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Malaria Journal
Published in: Malaria Journal 1/2021

Open Access 01-12-2021 | Plasmodium Falciparum | Research

Dynamic changes in genetic diversity, drug resistance mutations, and treatment outcomes of falciparum malaria from the low-transmission to the pre-elimination phase on the islands of São Tomé and Príncipe

Authors: Ying-An Chen, Tsen-Ju Shiu, Lien-Fen Tseng, Chien-Fu Cheng, Wei-Liang Shih, Arlindo Vicente de Assunção Carvalho, Kun-Hsien Tsai

Published in: Malaria Journal | Issue 1/2021

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Abstract

Background

With effective vector control and case management, substantial progress has been made towards eliminating malaria on the islands of São Tomé and Príncipe (STP). This study assessed the dynamic changes in the genetic diversity of Plasmodium falciparum, the anti-malarial drug resistance mutations, and malaria treatment outcomes between 2010 and 2016 to provide insights for the prevention of malaria rebounding.

Methods

Polymorphic regions of merozoite surface proteins 1 and 2 (msp1 and msp2) were sequenced in 118 dried blood spots (DBSs) collected from malaria patients who had visited the Central Hospital in 2010–2016. Mutations in the multi-drug resistance I (pfmdr1), chloroquine resistance transporter (pfcrt), and kelch 13 (pfk13) genes were analysed by polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) and sequencing in 111 DBSs. A total of 7482 cases that completed a 28-day follow-up were evaluated for treatment outcomes based on the microscopic results. Regression models were used to characterize factors associated with levels of parasite density and treatment failures.

Results

Parasite strains in STP showed significant changes during and after the peak incidence in 2012. The prevalent allelic type in msp1 changed from K1 to MAD20, and that in msp2 changed from 3D7/IC to FC27. The dominant alleles of drug-resistance markers were pfmdr1 86Y, 184F, D1246, and pfcrt 76 T (Y-F-D-T, 51.4%). The average parasite density in malaria cases declined threefold from low-transmission (2010–2013) to pre-elimination period (2014–2016). Logistic regression models showed that patients with younger age (OR for age = 0.97–0.98, p < 0.001), higher initial parasite density (log10-transformed, OR = 1.44, p < 0.001), and receiving quinine treatment (compared to artemisinin-based combination therapy, OR = 1.91–1.96, p < 0.001) were more likely to experience treatment failures during follow-up.

Conclusions

Plasmodium falciparum in STP had experienced changes in prevalent strains, and increased mutation frequencies in drug-resistance genes from the low-transmission to the pre-elimination settings. Notably, patients with younger age and receiving quinine treatment were more likely to show parasitological treatment failure during follow-up. Therapeutic efficacy should be carefully monitored to inform future treatment policy in STP.
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Literature
1.
WHO. World malaria report 2020. Geneva, World Health Organization, 2020.
2.
Ashton RA, Prosnitz D, Andrada A, Herrera S, Yé Y. Evaluating malaria programmes in moderate- and low-transmission settings: practical ways to generate robust evidence. Malar J. 2020;19:75.PubMedPubMedCentralCrossRef
3.
WHO. A framework for malaria elimination. Geneva, World Health Organization, 2017.
4.
Chen YA, Lien JC, Tseng LF, Cheng CF, Lin WY, Wang HY, et al. Effects of indoor residual spraying and outdoor larval control on Anopheles coluzzii from São Tomé and Príncipe, two islands with pre-eliminated malaria. Malar J. 2019;18:405.PubMedPubMedCentralCrossRef
5.
Tseng LF, Chang WC, Ferreira MC, Wu CH, Rampão HS, Lien JC. Rapid control of malaria by means of indoor residual spraying of alphacypermethrin in the Democratic Republic of São Tomé and Príncipe. Am J Trop Med Hyg. 2008;78:248–50.PubMedCrossRef
6.
Pinto J, Sousa CA, Gil V, Ferreira C, Goncalves L, Lopes D, et al. Malaria in Sao Tome and Principe: parasite prevalences and vector densities. Acta Trop. 2000;76:185–93.PubMedCrossRef
7.
Lee PW, Liu CT, do Rosario VE, de Sousa B, Rampao HS, Shaio MF. Potential threat of malaria epidemics in a low transmission area, as exemplified by Sao Tome and Principe. Malar J. 2010;9:264.PubMedPubMedCentralCrossRef
8.
Salgueiro P, Vicente JL, Figueiredo RC, Pinto J. Genetic diversity and population structure of Plasmodium falciparum over space and time in an African archipelago. Infect Genet Evol. 2016;43:252–60.PubMedCrossRef
9.
Beeson JG, Drew DR, Boyle MJ, Feng G, Fowkes FJI, Richards JS. Merozoite surface proteins in red blood cell invasion, immunity and vaccines against malaria. FEMS Microbiol Rev. 2016;40:343–72.PubMedPubMedCentralCrossRef
10.
Conway DJ, Cavanagh DR, Tanabe K, Roper C, Mikes ZS, Sakihama N, et al. A principal target of human immunity to malaria identified by molecular population genetic and immunological analyses. Nat Med. 2000;6:689–92.PubMedCrossRef
11.
Snounou G, Zhu X, Siripoon N, Jarra W, Thaithong S, Brown KN, et al. Biased distribution of msp1 and msp2 allelic variants in Plasmodium falciparum populations in Thailand. Trans R Soc Trop Med Hyg. 1999;93:369–74.PubMedCrossRef
12.
Mwingira F, Nkwengulila G, Schoepflin S, Sumari D, Beck H-P, Snounou G, et al. Plasmodium falciparum msp1, msp2 and glurp allele frequency and diversity in sub-Saharan Africa. Malar J. 2011;10:79.PubMedPubMedCentralCrossRef
13.
Miller LH, Roberts T, Shahabuddin M, McCutchan TF. Analysis of sequence diversity in the Plasmodium falciparum merozoite surface protein-1 (MSP-1). Mol Biochem Parasitol. 1993;59:1–14.PubMedCrossRef
14.
Smythe JA, Coppel RL, Day KP, Martin RK, Oduola AM, Kemp DJ, et al. Structural diversity in the Plasmodium falciparum merozoite surface antigen 2. Proc Natl Acad Sci USA. 1991;88:1751–5.PubMedPubMedCentralCrossRef
15.
Teklehaimanot HD, Teklehaimanot A, Kiszewski A, Rampao HS, Sachs JD. Malaria in Sao Tome and Principe: on the brink of elimination after three years of effective antimalarial measures. Am J Trop Med Hyg. 2009;80:133–40.PubMedCrossRef
16.
17.
Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2014;371:411–23.PubMedPubMedCentralCrossRef
18.
19.
Venkatesan M, Gadalla NB, Stepniewska K, Dahal P, Nsanzabana C, Moriera C, et al. Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multi-drug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine. Am J Trop Med Hyg. 2014;91:833–43.PubMedPubMedCentralCrossRef
20.
Tomás G, Seco L, Seixas S, Faustino P, Lavinha J, Rocha J. The peopling of São Tomé (Gulf of Guinea): origins of slave settlers and admixture with the Portuguese. Hum Biol. 2002;74:397–411.PubMedCrossRef
21.
Wooden J, Kyes S, Sibley CH. PCR and strain identification in Plasmodium falciparum. Parasitol Today. 1993;9:303–5.PubMedCrossRef
22.
Somé AF, Bazié T, Zongo I, Yerbanga RS, Nikiéma F, Neya C, et al. Plasmodium falciparum msp1 and msp2 genetic diversity and allele frequencies in parasites isolated from symptomatic malaria patients in Bobo-Dioulasso, Burkina Faso. Parasit Vectors. 2018;11:323.PubMedPubMedCentralCrossRef
23.
24.
WHO. Methods and techniques for clinical trials on antimalarial drug efficacy: genotyping to identify parasite populations. Geneva, World Health Organization, 2007.
25.
Mehlotra RK, Fujioka H, Roepe PD, Janneh O, Ursos LMB, Jacobs Lorena V, et al. Evolution of a unique Plasmodium falciparum chloroquine-resistance phenotype in association with pfcrt polymorphism in Papua New Guinea and South America. Proc Natl Acad Sci USA. 2001;98:12689–94.PubMedPubMedCentralCrossRef
26.
Lu F, Culleton R, Zhang M, Ramaprasad A, von Seidlein L, Zhou H, et al. Emergence of indigenous artemisinin-resistant Plasmodium falciparum in Africa. N Engl J Med. 2017;376:991–3.PubMedCrossRef
27.
Lopes D, Rungsihirunrat K, Nogueira F, Seugorn A, Gil JP, do Rosário VE, et al. Molecular characterisation of drug-resistant Plasmodium falciparum from Thailand. Malar J. 2002;1:12.PubMedPubMedCentralCrossRef
28.
Veiga MI, Ferreira PE, Bjorkman A, Gil JP. Multiplex PCR-RFLP methods for pfcrt, pfmdr1 and pfdhfr mutations in Plasmodium falciparum. Mol Cell Probes. 2006;20:100–4.PubMedCrossRef
29.
Kang JM, Moon SU, Kim JY, Cho SH, Lin K, Sohn WM, et al. Genetic polymorphism of merozoite surface protein-1 and merozoite surface protein-2 in Plasmodium falciparum field isolates from Myanmar. Malar J. 2010;9:131.PubMedPubMedCentralCrossRef
30.
WHO. Methods for surveillance of antimalarial drug efficacy. Geneva, World Health Organization, 2009.
31.
WHO. Malaria terminology. Geneva, World Health Organization, 2016.
32.
Chen JT, Li J, Zha GC, Huang G, Huang ZX, Xie DD, et al. Genetic diversity and allele frequencies of Plasmodium falciparum msp1 and msp2 in parasite isolates from Bioko Island, Equatorial Guinea. Malar J. 2018;17:458.PubMedPubMedCentralCrossRef
33.
Huang B, Tuo F, Liang Y, Wu W, Wu G, Huang S, et al. Temporal changes in genetic diversity of msp-1, msp-2, and msp-3 in Plasmodium falciparum isolates from Grande Comore Island after introduction of ACT. Malar J. 2018;17:83.PubMedPubMedCentralCrossRef
34.
Daniels R, Chang HH, Séne PD, Park DC, Neafsey DE, Schaffner SF, et al. Genetic surveillance detects both clonal and epidemic transmission of malaria following enhanced intervention in Senegal. PLoS ONE. 2013;8: e60780.PubMedPubMedCentralCrossRef
35.
Obaldia N 3rd, Baro NK, Calzada JE, Santamaria AM, Daniels R, Wong W, et al. Clonal outbreak of Plasmodium falciparum infection in eastern Panama. J Infect Dis. 2015;211:1087–96.PubMedCrossRef
36.
Lê HG, Kang JM, Jun H, Lee J, Thái TL, Myint MK, et al. Changing pattern of the genetic diversities of Plasmodium falciparum merozoite surface protein-1 and merozoite surface protein-2 in Myanmar isolates. Malar J. 2019;18:241.PubMedPubMedCentralCrossRef
37.
38.
Noranate N, Prugnolle F, Jouin H, Tall A, Marrama L, Sokhna C, et al. Population diversity and antibody selective pressure to Plasmodium falciparum MSP1 block2 locus in an African malaria-endemic setting. BMC Microbiol. 2009;9:219.PubMedPubMedCentralCrossRef
39.
Guerra CA, Fuseini G, Donfack OT, Smith JM, Ondo Mifumu TA, Akadiri G, et al. Malaria outbreak in Riaba district, Bioko Island: lessons learned. Malar J. 2020;19:277.PubMedPubMedCentralCrossRef
40.
Guerra CA, Kang SY, Citron DT, Hergott DEB, Perry M, Smith J, et al. Human mobility patterns and malaria importation on Bioko Island. Nat Commun. 2019;10:2332.PubMedPubMedCentralCrossRef
41.
Bradley J, Monti F, Rehman AM, Schwabe C, Vargas D, Garcia G, et al. Infection importation: a key challenge to malaria elimination on Bioko Island, Equatorial Guinea. Malar J. 2015;14:46.PubMedPubMedCentralCrossRef
42.
43.
WHO. Guidelines for the Treatment of Malaria (3rd edn). Geneva, World Health Organization, 2015.
44.
Ferreira ID, Lopes D, Martinelli A, Ferreira C, Do Rosário VE, Cravo P. In vitro assessment of artesunate, artemether and amodiaquine susceptibility and molecular analysis of putative resistance-associated mutations of Plasmodium falciparum from São Tomé and Príncipe. Trop Med Int Health. 2007;12:353–62.PubMedCrossRef
45.
46.
Li J, Chen J, Xie D, Monte Nguba SM, Eyi JUM, Matesa RA, et al. High prevalence of pfmdr1 N86Y and Y184F mutations in Plasmodium falciparum isolates from Bioko Island, Equatorial Guinea. Pathog Glob Health. 2014;108:339–43.PubMedPubMedCentralCrossRef
47.
Li J, Chen J, Xie D, Eyi UM, Matesa RA, Obono MMO, et al. Molecular mutation profile of Pfcrt and Pfmdr1 in Plasmodium falciparum isolates from Bioko Island, Equatorial Guinea. Infect Genet Evol. 2015;36:552–6.PubMedCrossRef
48.
Sondo P, Derra K, Lefevre T, Diallo Nakanabo S, Tarnagda Z, Zampa O, et al. Genetically diverse Plasmodium falciparum infections, within-host competition and symptomatic malaria in humans. Sci Rep. 2019;9:127.PubMedPubMedCentralCrossRef
49.
Baptista JL, Das Neves I, D’Alessandro U, Hendrix L, Wéry M. Plasmodium falciparum chloroquine and quinine sensitivity in asymptomatic and symptomatic children in São Tomé Island. Trop Med Int Health. 1997;2:582–8.PubMedCrossRef
50.
Esamai F, Tenge CN, Ayuo PO, Ong’or WO, Obala A, Jakait B. A randomized open label clinical trial to compare the efficacy and safety of intravenous quinine followed by oral malarone vs intravenous quinine followed by oral quinine in the treatment of severe malaria. J Trop Pediatr. 2005;51:17–24.PubMedCrossRef
51.
Mårtensson A, Strömberg J, Sisowath C, Msellem MI, Gil JP, Montgomery SM, et al. Efficacy of artesunate plus amodiaquine versus that of artemether-lumefantrine for the treatment of uncomplicated childhood Plasmodium falciparum malaria in Zanzibar, Tanzania. Clin Infect Dis. 2005;41:1079–86.PubMedCrossRef
52.
Kofoed PE, Mapaba E, Lopes F, Pussick F, Aaby P, Rombo L. Comparison of 3, 5 and 7 days’ treatment with Quinimax for falciparum malaria in Guinea-Bissau. Trans R Soc Trop Med Hyg. 1997;91:462–4.PubMedCrossRef
53.
Achan J, Talisuna AO, Erhart A, Yeka A, Tibenderana JK, Baliraine FN, et al. Quinine, an old antimalarial drug in a modern world: role in the treatment of malaria. Malar J. 2011;10:144.PubMedPubMedCentralCrossRef
54.
Achan J, Tibenderana JK, Kyabayinze D, Wabwire Mangen F, Kamya MR, Dorsey G, et al. Effectiveness of quinine versus artemether-lumefantrine for treating uncomplicated falciparum malaria in Ugandan children: randomised trial. BMJ. 2009;339: b2763.PubMedPubMedCentralCrossRef
55.
Tinto H, Rwagacondo C, Karema C, Mupfasoni D, Vandoren W, Rusanganwa E, et al. In-vitro susceptibility of Plasmodium falciparum to monodesethylamodiaquine, dihydroartemisinin and quinine in an area of high chloroquine resistance in Rwanda. Trans R Soc Trop Med Hyg. 2006;100:509–14.PubMedCrossRef
56.
Pradines B, Mabika Mamfoumbi M, Parzy D, Owono Medang M, Lebeau C, Mourou Mbina JR, et al. In vitro susceptibility of Gabonese wild isolates of Plasmodium falciparum to artemether, and comparison with chloroquine, quinine, halofantrine and amodiaquine. Parasitology. 1998;117:541–5.PubMedCrossRef
57.
Cheruiyot J, Ingasia LA, Omondi AA, Juma DW, Opot BH, Ndegwa JM, et al. Polymorphisms in Pfmdr1, Pfcrt, and Pfnhe1 genes are associated with reduced in vitro activities of quinine in Plasmodium falciparum isolates from western Kenya. Antimicrob Agents Chemother. 2014;58:3737–43.PubMedPubMedCentralCrossRef
58.
WHO. World malaria report 2019. Geneva, World Health Organization, 2019.
59.
Silva JRdA, Ramos AdS, Machado M, de Moura DF, Neto Z, Canto-Cavalheiro MM, et al. A review of antimalarial plants used in traditional medicine in communities in Portuguese-speaking countries: Brazil, Mozambique, Cape Verde, Guinea-Bissau, São Tomé and Príncipe and Angola. Mem Inst Oswaldo Cruz. 2011;106:142–58.PubMedCrossRef
60.
Uwimana A, Legrand E, Stokes BH, Ndikumana J-LM, Warsame M, Umulisa N, et al. Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda. Nat Med. 2021;27:1113–5.PubMedPubMedCentralCrossRef
61.
Balikagala B, Fukuda N, Ikeda M, Katuro OT, Tachibana S-I, Yamauchi M, et al. Evidence of artemisinin-resistant malaria in Africa. N Engl J Med. 2021;385:1163–71.PubMedCrossRef
Metadata
Title
Dynamic changes in genetic diversity, drug resistance mutations, and treatment outcomes of falciparum malaria from the low-transmission to the pre-elimination phase on the islands of São Tomé and Príncipe
Authors
Ying-An Chen
Tsen-Ju Shiu
Lien-Fen Tseng
Chien-Fu Cheng
Wei-Liang Shih
Arlindo Vicente de Assunção Carvalho
Kun-Hsien Tsai
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Malaria Journal / Issue 1/2021
Electronic ISSN: 1475-2875
DOI
https://doi.org/10.1186/s12936-021-04007-3

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