Rehana Hassen Anthro 408 Rough Draft Research Paper Malaria, Drug Resistance in South East Asia Resistance to the world’s best and most effective anti-malarial drugs is widespread across mainland Southeast Asia, and this has severely threatened the global malaria control and elimination initiatives. In the recent past, however, there had been a significant outbreak of malaria in these tourists attractions site of Southeastern Asia. Malaria has always been neglected even though research has shown a lot of susceptibility of the disease across those mentioned above Southeast Asian countries. Importantly, scientists are concerned that the resistant parasite can spread to another part of the world if not they will not be eliminated on time. Due to these concerns, this paper examines the origin of anti-malarial drugs parasites and the strategies that can be applied to eliminate the resistance. Antimalarial drug resistance is not a new challenge. This is because during the periods of the 1970s and 1980s, Plasmodium falciparum which is a species of parasite that is causing most rapid and most common severe malarial infections was reported to have developed resistance to the initially developed malaria medicines such as sulfadoxine-pyrimethamine (SP) and chloroquine. As a result, Artemisinin-based combination therapies or ACTs, which was introduced in the 1990s were the most efficient and effective medicine in the treatment of malaria. Additionally, which is extracted from Artemisia annual (sweet wormwood plant) was used together with other antimalarial drugs (Artemether-Quinine Meta-analysis Study Group, 2011). However, artemisinin usually kills all the malarial parasites and the application of a combination of several drugs as opposed to using one drug assist in ensuring that other drugs will kill any parasite that remains before the resistant parasite is spread. However, in South East Asia, some malaria parasite developed resistance to artemisinin-based drugs. Primarily, resistance can acknowledge when there is a significant delay in the time it takes for the malaria parasite to be cleared for the infected individual since this shows a decline in the efficacy of the medicine. Resistance to be first reported in Thailand along the Thailand-Cambodia border in 2008 and it has continued spreading to another region. To date, it has been identified in four countries Cambodia, Vietnam, Thailand, and Myanmar (Amato, Pearson, Almagro-Garcia, Amaratunga, and Suon, 2018). Specifically, a recent study in the Lancet infectious diseases established that the first line resistance to malaria in Southeast Asia started merging several years before it was first identified and it is linked to an aggressive strain which has spread across the area. According to the experts, these findings raise important questions on the future efforts of global malaria control as noted by Amato et al., (2018). Furthermore, the discovery of a malaria strain which is resistant to artemisinin-based combination therapy (ACT), which is the most recommended most effective first-line malaria treatment should be a concern since it will tremendously derail all the progress that has been made against malaria parasites. For instance, according Amato et al., (2018), since 2010, the global malaria incidence has reduced by almost 20% with the most declines reported in Southeast Asia and mortality due to malaria has declined to 44% and this is mostly due to ACT. However, there was the first clinical report in 2013 about the malaria treatment failure among the patients after taking piperaquine and dihydroartemisinin, which if a type of ACT, started emerging in western parts of Cambodia five years after its introduction. Since this time, treatment failure frequencies among patients receiving this combination treatment begin increasing throughout Cambodia and the neighboring countries such as Vietnam, Thailand, and Myanmar (Dondorp, Newton, Mayxay, Van Damme, Smithui, Yeung, McGready, 2014) Importantly, the experts have been alarmed by the outbreak in Thailand, Cambodia, Laos, and presently in Vietnam of untreatable malaria with the most recent and most effective drugs. As a result, the experts have been requesting for the World Health Organization to declare a public health emergency of global concern as it did with Zika virus in Brazil and Ebola in West Africa (Dondorp et al., 2014). This is because, today, there is no equally effective and best drug to cure malaria, and the artemisinin resistance spread across Asia and beyond could be among the catastrophic set back to global efforts of controlling and eliminating malaria. Moreover, mortality rates and rates of infection could significantly increase in the region thus reversing the progress made in the control of malaria (Dondorp et al., 2014). This predicament is at the prospect of losing artemisinin drug efficacy which together with insecticide-impregnated bed nets are the most potent methods of combatting malaria. Importantly, it was expected that malarial infections which are responsible for more than half a million death annually, mostly pregnant women and children could be eliminated. However, these international efforts could all be in vain if the malaria resistance continues spreading under the radar, as the experts discovered it has done for years in southeast Cambodia. For instance, according to a study by Bharati and Ganguly (2013), which investigated the situation in Cambodia from 2008 to 2013, it was primarily reported the drugs were ineffective. This study examined DNA sequence data from about 1600 1500 Plasmodium falciparum parasites for Southeast Asia including 500 collected from Cambodia from 2007 to 2013 (Bharati and Ganguly, 2013). Artemisinins medicines are given together with other antimalarials so that in case one of the drugs starts failing; the others can still effectively eradicate the parasite. Primarily, the combination was dihydroartemisinin and piperaquine (DHA-PPQ) in Cambodia, and the study discovered that single parasite strains were resistant to both medicines from 2008, which was the first year for the drugs to be used and the resistance rapidly spread to other regions. According to the result of the genome sequence, two dihydroartemisinin-piperaquine resistance genetic markers were prominent in the collected samples and was also evident in all 700 0f the 1500 samples (48%) contained mutations of the Kelch13 gene that is responsible for artemisinin resistance, and 200 0f 1500 contained amplification of the plasmepsin 2 and 3 genes which is a piperaquine resistance marker (Bharati and Ganguly, 2013). However, the mutations were more evident in the samples collected from western Cambodia. Later, the scientists searched for samples which had a combination of the markers and discovered 160 parasites which resisted dihydroartemisinin-piperaquine. Importantly, about 90% of the predominant Klech13 mutation lineage (KEL1 lineage) with one predominant plasmepsin two and three mutations lineage (PLA1 lineage) were discovered (Bharati and Ganguly, 2013). Furthermore, investigation showed that these lineages combined in 2008, just sometime after the introduction of dihydroartemisinin-piperaquine therapy. This combination of PLA1 and KEL1 lineages was first confined to western parts of Cambodia, but over time it grew in frequency from 18% of the sample in 208 to 68% of samples in 2013. Additionally, between 2012 and 2013, the researchers established that the resistant parasite had shifted the northern parts of Cambodia and the around Laos. Moreover, the researchers are convinced that the dihydroartemisinin-piperaquine resistant parasites that were found in Laos and Thailand between 2104 and 2016 are likely to have come from KEL1/PLA1 co-lineage (Bharati and Ganguly, 2013). Furthermore, this study has provided by far the most elaborate and comprehensive examination of the parasites that are responsible for the malaria-resistant drugs in Southeast Asia. This is because it shows that resistance to the drug combination appeared almost after the introduction of the therapy as the first-line treatment and that it spread aggressively and rapidly after some time. Also, the study established that even though artemisinin resistance was already present in western Cambodia in 2008, a diverse set of Klech13 mutations was mainly responsible for the resistance. However, the fast spread of KEL1/PLA1 co-lineage demonstrated that that lineage is acquiring more aggressive biological fitness (Dondorp, Newton, Mayxay, Van, Yeung, and McGready, 2014). Most importantly, this finding had severe implications for the effectiveness of ACT Southeast Asia and other regions that are malaria-endemic (Dondorp et al., 2014). Currently, resistance to is limited to the Mekong sub-region, but when it reaches Africa which ranks highest in malaria-pandemics, the result could be devastating. Therefore, this finding reminded them of how chloroquine-resistant malaria began and spread all over the world. This is because the result of the study were expressive of the evolution of chloroquine resistance, wherein pfcrt (P falciparum chloroquine resistance transporter) alleles were discovered in southeast Asia before spreading to Africa leading to more than a million dead. As a result, this scene must be avoided for artemisinin combination treatment (Dondorp et al., 2014). The current situation on Southeast Asia is deadly and fragile since malaria is still incurable and as the scientist suggests, the ACT effectiveness in Southeast Asia could be controlled by the strategic management of treatment and possible application of which is another form of ACT. Nonetheless, there is still uncertainty on the reaction of the parasite and how it will respond to the new technique, and one of the main concerns with this management strategy is that switching therapies could be followed by a similar switch in drug resistance (Dondorp et al., 2014). Similarly, due to this resistance, scientist opted to change the companion drug from piperaquine to mefloquine, which was still effective. However, there was likelihood that the parasite would develop resistance towards that drug also. Therefore another option was using three to four medicines instead of just two, yet future strategies must be constant genetic sequencing and surveillance of the parasite to solve this resistance and to which drugs are allowing only the application of new drugs where they are required (Dondorp et al., 2014). Importantly, International Artemisinin Study (2015) examined the genome sequence data from 1500 p falciparum samples from 12 locations across Southeast Asia including 500 samples were collected on Cambodia from 2008 and 2013. In this study, Dihydroartemisinin-piperaquine was introduced as first-line malaria treatment in southeast Cambodia and in spite of artemisinin resistance emergence resistance Cambodia; the treatment combination was effective initially even though there was a delay in effectiveness. Mainly, what this result shows is that experts now have tools for tracking genetic mutations in malaria and can respond expeditiously to contain the resistance spread. Therefore, by using the right technology and concerted efforts, a significant outbreak in malaria drug resistance should not go unidentified in the future, and the global health emergence risk should be minimized (International Artemisinin Study, 2015). Also, experts have suggested that there should be more than just high-resolution genetic surveillance. The reason is that drug resistance strain usually starts developing in the Mekong region and then begins spreading everywhere. Hence the countries in that region and the global health organization should be pushing to eliminate malaria in that region by having aggressive malaria eradication using the necessary means (International Artemisinin Study, 2015). Fundamentally, containing and controlling the antimalarial resistance in Southeast Asia and preventing the resistant virus from spreading to other areas mostly Africa should be a global health priority. Mostly, continuous drug resistance maintenance in malaria-endemic regions tighter with research on the various contribution elements will help health practitioners to more effectively control and prevent the spread of drug resistance (Trung, Bortel, Sochantha, Keokenchanh, Quang, Cong, Coosemans, 2013). Additionally, a significant focus on resistance containment programs should involve completely shunning the application of monotherapies that are based on artemisinin. For instance, in South East Asia where the transmission of malaria is relatively low, containment programs should emphasize the eradication of P. falciparum parasites. This is because the elimination of these parasites would be the best strategy to stop the resistance completely. However, areas with a high rate of malaria transmission such as Cambodia, decreasing the resistance spread risks may be possible by investing more in malaria control efforts (Trung et al., 2013). In summary, resistance to the world’s best and most effective anti-malarial drugs is widespread across the mainland southeast Asia and scientists are concerned that the resistant parasite can spread to another part of the world if not they will not be eliminated on time. Researchers have established that the resistance originated from KEL1/PLA1 co-lineage mutation. Also, it is evident it began in Cambodia before spreading to other regions. Most importantly, scientists have proposed various techniques of eliminating the drug-resistant parasites such suing another ACT combination. However, each of the scientific strategies methods have some uncertainties and risks since the drug switch can also result in a resistance switch. Therefore more research should be done to develop the most comprehensive and effective elimination of the resistance malarial parasites. Most importantly, most of these parasites originate from the Mekong region. As a result, all the neighboring countries and the globe as a whole should focus more on eliminating malaria in this region and combat the situation early. References Artemether-Quinine Meta-analysis Study Group. (2011). A meta-analysis using individual Patient data of trials comparing artemether with quinine in the treatment of severe falciparum malaria in Southeast Asia. Transactions of the Royal Society of Tropical Medicine and Hygiene, 95(6), 637-650. Amato, R., Pearson, R. D., Almagro-Garcia, J., Amaratunga, C., Lim, P., Suon, S., & Fairhurst, R. M. (2018). Origins of the current outbreak of multidrug-resistant malaria in Southeast Asia: a retrospective genetic study. The Lancet Infectious Diseases, 18(3), 337-345. Retrieved on October 25, 2018, from; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835763/ Bharati, K., & Ganguly, N. K. (2013). Tackling the malaria problem in South-East Asia Region: the need for a change in policy?. The Indian journal of medical research, 137(1), 36. Retrieved on October 25, 2018, from; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657896/ Dondorp, A. M., Newton, P. N., Mayxay, M., Van Damme, W., Smithuis, F. M., Yeung, S., ... & McGready, R. (2014). Fake antimalarials in Southeast Asia are a major impediment to malaria control: a multinational cross‐sectional survey on the prevalence of fake antimalarials. Tropical Medicine & International Health, 9(12), 1241-1246. International Artemisinin Study Group. (2015). Artesunate combinations for treatment of malaria In Southeast Asia: a meta-analysis. The Lancet, 363(9402), 9-17. Trung, H. D., Van Bortel, W., Sochantha, T., Keokenchanh, K., Quang, N. T., Cong, L. D., & Coosemans, M. (2013). Malaria transmission and major malaria vectors in different geographical areas of Southeast Asia. Tropical Medicine & International Health, 9(2), 230-237.
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