The Emergence of Multiple Drug-Resistant Malaria along the Thailand/Myanmar Border

By Sashini Ranawana       

The bite of a single mosquito can most often spell disaster. In the socially fragmented and culturally dynamic central border region separating Thailand from Myanmar, this is a widely accepted reality.  Regional social factors have exacerbated the rate and severity of malarial infections, namely those by the Plasmodium falciparum and Plasmodium vivax parasites, turning them into a pressing issue. These factors affect the communities of international migrants, refugees and ethnic minority groups who constantly shift between Myanmar and Thailand. Their susceptibility to malaria parasites is often intensified  by their subsistence lifestyle in non-permanent dwellings and their limited knowledge on protection against mosquitos. Such groups are additionally forced to deal with communication barriers and a lack of access to basic clinics offering malaria antigen detection tests and treatments (Parker et al, 2015). Thus, the combination of nebulous healthcare and migration policies of the area have contributed to the upward spiral of malaria cases in the period leading up to the 1990s. 

Nonetheless, the recent collaborative efforts of government organisations and academic research centers have resulted in a significant reduction in malaria infections. With the implementation of ‘Targeted Mass Treatment’ schemes, in a bid to eradicate asymptomatic cases, and community awareness programs, the threat of malaria has been temporarily curbed. Representative data taken from ten Thai border provinces indicate a 73.7% decrease in total cases, from 111,680 in 2000 to 29,420 in 2012 (Shoklo Malaria Research Unit, 2013). Malaria’s significance as a regional priority health concern is diminishing. Anti-malarial drugs have hugely contributed to this change. 

Improved access to the most current and effective drugs against malaria has come almost hand-in-hand with social service development in many of the communities at the Thai border. Treatments have been tested and used in rapid succession, from the initial chloroquine and sulfadoxine-pyrimethamine  to the promising mefloquine, and more recently to novel Artemisinin-based Combination Therapy (ACT) drugs such as mefloquine-artesunate (Phyo et al, 2016) Their common mode of action of targeting human erythrocytes and liver cells is at the core of this battle between parasite and host. 

The early stages of a malaria infection involve the invasion and exploitation of the liver cell’s machinery, a mechanism which utilizes the aquaporin-3 proteins and nutrients of the cell for parasitic replication. From here, the red blood cells provide the next point of refuge, and in this way, the parasite is able to avoid attack by the host’s immune system (Burns et al, 2019). It is at this erythrocytic stage of development that anti-malarials, which disrupt the parasite’s enzymatic functions, are the most effective. In the case of chloroquine, inhibition of the host cell’s heme polymerase enzyme prevents the formation of hemozoin, a protein necessary for the rupture of erythrocytes (Slater, 1993) Any further invasion of red blood cells is prevented, allowing the remaining parasitic biomass to be rapidly cleared up. The anti-malarial sulfadoxine-pyrimethamine also works in a similar way: by preventing the enzymes dihydropteroate synthase and dihydrofolate reductase from catalysing the production and use of folate in the host cell (Yaro, 2009). With the parasite’s DNA synthesis and reproduction pathways dependent on this single absent biomolecule, the infection cycle eventually breaks down. More recently, ACT drugs have emerged as the preferred treatment for non-severe malaria. The combination of an artemisinin-derivative with a companion drug provides two separate mechanisms for parasitic elimination, thereby reducing the chance of any single resistant malaria strains surviving. Theoretically, this form of therapy seems highly effective. Reality, however, is much bleaker. 

Drug resistance in the malaria parasite population is developing at an exponential rate, while the list of effective drugs is rapidly shrinking. In this sense, the Thai/Myanmar border is essentially a microcosm of malaria hotspots around the world. After mefloquine was introduced in 1985, the drug-resistance conferring Pfmdr1 gene was found to be taking up roots in the parasite genome (Price, 1999). The situation has now become even more dire, with the emergence of ACT resistant parasites. Two particular mutations of the chromosome 13-residing kelch gene (K13), E252Q and C580Y, have been associated with a decreased responsiveness to the artemisinin-derivative artesunate. The latter mutation has much more severe implications. However, it is the genomic presence of both K13 and Pfmdr1 mutations which are responsible for the sheer increase in parasitic survival rates (Phyo et al, 2016). Malaria strains at the Thai/Myanmar border appear to be at the forefront of this fight against anti-malarials. A host of region-specific factors are responsible for this: the distribution of subpar medicines; the prescription of insufficient drug doses, resulting in the survival of some parasites in patients; and the inability of genetic recombination to eliminate resistance-conferring genes from the parasitic gene pool (Parker et al, 2015) As a result, the border provinces are effectively an incubator from which multiple drug-resistant malaria strains can spread to infinitely larger city populations. 

The use of different ACT drugs is the next step in tackling drug-resistant malaria. Combinations of artemether-lumefantrine and dihydroartemisinin-piperaquine are now gaining fame on prescription sheets (Hutagalung, 2005). This is only a temporary solution. A selective pressure is always accompanied by a phenotypic adaptation, and in the case of malaria, drug use will continue to favour the selective survival of resistant parasites. Any further attempts at malaria eradication will depend on the discovery of new molecular targets, which could be any one of the numerous biomolecules involved at different stages of the infection cycle. The future of malaria at the Thai/Myanmar border is ambiguous, and fresh ideas on parasite-drug interactions are needed to turn the tide in our favour. 

References:

Hutagalung, R., (2005). A randomized trial of artemether-lumefantrine versus mefloquine-artesunate for the treatment of uncomplicated multi-drug resistant Plasmodium falciparum on the western border of Thailand. Malaria Journal [online]. 4(46). [Accessed 25 August 2020]. Available from: doi: 10.1186/1475-2875-4-46

Price, R N., (1999). The pfmdr1 Gene Is Associated with a Multidrug-Resistant Phenotype in Plasmodium falciparum from the Western Border of Thailand. Antimicrobial Agents and Chemotherapy [online]. 43(12), 2943-2949. [Accessed 24 August 2020]. Available from: 10.1128/AAC.43.12.2943

Slater, A F., (1993). Chloroquine: mechanism of drug action and resistance in Plasmodium falciparum. Pharmacology & Therapeutics [online]. 53(2), 203-235. [Accessed 22 August 2020]. Available from: doi: 10.1016/0163-7258(93)90056-j

Yaro, A., (2009). Mechanisms of sulfadoxine pyrimethamine resistance and health implication in Plasmodium falciparum malaria: A mini review. Annals of Tropical Medicine and Public Health [online]. 2(1), 20-23. [Accessed 23 August 2020]. Available from: http://www.atmph.org/article.asp?issn=1755-6783;year=2009;volume=2;issue=1;spage=20;epage=23;aulast=Yaro

Burns, A L. et al., (2019). Targeting malaria parasite invasion of red blood cells as an antimalarial strategy. FEMS Microbiology Review [online]. 43(3), 223-238. [Accessed 22 August 2020]. Available from: doi: 10.1093/femsre/fuz005

Parker, D M. et al., (2015). Malaria ecology along the Thailand-Myanmar border. Malaria Journal [online]. 14(388). [Accessed 20 August 2020]. Available from: doi: 10.1186/s12936-015-0921-y

Phyo, A P. et al., (2016). Declining Efficacy of Artemisinin Combination Therapy Against P. Falciparum Malaria on the Thai–Myanmar Border (2003–2013): The Role of Parasite Genetic Factors. Clinical Infectious Diseases [online]. 63(6), 784-791. [Accessed 20 August 2020]. Available from: doi: 10.1093/cid/ciw388

Shoklo Malaria Research Unit, (2013). Malaria epidemiology along the Thai-Myanmar border [Data set]. Mae Sot: Mahidol Oxford. [Accessed 21 August 2020]. Available from: https://www.shoklo-unit.com/sites/default/files/reports/malaria-task-force.pdf

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