Plasmodium falciparum and Plasmodium vivax infections are important causes of adverse pregnancy outcomes in the Asia-Pacific region. We hypothesised that monthly intermittent preventive treatment (IPT) or intermittent screening and treatment (IST) with dihydroartemisinin-piperaquine is more effective in reducing malaria in pregnancy than the existing single screening and treatment (SST) strategy, which is used to screen women for malaria infections at the first antenatal visit followed by passive case detection, with management of febrile cases.
Anopheles sundaicus s.l. is an important malaria vector primarily found in coastal landscapes of western and central Indonesia. The species complex has a wide geographical distribution in South and Southeast Asia and exhibits ecological and behavioural variability over its range. Studies on understanding the distribution of different members in the complex and their bionomics related to malaria transmission might be important guiding more effective vector intervention strategies. Female An. sundaicus s.l. were collected from seven provinces, 12 locations in Indonesia representing Sumatra: North Sumatra, Bangka-Belitung, South Lampung, and Bengkulu; in Java: West Java; and the Lesser Sunda Islands: West Nusa Tenggara and East Nusa Tenggara provinces. Sequencing of ribosomal DNA ITS2 gene fragments and two mitochondrial DNA gene markers, COI and cytb, enabled molecular identification of morphologically indistinguishable members of the complex. Findings allowed inference on the distribution of the An. sundaicus s.l. present in Indonesia and further illustrate the phylogenetic relationships of An. epiroticus within the complex. A total of 370 An. sundaicus s.l specimens were analysed for the ITS2 fragment. The ITS2 sequence alignment revealed two consistent species-specific point mutations, a T>C transition at base 479 and a G>T transversion at base 538 that differentiated five haplotypes: TG, CG, TT, CT, and TY. The TG haplotype matched published An. epiroticus-indicative sequences from Thailand, Vietnam and peninsular Malaysia. The previously described insertion event (base 603) was observed in all identified specimens. Analysis of the COI and cytb genes revealed no consistent nucleotide variations that could definitively distinguish An. epiroticus from other members in the Sundaicus Complex. The findings indicate and support the existence of An. epiroticus in North Sumatra and Bangka-Belitung archipelago. Further studies are recommended to determine the full distributional extent of the Sundaicus complex in Indonesia and investigate the role of these species in malaria transmission.
Polymorphism or mutation in specific genes of P. falciparum and P. vivax is involved in the resistance to sulfadoxine-pyrimethamine (SP) antimalarial drug . On the other hand msp-2 gene plays an important role in drug resistance related genotyping. This study was undertaken as a basic information in assessing the urgent of development of malaria vaccine that can be created by ionizing radiation. Deoxy ribonucleic acid (DNA) of blood from malaria infected outpatients in Dok II Hospital of Jayapura for November 2014 period was amplified using nested polymerase chain reaction (PCR) and followed by restriction fragment length polymorphism (RFLP) analysis to determine the polymorphisms of SP resistance. Among 15 samples tested for dhfr gene, 9 (60%) and 8 (53%) samples showed positive result for polymorphisms in JR78/79 and F/108DH primers, respectively. For dhps gene by using JR84/85 and L/L primers 7 samples were positive mutant. These frequencies are lower compared to results of other research. Of these 15 samples examined, 3 had 3D7 alleles and 4 had FC27 alleles of the msp2 gene. No mutated S1105 and S1240 alleles and 6 mutant VDT alleles were found in P. vivax . It can be concluded that the resistance of parasites to SP was quite high, indicating the highly urgency to develop malaria vaccine.
Dihydroartemisinin-piperaquine has been Indonesia's first-line anti-malarial treatment since 2008. Annual therapeutic efficacy studies (TES) done in the last 12 years showed continued high treatment efficacy in uncomplicated Plasmodium falciparum malaria. Although these studies did not show evidence for artemisinin resistance, a slight increase in Late Treatment Failure was observed over time. It is highlight to explore the evolution of genetic markers for ACT partner drug resistance since adopting DHA-PPQ.Dry blood spots were identified from a mass blood survey of uncomplicated falciparum malaria patients (N = 50) in Sumba from 2010 to 2018. Analysis of genotypic profile (N = 51) and a Therapeutic Efficacy Study (TES) from Papua (N = 142) from 2020 to 2021, 42-day follow-up. PCR correction using msp1, msp2, and glurp was used to distinguish recrudescence and reinfection. Parasite DNA from DBSs was used for genotyping molecular markers for antimalaria drug resistance, including in Pfk13, pfcrt, and pfmdr1, as well as gene copy number variation in pfpm2/3 and pfmdr1.The study revealed the absence of SNPs associated with ART resistance and several novel SNPs such as L396F, I526V, M579I and N537S (4.25%). In Sumba, the mutant haplotype SDD of pfmdr1 was found in one-third of the isolates, while only 8.9% in Papua. None of the pfcrt mutations linked to piperaquine resistance were observed, but 71% of isolates had pfcrt I356L. Amplification of the pfpm2/3 genes was in Sumba (17.02%) and Papua (13.7%), while pfmdr1 copy number prevalence was low (3.8%) in both areas. For the TES study, ten recurrences of infection were observed on days 28, 35, and 42. Late parasitological failure (LPF) was observed in 10/117 (8.5%) subjects by microscopy. PCR correction revealed that all nine cases were re-infections and one was confirmed as recrudescence.This study revealed that DHA-PPQ is still highly effective against P. falciparum. The genetic architecture of the parasite P. falciparum isolates during 2010-2021 revealed single copy of Pfpm2 and pfmdr1 were highly prevalent. The slight increase in DHA-PPQ LTF alerts researchers to start testing other ACTs as alternatives to DHA-PPQ for baseline data in order to get a chance of achieving malaria elimination wants by 2030.
Abstract A cluster randomized, double-blinded, placebo-controlled trial was conducted to estimate protective efficacy of a spatial repellent against malaria infection at Sumba, Indonesia. Following radical cure in 1,341 children aged ≥ 6 months - ≤5 years in 24 clusters, households were given transfluthrin or placebo passive emanators (devices designed to release vaporized chemical). Monthly blood screening and biweekly human-landing mosquito catches were performed during 10-months baseline (June 2015 to March 2016) and a 24-month intervention period (April 2016 to April 2018). Screening detected 164 first-time infections and an accumulative total of 459 infections in 667 subjects in placebo-control households; and 134 first-time and 253 accumulative total infections among 665 subjects in active intervention households. The 24-cluster protective effect of 27.7% and 31.3%, for time to first-event and overall (total new) infections, respectively, was not statistically significant. Purportedly, this was due in part to zero to low incidence in some clusters, undermining the ability to detect a protective effect. Subgroup analysis of 19 clusters where at least one infection occurred during baseline showed 33.3% ( p -value = 0.083) and 40.9% ( p -value = 0.0236, statistically significant at the 1-sided 5% significance level) protective effect to first-infection and overall infections, respectively. Among 12 moderate-to high-risk clusters, a statistically significant decrease on infection by intervention was detected (60% protective efficacy). Primary entomological analysis of impact was inconclusive. While this study suggests spatial repellents prevent malaria, additional evidence is required to demonstrate the product class provides an operationally feasible and effective means of reducing malaria transmission.
In the ITS2 fragment sequence analysis subsection of the Results, there is an error in the fifth sentence of the first paragraph.The correct sentence is: For example, a sample from western Sumba (SM1-108) possessed a G>T transversion at nt 538 but lacked a base transition at nt 479 (Fig 2).The images for Figs 3 and 4 are incorrectly switched.The image that appears as Fig 3 should be Fig 4, and the image that appears as Fig 4 should be Fig 3.The figure captions appear in the correct order.Please view the images in the correct order here.Fig 3.The heteroduplex Y (C/T) at nt 538 of the ITS2 fragment observed in 9 Anopheles sundaicus s.l.samples from Bangka-Belitung Province showing evidence of natural species introgression.
Dihydroartemisinin-piperaquine (DP) is a long-acting artemisinin combination treatment that provides effective chemoprevention and has been proposed as an alternative antimalarial drug for intermittent preventive therapy in pregnancy (IPTp). Several pharmacokinetic studies have shown that dose adjustment may not be needed for the treatment of malaria in pregnancy with DP. However, there are limited data on the optimal dosing for IPTp. This study aimed to evaluate the population pharmacokinetics of piperaquine given as IPTp in pregnant women. Pregnant women were enrolled in clinical trials conducted in Kenya and Indonesia and treated with standard 3-day courses of DP, administered in 4- to 8-week intervals from the second trimester until delivery. Pharmacokinetic blood samples were collected for piperaquine drug measurements before each treatment round, at the time of breakthrough symptomatic malaria, and at delivery. Piperaquine population pharmacokinetic properties were investigated using nonlinear mixed-effects modeling with a prior approach. In total, data from 366 Kenyan and 101 Indonesian women were analyzed. The pharmacokinetic properties of piperaquine were adequately described using a flexible transit absorption (n = 5) followed by a three-compartment disposition model. Gestational age did not affect the pharmacokinetic parameters of piperaquine. After three rounds of monthly IPTp, 9.45% (95% confidence interval [CI], 1.8 to 26.5%) of pregnant women had trough piperaquine concentrations below the suggested target concentration (10.3 ng/ml). Translational simulations suggest that providing the full treatment course of DP at monthly intervals provides sufficient protection to prevent malaria infection. Monthly administration of DP has the potential to offer optimal prevention of malaria during pregnancy. (This study has been registered at ClinicalTrials.gov under identifier NCT01669941 and in the ISRCTN under number ISRCTN34010937.).
The East Nusa Tenggara province, Indonesia, contributed to 5% of malaria cases nationally in 2020, with other mosquito-borne diseases, such as dengue and filariasis also being endemic. Monitoring of spatial and temporal vector species compositions and bionomic traits is an efficient method for generating evidence towards intervention strategy optimization and meeting disease elimination goals.The impact of a spatial repellent (SR) on human biting mosquitoes was evaluated as part of a parent cluster-randomized, double-blinded, placebo-controlled trial, in Sumba, East Nusa Tenggara. A 10-month (June 2015-March 2016) baseline study was followed by a 24-month intervention period (April 2016 to April 2018)-where half the clusters were randomly assigned either a passive transfluthrin emanator or a placebo control.Human-landing mosquito catches documented a reduction in landing rates related to the SR. Overall, there was a 16.4% reduction (21% indoors, and 11.3% outdoors) in human biting rates (HBR) for Anopheles. For Aedes, there was a 44.3% HBR reduction indoors and a 35.6% reduction outdoors. This reduction was 38.3% indoors and 39.1% outdoors for Armigeres, and 36.0% indoors and 32.3% outdoors for Culex species. Intervention impacts on the HBRs were not significant and are attributed to large inter-household and inter cluster variation. Anopheles flavirostris, Anopheles balabacensis and Anopheles maculatus individually impacted the overall malaria infections hazard rate with statistically significance. Though there was SR-based protection against malaria for all Anopheles species (except Anopheles sundaicus), only five (Anopheles aconitus, Anopheles kochi, Anopheles tessellatus, An. maculatus and An. sundaicus) demonstrated statistical significance. The SR numerically reduced Anopheles parity rates indoors and outdoors when compared to the placebo.Evidence demonstrating that Anopheles vectors bite both indoors and outdoors indicates that currently implemented indoor-based vector control tools may not be sufficient to eliminate malaria. The documented impact of the SR intervention on Aedes, Armigeres and Culex species points to its importance in combatting other vector borne diseases. Studies to determine the impact of spatial repellents on other mosquito-borne diseases is recommended.
Mosquito sampling methods target different aspects of mosquito behavior and are subject to trap and location specific biases. The barrier screen sampling method was developed and tested to sample free-flying, blood-fed, and host-seeking mosquitoes. During a pilot study, this method was useful in obtaining an unbiased sample of mosquitoes flying between outdoor larval habitats, and sites where blood meals were obtained. However, a relatively small number of blood-fed Anopheles mosquitoes were collected in Indonesia during the pilot study. The sampling method was extended in South Lampung, Indonesia, to enable the collection of blood-fed mosquitoes. This study aimed to intercept mosquitoes flying between human habitations and larval habitats with a barrier screen and to characterize mosquito composition, flight characteristics (direction, height and time), abdominal status, and parity. Barrier screens intercepted 15 different mosquito species in South Lampung: eight Anopheles spp. and seven Culex spp. Species compositions varied among the villages in South Lampung. About 15% of Anopheles spp. caught were blood-fed, of which 28.2% of those tested had fed on humans. This is the first time human blood-fed anophelines have been collected in Indonesia using barrier screens. Blood meals identified included cow, dog, goat, and human, as well as mixed blood meals. Activity of unfed An. subpictus, the primary vector collected, flying towards human habitations peaked between 20:00–12:00 h, with a slow decline in activity until 18:00 h. Unfed and fed An. sundaicus, had a different activity profile compared to An. subpictus. Other species demonstrated varied peak activity times, with earlier activity occurring as a general trend. For the Anopheles mosquitoes collected, 55.5% were collected below 0.5 m and 83.9% were captured resting < 1 m from the ground. Parity dissections enabled age structure by species, which revealed species-specific traits such as nulliparous An. subpictus being more active early in the night relative to An. sundaicus. This study demonstrates that barrier screens are an effective mosquito sampling method that can be used to gain insights into local mosquito species composition, flight characteristics (direction, height and time), abdominal status, and parity.
Malaria is a serious public health problem in Indonesia, particularly in areas outside Java and Bali. The spread of resistance to the currently available anti-malarial drugs or insecticides used for mosquito control would cause an increase in malaria transmission. To better understand patterns of transmission and resistance in Indonesia, an integrated mosquito survey was conducted in three areas with different malaria endemicities, Purworejo in Central Java, South Lampung District in Sumatera and South Halmahera District in North Mollucca. Mosquitoes were collected from the three areas through indoor and outdoor human landing catches (HLC) and indoor restinging catches. Specimens were identified morphologically by species and kept individually in 1.5 ml Eppendorf microtube. A fragment of the VGSC gene from 95 mosquito samples was sequenced and kdr allelic variation determined. The molecular analysis of these anopheline mosquitoes revealed the existence of the 1014F allele in 4 major malaria vectors from South Lampung. These species include, Anopheles sundaicus, Anopheles aconitus, Anopheles subpictus and Anopheles vagus. The 1014F allele was not found in the other areas. The finding documents the presence of this mutant allele in Indonesia, and implies that selection pressure on the Anopheles population in this area has occurred. Further studies to determine the impact of the resistance allele on the efficacy of pyrethroids in control programmes are needed.
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