| Summary: | This review article aims to investigate the genotypic profiles of <i>Plasmodium falciparum</i> and <i>Plasmodium vivax</i> isolates collected across a wide geographic region and their association with resistance to anti-malarial drugs used in Indonesia. A systematic review was conducted between 1991 and date. Search engines, such as PubMed, Science Direct, and Google Scholar, were used for articles published in English and Indonesian to search the literature. Of the 471 initially identified studies, 61 were selected for 4316 <i>P. falciparum</i> and 1950 <i>P. vivax</i> individual infections. The studies included 23 molecular studies and 38 therapeutic efficacy studies. K76T was the most common <i>pfcrt</i> mutation. K76<u><strong>N</strong></u> (2.1%) was associated with the haplotype CVMN<u><strong>N</strong></u>. By following dihydroartemisinin–piperaquine (DHA–PPQ) therapy, the mutant <i>pfmdr1</i> alleles 86Y and 1034C were selected. Low prevalence of haplotype N86<u><strong>Y</strong></u>/Y184/D1246<u><strong>Y</strong></u> <i>pfmdr1</i> reduces susceptibility to AS–AQ. SNP mutation <i>pvmdr1</i> Y976F reached 96.1% in Papua and East Nusa Tenggara. Polymorphism analysis in the <i>pfdhfr</i> gene revealed 94/111 (84.7%) double mutants S108<u><strong>N</strong></u>/C59<u>R</u> or S108<u><strong>T</strong></u>/A16<u><strong>V</strong></u> in Central Java. The predominant <i>pfdhfr</i> haplotypes (based on alleles 16, 51, 59,108, 164) found in Indonesia were ANC<u><strong>N</strong></u>I, ANCSI, AN<u><strong>RN</strong></u>I, and AN<u><strong>RN</strong></u>L. Some isolates carried A437<u><strong>G</strong></u> (35.3%) or A437<u><strong>G</strong></u>/K540<u><strong>E</strong></u> SNPs (26.5%) in <i>pfdhps</i>. Two novel <i>pfdhps</i> mutant alleles, I588<u><strong>F</strong></u>/<u><strong>G</strong></u> and K540<u><strong>T</strong></u>, were associated with six <i>pfdhps</i> haplotypes. The highest prevalence of <i>pvdhfr</i> quadruple mutation (F57<u><strong>L</strong></u>/S58<u><strong>R</strong></u>/T61<u><strong>M</strong></u>/S117<u><strong>T</strong></u>) (61.8%) was detected in Papua. In <i>pvdhps</i>, the only polymorphism before and after 2008 was 383G mutation with 19% prevalence. There were no mutations in the <i>pfk13</i> gene reported with validated and candidate or associated <i>k13</i> mutation. An increased copy number of <i>pfpm2</i>, associated with piperaquine resistance, was found only in cases of reinfection. Meanwhile, mutation of <i>pvk12</i> and <i>pvpm4</i> I165V is unlikely associated with ART and PPQ drug resistance. DHA–PPQ is still effective in treating uncomplicated falciparum and vivax malaria. Serious consideration should be given to interrupt local malaria transmission and dynamic patterns of resistance to anti-malarial drugs to modify chemotherapeutic policy treatment strategies. The presence of several changes in <i>pfk13</i> in the parasite population is of concern and highlights the importance of further evaluation of parasitic ART susceptibility in Indonesia.
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