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Safety and effectiveness of mass drug administration to accelerate elimination of artemisinin-resistant falciparum malaria: A pilot trial in four villages of Eastern Myanmar.

ABSTRACT: Background: Artemisinin and partner drug-resistant falciparum malaria is expanding over the Greater Mekong Sub-region (GMS). Eliminating falciparum malaria in the GMS while drugs still retain enough efficacy could prevent global spread of antimalarial resistance. Eliminating malaria rapidly requires targeting the reservoir of asymptomatic parasite carriers. This pilot trial aimed to evaluate the acceptability, safety, feasibility and effectiveness of mass-drug administration (MDA) in reducing malaria in four villages in Eastern Myanmar. Methods: Villages with ?30% malaria prevalence were selected. Long-lasting insecticidal bednets (LLINs) and access to malaria early diagnosis and treatment (EDT) were provided. Two villages received MDA immediately and two were followed for nine months pre-MDA. MDA consisted of a 3-day supervised course of dihydroartemisinin-piperaquine and single low-dose primaquine administered monthly for three months. Adverse events (AE) were monitored by interviews and consultations. Malaria prevalence was assessed by ultrasensitive PCR quarterly for 24 months. Symptomatic malaria incidence,entomological indices, and antimalarial resistance markers were monitored. Results: MDA was well tolerated. There were no serious AE and mild to moderate AE were reported in 5.6%(212/3931) interviews. In the smaller villages, participation to three MDA courses was 61% and 57%, compared to 28% and 29% in the larger villages. Baseline prevalence was higher in intervention than in control villages (18.7% (95%CI=16.1-21.6) versus 6.8%(5.2-8.7), p<0.0001) whereas three months after starting MDA, prevalence was lower in intervention villages (0.4%(0.04-1.3) versus 2.7%(1.7-4.1), p=0.0014). After nine months the difference was no longer significant (2.0%(1.0-3.5) versus 0.9%(0.04-1.8), p=0.10). M0-M9 symptomatic falciparum incidence was similar between intervention and control. Before/after MDA comparisons showed that asymptomatic P. falciparum carriage and anopheline vector positivity decreased significantly whereas prevalence of the artemisinin-resistance molecular marker remained stable. Conclusions: This MDA was safe and feasible, and, could accelerate elimination of P. falciparum in addition to EDT and LLINs when community participation was sufficient.

SUBMITTER: Landier J

PROVIDER: S-EPMC5635445 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Safety and effectiveness of mass drug administration to accelerate elimination of artemisinin-resistant falciparum malaria: A pilot trial in four villages of Eastern Myanmar.

Landier Jordi J Kajeechiwa Ladda L Thwin May Myo MM Parker Daniel M DM Chaumeau Victor V Wiladphaingern Jacher J Imwong Mallika M Miotto Olivo O Patumrat Krittaya K Duanguppama Jureeporn J Cerqueira Dominique D Malleret Benoit B Rénia Laurent L Nosten Suphak S von Seidlein Lorenz L Ling Clare C Proux Stéphane S Corbel Vincent V Simpson Julie A JA Dondorp Arjen M AM White Nicholas J NJ Nosten François H FH

Wellcome open research 20170906

<b>Background:</b> Artemisinin and partner drug-resistant falciparum malaria is expanding over the Greater Mekong Sub-region (GMS). Eliminating falciparum malaria in the GMS while drugs still retain enough efficacy could prevent global spread of antimalarial resistance. Eliminating malaria rapidly requires targeting the reservoir of asymptomatic parasite carriers. This pilot trial aimed to evaluate the acceptability, safety, feasibility and effectiveness of mass-drug administration (MDA) in redu ...[more]

PMID: 29062913

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Project description:BackgroundMalaria elimination requires a variety of approaches individually optimized for different transmission settings. A recent field study in an area of low seasonal transmission in South West Cambodia demonstrated dramatic reductions in malaria parasite prevalence following both mass drug administration (MDA) and high treatment coverage of symptomatic patients with artemisinin-piperaquine plus primaquine. This study employed multiple combined strategies and it was unclear what contribution each made to the reductions in malaria.Method and findingsA mathematical model fitted to the trial results was used to assess the effects of the various components of these interventions, design optimal elimination strategies, and explore their interactions with artemisinin resistance, which has recently been discovered in Western Cambodia. The modelling indicated that most of the initial reduction of P. falciparum malaria resulted from MDA with artemisinin-piperaquine. The subsequent continued decline and near elimination resulted mainly from high coverage with artemisinin-piperaquine treatment. Both these strategies were more effective with the addition of primaquine. MDA with artemisinin combination therapy (ACT) increased the proportion of artemisinin resistant infections, although much less than treatment of symptomatic cases with ACT, and this increase was slowed by adding primaquine. Artemisinin resistance reduced the effectiveness of interventions using ACT when the prevalence of resistance was very high. The main results were robust to assumptions about primaquine action, and immunity.ConclusionsThe key messages of these modelling results for policy makers were: high coverage with ACT treatment can produce a long-term reduction in malaria whereas the impact of MDA is generally only short-term; primaquine enhances the effect of ACT in eliminating malaria and reduces the increase in proportion of artemisinin resistant infections; parasite prevalence is a better surveillance measure for elimination programmes than numbers of symptomatic cases; combinations of interventions are most effective and sustained efforts are crucial for successful elimination.

Project description:BackgroundArtemisinin resistance has been reported in Greater Mekong Sub-region countries, including Myanmar. After discovery of artemisinin resistance marker (K13), molecular surveillance on artemisinin resistance in endemic regions have been conducted. As the migrant population represents a high percentage of malaria cases, molecular surveillance of artemisinin resistance among migrant workers is of great concern.MethodsA cross-sectional survey was conducted in Shwegyin Township, where migrants work in the goldmines. Blood samples were collected from uncomplicated Plasmodium falciparum-infected migrant workers by active and passive cases screening with rapid diagnostic testing (RDT) and microscopy. Amplification and sequence analysis of artemisinin resistance molecular markers, such as k13, pfarps10, pffd, pfmdr2, pfmrp1, pfrad5, and pfcnbp, were carried out and pfmdr1 copy number analysis was conducted by real-time PCR.ResultsAmong the 100 falciparum-infected patients, most were male (90%), of working age (20-40 years) with median parasite density of 11,166 parasites/µL (range 270-110,472 parasites/µL). Artemisinin resistance molecular marker, k13 mutations were detected in (21/100, 21.0%) in which composed of a validated marker, C580Y (9/21, 42.9%) and candidate markers such as P574L (5/21, 23.8%), P667T (5/21, 23.8%) and M476I (2/21, 9.5%). Underlying genetic markers predisposing to become k13 mutants were found as V127M of pfarps10 (41/100, 41.0%), D153Y of pffd (64/100, 64.0%), T484I of pfmdr2 (58/100, 58.0%) and F1390I of pfmrp1 (24/100, 24.0%). The pfmdr1 copy number analysis revealed six copy numbers (1/100, 1.0%), three (2/100, 2.0%), two (8/100, 8.0%) and only one copy number (89/100, 89.0%). Only one sample showed both k13 mutation (P667T) and multiple copy number of pfmdr1.ConclusionsHigh mutant rate of artemisinin resistance markers and relatively high pfmdr1 copy number among isolates collected from migrant goldmine workers alert the importance of containment measures among this target population. Clinical and molecular surveillance of artemisinin resistance among migrants should be scaled up.

Project description:BackgroundPotentially untreatable Plasmodium falciparum malaria threatens the Greater Mekong subregion. A previous series of pilot projects in Myanmar, Laos, Cambodia, and Vietnam suggested that mass drug administration was safe, and when added to provision of early diagnosis and treatment, could reduce the reservoir of P falciparum and interrupts transmission. We examined the effects of a scaled-up programme of this strategy in four townships of eastern Myanmar on the incidence of P falciparum malaria.MethodsThe programme was implemented in the four townships of Myawaddy, Kawkareik, Hlaingbwe, and Hpapun in Kayin state, Myanmar. Increased access to early diagnosis and treatment of malaria was provided to all villages through community-based malaria posts equipped with rapid diagnostic tests, and treatment with artemether-lumefantrine plus single low-dose primaquine. Villages were identified as malarial hotspots (operationally defined as >40% malaria, of which 20% was P falciparum) with surveys using ultrasensitive quantitative PCR either randomly or targeted at villages where the incidence of clinical cases of P falciparum malaria remained high (ie, >100 cases per 1000 individuals per year) despite a functioning malaria post. During each survey, a 2 mL sample of venous blood was obtained from randomly selected adults. Hotspots received targeted mass drug administration with dihydroartemisinin-piperaquine plus single-dose primaquine once per month for 3 consecutive months in addition to the malaria posts. The main outcome was the change in village incidence of clinical P falciparum malaria, quantified using a multivariate, generalised, additive multilevel model. Malaria prevalence was measured in the hotspots 12 months after mass drug administration.FindingsBetween May 1, 2014, and April 30, 2017, 1222 malarial posts were opened, providing early diagnosis and treatment to an estimated 365 000 individuals. Incidence of P falciparum malaria decreased by 60 to 98% in the four townships. 272 prevalence surveys were undertaken and 69 hotspot villages were identified. By April 2017, 50 hotspots were treated with mass drug administration. Hotspot villages had a three times higher incidence of P falciparum at malarial posts than neighbouring villages (adjusted incidence rate ratio [IRR] 2·7, 95% CI 1·8-4·4). Early diagnosis and treatment was associated with a significant decrease in P falciparum incidence in hotspots (IRR 0·82, 95% CI 0·76-0·88 per quarter) and in other villages (0·75, 0·73-0·78 per quarter). Mass drug administration was associated with a five-times decrease in P falciparum incidence within hotspot villages (IRR 0·19, 95% CI 0·13-0·26). By April, 2017, 965 villages (79%) of 1222 corresponding to 104 village tracts were free from P falciparum malaria for at least 6 months. The prevalence of wild-type genotype for K13 molecular markers of artemisinin resistance was stable over the three years (39%; 249/631).InterpretationProviding early diagnosis and effective treatment substantially decreased village-level incidence of artemisinin-resistant P falciparum malaria in hard-to-reach, politically sensitive regions of eastern Myanmar. Targeted mass drug administration significantly reduced malaria incidence in hotspots. If these activities could proceed in all contiguous endemic areas in addition to standard control programmes already implemented, there is a possibility of subnational elimination of P falciparum.FundingThe Bill & Melinda Gates Foundation, the Regional Artemisinin Initiative (Global Fund against AIDS, Tuberculosis and Malaria), and the Wellcome Trust.

Project description:BackgroundArtemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance.MethodsIn two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance.ResultsWe studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P=0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups.ConclusionsP. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.)

Dataset Information

Safety and effectiveness of mass drug administration to accelerate elimination of artemisinin-resistant falciparum malaria: A pilot trial in four villages of Eastern Myanmar.

Publications

Safety and effectiveness of mass drug administration to accelerate elimination of artemisinin-resistant falciparum malaria: A pilot trial in four villages of Eastern Myanmar.

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