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The Lancet. Microbe Aug 2022High-quality evidence for the therapeutic efficacy and effectiveness of antimalarials for infections caused by Plasmodium malariae, Plasmodium ovale spp, and...
Effectiveness of pyronaridine-artesunate against Plasmodium malariae, Plasmodium ovale spp, and mixed-Plasmodium infections: a post-hoc analysis of the CANTAM-Pyramax trial.
BACKGROUND
High-quality evidence for the therapeutic efficacy and effectiveness of antimalarials for infections caused by Plasmodium malariae, Plasmodium ovale spp, and mixed-Plasmodium infections is scarce. In this study, we aimed to analyse the efficacy of pyronaridine-artesunate for the treatment of non-falciparum and mixed-species Plasmodium infections from a large phase 3b/4 clinical trial in central Africa.
METHODS
This post-hoc analysis was done in a random subset of samples from two sites (in the Democratic Republic of the Congo and in Gabon) of the CANTAM-Pyramax trial assessing pyronaridine-artesunate therapy. We randomly selected paired dried blood spot samples from day 0 and day 28 (or unforeseen visit) and analysed them by quantitative PCR for mixed Plasmodium infections or non-falciparum mono-infections. Day 28 (or unforeseen visit) samples positive for non-falciparum malaria were re-assessed by microscopy to identify microscopic versus submicroscopic infections. Analyses were done on two sample sets: a per-protocol set and an intention-to-treat set.
FINDINGS
Among 1502 randomly selected samples, 192 (12·8%) showed mixed-Plasmodium infections or non-falciparum mono-infections. We did not detect P vivax in the samples. For both the per-protocol and intention-to-treat sets, the overall day 28 cure rates for P malariae, P ovale curtisi, and P ovale wallikeri were 96·3% or higher (95% CIs from 81·0-99·9 to 95·7-100). Cure rates were consistently high in P malariae (99·2%, 95·7-100) and P ovale spp (97·9%, 88·7-99·9, for P ovale curtisi and 96·3%, 81·0-99·9, for P ovale wallikeri) infections.
INTERPRETATION
This post-hoc analysis provides important evidence supporting the high efficacy of pyronaridine-artesunate against mono-infections with P malariae, P ovale curtisi, or P ovale wallikeri and mixed-Plasmodium infections in a real-world setting.
FUNDING
Medicines for Malaria Venture.
Topics: Artesunate; Drug Combinations; Humans; Malaria; Naphthyridines; Plasmodium malariae; Plasmodium ovale
PubMed: 35654079
DOI: 10.1016/S2666-5247(22)00092-1 -
British Journal of Clinical Pharmacology Jun 2022Methaemoglobin results from the oxidation of ferrous to ferric iron in the centre of the haem moiety of haemoglobin. The production of dose-dependent methaemoglobinaemia... (Review)
Review
Methaemoglobin results from the oxidation of ferrous to ferric iron in the centre of the haem moiety of haemoglobin. The production of dose-dependent methaemoglobinaemia by 8-aminoquinoline antimalarial drugs appears to be associated with, but is not directly linked to, therapeutic efficacy against latent Plasmodium vivax and Plasmodium ovale malarias (radical cure). Iatrogenic methaemoglobinaemia may be a useful pharmacodynamic measure in 8-aminoquinoline drug and dose optimization.
Topics: Aminoquinolines; Antimalarials; Humans; Methemoglobinemia; Plasmodium vivax
PubMed: 34997616
DOI: 10.1111/bcp.15219 -
Emerging Infectious Diseases Aug 2018Human malaria parasites have rarely been reported from free-ranging great apes. Our study confirms the presence of the human malaria parasite Plasmodium ovale wallikeri...
Human malaria parasites have rarely been reported from free-ranging great apes. Our study confirms the presence of the human malaria parasite Plasmodium ovale wallikeri in western lowland gorillas and humans in Dzanga Sangha Protected Areas, Central African Republic, and discusses implications for malaria epidemiology.
Topics: Animals; Ape Diseases; Central African Republic; DNA, Protozoan; Feces; Genotype; Gorilla gorilla; Humans; Malaria; Phylogeny; Plasmodium ovale; Polymerase Chain Reaction; RNA, Ribosomal, 18S
PubMed: 30016237
DOI: 10.3201/eid2408.180010 -
PloS One 2019Plasmodium ovale curtisi and Plasmodium ovale wallikeri are two sympatric human malaria species prevalent in Africa, Asia and Oceania. The reported prevalence of both P....
Plasmodium ovale curtisi and Plasmodium ovale wallikeri are two sympatric human malaria species prevalent in Africa, Asia and Oceania. The reported prevalence of both P. ovale spp. was relatively low compared to other malaria species, but more sensitive molecular detection techniques have shown that asymptomatic low-density infections are more common than previously thought. Whole genome sequencing of both P. ovale spp. revealed genetic dissociation between P. ovale curtisi and P. ovale wallikeri suggesting a species barrier. In this study we further evaluate such a barrier by assessing polymorphisms in the genes of three vaccine candidate surface protein: circumsporozoite protein/ thrombospondin-related anonymous-related protein (ctrp), circumsporozoite surface protein (csp) and merozoite surface protein 1 (msp1). The complete coding sequence of ctrp and csp, and a partial fragment of msp1 were isolated from 25 P. ovale isolates and compared to previously reported reference sequences. A low level of nucleotide diversity (Pi = 0.02-0.10) was observed in all three genes. Various sizes of tandem repeats were observed in all ctrp, csp and msp1 genes. Both tandem repeat unit and nucleotide polymorphism in all three genes exhibited clear dimorphism between P. ovale curtisi and P. ovale wallikeri, supporting evidence of non-recombination between these two species.
Topics: Amino Acid Sequence; Antigens, Protozoan; Conserved Sequence; Genes, Protozoan; Nucleotides; Phylogeny; Plasmodium ovale; Protozoan Proteins; Tandem Repeat Sequences
PubMed: 31170213
DOI: 10.1371/journal.pone.0217795 -
Malaria Journal Sep 2012In this position paper, the European Society for Clinical Microbiology and Infectious Diseases, Study Group on Clinical Parasitology, summarizes main issues regarding... (Review)
Review
In this position paper, the European Society for Clinical Microbiology and Infectious Diseases, Study Group on Clinical Parasitology, summarizes main issues regarding the management of imported malaria cases. Malaria is a rare diagnosis in Europe, but it is a medical emergency. A travel history is the key to suspecting malaria and is mandatory in patients with fever. There are no specific clinical signs or symptoms of malaria although fever is seen in almost all non-immune patients. Migrants from malaria endemic areas may have few symptoms.Malaria diagnostics should be performed immediately on suspicion of malaria and the gold- standard is microscopy of Giemsa-stained thick and thin blood films. A Rapid Diagnostic Test (RDT) may be used as an initial screening tool, but does not replace urgent microscopy which should be done in parallel. Delays in microscopy, however, should not lead to delayed initiation of appropriate treatment. Patients diagnosed with malaria should usually be hospitalized. If outpatient management is preferred, as is the practice in some European centres, patients must usually be followed closely (at least daily) until clinical and parasitological cure. Treatment of uncomplicated Plasmodium falciparum malaria is either with oral artemisinin combination therapy (ACT) or with the combination atovaquone/proguanil. Two forms of ACT are available in Europe: artemether/lumefantrine and dihydroartemisinin/piperaquine. ACT is also effective against Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi, but these species can be treated with chloroquine. Treatment of persistent liver forms in P. vivax and P. ovale with primaquine is indicated after excluding glucose 6 phosphate dehydrogenase deficiency. There are modified schedules and drug options for the treatment of malaria in special patient groups, such as children and pregnant women. The potential for drug interactions and the role of food in the absorption of anti-malarials are important considerations in the choice of treatment.Complicated malaria is treated with intravenous artesunate resulting in a much more rapid decrease in parasite density compared to quinine. Patients treated with intravenous artesunate should be closely monitored for haemolysis for four weeks after treatment. There is a concern in some countries about the lack of artesunate produced according to Good Manufacturing Practice (GMP).
Topics: Antimalarials; Clinical Laboratory Techniques; Clinical Medicine; Communicable Disease Control; Emigration and Immigration; Europe; Humans; Malaria; Plasmodium; Travel
PubMed: 22985344
DOI: 10.1186/1475-2875-11-328 -
Nature Communications Jul 2015Experimental studies of Plasmodium parasites that infect humans are restricted by their host specificity. Humanized mice offer a means to overcome this and further...
Experimental studies of Plasmodium parasites that infect humans are restricted by their host specificity. Humanized mice offer a means to overcome this and further provide the opportunity to observe the parasites in vivo. Here we improve on previous protocols to achieve efficient double engraftment of TK-NOG mice by human primary hepatocytes and red blood cells. Thus, we obtain the complete hepatic development of P. falciparum, the transition to the erythrocytic stages, their subsequent multiplication, and the appearance of mature gametocytes over an extended period of observation. Furthermore, using sporozoites derived from two P. ovale-infected patients, we show that human hepatocytes engrafted in TK-NOG mice sustain maturation of the liver stages, and the presence of late-developing schizonts indicate the eventual activation of quiescent parasites. Thus, TK-NOG mice are highly suited for in vivo observations on the Plasmodium species of humans.
Topics: Animals; Disease Models, Animal; Erythrocyte Transfusion; Female; Hepatocytes; Humans; Life Cycle Stages; Liver; Malaria; Male; Mice, Transgenic; Plasmodium falciparum; Plasmodium ovale; Sporozoites
PubMed: 26205537
DOI: 10.1038/ncomms8690 -
Scientific Reports Jan 2018Plasmodium ovale curtisi (Poc) and Plasmodium ovale wallikeri (Pow) have been described as two distinct species, only distinguishable by molecular methods such as PCR....
Plasmodium ovale curtisi (Poc) and Plasmodium ovale wallikeri (Pow) have been described as two distinct species, only distinguishable by molecular methods such as PCR. Because of no well-defined endemic area and a variable clinical presentation as higher thrombocytopenia and nausea associated with Pow infection and asymptomatic forms of the pathology with Poc infection, rapid and specific identification of Plasmodium ovale curtisi and Plasmodium ovale wallikeri are needed. The aim of the study was to evaluate a new quantitative real-time PCR coupled with high resolution melting revelation (qPCR-HRM) for identification of both species. Results were compared with a nested-PCR, considered as a gold standard for Pow and Poc distinction. 356 samples including all human Plasmodium species at various parasitaemia were tested. The qPCR-HRM assay allowed Poc and Pow discrimination in 66 samples tested with a limit of detection evaluated at 1 parasite/µL. All these results were concordant with nested-PCR. Cross-reaction was absent with others blood parasites. The qPCR-HRM is a rapid and convenient technique to Poc and Pow distinction.
Topics: Base Sequence; Humans; Malaria; Molecular Typing; Phylogeny; Phylogeography; Plasmodium ovale; RNA, Ribosomal, 18S; Real-Time Polymerase Chain Reaction; Reproducibility of Results; Sensitivity and Specificity; Sequence Analysis, DNA
PubMed: 29321578
DOI: 10.1038/s41598-017-18026-1 -
Clinical Infectious Diseases : An... Dec 2021In a cross-sectional molecular study in the Democratic Republic of the Congo, 78% of households had ≥1 member infected with Plasmodium falciparum, Plasmodium vivax,...
In a cross-sectional molecular study in the Democratic Republic of the Congo, 78% of households had ≥1 member infected with Plasmodium falciparum, Plasmodium vivax, and/or Plasmodium ovale spp.; 47% of children and 33% of adults tested positive for ≥1 species. Risk factors varied by species and age group.
Topics: Adult; Child; Cross-Sectional Studies; Democratic Republic of the Congo; Humans; Malaria, Falciparum; Plasmodium falciparum; Plasmodium ovale; Plasmodium vivax; Prevalence
PubMed: 33238298
DOI: 10.1093/cid/ciaa1772 -
The Journal of Molecular Diagnostics :... Oct 2021Plasmodium malariae and Plasmodium ovale are increasingly gaining public health attention as the global transmission of falciparum malaria is decreasing. However, the...
Plasmodium malariae and Plasmodium ovale are increasingly gaining public health attention as the global transmission of falciparum malaria is decreasing. However, the absence of reliable Plasmodium species-specific detection tools has hampered accurate diagnosis of these minor Plasmodium species. In this study, SYBR Green-based real-time PCR assays were developed for the detection of P. malariae and P. ovale using cooperative primers that significantly limit the formation and propagation of primers-dimers. Both the P. malariae and P. ovale cooperative primer-based assays had at least 10-fold lower detection limit compared with the corresponding conventional primer-based assays. More important, the cooperative primer-based assays were evaluated in a cross-sectional study using 560 samples obtained from two health facilities in Ghana. The prevalence rates of P. malariae and P. ovale among the combined study population were 18.6% (104/560) and 5.5% (31/560), respectively. Among the Plasmodium-positive cases, P. malariae and P. ovale mono-infections were 3.6% (18/499) and 1.0% (5/499), respectively, with the remaining being co-infections with Plasmodium falciparum. The study demonstrates the public health importance of including detection tools with lower detection limits in routine diagnosis and surveillance of nonfalciparum species. This will be necessary for comprehensively assessing the effectiveness of malaria interventions and control measures aimed toward global malaria elimination.
Topics: Adolescent; Adult; Child; Child, Preschool; Coinfection; Cross-Sectional Studies; DNA Primers; Female; Ghana; Humans; Limit of Detection; Malaria, Falciparum; Male; Plasmodium falciparum; Plasmodium malariae; Plasmodium ovale; Prevalence; RNA, Ribosomal, 18S; Real-Time Polymerase Chain Reaction; Young Adult
PubMed: 34425259
DOI: 10.1016/j.jmoldx.2021.07.022 -
Clinical Microbiology and Infection :... May 2013Malaria rapid diagnostic tests (RDTs) are instrument-free tests that provide results within 20 min and can be used by community health workers. RDTs detect antigens... (Review)
Review
Malaria rapid diagnostic tests (RDTs) are instrument-free tests that provide results within 20 min and can be used by community health workers. RDTs detect antigens produced by the Plasmodium parasite such as Plasmodium falciparum histidine-rich protein-2 (PfHPR2) and Plasmodium lactate dehydrogenase (pLDH). The accuracy of RDTs for the diagnosis of uncomplicated P. falciparum infection is equal or superior to routine microscopy (but inferior to expert microscopy). Sensitivity for Plasmodium vivax is 75-100%; for Plasmodium ovale and Plasmodium malariae, diagnostic performance is poor. Design limitations of RDTs include poor sensitivity at low parasite densities, susceptibility to the prozone effect (PfHRP2-detecting RDTs), false-negative results due to PfHRP2 deficiency in the case of pfhrp2 gene deletions (PfHRP2-detecting RDTs), cross-reactions between Plasmodium antigens and detection antibodies, false-positive results by other infections and susceptibility to heat and humidity. End-user's errors relate to safety, procedure (delayed reading, incorrect sample and buffer volumes) and interpretation (not recognizing invalid test results, disregarding faint test lines). Withholding antimalarial treatment in the case of negative RDT results tends to be infrequent and tendencies towards over-prescription of antibiotics have been noted. Numerous shortcomings in RDT kits' labelling, instructions for use (correctness and readability) and contents have been observed. The World Health Organization and partners actively address quality assurance of RDTs by comparative testing of RDTs, inspections of manufacturing sites, lot testing and training tools but no formal external quality assessment programme of end-user performance exists. Elimination of malaria requires RDTs with lower detection limits, for which nucleic acid amplification tests are under development.
Topics: Antigens, Protozoan; Cross Reactions; Diagnostic Tests, Routine; Endemic Diseases; False Negative Reactions; Humans; Malaria; Sensitivity and Specificity
PubMed: 23438048
DOI: 10.1111/1469-0691.12151