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      Chloroquine and Sulfadoxine–Pyrimethamine Resistance in Sub-Saharan Africa—A Review

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          Abstract

          Malaria is a great concern for global health and accounts for a large amount of morbidity and mortality, particularly in Africa, with sub-Saharan Africa carrying the greatest burden of the disease. Malaria control tools such as insecticide-treated bed nets, indoor residual spraying, and antimalarial drugs have been relatively successful in reducing the burden of malaria; however, sub-Saharan African countries encounter great challenges, the greatest being antimalarial drug resistance. Chloroquine (CQ) was the first-line drug in the 20th century until it was replaced by sulfadoxine–pyrimethamine (SP) as a consequence of resistance. The extensive use of these antimalarials intensified the spread of resistance throughout sub-Saharan Africa, thus resulting in a loss of efficacy for the treatment of malaria. SP was replaced by artemisinin-based combination therapy (ACT) after the emergence of resistance toward SP; however, the use of ACTs is now threatened by the emergence of resistant parasites. The decreased selective pressure on CQ and SP allowed for the reintroduction of sensitivity toward those antimalarials in regions of sub-Saharan Africa where they were not the primary drug for treatment. Therefore, the emergence and spread of antimalarial drug resistance should be tracked to prevent further spread of the resistant parasites, and the re-emergence of sensitivity should be monitored to detect the possible reappearance of sensitivity in sub-Saharan Africa.

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          Most cited references179

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          Reemergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi.

          In 1993, Malawi became the first African country to replace chloroquine with sulfadoxine-pyrimethamine nationwide in response to high rates of chloroquine-resistant falciparum malaria. To determine whether withdrawal of chloroquine can lead to the reemergence of chloroquine sensitivity, the prevalence of the pfcrt 76T molecular marker for chloroquine-resistant Plasmodium falciparum malaria was retrospectively measured in Blantyre, Malawi. The prevalence of the chloroquine-resistant pfcrt genotype decreased from 85% in 1992 to 13% in 2000. In 2001, chloroquine cleared 100% of 63 asymptomatic P. falciparum infections, no isolates were resistant to chloroquine in vitro, and no infections with the chloroquine-resistant pfcrt genotype were detected. A concerted national effort to withdraw chloroquine from use has been followed by a return of chloroquine-sensitive falciparum malaria in Malawi. The reintroduction of chloroquine, ideally in combination with another antimalarial drug, should be considered in areas where chloroquine resistance has declined and safe and affordable alternatives remain unavailable.
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            A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites

            Artemisinin and its derivatives (ARTs) are the frontline drugs against malaria, but resistance is jeopardizing their effectiveness. ART resistance is mediated by mutations in the parasite’s Kelch13 protein, but Kelch13 function and its role in resistance remain unclear. In this study, we identified proteins located at a Kelch13-defined compartment. Inactivation of eight of these proteins, including Kelch13, rendered parasites resistant to ART, revealing a pathway critical for resistance. Functional analysis showed that these proteins are required for endocytosis of hemoglobin from the host cell. Parasites with inactivated Kelch13 or a resistance-conferring Kelch13 mutation displayed reduced hemoglobin endocytosis. ARTs are activated by degradation products of hemoglobin. Hence, reduced activity of Kelch13 and its interactors diminishes hemoglobin endocytosis and thereby ART activation, resulting in parasite resistance.
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              Malaria

              Malaria is the most important parasitic infection in people, accounting for more than 1 million deaths a year. Malaria has become a priority for the international health community and is now the focus of several new initiatives. Prevention and treatment of malaria could be greatly improved with existing methods if increased financial and labour resources were available. However, new approaches for prevention and treatment are needed. Several new drugs are under development, which are likely to be used in combinations to slow the spread of resistance, but the high cost of treatments would make sustainability difficult. Insecticide-treated bed-nets provide a simple but effective means of preventing malaria, especially with the development of longlasting nets in which insecticide is incorporated into the net fibres. One malaria vaccine, RTS,S/AS02, has shown promise in endemic areas and will shortly enter further trials. Other vaccines are being studied in clinical trials, but it will probably be at least 10 years before a malaria vaccine is ready for widespread use.
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                Author and article information

                Contributors
                Journal
                Front Genet
                Front Genet
                Front. Genet.
                Frontiers in Genetics
                Frontiers Media S.A.
                1664-8021
                25 June 2021
                2021
                : 12
                : 668574
                Affiliations
                [1] 1Discipline of Genetics, School of Life Sciences, University of KwaZulu-Natal , Westville, South Africa
                [2] 2Office of Malaria Research, South African Medical Research Council , Cape Town, South Africa
                Author notes

                Edited by: Apichai Tuanyok, University of Florida, United States

                Reviewed by: Rajeev Kumar Mehlotra, Case Western Reserve University, United States; Chenqi Wang, University of South Florida, United States

                *Correspondence: Moses Okpeku, okpekum@ 123456ukzn.ac.za

                This article was submitted to Evolutionary and Genomic Microbiology, a section of the journal Frontiers in Genetics

                Article
                10.3389/fgene.2021.668574
                8267899
                34249090
                65797fc4-05e2-4d49-8917-a3b2e0b825f6
                Copyright © 2021 Roux, Maharaj, Oyegoke, Akoniyon, Adeleke, Maharaj and Okpeku.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 16 February 2021
                : 20 April 2021
                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 180, Pages: 15, Words: 0
                Categories
                Genetics
                Review

                Genetics
                antimalarial drug resistance,chloroquine,malaria,malaria control,sulfadoxine–pyrimethamine

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