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BMC Medicine Sep 2022In 2012, the World Health Organization (WHO) recommended single low-dose (SLD, 0.25 mg/kg) primaquine to be added as a Plasmodium (P.) falciparum gametocytocide to... (Meta-Analysis)
Meta-Analysis
BACKGROUND
In 2012, the World Health Organization (WHO) recommended single low-dose (SLD, 0.25 mg/kg) primaquine to be added as a Plasmodium (P.) falciparum gametocytocide to artemisinin-based combination therapy (ACT) without glucose-6-phosphate dehydrogenase (G6PD) testing, to accelerate malaria elimination efforts and avoid the spread of artemisinin resistance. Uptake of this recommendation has been relatively slow primarily due to safety concerns.
METHODS
A systematic review and individual patient data (IPD) meta-analysis of single-dose (SD) primaquine studies for P. falciparum malaria were performed. Absolute and fractional changes in haemoglobin concentration within a week and adverse effects within 28 days of treatment initiation were characterised and compared between primaquine and no primaquine arms using random intercept models.
RESULTS
Data comprised 20 studies that enrolled 6406 participants, of whom 5129 (80.1%) had received a single target dose of primaquine ranging between 0.0625 and 0.75 mg/kg. There was no effect of primaquine in G6PD-normal participants on haemoglobin concentrations. However, among 194 G6PD-deficient African participants, a 0.25 mg/kg primaquine target dose resulted in an additional 0.53 g/dL (95% CI 0.17-0.89) reduction in haemoglobin concentration by day 7, with a 0.27 (95% CI 0.19-0.34) g/dL haemoglobin drop estimated for every 0.1 mg/kg increase in primaquine dose. Baseline haemoglobin, young age, and hyperparasitaemia were the main determinants of becoming anaemic (Hb < 10 g/dL), with the nadir observed on ACT day 2 or 3, regardless of G6PD status and exposure to primaquine. Time to recovery from anaemia took longer in young children and those with baseline anaemia or hyperparasitaemia. Serious adverse haematological events after primaquine were few (9/3, 113, 0.3%) and transitory. One blood transfusion was reported in the primaquine arms, and there were no primaquine-related deaths. In controlled studies, the proportions with either haematological or any serious adverse event were similar between primaquine and no primaquine arms.
CONCLUSIONS
Our results support the WHO recommendation to use 0.25 mg/kg of primaquine as a P. falciparum gametocytocide, including in G6PD-deficient individuals. Although primaquine is associated with a transient reduction in haemoglobin levels in G6PD-deficient individuals, haemoglobin levels at clinical presentation are the major determinants of anaemia in these patients.
TRIAL REGISTRATION
PROSPERO, CRD42019128185.
Topics: Antimalarials; Artemisinins; Child; Child, Preschool; Glucosephosphate Dehydrogenase; Hemoglobins; Humans; Malaria, Falciparum; Plasmodium falciparum; Primaquine
PubMed: 36109733
DOI: 10.1186/s12916-022-02504-z -
Parasitology Research Oct 2022A plethora of studies analyse the molecular markers of drug resistance and hence help in guiding the evidence-based malaria treatment policies in India. For reporting... (Review)
Review
A plethora of studies analyse the molecular markers of drug resistance and hence help in guiding the evidence-based malaria treatment policies in India. For reporting mutations, a number of techniques including DNA sequencing, restriction-fragment length polymorphism and mutation-specific polymerase chain reaction have been employed across numerous studies, including variations in the methodology used. However, there is no sufficient data from India comparing these methods as well as report the prevalence of polymorphisms in SP drug resistance molecular markers independently using such methods. Therefore, all data from Indian studies available for molecular marker studies of Plasmodium falciparum drug resistance to sulphadoxine-pyrimethamine was gathered, and a systematic review was performed. This systematic review identifies the molecular methods in use in India and compares each method for detecting sulphadoxine-pyrimethamine drug resistance marker. To delay the spread of drug-resistant parasite strains, a simplified and standardized molecular method is much needed which can be obtained by analysing the performance of each method in use and answering the necessity of newer methodological approaches.
Topics: Antimalarials; Drug Combinations; Drug Resistance; Humans; India; Malaria, Falciparum; Plasmodium falciparum; Pyrimethamine; Sulfadoxine
PubMed: 35980472
DOI: 10.1007/s00436-022-07623-3 -
PloS One 2022The artemisinin derivatives are the preferred antimalaria drugs for treating severe Plasmodium falciparum malaria. However, their clinical effectiveness compared to each... (Meta-Analysis)
Meta-Analysis
Comparative efficacy and safety of the artemisinin derivatives compared to quinine for treating severe malaria in children and adults: A systematic update of literature and network meta-analysis.
BACKGROUND
The artemisinin derivatives are the preferred antimalaria drugs for treating severe Plasmodium falciparum malaria. However, their clinical effectiveness compared to each other is unknown. Our objective, therefore, was to evaluate the efficacy and safety of the artemisinin derivatives and quinine for treating severe P. falciparum malaria in children and adults using a network meta-analysis.
METHODS AND FINDINGS
Review protocol was registered with PROSPERO, CRD42020218190. We updated the search strategies of three Cochrane systematic reviews which included published and unpublished randomised control trials (RCTs) that have compared specific artemisinin derivatives to quinine in treating severe malaria. Search included CENTRAL, MEDLINE, Embase, LILACS, ISI Web of Science and trial registries up to February 2021. We screened studies, extracted data, assessed risk of bias, and quality of evidence in duplicate. Separate network meta-analyses in the frequentist framework, using a random effects model, with quinine as reference, were conducted for adults and children, and rankings were produced using p-scores to assess mortality, parasite clearance, coma recovery, fever clearance, neurological sequela and adverse events. Searches identified 818 citations, 33 RCTs were eligible. We pooled 7795 children and 3182 adults. The networks involved artesunate, artemether, rectal artemisinin, arteether and quinine. Compared to quinine, artesunate reduced mortality in children (risk ratio (RR), 0.76; 95%CI [0.65 to 0.89], moderate quality), adults (RR, 0.55; 95%CI [0.40 to 0.75], moderate quality) and in cerebral malaria (RR, 0.72; 95%CI [0.55 to 0.94], moderate quality). Compared to rectal artemisinin and intramuscular arteether, the efficacy and safety of parenteral artesunate, and intramuscular artemether in treating severe malaria are not clear. Rankings showed that none of the artemisinin drugs were consistently superior in all the outcomes assessed. Indirect evidence produced were of very low ratings due to suspected publication bias and imprecision.
CONCLUSIONS
Artesunate reduces mortality compared to quinine for both adults and children in Asia and Africa including cerebral malaria. The artemisinin derivatives remain the best treatment for severe malaria but their comparative clinical effectiveness is yet to be fully explored.
Topics: Adult; Antimalarials; Artemether; Artemisinins; Artesunate; Child; Humans; Malaria, Cerebral; Malaria, Falciparum; Network Meta-Analysis; Quinine
PubMed: 35857773
DOI: 10.1371/journal.pone.0269391 -
Nature Communications Jul 2022The cause of malaria transmission has been known for over a century but it is still unclear whether entomological measures are sufficiently reliable to inform policy...
The cause of malaria transmission has been known for over a century but it is still unclear whether entomological measures are sufficiently reliable to inform policy decisions in human health. Decision-making on the effectiveness of new insecticide-treated nets (ITNs) and the indoor residual spraying of insecticide (IRS) have been based on epidemiological data, typically collected in cluster-randomised control trials. The number of these trials that can be conducted is limited. Here we use a systematic review to highlight that efficacy estimates of the same intervention may vary substantially between trials. Analyses indicate that mosquito data collected in experimental hut trials can be used to parameterize mechanistic models for Plasmodium falciparum malaria and reliably predict the epidemiological efficacy of quick-acting, neuro-acting ITNs and IRS. Results suggest that for certain types of ITNs and IRS using this framework instead of clinical endpoints could support policy and expedite the widespread use of novel technologies.
Topics: Animals; Culicidae; Humans; Insecticide-Treated Bednets; Insecticides; Malaria; Mosquito Control; Mosquito Vectors
PubMed: 35790746
DOI: 10.1038/s41467-022-30700-1 -
PLoS Neglected Tropical Diseases Jun 2022In areas with both Plasmodium vivax and Plasmodium falciparum malaria, interventions can reduce the burden of both species but the impact may vary due to their different...
BACKGROUND
In areas with both Plasmodium vivax and Plasmodium falciparum malaria, interventions can reduce the burden of both species but the impact may vary due to their different biology. Knowing the expected relative impact on the two species over time for vector- and drug-based interventions, and the factors affecting this, could help plan and evaluate intervention strategies.
METHODS
For three interventions (treated bed nets (ITN), mass drug administration (MDA) and indoor residual spraying (IRS)), we identified studies providing information on the proportion of clinical illness and patent infections attributed to P. vivax over time using a literature search. The change in the proportion of malaria attributed to P. vivax up to two years since implementation was estimated using logistic regression accounting for clustering with random effects. Potential factors (intervention type, coverage, relapse pattern, transmission intensity, seasonality, initial proportion of P. vivax and round of intervention) were assessed.
RESULTS
In total there were 55 studies found that led to 72 series of time-points for clinical case data and 69 series for patent infection data. The main reason of study exclusion was insufficient information on interventions. There was considerable variation in the proportion of malaria attributed to P. vivax over time by study and location for all of the interventions. Overall, there was an increase apart from MDA in the short-term. The potential factors could not be ruled in or out. Although not consistently significant, coverage, transmission intensity and relapse pattern are possible factors that explain some of the variation found.
CONCLUSION
While there are reports of an increase in the proportion of malaria due to P. vivax following interventions in the long-term, there was substantial variation for the shorter time-scales considered in this study (up to 24 months for IRS and ITN, and up to six months for MDA). The large variability points to the need for the monitoring of both species after an intervention. Studies should report intervention timing and characteristics to allow inclusion in systematic reviews.
Topics: Humans; Malaria; Malaria, Falciparum; Malaria, Vivax; Plasmodium falciparum; Plasmodium vivax; Recurrence
PubMed: 35767578
DOI: 10.1371/journal.pntd.0010541 -
The Cochrane Database of Systematic... Jun 2022The World Health Organization (WHO) recommends artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria. Concerns about... (Review)
Review
BACKGROUND
The World Health Organization (WHO) recommends artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria. Concerns about artemisinin resistance have led to global initiatives to develop new partner drugs to protect artemisinin derivatives in ACT. Pyronaridine-artesunate is a novel ACT.
OBJECTIVES
To evaluate the efficacy of pyronaridine-artesunate compared to alternative ACTs for treating people with uncomplicated P falciparum malaria, and to evaluate the safety of pyronaridine-artesunate and other pyronaridine treatments compared to alternative treatments.
SEARCH METHODS
We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; Embase; and LILACS. We also searched ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, and the ISRCTN registry for ongoing or recently completed trials. The date of the last search was 27 October 2021.
SELECTION CRITERIA
For the efficacy analysis, we included randomized controlled trials (RCTs) of pyronaridine-artesunate for treating uncomplicated P falciparum malaria. For the safety analysis, we included RCTs that used pyronaridine alone or in combination with any other antimalarials. In addition to these analyses, we conducted a separate systematic review summarizing data on safety from non-randomized studies (NRS) of any patient receiving pyronaridine (NRS safety review). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data and assessed the certainty of the evidence. We meta-analysed data to calculate risk ratios (RRs) for treatment failures between comparisons, and for safety outcomes between and across comparisons.
MAIN RESULTS
We included 10 relevant RCTs. Seven RCTs were co-funded by Shin Poong Pharmaceuticals, and three were funded by government agencies. Efficacy analysis (RCTs) For the efficacy analysis, we identified five RCTs comprising 5711 participants. This included 4465 participants from 13 sites in Africa, and 1246 participants from five sites in Asia. The analysis included 541 children aged less than five years. Overall, pyronaridine-artesunate had a polymerase chain reaction (PCR)-adjusted treatment failure rate of less than 5%. We evaluated pyronaridine-artesunate versus the following. • Artemether-lumefantrine. Pyronaridine artesunate may perform better for PCR-adjusted failures at day 28 (RR 0.59, 95% confidence interval (CI) 0.26 to 1.31; 4 RCTs, 3068 participants, low-certainty evidence); for unadjusted failures at day 28 (RR 0.27, 95% CI 0.13 to 0.58; 4 RCTs, 3149 participants, low-certainty evidence); and for unadjusted failures at day 42 (RR 0.61, 95% CI 0.46 to 0.82; 4 RCTs, 3080 participants, low-certainty evidence). For PCR-adjusted failures at day 42, there may be little or no difference between groups (RR 0.86, 95% CI 0.49 to 1.51; 4 RCTs, 2575 participants, low-certainty evidence). • Artesunate-amodiaquine. Pyronaridine artesunate may perform better for PCR-adjusted failures at day 28 (RR 0.55, 95% CI 0.11 to 2.77; 1 RCT, 1245 participants, low-certainty evidence); probably performs better for unadjusted failures at day 28 (RR 0.49, 95% CI 0.30 to 0.81; 1 RCT, 1257 participants, moderate-certainty evidence); may make little or no difference for PCR-adjusted failures at day 42 (RR 0.98, 95% CI 0.20 to 4.83; 1 RCT, 1091 participants, low-certainty evidence); and probably makes little or no difference for unadjusted failures at day 42 (RR 0.98, 95% CI 0.78 to 1.23; 1 RCT, 1235 participants, moderate-certainty evidence). • Mefloquine plus artesunate. Pyronaridine artesunate may perform better for PCR-adjusted failures at day 28 (RR 0.37, 95% CI 0.13 to 1.05; 1 RCT, 1117 participants, low-certainty evidence); probably performs better for unadjusted failures at day 28 (RR 0.36, 95% CI 0.17 to 0.78; 1 RCT, 1120 participants, moderate-certainty evidence); may make little or no difference for unadjusted failures at day 42 (RR 0.84, 95% CI 0.54 to 1.31; 1 RCT, 1059 participants, low-certainty evidence); but may lead to higher PCR-adjusted failures at day 42 (RR 1.80, 95% CI 0.90 to 3.57; 1 RCT, 1037 participants, low-certainty evidence). Safety analysis (RCTs) For the RCT safety analysis, we identified eight RCTs, one of which was delineated by study site, comparing pyronaridine-artesunate to other antimalarials. Pyronaridine-artesunate was associated with raised liver enzymes compared to other antimalarials: alanine aminotransferase (ALT) (RR 3.59, 95% CI 1.76 to 7.33; 8 RCTS, 6669 participants, high-certainty evidence) and aspartate transaminase (AST) (RR 2.22, 95% CI 1.12 to 4.41; 8 RCTs, 6669 participants, moderate-certainty evidence). No such effect was demonstrated with bilirubin (RR 1.03, 95% CI 0.49 to 2.18; 7 RCTs, 6384 participants, moderate-certainty evidence). There was one reported case in which raised ALT occurred with raised bilirubin. No study reported severe drug-induced liver injury. Electrocardiograph (ECG) abnormalities were less common with pyronaridine-artesunate compared to other antimalarials. We identified no other safety concerns. NRS safety review A review on safety in NRS allowed us to increase the population within which safety was assessed. We included seven studies with 9546 participants: five single-arm observational studies, one cohort event monitoring study, and one dose-escalation study. All studies provided data on adverse event frequency, with a small number of participants experiencing serious adverse events and adverse effects related to pyronaridine: serious adverse events average 0.37%; drug-related 9.0%. In two studies reporting elevations in liver enzymes, small percentages of participants (2.4% and 14.1% respectively) experienced increases in either ALT, AST, or bilirubin on day 7; however, these were small increases that returned to normal by day 42. AUTHORS' CONCLUSIONS: Pyronaridine-artesunate was efficacious against uncomplicated P falciparum malaria; achieved a PCR-adjusted treatment failure rate of less than 5% at days 28 and 42; and may be at least as good as, or better than, other marketed ACTs. Pyronaridine-artesunate increases the risk of episodes of abnormally raised ALT. The observational data did not signal an excess of clinically important adverse effects.
Topics: Antimalarials; Artemisinins; Artesunate; Bilirubin; Child; Drug Combinations; Humans; Malaria, Falciparum; Naphthyridines
PubMed: 35726133
DOI: 10.1002/14651858.CD006404.pub4 -
Malaria Journal Jun 2022The World Health Organization (WHO) recommends surveillance of molecular markers of resistance to anti-malarial drugs. This is particularly important in the case of mass... (Review)
Review
The World Health Organization (WHO) recommends surveillance of molecular markers of resistance to anti-malarial drugs. This is particularly important in the case of mass drug administration (MDA), which is endorsed by the WHO in some settings to combat malaria. Dihydroartemisinin-piperaquine (DHA-PPQ) is an artemisinin-based combination therapy which has been used in MDA. This review analyses the impact of MDA with DHA-PPQ on the evolution of molecular markers of drug resistance. The review is split into two parts. Section I reviews the current evidence for different molecular markers of resistance to DHA-PPQ. This includes an overview of the prevalence of these molecular markers in Plasmodium falciparum Whole Genome Sequence data from the MalariaGEN Pf3k project. Section II is a systematic literature review of the impact that MDA with DHA-PPQ has had on the evolution of molecular markers of resistance. This systematic review followed PRISMA guidelines. This review found that despite being a recognised surveillance tool by the WHO, the surveillance of molecular markers of resistance following MDA with DHA-PPQ was not commonly performed. Of the total 96 papers screened for eligibility in this review, only 20 analysed molecular markers of drug resistance. The molecular markers published were also not standardized. Overall, this warrants greater reporting of molecular marker prevalence following MDA implementation. This should include putative pfcrt mutations which have been found to convey resistance to DHA-PPQ in vitro.
Topics: Antimalarials; Artemisinins; Biomarkers; Drug Resistance; Humans; Malaria, Falciparum; Mass Drug Administration; Piperazines; Plasmodium falciparum; Quinolines
PubMed: 35690758
DOI: 10.1186/s12936-022-04181-y -
The Lancet Regional Health. Southeast... Jul 2022The long-term maintenance of parasite biomass below the detection threshold of microscopy may stymie malaria elimination. Variation in microscopists' competencies to...
BACKGROUND
The long-term maintenance of parasite biomass below the detection threshold of microscopy may stymie malaria elimination. Variation in microscopists' competencies to detect and correctly identify parasite species reflect in microscopy sensitivity, resulting in incorrect species-specific burden.
METHODS
The study estimated SMI pooled burden from published reports using a random effect model & identifies their hotspots in India. The study applied a prediction model for the first time on Indian data, emphasizing the importance of such models that can predict PCR-prevalence from slide- prevalence.
FINDINGS
A total of 17,449 samples from 39 districts were examined for by microscopy and PCR. The overall heterogeneity in clinic-based and community-based studies was 91% and 96%, respectively, with the pooled prevalence of 3.63%. The SMI prevalence in individual studies ranged from 38.4% to 0.4%. Sensitivity of microscopy for mono- (91%) was found to be better than mono- (82 %). But surprisingly, it was much lower for mixed PfPv (45%).
INTERPRETATION
Primary regional data in the form of SMIs hot spots should be generated from countries on the verge of malaria elimination, and genetic monitoring should be integrated into national programs, particularly in key areas for successful malaria elimination.
FUNDING
Not applicable.
PubMed: 37383294
DOI: 10.1016/j.lansea.2022.05.001 -
Frontiers in Genetics 2022infects millions and kills thousands of people annually the world over. With the emergence of artemisinin and/or multidrug resistant strains of the pathogen, it has...
infects millions and kills thousands of people annually the world over. With the emergence of artemisinin and/or multidrug resistant strains of the pathogen, it has become even more challenging to control and eliminate the disease. Multiomics studies of the parasite have started to provide a glimpse into the confounding genetics and mechanisms of artemisinin resistance and identified mutations in Kelch13 (K13) as a molecular marker of resistance. Over the years, thousands of genomes and transcriptomes of artemisinin-resistant/sensitive isolates have been documented, supplementing the search for new genes/pathways to target artemisinin-resistant isolates. This meta-analysis seeks to recap the genetic landscape and the transcriptional deregulation that demarcate artemisinin resistance in the field. To explore the genetic territory of artemisinin resistance, we use genomic single-nucleotide polymorphism (SNP) datasets from 2,517 isolates from 15 countries from the MalariaGEN Network (The Pf3K project, pilot data release 4, 2015) to dissect the prevalence, geographical distribution, and co-existing patterns of genetic markers associated with/enabling artemisinin resistance. We have identified several mutations which co-exist with the established markers of artemisinin resistance. Interestingly, K13-resistant parasites harbor α-ß hydrolase and putative HECT domain-containing protein genes with the maximum number of SNPs. We have also explored the multiple, publicly available transcriptomic datasets to identify genes from key biological pathways whose consistent deregulation may be contributing to the biology of resistant parasites. Surprisingly, glycolytic and pentose phosphate pathways were consistently downregulated in artemisinin-resistant parasites. Thus, this meta-analysis highlights the genetic and transcriptomic features of resistant parasites to propel further exploratory studies in the community to tackle artemisinin resistance.
PubMed: 35464842
DOI: 10.3389/fgene.2022.824483 -
Journal of Infection and Public Health May 2022A wide spread of chloroquine resistance prompted its discontinued use for treatment of uncomplicated malaria in several African countries. However, disappearances of... (Review)
Review
Molecular surveillance of chloroquine-resistant Plasmodium falciparum in sub-Saharan African countries after withdrawal of chloroquine for treatment of uncomplicated malaria: A systematic review.
BACKGROUND
A wide spread of chloroquine resistance prompted its discontinued use for treatment of uncomplicated malaria in several African countries. However, disappearances of chloroquine-resistant parasites have been reported in areas with restricted use of chloroquine. This review reports the current prevalence of chloroquine-resistant Plasmodium falciparum using Pfcrt K76T and Pfmdr1 N86Y genotypes.
METHODS
A PROSPERO registered systematic review searched evidence from PubMed/MEDLINE, Science Direct and Google Scholar. The search included studies on chloroquine-resistant/ susceptible P. falciparum in humans between January 1st, 2000 and May 15th, 2020. The search was conducted on 15th of May, 2020.
RESULTS
Out of 519 searched records, 15 studies qualified for final analysis with 8040 samples genotyped for Pfcrt K76T. Of 8040, 43.6% (837/1572; 95%CI: -0.9 to 88.1%) carried resistant genotypes versus 23.0% (1477/6468; 95%CI: 15.7-30.2%) while for 4698 samples analyzed for Pfmdr1 N86Y, 52.4% (592/1090; 95%CI: 42.3-62.5%) had resistant genotypes versus 25.9% (1314/3608; 95%CI: 5.8-46.0%), before and after chloroquine withdrawal, respectively. The median time since chloroquine withdrawal to data collection was 7.0 (interquartile range: 4.5-13.5) years. Low prevalence of resistant genotypes (Pfcrt K76T) was reported in Zambia (0%) in 2013, Malawi (0.1%) in 2009, Tanzania (0.2%) in 2018 and Madagascar (0.3%) in 2007 with significant variations in the included studies.
CONCLUSIONS
Chloroquine-resistant P. falciparum continues to disappear in countries with withdrawal of chloroquine. Areas with significant susceptible parasites, reintroduction of chloroquine can be considered, preferably in combination with other safe and affordable antimalarials.
Topics: Africa South of the Sahara; Antimalarials; Chloroquine; Drug Resistance; Humans; Malaria; Malaria, Falciparum; Membrane Transport Proteins; Plasmodium falciparum; Protozoan Proteins
PubMed: 35447389
DOI: 10.1016/j.jiph.2022.03.015