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Antimalarial Drug Resistance: Literature Review and Activities and Findings of the ICEMR Network.

ABSTRACT: Antimalarial drugs are key tools for the control and elimination of malaria. Recent decreases in the global malaria burden are likely due, in part, to the deployment of artemisinin-based combination therapies. Therefore, the emergence and potential spread of artemisinin-resistant parasites in southeast Asia and changes in sensitivities to artemisinin partner drugs have raised concerns. In recognition of this urgent threat, the International Centers of Excellence for Malaria Research (ICEMRs) are closely monitoring antimalarial drug efficacy and studying the mechanisms underlying drug resistance. At multiple sentinel sites of the global ICEMR network, research activities include clinical studies to track the efficacies of antimalarial drugs, ex vivo/in vitro assays to measure drug susceptibilities of parasite isolates, and characterization of resistance-mediating parasite polymorphisms. Taken together, these efforts offer an increasingly comprehensive assessment of the efficacies of antimalarial therapies, and enable us to predict the emergence of drug resistance and to guide local antimalarial drug policies. Here we briefly review worldwide antimalarial drug resistance concerns, summarize research activities of the ICEMRs related to drug resistance, and assess the global impacts of the ICEMR programs.

SUBMITTER: Cui L

PROVIDER: S-EPMC4574275 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Antimalarial Drug Resistance: Literature Review and Activities and Findings of the ICEMR Network.

Cui Liwang L Mharakurwa Sungano S Ndiaye Daouda D Rathod Pradipsinh K PK Rosenthal Philip J PJ

The American journal of tropical medicine and hygiene 20150810 3 Suppl

Antimalarial drugs are key tools for the control and elimination of malaria. Recent decreases in the global malaria burden are likely due, in part, to the deployment of artemisinin-based combination therapies. Therefore, the emergence and potential spread of artemisinin-resistant parasites in southeast Asia and changes in sensitivities to artemisinin partner drugs have raised concerns. In recognition of this urgent threat, the International Centers of Excellence for Malaria Research (ICEMRs) are ...[more]

PMID: 26259943

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Project description:BackgroundMalaria still constitutes a major public health menace, especially in tropical and subtropical countries. Close to half a million people mainly children in Africa, die every year from the disease. With the rising resistance to frontline drugs (artemisinin-based combinations), there is a need to accelerate the discovery and development of newer anti-malarial drugs. A systematic review was conducted to identify the African medicinal plants with significant antiplasmodial and/or anti-malarial activity, toxicity, as wells as assessing the variation in their activity between study designs (in vitro and in vivo).MethodsKey health-related databases including Google Scholar, PubMed, PubMed Central, and Science Direct were searched for relevant literature on the antiplasmodial and anti-malarial activities of African medicinal plants.ResultsIn total, 200 research articles were identified, a majority of which were studies conducted in Nigeria. The selected research articles constituted 722 independent experiments evaluating 502 plant species. Of the 722 studies, 81.9%, 12.4%, and 5.5% were in vitro, in vivo, and combined in vitro and in vivo, respectively. The most frequently investigated plant species were Azadirachta indica, Zanthoxylum chalybeum, Picrilima nitida, and Nauclea latifolia meanwhile Fabaceae, Euphorbiaceae, Annonaceae, Rubiaceae, Rutaceae, Meliaceae, and Lamiaceae were the most frequently investigated plant families. Overall, 248 (34.3%), 241 (33.4%), and 233 (32.3%) of the studies reported very good, good, and moderate activity, respectively. Alchornea cordifolia, Flueggea virosa, Cryptolepis sanguinolenta, Zanthoxylum chalybeum, and Maytenus senegalensis gave consistently very good activity across the different studies. In all, only 31 (4.3%) of studies involved pure compounds and these had significantly (p = 0.044) higher antiplasmodial activity relative to crude extracts. Out of the 198 plant species tested for toxicity, 52 (26.3%) demonstrated some degree of toxicity, with toxicity most frequently reported with Azadirachta indica and Vernonia amygdalina. These species were equally the most frequently inactive plants reported. The leaves were the most frequently reported toxic part of plants used. Furthermore, toxicity was observed to decrease with increasing antiplasmodial activity.ConclusionsAlthough there are many indigenous plants with considerable antiplasmodial and anti-malarial activity, the progress in the development of new anti-malarial drugs from African medicinal plants is still slothful, with only one clinical trial with Cochlospermum planchonii (Bixaceae) conducted to date. There is, therefore, the need to scale up anti-malarial drug discovery in the African region.

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.

Dataset Information

Antimalarial Drug Resistance: Literature Review and Activities and Findings of the ICEMR Network.

Publications

Antimalarial Drug Resistance: Literature Review and Activities and Findings of the ICEMR Network.

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