Publications by authors named "Nicholas J White"

676 Publications

Falciparum but not vivax malaria increases the risk of hypertensive disorders of pregnancy in women followed prospectively from the first trimester.

BMC Med 2021 Apr 27;19(1):98. Epub 2021 Apr 27.

Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.

Background: Malaria and hypertensive disorders of pregnancy (HDoP) affect millions of pregnancies worldwide, particularly those of young, first-time mothers. Small case-control studies suggest a positive association between falciparum malaria and risk of pre-eclampsia but large prospective analyses are lacking.

Methods: We characterized the relationship between malaria in pregnancy and the development of HDoP in a large, prospectively followed cohort. Pregnant women living along the Thailand-Myanmar border, an area of low seasonal malaria transmission, were followed at antenatal clinics between 1986 and 2016. The relationships between falciparum and vivax malaria during pregnancy and the odds of gestational hypertension, pre-eclampsia, or eclampsia were examined using logistic regression amongst all women and then stratified by gravidity.

Results: There were 23,262 singleton pregnancies in women who presented during the first trimester and were followed fortnightly. Falciparum malaria was associated with gestational hypertension amongst multigravidae (adjusted odds ratio (AOR) 2.59, 95%CI 1.59-4.23), whereas amongst primigravidae, it was associated with the combined outcome of pre-eclampsia/eclampsia (AOR 2.61, 95%CI 1.01-6.79). In contrast, there was no association between vivax malaria and HDoP.

Conclusions: Falciparum but not vivax malaria during pregnancy is associated with hypertensive disorders of pregnancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12916-021-01960-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077872PMC
April 2021

COVID-19 chemoprevention.

Int J Infect Dis 2021 Apr 24;107:31-33. Epub 2021 Apr 24.

Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijid.2021.04.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064811PMC
April 2021

Personalised randomised controlled trial designs-a new paradigm to define optimal treatments for carbapenem-resistant infections.

Lancet Infect Dis 2021 Apr 21. Epub 2021 Apr 21.

Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK; and Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam. Electronic address:

Antimicrobial resistance is impacting treatment decisions for, and patient outcomes from, bacterial infections worldwide, with particular threats from infections with carbapenem-resistant Enterobacteriaceae, Acinetobacter baumanii, or Pseudomonas aeruginosa. Numerous areas of clinical uncertainty surround the treatment of these highly resistant infections, yet substantial obstacles exist to the design and conduct of treatment trials for carbapenem-resistant bacterial infections. These include the lack of a widely acceptable optimised standard of care and control regimens, varying antimicrobial susceptibilities and clinical contraindications making specific intervention regimens infeasible, and diagnostic and recruitment challenges. The current single comparator trials are not designed to answer the urgent public health question, identified as a high priority by WHO, of what are the best regimens out of the available options that will significantly reduce morbidity, costs, and mortality. This scenario has an analogy in network meta-analysis, which compares multiple treatments in an evidence synthesis to rank the best of a set of available treatments. To address these obstacles, we propose extending the network meta-analysis approach to individual randomisation of patients. We refer to this approach as a Personalised RAndomised Controlled Trial (PRACTical) design that compares multiple treatments in an evidence synthesis, to identify, overall, which is the best treatment out of a set of available treatments to recommend, or how these different treatments rank against each other. In this Personal View, we summarise the design principles of personalised randomised controlled trial designs. Specifically, of a network of different potential regimens for life-threatening carbapenem-resistant infections, each patient would be randomly assigned only to regimens considered clinically reasonable for that patient at that time, incorporating antimicrobial susceptibility, toxicity profile, pharmacometric properties, availability, and physician assessment. Analysis can use both direct and indirect comparisons across the network, analogous to network meta-analysis. This new trial design will maximise the relevance of the findings to each individual patient, and enable the top-ranked regimens from any personalised randomisation list to be identified, in terms of both efficacy and safety.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1473-3099(20)30791-XDOI Listing
April 2021

The prevention and treatment of Plasmodium vivax malaria.

PLoS Med 2021 Apr 23;18(4):e1003561. Epub 2021 Apr 23.

Shoklo Malaria Research Unit-Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.

Cindy S Chu and co-authors review options for diagnosis, safe and radical cure, and relapse prevention of Plasmodium Vivax.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pmed.1003561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064578PMC
April 2021

Taking on Plasmodium vivax malaria: A timely and important challenge.

PLoS Med 2021 Apr 23;18(4):e1003593. Epub 2021 Apr 23.

Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

Lorenz von Seidlein and Nicholas White introduce a Collection on Plasmodium vivax malaria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pmed.1003593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064523PMC
April 2021

An open dataset of genome variation in 7,000 worldwide samples.

Wellcome Open Res 2021 24;6:42. Epub 2021 Feb 24.

Medical Research Council Unit The Gambia, at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia.

MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed.  Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12688/wellcomeopenres.16168.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008441PMC
February 2021

Guidelines should not pool evidence from uncomplicated and severe COVID-19.

Lancet 2021 04 23;397(10281):1262-1263. Epub 2021 Mar 23.

Infectious Diseases Data Observatory, Centre for Tropical Medicine and Global Health, University of Oxford, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(21)00469-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984863PMC
April 2021

Anti-malarial drug effects on parasite dynamics in vivax malaria.

Authors:
Nicholas J White

Malar J 2021 Mar 21;20(1):161. Epub 2021 Mar 21.

Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand.

Relapses of Plasmodium vivax malaria are prevented by 8-aminoquinolines. If hypnozoites survive, then the subsequent blood stage infections in early relapses (< 2 months) are suppressed by the slowly eliminated anti-malarial drugs used to treat the blood stage infection (chloroquine, artemisinin combination treatments), but they are not usually eliminated. The 8-aminoquinolines have significant blood stage activity which contributes to therapeutic responses. The latent interval from primary infection to early relapse depends on the number of activatable hypnozoites, the dose of anti-malarial, its pharmacokinetic properties, the level of resistance (minimum inhibitory concentration) and immunity. The dose-response relationship for radical curative efficacy of primaquine and tafenoquine is steep over the total dose range from 1.5 to 5 mg base/kg which may explain the poor efficacy of tafenoquine at the currently recommended dose.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12936-021-03700-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981980PMC
March 2021

A systematic review and an individual patient data meta-analysis of ivermectin use in children weighing less than fifteen kilograms: Is it time to reconsider the current contraindication?

PLoS Negl Trop Dis 2021 Mar 17;15(3):e0009144. Epub 2021 Mar 17.

WorldWide Antimalarial Resistance Network (WWARN), Oxford, United Kingdom.

Background: Oral ivermectin is a safe broad spectrum anthelminthic used for treating several neglected tropical diseases (NTDs). Currently, ivermectin use is contraindicated in children weighing less than 15 kg, restricting access to this drug for the treatment of NTDs. Here we provide an updated systematic review of the literature and we conducted an individual-level patient data (IPD) meta-analysis describing the safety of ivermectin in children weighing less than 15 kg.

Methodology/principal Findings: A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for IPD guidelines by searching MEDLINE via PubMed, Web of Science, Ovid Embase, LILACS, Cochrane Database of Systematic Reviews, TOXLINE for all clinical trials, case series, case reports, and database entries for reports on the use of ivermectin in children weighing less than 15 kg that were published between 1 January 1980 to 25 October 2019. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42017056515. A total of 3,730 publications were identified, 97 were selected for potential inclusion, but only 17 sources describing 15 studies met the minimum criteria which consisted of known weights of children less than 15 kg linked to possible adverse events, and provided comprehensive IPD. A total of 1,088 children weighing less than 15 kg were administered oral ivermectin for one of the following indications: scabies, mass drug administration for scabies control, crusted scabies, cutaneous larva migrans, myiasis, pthiriasis, strongyloidiasis, trichuriasis, and parasitic disease of unknown origin. Overall a total of 1.4% (15/1,088) of children experienced 18 adverse events all of which were mild and self-limiting. No serious adverse events were reported.

Conclusions/significance: Existing limited data suggest that oral ivermectin in children weighing less than 15 kilograms is safe. Data from well-designed clinical trials are needed to provide further assurance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pntd.0009144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968658PMC
March 2021

Does hydroxychloroquine still have any role in the COVID-19 pandemic?

Expert Opin Pharmacother 2021 Mar 16:1-10. Epub 2021 Mar 16.

Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

: The 4-aminoquinolines, chloroquine, and hydroxychloroquine have been used for over 70 years for malaria and rheumatological conditions, respectively. Their broad-spectrum antiviral activity, excellent safety profile, tolerability, low cost, and ready availability made them prime repurposing therapeutic candidates at the beginning of the COVID-19 pandemic.: Here, the authors discuss the history of hydroxychloroquine and chloroquine, the data which led to their widespread repurposing and adoption in COVID-19 and their complex pharmacokinetics. The evidence for the use of these drugs is assessed through animal experiments and the wealth of conflicting data and interpretations published during COVID-19, including the more informative results from randomized controlled trials (RCTs). The safety aspects of these drugs, in particular cardiotoxicity, are then reviewed.: The evidence from clinical trials in COVID-19 supports the well-established safety record of the 4-aminoquinolines at currently recommended dosage. In hospitalized patients with severe COVID-19 RCTs show clearly that the 4-aminoquinolines are not beneficial. The only treatments with proven benefit at this stage of infection are immunomodulators (dexamethasone, IL-6 receptor antagonists). No antiviral drugs have proven life-saving in late-stage COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14656566.2021.1898589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989952PMC
March 2021

Development and validation of an decision-tool to guide optimisation of intravenous artesunate dosing regimens for severe falciparum malaria patients.

Antimicrob Agents Chemother 2021 Mar 8. Epub 2021 Mar 8.

Centre for Epidemiology & Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.

Most deaths from severe falciparum malaria occur within 24 hours of presentation to hospital. Intravenous (i.v.) artesunate is the first-line treatment for severe falciparum malaria, but its efficacy may be compromised by delayed parasitological responses. In patients with severe malaria the life-saving benefit of the artemisinin derivatives is their ability to clear circulating parasites rapidly, before they can sequester and obstruct the microcirculation. To evaluate the dosing of i.v. artesunate for the treatment of artemisinin-sensitive and reduced ring stage sensitivity to artemisinin severe falciparum malaria infections Bayesian pharmacokinetic-pharmacodynamic modelling of data from 94 patients with severe malaria (80 children from Africa and 14 adults from Southeast Asia) was performed. Assuming delayed parasite clearance reflects a loss of ring stage sensitivity to artemisinin derivatives, the median (95% credible interval) percentage of patients clearing ≥99% parasites within 24 hours (PC24≥99%) for standard (2.4 mg/kg i.v. artesunate at 0 and 12 hours) and simplified (4 mg/kg i.v. artesunate at 0 hours) regimens were 65% (52.5%-74.5%) versus 44% (25%-61.5%) for adults, 62% (51.5%-74.5%) versus 39% (20.5%-58.5%) for larger children (≥20 kg) and 60% (48.5%-70%) versus 36% (20%-53.5%) for smaller children (<20 kg). The upper limit of the credible intervals for all regimens was below a PC24≥99% of 80%, a threshold achieved on average in clinical studies of severe falciparum malaria infections. Rapid clearance of parasites, where there is loss of ring stage sensitivity to artemisinin, in patients with severe falciparum malaria is compromised with the currently recommended and proposed simplified i.v. artesunate dosing regimens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.02346-20DOI Listing
March 2021

Remote-Controlled and Pulse Pressure-Guided Fluid Treatment for Adult Patients with Viral Hemorrhagic Fevers.

Am J Trop Med Hyg 2021 Feb 16. Epub 2021 Feb 16.

1Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

Circulatory shock, caused by severe intravascular volume depletion resulting from gastrointestinal losses and profound capillary leak, is a common clinical feature of viral hemorrhagic fevers, including Ebola virus disease, Marburg hemorrhagic fever, and Lassa fever. These conditions are associated with high case fatality rates, and they carry a significant risk of infection for treating personnel. Optimized fluid therapy is the cornerstone of management of these diseases, but there are few data on the extent of fluid losses and the severity of the capillary leak in patients with VHFs, and no specific guidelines for fluid resuscitation and hemodynamic monitoring exist. We propose an innovative approach for monitoring VHF patients, in particular suited for low-resource settings, facilitating optimizing fluid therapy through remote-controlled and pulse pressure-guided fluid resuscitation. This strategy would increase the capacity for adequate supportive care, while decreasing the risk for virus transmission to health personnel.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4269/ajtmh.20-1515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045617PMC
February 2021

Hydroxychloroquine in Hospitalized Patients with Covid-19. Reply.

N Engl J Med 2021 03 10;384(9):882. Epub 2021 Feb 10.

University of Oxford, Oxford, United Kingdom

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMc2035374DOI Listing
March 2021

Protective effect of Mediterranean-type glucose-6-phosphate dehydrogenase deficiency against malaria.

Elife 2021 Feb 5;10. Epub 2021 Feb 5.

Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy. The severe Mediterranean variant (G6PD Med) found across Europe and Asia is thought to confer protection against malaria, but its effect is unclear. We fitted a Bayesian statistical model to observed G6PD Med allele frequencies in 999 Pashtun patients presenting with acute malaria and 1408 population controls. G6PD Med was associated with reductions in symptomatic malaria incidence of 76% (95% credible interval [CI], 58-88) in hemizygous males and homozygous females combined and 55% (95% CI, 38-68) in heterozygous females. Unless there is very large population stratification within the Pashtun (confounding these results), the G6PD Med genotype confers a very large and gene-dose proportional protective effect against acute vivax malaria. The proportion of patients with vivax malaria at risk of haemolysis following 8-aminoquinoline radical cure is substantially overestimated by studies measuring G6PD deficiency prevalence in healthy subjects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.62448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884069PMC
February 2021

Reply to Aung et al.

Authors:
Nicholas J White

Clin Infect Dis 2021 02;72(3):536-538

Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850525PMC
February 2021

Pharmacokinetic Study of Rectal Artesunate in Children with Severe Malaria in Africa.

Antimicrob Agents Chemother 2021 03 18;65(4). Epub 2021 Mar 18.

Kinshasa School of Public Health, University of Kinshasa, Kinshasa, Democratic Republic of Congo.

When severe malaria is suspected in children, the WHO recommends pretreatment with a single rectal dose of artesunate before referral to an appropriate facility. This was an individually randomized, open-label, 2-arm, crossover clinical trial in 82 Congolese children with severe malaria to characterize the pharmacokinetics of rectal artesunate. At admission, children received a single dose of rectal artesunate (10 mg/kg of body weight) followed 12 h later by intravenous artesunate (2.4 mg/kg) or the reverse order. All children also received standard doses of intravenous quinine. Artesunate and dihydroartemisinin were measured at 11 fixed intervals, following 0- and 12-h drug administrations. Clinical, laboratory, and parasitological parameters were measured. After rectal artesunate, artesunate and dihydroartemisinin showed large interindividual variability (peak concentrations of dihydroartemisinin ranged from 5.63 to 8,090 nM). The majority of patients, however, reached previously suggested IC and IC values (98.7% and 92.5%, respectively) of combined concentrations of artesunate and dihydroartemisinin between 15 and 30 min after drug administration. The median (interquartile range [IQR]) time above IC and IC was 5.68 h (2.90 to 6.08) and 2.74 h (1.52 to 3.75), respectively. The absolute rectal bioavailability (IQR) was 25.6% (11.7 to 54.5) for artesunate and 19.8% (10.3 to 35.3) for dihydroartemisinin. The initial 12-h parasite reduction ratio was comparable between rectal and intravenous artesunate: median (IQR), 84.3% (50.0 to 95.4) versus 69.2% (45.7 to 93.6), respectively ( = 0.49). Despite large interindividual variability, rectal artesunate can initiate and sustain rapid parasiticidal activity in most children with severe malaria while they are transferred to a facility where parenteral artesunate is available. (This study has been registered at ClinicalTrials.gov under identifier NCT02492178.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.02223-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097454PMC
March 2021

Identification of the metabolites of ivermectin in humans.

Pharmacol Res Perspect 2021 02;9(1):e00712

Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

Mass drug administration of ivermectin has been proposed as a possible malaria elimination tool. Ivermectin exhibits a mosquito-lethal effect well beyond its biological half-life, suggesting the presence of active slowly eliminated metabolites. Human liver microsomes, primary human hepatocytes, and whole blood from healthy volunteers given oral ivermectin were used to identify ivermectin metabolites by ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry. The molecular structures of metabolites were determined by mass spectrometry and verified by nuclear magnetic resonance. Pure cytochrome P450 enzyme isoforms were used to elucidate the metabolic pathways. Thirteen different metabolites (M1-M13) were identified after incubation of ivermectin with human liver microsomes. Three (M1, M3, and M6) were the major metabolites found in microsomes, hepatocytes, and blood from volunteers after oral ivermectin administration. The chemical structure, defined by LC-MS/MS and NMR, indicated that M1 is 3″-O-demethyl ivermectin, M3 is 4-hydroxymethyl ivermectin, and M6 is 3″-O-demethyl, 4-hydroxymethyl ivermectin. Metabolic pathway evaluations with characterized cytochrome P450 enzymes showed that M1, M3, and M6 were produced primarily by CYP3A4, and that M1 was also produced to a small extent by CYP3A5. Demethylated (M1) and hydroxylated (M3) ivermectin were the main human in vivo metabolites. Further studies are needed to characterize the pharmacokinetic properties and mosquito-lethal activity of these metabolites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/prp2.712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836931PMC
February 2021

Randomized Controlled Trial of the Electrocardiographic Effects of Four Antimalarials for Pregnant Women with Uncomplicated Malaria on the Thailand-Myanmar Border.

Antimicrob Agents Chemother 2021 03 18;65(4). Epub 2021 Mar 18.

Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand

Quinoline antimalarials cause drug-induced electrocardiographic QT prolongation, a potential risk factor for torsade de pointes. The effects of currently used antimalarials on the electrocardiogram (ECG) were assessed in pregnant women with malaria. Pregnant women with microscopy-confirmed parasitemia of any malaria species were enrolled in an open-label randomized controlled trial on the Thailand-Myanmar border from 2010 to 2016. Patients were randomized to the standard regimen of dihydroartemisinin-piperaquine (DP) or artesunate-mefloquine (ASMQ) or an extended regimen of artemether-lumefantrine (AL+). Recurrent infections were treated with chloroquine. Standard 12-lead electrocardiograms were assessed on day 0, 4 to 6 h following the last dose, and day 7. QT was corrected for the heart rate by a linear mixed-effects model-derived population-based correction formula (QTcP = QT/RR). A total of 86 AL+, 82 ASMQ, 88 DP, and 21 chloroquine-treated episodes were included. No patients had an uncorrected QT interval nor QTcP of >480 ms at any time. QTcP corresponding to peak drug concentration was longer in the DP group (adjusted predicted mean difference, 17.84 ms; 95% confidence interval [CI], 11.58 to 24.10;  < 0.001) and chloroquine group (18.31 ms; 95% CI, 8.78 to 27.84;  < 0.001) than in the AL+ group, but not different in the ASMQ group (2.45 ms; 95% CI, -4.20 to 9.10;  = 0.47) by the multivariable linear mixed-effects model. There was no difference between DP and chloroquine ( = 0.91). QTc prolongation resulted mainly from widening of the JT interval. In pregnant women, none of the antimalarial drug treatments exceeded conventional thresholds for an increased risk of torsade de pointes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.02473-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097415PMC
March 2021

Is malaria parasite ex-vivo viability reduction really "superior" to observed parasite clearance rate?

J Infect Dis 2020 Dec 28. Epub 2020 Dec 28.

Mahidol Oxford Research Unit,Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiaa790DOI Listing
December 2020

Time-to-death is a potential confounder in observational studies of blood transfusion in severe malaria.

Lancet Haematol 2021 01 22;8(1):e12. Epub 2020 Dec 22.

Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-3026(20)30395-1DOI Listing
January 2021

Triple artemisinin-based combination therapies for malaria: proceed with caution - Authors' reply.

Lancet 2021 12;396(10267):1976-1977

Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(20)32677-5DOI Listing
December 2021

The risk of Plasmodium vivax parasitaemia after P. falciparum malaria: An individual patient data meta-analysis from the WorldWide Antimalarial Resistance Network.

PLoS Med 2020 11 19;17(11):e1003393. Epub 2020 Nov 19.

MARIB-Malaria Research Initiative Bandarban, Vienna, Austria.

Background: There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial.

Methods And Findings: A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. The median age was 17.0 years (interquartile range [IQR] = 9.0-29.0 years; range = 0-80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P. falciparum was 31.1% (95% CI 28.9-33.4) after AL, 14.1% (95% CI 10.8-18.3) after AA, 7.4% (95% CI 6.7-8.1) after AM, and 4.5% (95% CI 3.9-5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6-43.3), 42.4% (95% CI 34.7-51.2), 22.8% (95% CI 21.2-24.4), and 12.8% (95% CI 11.4-14.5), respectively. In multivariable analyses, the highest rate of P. vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0-19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6-8.5; p < 0.001), AA (AHR = 2.3, 95% CI 1.4-3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0-1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4-2.3; p < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high.

Conclusions: In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pmed.1003393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676739PMC
November 2020

Transmission of Artemisinin-Resistant Malaria Parasites to Mosquitoes under Antimalarial Drug Pressure.

Antimicrob Agents Chemother 2020 12 16;65(1). Epub 2020 Dec 16.

Department of Life Sciences, Imperial College London, London, United Kingdom

Resistance to artemisinin-based combination therapy (ACT) in the parasite is threatening to reverse recent gains in reducing global deaths from malaria. While resistance manifests as delayed parasite clearance in patients, the phenotype can only spread geographically via the sexual stages and mosquito transmission. In addition to their asexual killing properties, artemisinin and its derivatives sterilize sexual male gametocytes. Whether resistant parasites overcome this sterilizing effect has not, however, been fully tested. Here, we analyzed clinical isolates from the Greater Mekong Subregion, each demonstrating delayed clinical clearance and known resistance-associated polymorphisms in the (PfK13) gene. As well as demonstrating reduced asexual sensitivity to drug, certain PfK13 isolates demonstrated a marked reduction in sensitivity to artemisinin in an male gamete formation assay. Importantly, this same reduction in sensitivity was observed when the most resistant isolate was tested directly in mosquito feeds. These results indicate that, under artemisinin drug pressure, while sensitive parasites are blocked, resistant parasites continue transmission. This selective advantage for resistance transmission could favor acquisition of additional host-specificity or polymorphisms affecting partner drug sensitivity in mixed infections. Favored resistance transmission under ACT coverage could have profound implications for the spread of multidrug-resistant malaria beyond Southeast Asia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.00898-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927852PMC
December 2020

A cautionary note on the use of unsupervised machine learning algorithms to characterise malaria parasite population structure from genetic distance matrices.

PLoS Genet 2020 10 9;16(10):e1009037. Epub 2020 Oct 9.

Department of Statistics, University of Oxford, Oxford, United Kingdom.

Genetic surveillance of malaria parasites supports malaria control programmes, treatment guidelines and elimination strategies. Surveillance studies often pose questions about malaria parasite ancestry (e.g. how antimalarial resistance has spread) and employ statistical methods that characterise parasite population structure. Many of the methods used to characterise structure are unsupervised machine learning algorithms which depend on a genetic distance matrix, notably principal coordinates analysis (PCoA) and hierarchical agglomerative clustering (HAC). PCoA and HAC are sensitive to both the definition of genetic distance and algorithmic specification. Importantly, neither algorithm infers malaria parasite ancestry. As such, PCoA and HAC can inform (e.g. via exploratory data visualisation and hypothesis generation), but not answer comprehensively, key questions about malaria parasite ancestry. We illustrate the sensitivity of PCoA and HAC using 393 Plasmodium falciparum whole genome sequences collected from Cambodia and neighbouring regions (where antimalarial resistance has emerged and spread recently) and we provide tentative guidance for the use and interpretation of PCoA and HAC in malaria parasite genetic epidemiology. This guidance includes a call for fully transparent and reproducible analysis pipelines that feature (i) a clearly outlined scientific question; (ii) a clear justification of analytical methods used to answer the scientific question along with discussion of any inferential limitations; (iii) publicly available genetic distance matrices when downstream analyses depend on them; and (iv) sensitivity analyses. To bridge the inferential disconnect between the output of non-inferential unsupervised learning algorithms and the scientific questions of interest, tailor-made statistical models are needed to infer malaria parasite ancestry. In the absence of such models speculative reasoning should feature only as discussion but not as results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1009037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577480PMC
October 2020

Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19.

N Engl J Med 2020 Nov 8;383(21):2030-2040. Epub 2020 Oct 8.

The affiliations of the members of the writing committee are as follows: the Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine (P.H., J.T., J.A.W., N.J.W.), Nuffield Department of Population Health (M.M., L.L., J.L.B., N.S., J.R.E., E.J., R.H., M.J.L.), the Medical Research Council (MRC) Population Health Research Unit (N.S., J.R.E., R.H., M.J.L.), University of Oxford, the Oxford University Hospitals NHS Foundation Trust (K.J., M.J.L.), and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (M.J.L.), Oxford, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester (M.W.), the Regional Infectious Diseases Unit, North Manchester General Hospital (A.U.), University of Manchester (A.U., T.F.), and Manchester University NHS Foundation Trust (T.F.), Manchester, the Research and Development Department, Northampton General Hospital, Northampton (E.E.), the Department of Respiratory Medicine, North Tees and Hartlepool NHS Foundation Trust, Stockton-on-Tees (B.P.), University Hospitals Birmingham NHS Foundation Trust and Institute of Microbiology and Infection, University of Birmingham, Birmingham (T.W.), James Cook University Hospital, Middlesbrough (J.W.), North West Anglia NHS Foundation Trust, Peterborough (J.F.), the Department of Infectious Diseases, Cardiff and Vale University Health Board, and the Division of Infection and Immunity, Cardiff University, Cardiff (J.U.), Roslin Institute, University of Edinburgh, Edinburgh (J.K.B.), the School of Life Course Sciences, King's College London (L.C.C.), and the Intensive Care National Audit and Research Centre (K.R.), London, the NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton (S.N.F.), the Department of Mathematics and Statistics, Lancaster University, Lancaster (T.J.), the MRC Biostatistics Unit, University of Cambridge, Cambridge (T.J.), and the Respiratory Medicine Department, Nottingham University Hospitals NHS Trust (W.S.L.), and the School of Medicine, University of Nottingham (A.M., E.J.), Nottingham - all in the United Kingdom; and the Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand (J.T., J.A.W., N.J.W.).

Background: Hydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (Covid-19) on the basis of in vitro activity and data from uncontrolled studies and small, randomized trials.

Methods: In this randomized, controlled, open-label platform trial comparing a range of possible treatments with usual care in patients hospitalized with Covid-19, we randomly assigned 1561 patients to receive hydroxychloroquine and 3155 to receive usual care. The primary outcome was 28-day mortality.

Results: The enrollment of patients in the hydroxychloroquine group was closed on June 5, 2020, after an interim analysis determined that there was a lack of efficacy. Death within 28 days occurred in 421 patients (27.0%) in the hydroxychloroquine group and in 790 (25.0%) in the usual-care group (rate ratio, 1.09; 95% confidence interval [CI], 0.97 to 1.23; P = 0.15). Consistent results were seen in all prespecified subgroups of patients. The results suggest that patients in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98). Among the patients who were not undergoing mechanical ventilation at baseline, those in the hydroxychloroquine group had a higher frequency of invasive mechanical ventilation or death (30.7% vs. 26.9%; risk ratio, 1.14; 95% CI, 1.03 to 1.27). There was a small numerical excess of cardiac deaths (0.4 percentage points) but no difference in the incidence of new major cardiac arrhythmia among the patients who received hydroxychloroquine.

Conclusions: Among patients hospitalized with Covid-19, those who received hydroxychloroquine did not have a lower incidence of death at 28 days than those who received usual care. (Funded by UK Research and Innovation and National Institute for Health Research and others; RECOVERY ISRCTN number, ISRCTN50189673; ClinicalTrials.gov number, NCT04381936.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2022926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556338PMC
November 2020

COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology.

PLoS Med 2020 09 3;17(9):e1003252. Epub 2020 Sep 3.

Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

Nicholas White and coauthors discuss chloroquine and hydroxychloroquine pharmacology in the context of possible treatment of SARS-CoV-2 infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pmed.1003252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470382PMC
September 2020

No evidence that chloroquine or hydroxychloroquine induce hemolysis in G6PD deficiency.

Blood Cells Mol Dis 2020 11 7;85:102484. Epub 2020 Aug 7.

Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcmd.2020.102484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413154PMC
November 2020

Molecular epidemiology of resistance to antimalarial drugs in the Greater Mekong subregion: an observational study.

Lancet Infect Dis 2020 12 14;20(12):1470-1480. Epub 2020 Jul 14.

Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Background: The Greater Mekong subregion is a recurrent source of antimalarial drug resistance in Plasmodium falciparum malaria. This study aimed to characterise the extent and spread of resistance across this entire region between 2007 and 2018.

Methods: P falciparum isolates from Myanmar, Thailand, Laos, and Cambodia were obtained from clinical trials and epidemiological studies done between Jan 1, 2007, and Dec 31, 2018, and were genotyped for molecular markers (pfkelch, pfcrt, pfplasmepsin2, and pfmdr1) of antimalarial drug resistance. Genetic relatedness was assessed using microsatellite and single nucleotide polymorphism typing of flanking sequences around target genes.

Findings: 10 632 isolates were genotyped. A single long pfkelch Cys580Tyr haplotype (from -50 kb to +31·5 kb) conferring artemisinin resistance (PfPailin) now dominates across the eastern Greater Mekong subregion. Piperaquine resistance associated with pfplasmepsin2 gene amplification and mutations in pfcrt downstream of the Lys76Thr chloroquine resistance locus has also developed. On the Thailand-Myanmar border a different pfkelch Cys580Tyr lineage rose to high frequencies before it was eliminated. Elsewhere in Myanmar the Cys580Tyr allele remains widespread at low allele frequencies. Meanwhile a single artemisinin-resistant pfkelch Phe446Ile haplotype has spread across Myanmar. Despite intense use of dihydroartemisinin-piperaquine in Kayin state, eastern Myanmar, both in treatment and mass drug administrations, no selection of piperaquine resistance markers was observed. pfmdr1 amplification, a marker of resistance to mefloquine, remains at low prevalence across the entire region.

Interpretation: Artemisinin resistance in P falciparum is now prevalent across the Greater Mekong subregion. In the eastern Greater Mekong subregion a multidrug resistant P falciparum lineage (PfPailin) dominates. In Myanmar a long pfkelch Phe446Ile haplotype has spread widely but, by contrast with the eastern Greater Mekong subregion, there is no indication of artemisinin combination therapy (ACT) partner drug resistance from genotyping known markers, and no evidence of spread of ACT resistant P falciparum from the east to the west. There is still a window of opportunity to prevent global spread of ACT resistance.

Funding: Thailand Science Research and Innovation, Initiative 5%, Expertise France, Wellcome Trust.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1473-3099(20)30228-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689289PMC
December 2020

Advances and roadblocks in the treatment of malaria.

Br J Clin Pharmacol 2020 Jul 12. Epub 2020 Jul 12.

Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

The deployment of artesunate for severe malaria and the artemisinin combination therapies (ACTs) for uncomplicated malaria has been a major advance in antimalarial therapeutics. These drugs have reduced treated mortality, accelerated recovery and reduced treatment failure rates and transmission from the treated infection. Artemisinin derivatives remain highly effective against falciparum malaria in most malaria endemic areas, but significant resistance has emerged in the Greater Mekong subregion of Southeast Asia. Resistance to artemisinins was followed by resistance to the ACT partner drugs, and fit multidrug resistant parasite lineages have now spread widely across the region. ACTs remain highly effective against P. vivax and the other malaria species. Recent studies have shown that radical curative regimens of primaquine (to prevent relapse) can be shortened to 7 days, and that the newly introduced single dose tafenoquine is an alternative, although the currently recommended dose is insufficient in Southeast Asia and Oceania. Targeted malaria elimination using focal mass treatments with dihydroartemisinin-piperaquine have proved safe and effective malaria elimination accelerators, but progress overall towards malaria elimination is slow. Indeed since 2015 overall malaria case numbers globally have risen. As new drugs will not become widely available in the near future, active measures to preserve the current antimalarials should be given the highest priority.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcp.14474DOI Listing
July 2020

Concentration-dependent mortality of chloroquine in overdose.

Elife 2020 07 8;9. Epub 2020 Jul 8.

Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

Hydroxychloroquine and chloroquine are used extensively in malaria and rheumatological conditions, and now in COVID-19 prevention and treatment. Although generally safe they are potentially lethal in overdose. In-vitro data suggest that high concentrations and thus high doses are needed for COVID-19 infections, but as yet there is no convincing evidence of clinical efficacy. Bayesian regression models were fitted to survival outcomes and electrocardiograph QRS durations from 302 prospectively studied French patients who had taken intentional chloroquine overdoses, of whom 33 died (11%), and 16 healthy volunteers who took 620 mg base chloroquine single doses. Whole blood concentrations of 13.5 µmol/L (95% credible interval 10.1-17.7) were associated with 1% mortality. Prolongation of ventricular depolarization is concentration-dependent with a QRS duration >150 msec independently highly predictive of mortality in chloroquine self-poisoning. Pharmacokinetic modeling predicts that most high dose regimens trialled in COVID-19 are unlikely to cause serious cardiovascular toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.58631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417172PMC
July 2020