-
BMC Medicine Sep 2015Achieving adequate antimalarial drug exposure is essential for curing malaria. Day 7 blood or plasma lumefantrine concentrations provide a simple measure of drug... (Meta-Analysis)
Meta-Analysis Review
Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: a systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data.
BACKGROUND
Achieving adequate antimalarial drug exposure is essential for curing malaria. Day 7 blood or plasma lumefantrine concentrations provide a simple measure of drug exposure that correlates well with artemether-lumefantrine efficacy. However, the 'therapeutic' day 7 lumefantrine concentration threshold needs to be defined better, particularly for important patient and parasite sub-populations.
METHODS
The WorldWide Antimalarial Resistance Network (WWARN) conducted a large pooled analysis of individual pharmacokinetic-pharmacodynamic data from patients treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria, to define therapeutic day 7 lumefantrine concentrations and identify patient factors that substantially alter these concentrations. A systematic review of PubMed, Embase, Google Scholar, ClinicalTrials.gov and conference proceedings identified all relevant studies. Risk of bias in individual studies was evaluated based on study design, methodology and missing data.
RESULTS
Of 31 studies identified through a systematic review, 26 studies were shared with WWARN and 21 studies with 2,787 patients were included. Recrudescence was associated with low day 7 lumefantrine concentrations (HR 1.59 (95% CI 1.36 to 1.85) per halving of day 7 concentrations) and high baseline parasitemia (HR 1.87 (95% CI 1.22 to 2.87) per 10-fold increase). Adjusted for mg/kg dose, day 7 concentrations were lowest in very young children (<3 years), among whom underweight-for-age children had 23% (95% CI -1 to 41%) lower concentrations than adequately nourished children of the same age and 53% (95% CI 37 to 65%) lower concentrations than adults. Day 7 lumefantrine concentrations were 44% (95% CI 38 to 49%) lower following unsupervised treatment. The highest risk of recrudescence was observed in areas of emerging artemisinin resistance and very low transmission intensity. For all other populations studied, day 7 concentrations ≥200 ng/ml were associated with >98% cure rates (if parasitemia <135,000/μL).
CONCLUSIONS
Current artemether-lumefantrine dosing recommendations achieve day 7 lumefantrine concentrations ≥200 ng/ml and high cure rates in most uncomplicated malaria patients. Three groups are at increased risk of treatment failure: very young children (particularly those underweight-for-age); patients with high parasitemias; and patients in very low transmission intensity areas with emerging parasite resistance. In these groups, adherence and treatment response should be monitored closely. Higher, more frequent, or prolonged dosage regimens should now be evaluated in very young children, particularly if malnourished, and in patients with hyperparasitemia.
Topics: Antimalarials; Artemether; Artemisinins; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Recurrence; Treatment Failure
PubMed: 26381375
DOI: 10.1186/s12916-015-0456-7 -
Malaria Journal Dec 2017There is no agreed standard method to assess the efficacy of anti-malarials for uncomplicated falciparum in pregnancy despite an increased risk of adverse outcomes for... (Meta-Analysis)
Meta-Analysis Review
Systematic literature review and meta-analysis of the efficacy of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: methodological challenges.
BACKGROUND
There is no agreed standard method to assess the efficacy of anti-malarials for uncomplicated falciparum in pregnancy despite an increased risk of adverse outcomes for the mother and the fetus. The aim of this review is to present the currently available evidence from both observational and interventional cohort studies on anti-malarial efficacy in pregnancy and summarize the variability of assessment and reporting found in the review process.
METHODS
Efficacy methodology and assessment of artemisinin-based treatments (ABT) and quinine-based treatments (QBT) were reviewed systematically using seven databases and two clinical trial registries (protocol registration-PROSPERO: CRD42017054808). Pregnant women in all trimesters with parasitologically confirmed uncomplicated falciparum malaria were included irrespective of symptoms. This review attempted to re-calculate proportions of treatment success applying the same definition as the standard WHO methodology for non-pregnant populations. Aggregated data meta-analyses using data from randomized control trials (RCTs) comparing different treatments were performed by random effects model.
RESULTS
A total of 48 eligible efficacy studies were identified including 7279 treated Plasmodium falciparum episodes. While polymerase chain reaction (PCR) was used in 24 studies for differentiating recurrence, the assessment and reporting of treatment efficacy was heterogeneous. When the same definition could be applied, PCR-corrected treatment failure of ≥ 10% at any time points was observed in 3/30 ABT and 3/7 QBT arms. Ten RCTs compared different combinations of ABT but there was a maximum of two published RCTs with PCR-corrected outcomes for each comparison. Five RCTs compared ABT and QBT. Overall, the risk of treatment failure was significantly lower in ABT than in QBT (risk ratio 0.22, 95% confidence interval 0.07-0.63), although the actual drug combinations and outcome endpoints were different. First trimester women were included in 12 studies none of which were RCTs of ABT.
CONCLUSIONS
Efficacy studies in pregnancy are not only limited in number but use varied methodological assessments. In five RCTs with comparable methodology, ABT resulted in higher efficacy than QBT in the second and third trimester of pregnancy. Individual patient data meta-analysis can include data from observational cohort studies and could overcome some of the limitations of the current assessment given the paucity of data in this vulnerable group.
Topics: Antimalarials; Artemisinins; Drug Therapy, Combination; Female; Humans; Malaria, Falciparum; Pregnancy; Pregnancy Complications, Parasitic; Quinine
PubMed: 29237461
DOI: 10.1186/s12936-017-2135-y -
Open Forum Infectious Diseases Jul 2019Malaria transmission through blood transfusion is an accidental but preventable cause of malaria infection and is increasingly becoming a matter of concern for blood...
BACKGROUND
Malaria transmission through blood transfusion is an accidental but preventable cause of malaria infection and is increasingly becoming a matter of concern for blood transfusion services. This systematic review was conducted to provide a summary of evidence about the prevalence of infection in asymptomatic blood donors and the effectiveness of screening methods used based on the available literature.
METHODS
PRISMA guidelines were followed. Scopus, PubMed, Science Direct, and EMBASE were searched from 1982 to October 10, 2017. All peer-reviewed original research articles describing the prevalence of malaria parasitemia in blood donors with different diagnostic methods were included. The random-effects model was applied to assess the effects of heterogeneity among the selected studies. Incoherence and heterogeneity between studies were quantified by index and Cochran's Q test. Publication and population bias was assessed with funnel plots and Egger's regression asymmetry test. All statistical analyses were performed using Stata (version 2.7.2).
RESULTS
Seventy-one studies from 21 countries, 5 continents, were included in the present systematic review. The median prevalence of malaria parasitemia among 984 975 asymptomatic healthy blood donors was 10.54%, 5.36%, and 0.38% by microscopy, molecular methods (polymerase chain reaction), and rapid diagnostic tests, respectively. The most commonly detected species was .
CONCLUSIONS
This systematic review demonstrates that compared with other transfusion-linked infections, that is, HIV, HCV, and HBV, transfusion-transmitted malaria is one of the most significant transfusion-associated infections especially in Sub-Saharan Africa. Future work must aim to understand the clinical significance of transfusion-transmitted malaria in malaria-endemic settings.
PubMed: 31334300
DOI: 10.1093/ofid/ofz283 -
Malaria Journal Aug 2021Artemisinin-based combination therapy (ACT) was deployed in 2005 as an alternative to chloroquine and is considered the most efficacious treatment currently available... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Artemisinin-based combination therapy (ACT) was deployed in 2005 as an alternative to chloroquine and is considered the most efficacious treatment currently available for uncomplicated falciparum malaria. While widespread artemisinin resistance has not been reported to date in Africa, recent studies have reported partial resistance in Rwanda. The purpose of this study is to provide a current systematic review and meta-analysis on ACT at Mali study sites, where falciparum malaria is highly endemic.
METHODS
A systematic review of the literature maintained in the bibliographic databases accessible through the PubMed, ScienceDirect and Web of Science search engines was performed to identify research studies on ACT occurring at Mali study sites. Selected studies included trials occurring at Mali study sites with reported polymerase chain reaction (PCR)-corrected adequate clinical and parasite response rates (ACPRcs) at 28 days. Data were stratified by treatment arm (artemether-lumefantrine (AL), the first-line treatment for falciparum malaria in Mali and non-AL arms) and analysed using random-effects, meta-analysis approaches.
RESULTS
A total of 11 studies met the inclusion criteria, and a risk of bias assessment carried out by two independent reviewers determined low risk of bias among all assessed criteria. The ACPRc for the first-line AL at Mali sites was 99.0% (95% CI (98.3%, 99.8%)), while the ACPRc among non-AL treatment arms was 98.9% (95% CI (98.3%, 99.5%)). The difference in ACPRcs between non-AL treatment arms and AL treatment arms was not statistically significant (p = .752), suggesting that there are potential treatment alternatives beyond the first-line of AL in Mali.
CONCLUSIONS
ACT remains highly efficacious in treating uncomplicated falciparum malaria in Mali. Country-specific meta-analyses on ACT are needed on an ongoing basis for monitoring and evaluating drug efficacy patterns to guide local malaria treatment policies, particularly in the wake of observed artemisinin resistance in Southeast Asia and partial resistance in Rwanda.
Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Humans; Malaria, Falciparum; Mali; Plasmodium falciparum
PubMed: 34461901
DOI: 10.1186/s12936-021-03890-0 -
Diagnostics (Basel, Switzerland) Mar 2021Rapid diagnostic tests (RDTs) have become a mainstay of malaria diagnosis in endemic countries since their implementation in the 1990s. We conducted a 30-year systematic... (Review)
Review
Rapid diagnostic tests (RDTs) have become a mainstay of malaria diagnosis in endemic countries since their implementation in the 1990s. We conducted a 30-year systematic review and meta-analysis on malaria RDTs performance in India. Outcomes of interest were sensitivity (Se), specificity (Sp), positive/negative likelihood ratio (PLR/NLR), and diagnostic odd ratio (DOR). Among the 75 studies included, most of the studies were cross-sectional (65.3%), hospital-based (77.3%), and targeted febrile patients (90.6%). Nearly half of RDTs were designed for detecting only (47.5%) while the rest were for and (11.9%), and /Pan- except for (32.3%). When compared to light microscopy (gold standard), pooled estimates of performances were: Se = 97.0%, Sp = 96.0%, PLR = 22.4, NLR = 0.02 and DOR = 1080. In comparison to polymerase chain reaction, the RDTs showed Se = 89.0% and Sp = 99.0%. Performance outcomes (Se and Sp) were similar for RDT targeting only, but decreased for mixed and non-falciparum infections. Performances of malaria RDTs are still high India. However, there is a need for developing RDTs with regard to targeting minor malarial species, individuals carrying only mature gametocytes, and -deleted parasites.
PubMed: 33806066
DOI: 10.3390/diagnostics11040590 -
Travel Medicine and Infectious Disease 2021In 2018, tafenoquine was approved for malaria chemoprophylaxis. We evaluated all available data on the safety and efficacy of tafenoquine chemoprophylaxis. (Meta-Analysis)
Meta-Analysis
BACKGROUND
In 2018, tafenoquine was approved for malaria chemoprophylaxis. We evaluated all available data on the safety and efficacy of tafenoquine chemoprophylaxis.
METHODS
This systematic review followed the PRISMA guidelines and was registered on PROSPERO (CRD42019123839). We searched PubMed, Embase, Scopus, CINAHL and Cochrane databases. Two authors (JDM, PS) screened all papers.
RESULTS
We included 44 papers in the qualitative and 9 in the quantitative analyses. These 9 randomized, controlled trials included 2495 participants, aged 12-60 years with 27.3% women. Six studies were conducted in Plasmodium spp.-endemic regions; two were human infection studies. 200 mg weekly tafenoquine and higher dosages lead to a significant reduction of Plasmodium spp. infection compared to placebo and were comparable to 250 mg mefloquine weekly with a protective efficacy between 77.9 and 100% or a total risk ratio of 0.22 (95%-CI: 0.07-0.73; p = 0.013) in favour of tafenoquine. Adverse events (AE) were comparable in frequency and severity between tafenoquine and comparator arms. One study reported significantly more gastrointestinal events in tafenoquine users (p ≤ 0.001). Evidence of increased, reversible, asymptomatic vortex keratopathy in subjects with prolonged tafenoquine exposures was found. A single, serious event of decreased macular sensitivity occurred.
CONCLUSION
This systematic review and meta-analysis of trials of G6PD-normal adults show that weekly tafenoquine 200 mg is well tolerated and effective as malaria chemoprophylaxis focusing primarily on Plasmodium falciparum but also on Plasmodium vivax. Our safety analysis is limited by heterogenous methods of adverse events reporting. Further research is indicated on the use of tafenoquine in diverse traveller populations.
Topics: Adult; Aminoquinolines; Antimalarials; Chemoprevention; Female; Humans; Malaria; Male
PubMed: 33227500
DOI: 10.1016/j.tmaid.2020.101908 -
Bioorganic Chemistry Feb 2024The increasing resistance of various malarial parasite strains to drugs has made the production of a new, rapid-acting, and efficient antimalarial drug more necessary,... (Review)
Review
The increasing resistance of various malarial parasite strains to drugs has made the production of a new, rapid-acting, and efficient antimalarial drug more necessary, as the demand for such drugs is growing rapidly. As a major global health concern, various methods have been implemented to address the problem of drug resistance, including the hybrid drug concept, combination therapy, the development of analogues of existing medicines, and the use of drug resistance reversal agents. Artemisinin and its derivatives are currently used against multidrug- resistant P. falciparum species. However, due to its natural origin, its use has been limited by its scarcity in natural resources. As a result, finding a substitute becomes more crucial, and the peroxide group in artemisinin, responsible for the drugs biological action in the form of 1,2,4-trioxane, may hold the key to resolving this issue. The literature suggests that 1,2,4-trioxanes have the potential to become an alternative to current malaria drugs, as highlighted in this review. This is why 1,2,4-trioxanes and their derivatives have been synthesized on a large scale worldwide, as they have shown promising antimalarial activity in vivo and in vitro against Plasmodium species. Consequently, the search for a more convenient, environment friendly, sustainable, efficient, and effective synthetic pathway for the synthesis of 1,2,4-trioxanes continues. The aim of this work is to provide a comprehensive analysis of the synthesis and mechanism of action of 1,2,4-trioxanes. This systematic review highlights the most recent summaries of derivatives of 1,2,4-trioxane compounds and dimers with potential antimalarial activity from January 1988 to 2023.
Topics: Antimalarials; Artemisinins; Heterocyclic Compounds; Plasmodium falciparum
PubMed: 38134523
DOI: 10.1016/j.bioorg.2023.107043 -
Malaria Journal Dec 2014Malaria caused by Plasmodium vivax was long considered to have a low mortality, but recent reports from some geographical areas suggest that severe and complicated vivax... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Malaria caused by Plasmodium vivax was long considered to have a low mortality, but recent reports from some geographical areas suggest that severe and complicated vivax malaria may be more common than previously thought.
METHODS
The primary objective of this systematic review and meta-analysis was to describe the reported clinical characteristics and the geographical variation in prevalence of reported severe vivax malaria and its change over time derived from English-language articles published since 1900. Medline and Scopus databases were searched for original papers on severe vivax malaria, using as inclusion criteria modified 2010 WHO criteria for the diagnosis of severe falciparum malaria. Articles before 1949 were identified through reference lists in journals, textbooks, and personal collections of colleagues.
RESULTS
A total of 77 studies with reported severe vivax malaria and 63 studies with no reported severe vivax malaria (totaling 46,411 and 6,753 vivax malaria patients, respectively) were included. The 77 studies with reported severe vivax malaria were mainly from India (n = 33), USA (n = 8), Indonesia (n = 6), and Pakistan (n = 6). Vivax endemic countries not reporting severe vivax malaria beyond individual case reports included: the Greater Mekong Sub-region, China, North Korea, Bangladesh, Afghanistan, Middle East (except Qatar), the horn of Africa, and Madagascar. Only 17/77 reports were from before 2000. Vivax mono-infection was confirmed by PCR in 14 studies and co-morbidities were ruled out in 23 studies. Among the 77 studies reporting severe vivax malaria, severe thrombocytopenia (<50,000/mm3) was the most common "severe" manifestation (888/45,775 with pooled prevalence of 8.6%). The case fatality was 0.3% (353/46,411). Severity syndromes varied widely between different geographical areas, with severe anaemia being most prominent in areas of high transmission and chloroquine resistance.
CONCLUSION
Plasmodium vivax can cause severe and even fatal disease, but there is a recent increase in reports over the past 15 years with larger series restricted to a limited number of geographical areas. The biological basis of these variations is currently not known. More detailed epidemiological studies are needed which dissociate causation from association to refine the definition and estimate the prevalence of severe vivax malaria.
Topics: Adult; Child; Child, Preschool; Female; Global Health; Humans; Malaria, Vivax; Male; Prevalence; Survival Analysis; Topography, Medical
PubMed: 25486908
DOI: 10.1186/1475-2875-13-481 -
Infectious Diseases of Poverty Nov 2017As Ethiopia is one of the sub-Saharan countries with a great burden of malaria the effectiveness of first line anti-malarial drugs is the major concern. The aim of this... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
As Ethiopia is one of the sub-Saharan countries with a great burden of malaria the effectiveness of first line anti-malarial drugs is the major concern. The aim of this study was to synthesize the available evidence on the efficacy of artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Ethiopia. This was done by performing a meta-analysis of recent studies conducted in the country on this topic.
METHODS
Studies published between January 2010 and January 2017 that reported on the efficacy of artemether-lumefantrine in the treatment of P. falciparum malaria in Ethiopian patients were searched for using the PubMed and Google Scholar databases. Ten prospective single-arm cohort studies that followed patients for 28-42 days were included in this analysis. All of the included studies were deemed to be of high quality.
RESULTS
Ten studies involving 1179 patients that were eligible for meta-analysis were identified. At recruitment, the average parasite count per patient was 1 2981/μl of blood. On the third day of treatment, 96.7% and 98.5% of the study subjects become fever-free and parasite-free, respectively. Based on the per protocol analysis, the cure rate after use of artemether-lumefantrine was 98.2% (polymerase chain reaction corrected) and 97.01% (polymerase chain reaction uncorrected) after 28 days of follow-up. The reinfection rate within 28 days was 1.1% and the recrudescence rate was 1.9%.
CONCLUSIONS
This review found that the cure rate for uncomplicated P. falciparum malaria using artemether-lumefantrine in Ethiopia is still high enough to recommend the drug as a first-line agent. There should be careful periodic monitoring of the efficacy of this drug, as treatment failure may occur due to resistance, sub-therapeutic levels that may occur due to non-adherence, or inadequate absorption.
Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Ethiopia; Fluorenes; Humans; Malaria, Falciparum; Plasmodium falciparum
PubMed: 29137664
DOI: 10.1186/s40249-017-0372-5 -
Journal of the American College of... Mar 2021As one of the tropical diseases, malaria is endemic in developing countries. Severe malaria, mainly caused by the Plasmodium falciparum parasite, can result in...
As one of the tropical diseases, malaria is endemic in developing countries. Severe malaria, mainly caused by the Plasmodium falciparum parasite, can result in life-threatening complications. Traditionally, cardiac involvement has not been included as a frequent cause of morbidity and mortality. This could be due to under-reporting or underdiagnosing. Specific cardiovascular (CV) complications include electrocardiogram abnormalities, myocarditis, pericarditis, pericardial effusion, ischemic disease, and heart failure. According to the data analyzed, CV manifestations can lead to severe consequences. Possible theories related to the pathophysiological mechanisms related to CV compromise include an imbalanced pro-inflammatory cytokine response and/or erythrocyte sequestration by increased cytoadherence to endothelium. Although there is a paucity of data regarding cardiac manifestations of malaria, an algorithm for appropriate use of diagnostic tools to assess cardiac involvement has been developed in this paper. Furthermore, it is important to note that typical antimalarial treatment regimens can have fatal cardiac side-effects.
Topics: Algorithms; Anemia; Antimalarials; Cytokines; Heart Diseases; Humans; Incidence; Malaria; Prevalence
PubMed: 33632486
DOI: 10.1016/j.jacc.2020.12.042