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The effectiveness of three therapies for uncomplicated falciparum malaria was evaluated in Oddar Meanchey province in Northern Cambodia from 2009 to 2011.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this randomized, open-label, parallel group-controlled trial, 211 subjects at least 5\u00a0years old with uncomplicated falciparum malaria were treated with 3\u00a0days of directly observed therapy: 63 received artesunate\u2013mefloquine (AS\/MQ), 77 received dihydroartemisinin\u2013piperaquine (DHA\/PPQ), and 71 received atovaquone\u2013proguanil (ATQ\/PG). The subjects were followed for 42\u00a0days or until recurrent parasitaemia. Genotyping of\n                      <jats:italic>msp1<\/jats:italic>\n                      ,\n                      <jats:italic>msp2<\/jats:italic>\n                      , and\n                      <jats:italic>glurp<\/jats:italic>\n                      among individual parasite isolates distinguished recrudescence from reinfection.\n                      <jats:italic>Pfmdr1<\/jats:italic>\n                      copy number was measured by real-time PCR and half-maximal parasite inhibitory concentrations (IC\n                      <jats:sub>50<\/jats:sub>\n                      ) were measured in vitro by 48-h isotopic hypoxanthine incorporation assay.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The per-protocol PCR-adjusted efficacy (95% confidence interval) at 42\u00a0days was 80.6% (70.8\u201390.5%) for AS\/MQ, 97.2% (93.3\u2013100%) for DHA\/PPQ, and 92.9% (86.1\u201399.6%) for ATQ\/PG. On day 3, 57.9% remained parasitaemic in the AS\/MQ and DHA\/PPQ arms. At baseline, 46.9% had microscopic\n                      <jats:italic>Plasmodium falciparum<\/jats:italic>\n                      gametocytaemia. Both recurrences in the DHA\/PPQ arm lost\n                      <jats:italic>Pfmdr1<\/jats:italic>\n                      copy number amplification at recrudescence. All four recurrences in the ATQ\/PG arm were wild-type for cytochrome bc\n                      <jats:sub>1<\/jats:sub>\n                      . One subject withdrew from the ATQ\/PG arm due to drug allergy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This study was conducted at the epicentre of substantial multi-drug resistance that emerged soon thereafter. Occurring early in the national transition from AS\/MQ to DHA\/PPQ, both DHA\/PPQ and ATQ\/PG had acceptable efficacy against uncomplicated falciparum malaria. However, efficacy of AS\/MQ was only 80% with apparent mefloquine resistance based on elevated\n                      <jats:italic>Pfmdr1<\/jats:italic>\n                      copy number and IC\n                      <jats:sub>50<\/jats:sub>\n                      . By 2009, there was already significant evidence of artemisinin resistance not previously reported at the Northern Cambodia\u2013Thai border. This study suggests the basis for early development of significant DHA\/PPQ failures within 3\u00a0years of introduction. Artemisinin resistance likely occurred on the Northern border concurrently with that reported along the Western border in Pailin.\n                    <\/jats:p>\n                    <jats:p>\n                      <jats:italic>Trial registration<\/jats:italic>\n                      This legacy trial was conducted prior to International Committee of Medical Journal Editors\u2019 requirements for preregistration on ClinicalTrials.gov. The full protocol has been provided.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12936-022-04279-3","type":"journal-article","created":{"date-parts":[[2022,9,7]],"date-time":"2022-09-07T06:06:37Z","timestamp":1662530797000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Efficacy of three anti-malarial regimens for uncomplicated Plasmodium falciparum malaria in Cambodia, 2009\u20132011: a randomized controlled trial and brief review"],"prefix":"10.1186","volume":"21","author":[{"given":"Dysoley","family":"Lek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agus","family":"Rachmat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dustin","family":"Harrison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey","family":"Chin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suwanna","family":"Chaoratanakawee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Saunders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Menard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William O.","family":"Rogers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,9,7]]},"reference":[{"key":"4279_CR1","doi-asserted-by":"publisher","first-page":"12","DOI":"10.4269\/ajtmh.2001.64.12","volume":"64","author":"JF Trape","year":"2001","unstructured":"Trape JF. 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