Capacity Development through the US President's Malaria Initiative-Supported Antimalarial Resistance Monitoring in Africa Network.
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ABSTRACT:
SUBMITTER: Halsey ES
PROVIDER: S-EPMC5711327 | biostudies-other | 2017 Dec
REPOSITORIES: biostudies-other
Publications
Capacity Development through the US President's Malaria Initiative-Supported Antimalarial Resistance Monitoring in Africa Network.
Halsey Eric S ES Venkatesan Meera M Plucinski Mateusz M MM Talundzic Eldin E Lucchi Naomi W NW Zhou Zhiyong Z Mandara Celine I CI Moonga Hawela H Hamainza Busiku B Beavogui Abdoul Habib AH Kariuki Simon S Samuels Aaron M AM Steinhardt Laura C LC Mathanga Don P DP Gutman Julie J Denon Yves Eric YE Uwimana Aline A Assefa Ashenafi A Hwang Jimee J Shi Ya Ping YP Dimbu Pedro Rafael PR Koita Ousmane O Ishengoma Deus S DS Ndiaye Daouda D Udhayakumar Venkatachalam V
Emerging infectious diseases 20171201 13
Antimalarial drug resistance is an evolving global health security threat to malaria control. Early detection of Plasmodium falciparum resistance through therapeutic efficacy studies and associated genetic analyses may facilitate timely implementation of intervention strategies. The US President's Malaria Initiative-supported Antimalarial Resistance Monitoring in Africa Network has assisted numerous laboratories in partner countries in acquiring the knowledge and capability to independently moni ...[more]
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Project description:The use of an effective antimalarial drug is the cornerstone of malaria control. However, the development and spread of resistant Plasmodium falciparum strains have placed the global eradication of malaria in serious jeopardy. Molecular marker analysis constitutes the hallmark of the monitoring of Plasmodium drug-resistance. This study included 96 P. falciparum PCR-positive samples from southern Somalia. The P. falciparum chloroquine resistance transporter gene had high frequencies of K76T, A220S, Q271E, N326S, and R371I point mutations. The N86Y and Y184F mutant alleles of the P. falciparum multidrug resistance 1 gene were present in 84.7 and 62.4% of the isolates, respectively. No mutation was found in the P. falciparum Kelch-13 gene. This study revealed that chloroquine resistance markers are present at high frequencies, while the parasite remains sensitive to artemisinin (ART). The continuous monitoring of ART-resistant markers and in vitro susceptibility testing are strongly recommended to track resistant strains in real time.
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Project description:BackgroundTherapeutic efficacy studies in uncomplicated Plasmodium falciparum malaria are confounded by new infections, which constitute competing risk events since they can potentially preclude/pre-empt the detection of subsequent recrudescence of persistent, sub-microscopic primary infections.MethodsAntimalarial studies typically report the risk of recrudescence derived using the Kaplan-Meier (K-M) method, which considers new infections acquired during the follow-up period as censored. Cumulative Incidence Function (CIF) provides an alternative approach for handling new infections, which accounts for them as a competing risk event. The complement of the estimate derived using the K-M method (1 minus K-M), and the CIF were used to derive the risk of recrudescence at the end of the follow-up period using data from studies collated in the WorldWide Antimalarial Resistance Network data repository. Absolute differences in the failure estimates derived using these two methods were quantified. In comparative studies, the equality of two K-M curves was assessed using the log-rank test, and the equality of CIFs using Gray's k-sample test (both at 5% level of significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray's sub-distributional hazard model.ResultsData were available from 92 studies (233 treatment arms, 31,379 patients) conducted between 1996 and 2014. At the end of follow-up, the median absolute overestimation in the estimated risk of cumulative recrudescence by using 1 minus K-M approach was 0.04% (interquartile range (IQR): 0.00-0.27%, Range: 0.00-3.60%). The overestimation was correlated positively with the proportion of patients with recrudescence [Pearson's correlation coefficient (?): 0.38, 95% Confidence Interval (CI) 0.30-0.46] or new infection [?: 0.43; 95% CI 0.35-0.54]. In three study arms, the point estimates of failure were greater than 10% (the WHO threshold for withdrawing antimalarials) when the K-M method was used, but remained below 10% when using the CIF approach, but the 95% confidence interval included this threshold.ConclusionsThe 1 minus K-M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy declined, particularly when the observed proportion of new infection was high. The CIF approach provides an alternative approach for derivation of failure estimates in antimalarial trials, particularly in high transmission settings.
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Project description:In 2013, 78% of malaria deaths occurred in children aged 5 years and below, in sub-Saharan Africa. Treatment of severe malaria requires a health facility with inpatient care. However, in most sub-Sahara African countries, access to health facilities is a major problem. Pre-referral antimalarial treatments aim to delay the progress of severe malaria as patients seek to access health facilities. Rectal artesunate can be administered in the community as a pre-referral treatment in rural hard-to-reach areas. In Kenya, though pre-referral rectal artesunate has been included in the National Guidelines for pre-referral treatment, it is yet to be implemented in the public healthcare system. It is important, therefore, to establish its cost-utility compared to current parenteral treatments. This study evaluated the cost-utility of provision of pre-referral treatments by community health workers compared to similar services at a primary health facility.This was a decision model-based cost-utility analysis, comparing pre-referral antimalarial treatments provided by: community health workers (CHWs), primary health facility, direct access to a tertiary health facility and no access to treatment. A theoretical cohort, of 1000 children, who were below 5 years old; residing in rural hard-to-reach areas, was taken as the reference population. Data was collected through key informant interviews, to assess the costs, while key measures of effectiveness, were obtained from existing studies. The key measure of outcomes was Disability Adjusted Life Years (DALYS) averted. Probabilistic sensitivity analysis was carried out to assess the robustness of the model.Provision of rectal pre-referral treatment by community health workers was estimated to avert 13,276 DALYs, at a cost of $68,428 for a cohort of 1000 children. Provision of rectal pre-referral treatment at a primary health facility was estimated to avert 9993 DALYs, at a cost of $73,826 for a cohort of 1000 children, while going directly to a tertiary health facility was estimated to avert 15,801 DALYs, at a cost of $114,903 for a cohort of 1000 children. The incremental cost effectiveness ratios for provision of pre-referral treatment by community health care and primary health workers were $5.11 and $7.30 per DALYs averted respectively.Use of CHWs was more cost effective than provision of pre-referral treatments at a primary health facility especially, with high referral compliance. Rectal artesunate can easily be administered by community health workers, unlike parenteral pre-referral interventions.
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Project description:Molecular surveillance of Plasmodium falciparum parasites is important to track emerging and new mutations and trends in established mutations and should serve as an early warning system for antimalarial resistance. Dried blood spots were obtained from a Plasmodium falciparum malaria survey in school children conducted across eight counties in western Kenya in 2019. Real-time PCR identified 500 P. falciparum-positive samples that were amplified at five drug resistance loci for targeted amplicon deep sequencing (TADS). The absence of important kelch 13 mutations was similar to previous findings in Kenya pre-2019, and low-frequency mutations were observed in codons 569 and 578. The chloroquine resistance transporter gene codons 76 and 145 were wild type, indicating that the parasites were chloroquine and piperaquine sensitive, respectively. The multidrug resistance gene 1 haplotypes based on codons 86, 184, and 199 were predominantly present in mixed infections with haplotypes NYT and NFT, driven by the absence of chloroquine pressure and the use of lumefantrine, respectively. The sulfadoxine-pyrimethamine resistance profile was a "superresistant" combination of triple mutations in both Pfdhfr (51I 59R 108N) and Pfdhps (436H 437G 540E), rendering sulfadoxine-pyrimethamine ineffective. TADS highlighted the low-frequency variants, allowing the early identification of new mutations, Pfmdr1 codon 199S and Pfdhfr codon 85I and emerging 164L mutations. The added value of TADS is its accuracy in identifying mixed-genotype infections and for high-throughput monitoring of antimalarial resistance markers.
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Project description:BACKGROUND:Increasingly, biomedical researchers are encouraged or required by research funders and journals to share their data, but there's very little guidance on how to do that equitably and usefully, especially in resource-constrained settings. We performed an in-depth case study of one data sharing pioneer: the WorldWide Antimalarial Resistance Network (WWARN). METHODS:The case study included a records review, a quantitative analysis of WAARN-related publications, in-depth interviews with 47 people familiar with WWARN, and a witness seminar involving a sub-set of 11 interviewees. RESULTS:WWARN originally aimed to collate clinical, in vitro, pharmacological and molecular data into linked, open-access databases intended to serve as a public resource to guide antimalarial drug treatment policies. Our study describes how WWARN navigated challenging institutional and academic incentive structures, alongside funders' reluctance to invest in capacity building in malaria-endemic countries, which impeded data sharing. The network increased data contributions by focusing on providing free, online tools to improve the quality and efficiency of data collection, and by inviting collaborative authorship on papers addressing policy-relevant questions that could only be answered through pooled analyses. By July 1, 2016, the database included standardised data from 103 molecular studies and 186 clinical trials, representing 135,000 individual patients. Developing the database took longer and cost more than anticipated, and efforts to increase equity for data contributors are on-going. However, analyses of the pooled data have generated new methods and influenced malaria treatment recommendations globally. Despite not achieving the initial goal of real-time surveillance, WWARN has developed strong data governance and curation tools, which are now being adapted relatively quickly for other diseases. CONCLUSIONS:To be useful, data sharing requires investment in long-term infrastructure. To be feasible, it requires new incentive structures that favour the generation of reusable knowledge.
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