., Increased tolerance to artemisinin in Plasmodium falciparum is mediated by a quiescence mechanism (2010) Antimicrob Agents Chemother, 54, pp. 1872-1877. , https://doi.org/10.1128/AAC.01636-09, PMID: 20160056
Nyunt, M.H., Hlaing, T., Oo, H.W., Tin-Oo, L.-L.K., Phway, H.P., Wang, B., Molecular assessment of artemisinin resistance markers, polymorphisms in the K13 propeller, and a multidrug-resistance gene in the eastern and western border areas of Myanmar (2015) Clin Infect Dis, 60, pp. 1208-1215. , https://doi.org/10.1093/cid/ciu1160, PMID: 25537878