This distribution is consistent with previously published studies, showing localisation of mutations in specific geographical areas, such as Asn458Tyr and Arg561His in the eastern and northern GMS, Arg539Thr in southern and east GMS, and Ile543Thr and Tyr493His in east GMS.15 Such distribution supports the theory of independent emergence of artemisinin resistance in several locations, with Cys580Tyr sweeping through the region.29,30 On the border between Thailand and Myanmar, Cys580Tyr predominated until 2016, when Phe446Ile became more prevalent.
The increase in artemisinin resistance threatens malaria elimination in Asia by the target date of 2030 and could derail control efforts in other endemic regions. This study aimed to develop up-to-date spatial distribution visualisations of the kelch13 (K13) gene markers of artemisinin resistance in Plasmodium falciparum for policy makers.
In this systematic review and spatiotemporal analysis we used the WorldWide Antimalarial Resistance Network (WWARN) surveyor molecular markers of artemisinin resistance database. We updated the database by searching PubMed and SCOPUS for studies published between Jan 1, 1990, and March 31, 2021. Articles were included if they contained data on K13 markers of artemisinin resistance from patients' samples in Asia and articles already included in the WWARN database were excluded. Data were extracted from the published articles and authors were contacted when information was missing. We used the lowest administrative unit levels for the sampling locations of all the K13 data to describe the spatiotemporal distribution. The numbers of samples tested and those with each molecular marker in each administrative unit level were aggregated by year to calculate the marker prevalence over time.
Data were collated from 72 studies comprising K13 markers from 16 613 blood samples collected from 1991 to 2020 from 18 countries. Most samples were from Myanmar (3842 [23·1%]), Cambodia (3804 [22·9%]), and Vietnam (2663 [16·0%]). The median time between data collection and publication was 3·6 years (range 0·9–25·0, IQR 2·7 [2·5–5·2]). There was a steady increase in the prevalence of WHO-validated K13 markers, with the lowest of 4·3% in 2005 (n=47) and the highest of 62·9% in 2018 (n=264). Overall, the prevalence of Cys580Tyr mutation increased from 48·9% in 2002 to 84·9% in 2018.
From 2002 to 2018, there has been a steady increase in geographical locations and the proportion of infected people with validated artemisinin resistance markers. More consistent data collection, over more extended periods in the same areas with the rapid sharing of data are needed to map the spread and evolution of resistance to better inform policy decisions. Data in the literature are reported in a heterogeneous way leading to difficulties in pooling and interpretation. We propose here a tool with a set of minimum criteria for reporting future studies.
This research was funded in part by the Wellcome Trust.
The increased resistance to the currently effective antimalarial drugs against Plasmodium falciparum has necessitated the development of new drugs for malaria treatment. Many proteins have been predicted using various means as potential drug targets for the treatment of the P. falciparum malaria infection. Meanwhile, only a few studies went on to predict the 3-dimensional (3D) structure of potential target. Therefore, this study aimed to predict potential antimalarial drug targets against the deadliest malaria parasite P. falciparum as well as to determine the 3D structure and possible inhibitors of one of the targets. We employed machine learning approach to predict suitable drug targets in P. falciparum. Five of the predicted protein targets were considered as potential drug targets as they were non-homologous to their human counterparts. Out of these, we determined the physicochemical properties, predicted the 3D structure and carried out docking-based virtual screening of P. falciparum RNA pseudouridylate synthase, putative (PfRPuSP). The PfRPuSP was one of the potential five target proteins. Homology modelling and the ab initio methods were used to predict the 3D structure of PfRPuSP. Then, a compound library of 5621 molecules was constructed from PubChem and ChEMBL databases using 5-fluorouridine as the control inhibitor. Docking-based virtual screening was performed using Autodock 4.2 and Autodock Vina to select compounds with high binding affinity. A total of 11 compounds were selected based on their binding energies from 881 compounds which were manually examined after docking. Seven of the 11 compounds that exhibited remarkable interactions with the residues in the active sites of PfRPuSP were analysed. These compounds performed favourably when compared to the control inhibitor and predicted to bind better than 5-fluorouridine. These seven compounds are suggested as new potential lead structures for antimalarial treatment.
To contain multidrug-resistant Plasmodium falciparum, malaria elimination in the Greater Mekong subregion needs to be accelerated while current antimalarials remain effective. We evaluated the safety, effectiveness, and potential resistance selection of dihydroartemisinin–piperaquine mass drug administration (MDA) in a region with artemisinin resistance in Myanmar.
We did a cluster-randomised controlled trial in rural community clusters in Kayin (Karen) state in southeast Myanmar. Malaria prevalence was assessed using ultrasensitive quantitative PCR (uPCR) in villages that were operationally suitable for MDA (villages with community willingness, no other malaria control campaigns, and a population of 50–1200). Villages were eligible to participate if the prevalence of malaria (all species) in adults was greater than 30% or P falciparum prevalence was greater than 10% (or both). Contiguous villages were combined into clusters. Eligible clusters were paired based on P falciparum prevalence (estimates within 10%) and proximity. Community health workers provided routine malaria case management and distributed long-lasting insecticidal bed-nets (LLINs) in all clusters. Randomisation of clusters (1:1) to the MDA intervention group or control group was by public coin-flip. Group allocations were not concealed. Three MDA rounds (3 days of supervised dihydroartemisinin–piperaquine [target total dose 7 mg/kg dihydroartemisinin and 55 mg/kg piperaquine] and single low-dose primaquine [target dose 0·25 mg base per kg]) were delivered to intervention clusters. Parasitaemia prevalence was assessed at 3, 5, 10, 15, 21, 27, and 33 months. The primary outcomes were P falciparum prevalence at months 3 and 10. All clusters were included in the primary analysis. Adverse events were monitored from the first MDA dose until 1 month after the final dose, or until resolution of any adverse event occurring during follow-up. This trial is registered with ClinicalTrials.gov, NCT01872702.
Baseline uPCR malaria surveys were done in January, 2015, in 43 villages that were operationally suitable for MDA (2671 individuals). 18 villages met the eligibility criteria. Three villages in close proximity were combined into one cluster because a border between them could not be defined. This gave a total of 16 clusters in eight pairs. In the intervention clusters, MDA was delivered from March 4 to March 17, from March 30 to April 10, and from April 27 to May 10, 2015. The weighted mean absolute difference in P falciparum prevalence in the MDA group relative to the control group was −10·6% (95% CI −15·1 to −6·1; p=0·0008) at month 3 and −4·5% (−10·9 to 1·9; p=0·14) at month 10. At month 3, the weighted P falciparum prevalence was 1·4% (0·6 to 3·6; 12 of 747) in the MDA group and 10·6% (7·0 to 15·6; 56 of 485) in the control group. Corresponding prevalences at month 10 were 3·2% (1·5 to 6·8; 34 of 1013) and 5·8% (2·5 to 12·9; 33 of 515). Adverse events were reported for 151 (3·6%) of 4173 treated individuals. The most common adverse events were dizziness (n=109) and rash or itching (n=20). No treatment-related deaths occurred.
In this low-transmission setting, the substantial reduction in P falciparum prevalence resulting from support of community case management was accelerated by MDA. In addition to supporting community health worker case management and LLIN distribution, malaria elimination programmes should consider using MDA to reduce P falciparum prevalence rapidly in foci of higher transmission.
The Global Fund to Fight AIDS, Tuberculosis and Malaria.