Prof Nicholas J White FRS
|Research Area:||Global Health|
|Technology Exchange:||Mass spectrometry|
|Scientific Themes:||Tropical Medicine & Global Health and Immunology & Infectious Disease|
|Keywords:||malaria, drug discovery and therapeutics|
Professor White’s diverse interests include the epidemiology, pathophysiology and management of uncomplicated and severe malaria, meliodosis, enteric fever, tetanus, dengue haemorrhagic fever, Japanese encephalitis and tuberculosis. His particular interests at present include the pathophysiology and treatment of severe malaria, the prevention of antimalarial drug resistance using artemisinin-based combinations. and the biology of relapse in vivax malaria.
|Prof Nicholas PJ Day FMedSci FRCP||Tropical Medicine||University of Oxford||United Kingdom|
|Prof François H Nosten||Tropical Medicine||University of Oxford||United Kingdom|
|Prof Adrianus Dondorp||Tropical Medicine||University of Oxford||United Kingdom|
|Prof Jeremy Farrar||Tropical Medicine||University of Oxford||United Kingdom|
|Prof Paul Newton||Tropical Medicine||University of Oxford||United Kingdom|
|Prof Dominic Kwiatkowski||Wellcome Trust Centre for Human Genetics||University of Oxford||United Kingdom|
|Dr Olivo Miotto||Tropical Medicine||University of Oxford||United Kingdom|
|Prof Philippe J Guerin||Tropical Medicine||University of Oxford||United Kingdom|
|Dr Gareth Turner||Tropical Medicine||University of Oxford||United Kingdom|
|Dr Paul Turner||Tropical Medicine||University of Oxford||United Kingdom|
BACKGROUND: Severe malaria is a major cause of childhood death and often the main reason for paediatric hospital admission in sub-Saharan Africa. Quinine is still the established treatment of choice, although evidence from Asia suggests that artesunate is associated with a lower mortality. We compared parenteral treatment with either artesunate or quinine in African children with severe malaria. METHODS: This open-label, randomised trial was undertaken in 11 centres in nine African countries. Children (<15 years) with severe falciparum malaria were randomly assigned to parenteral artesunate or parenteral quinine. Randomisation was in blocks of 20, with study numbers corresponding to treatment allocations kept inside opaque sealed paper envelopes. The trial was open label at each site, and none of the investigators or trialists, apart from for the trial statistician, had access to the summaries of treatment allocations. The primary outcome measure was in-hospital mortality, analysed by intention to treat. This trial is registered, number ISRCTN50258054. FINDINGS: 5425 children were enrolled; 2712 were assigned to artesunate and 2713 to quinine. All patients were analysed for the primary outcome. 230 (8·5%) patients assigned to artesunate treatment died compared with 297 (10·9%) assigned to quinine treatment (odds ratio [OR] stratified for study site 0·75, 95% CI 0·63-0·90; relative reduction 22·5%, 95% CI 8·1-36·9; p=0·0022). Incidence of neurological sequelae did not differ significantly between groups, but the development of coma (65/1832 [3·5%] with artesunate vs 91/1768 [5·1%] with quinine; OR 0·69 95% CI 0·49-0·95; p=0·0231), convulsions (224/2712 [8·3%] vs 273/2713 [10·1%]; OR 0·80, 0·66-0·97; p=0·0199), and deterioration of the coma score (166/2712 [6·1%] vs 208/2713 [7·7%]; OR 0·78, 0·64-0·97; p=0·0245) were all significantly less frequent in artesunate recipients than in quinine recipients. Post-treatment hypoglycaemia was also less frequent in patients assigned to artesunate than in those assigned to quinine (48/2712 [1·8%] vs 75/2713 [2·8%]; OR 0·63, 0·43-0·91; p=0·0134). Artesunate was well tolerated, with no serious drug-related adverse effects. INTERPRETATION: Artesunate substantially reduces mortality in African children with severe malaria. These data, together with a meta-analysis of all trials comparing artesunate and quinine, strongly suggest that parenteral artesunate should replace quinine as the treatment of choice for severe falciparum malaria worldwide. FUNDING: The Wellcome Trust. Hide abstract
BACKGROUND: Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance. METHODS: In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance. RESULTS: We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P=0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups. CONCLUSIONS: P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.) Hide abstract
BACKGROUND: In the treatment of severe malaria, intravenous artesunate is more rapidly acting than intravenous quinine in terms of parasite clearance, is safer, and is simpler to administer, but whether it can reduce mortality is uncertain. METHODS: We did an open-label randomised controlled trial in patients admitted to hospital with severe falciparum malaria in Bangladesh, India, Indonesia, and Myanmar. We assigned individuals intravenous artesunate 2.4 mg/kg bodyweight given as a bolus (n=730) at 0, 12, and 24 h, and then daily, or intravenous quinine (20 mg salt per kg loading dose infused over 4 h then 10 mg/kg infused over 2-8 h three times a day; n=731). Oral medication was substituted when possible to complete treatment. Our primary endpoint was death from severe malaria, and analysis was by intention to treat. FINDINGS: We assessed all patients randomised for the primary endpoint. Mortality in artesunate recipients was 15% (107 of 730) compared with 22% (164 of 731) in quinine recipients; an absolute reduction of 34.7% (95% CI 18.5-47.6%; p=0.0002). Treatment with artesunate was well tolerated, whereas quinine was associated with hypoglycaemia (relative risk 3.2, 1.3-7.8; p=0.009). INTERPRETATION: Artesunate should become the treatment of choice for severe falciparum malaria in adults. Hide abstract
To determine the optimum duration of follow-up for the assessment of drug efficacy against Plasmodium falciparum malaria, 96 trial arms from randomized controlled trials (RCTs) with follow-up of 28 days or longer that were conducted between 1990 and 2003 were analyzed. These trials enrolled 13,772 patients, and participating patients comprised 23% of all patients enrolled in RCTs over the past 40 years; 61 (64%) trial arms were conducted in areas where the rate of malaria transmission was low, and 58 (50%) trial arms were supported by parasite genotyping to distinguish true recrudescences from reinfections. The median overall failure rate reported was 10% (range, 0 to 47%). The widely used day 14 assessment had a sensitivity of between 0 and 37% in identifying treatment failures and had no predictive value. Assessment at day 28 had a sensitivity of 66% overall (28 to 100% in individual trials) but could be used to predict the true failure rate if either parasite genotyping was performed (r(2) = 0.94) or if the entomological inoculation rate was known. In the assessment of drug efficacy against falciparum malaria, 28 days should be the minimum period of follow-up. Hide abstract
Antimalarial drug resistance emerges de novo predominantly in areas of low malaria transmission. Because of the logarithmic distribution of parasite numbers in human malaria infections, inadequately treated high biomass infections are a major source of de novo antimalarial resistance, whereas use of antimalarial prophylaxis provides a low resistance selection risk. Slowly eliminated antimalarials encourage resistance largely by providing a selective filter for resistant parasites acquired from others, and not by selecting resistance de novo. The de novo emergence of resistance can be prevented by use of antimalarial combinations. Artemisinin derivative combinations are particularly effective. Ensuring adequate treatment of the relatively few heavily infected patients would slow the emergence of resistance. Hide abstract
Lancet, 353 (9168), pp. 1965-1967. | Read more1999. Averting a malaria disaster.
Antimicrob Agents Chemother, 41 (7), pp. 1413-1422.1997. Assessment of the pharmacodynamic properties of antimalarial drugs in vivo.
An open randomised trial was conducted to compare ceftazidime (120 mg/kg/day) with "conventional therapy" (chloramphenicol 100 mg/kg/day, doxycycline 4 mg/kg/day, trimethoprim 10 mg/kg/day, and sulphamethoxazole 50 mg/kg/day) in the treatment of severe melioidosis. A paired restricted sequential trial designed to detect a reduction in mortality from 80 to 40% in culture-positive patients surviving greater than 48 hours was stopped after 22 months. Of the 161 patients entered into the study, 65 had bacteriologically confirmed melioidosis and 54 of these were septicaemic. Ceftazidime treatment was associated with a 50% (95% CI 19-81%) lower overall mortality than conventional treatment (74% vs 37%; p = 0.009) and should now become the treatment of choice for severe melioidosis. Hide abstract
Am J Trop Med Hyg, 32 (1), pp. 1-5. Read abstract1983. Quinine loading dose in cerebral malaria.
In cerebral malaria, the use of currently recommended doses of intravenous quinine may result in subtherapeutic plasma concentrations during the critical first 24 hours of treatment. A loading dose of quinine (20 mg/kg quinine dihydrochloride, equivalent to 16.7 mg/kg base, infused over 4 hours) proved a rapid and safe method of achieving plasma concentrations above the high minimum inhibitory concentrations for Plasmodium falciparum prevalent in Eastern Thailand. Hide abstract
We studied the occurrence, clinical manifestations, and mechanism of hypoglycemia in patients with falciparum malaria in eastern Thailand. Hypoglycemia, which was often severe and recurrent, occurred in 17 patients, including 12 in a series of 151 patients with cerebral malaria. Thirty episodes were investigated. Plasma concentrations of insulin and C peptide were inappropriately high, and lactate and alanine concentrations were significantly higher than in patients with falciparum malaria who were normoglycemic (P less than 0.05). Sixteen patients had received quinine; plasma quinine and insulin concentrations were correlated at the time of hypoglycemia (P = 0.007). In seven healthy fasting volunteers intravenous quinine increased the mean plasma insulin concentration (+/- S.D.) from 8.9 +/- 3.1 to 17.1 +/- 8.4 mU per liter (P = 0.02) and reduced the mean plasma glucose concentration from 88 +/- 20 to 68 +/- 23 mg per deciliter (P = 0.002). Our observations indicate that in falciparum malaria quinine-induced insulin secretion may precipitate hypoglycemia, but other factors, including the large glucose requirements of the malaria parasites may also contribute. This important complication, associated with pregnancy and severe disease, must be excluded in all patients with falciparum malaria who have impaired or deteriorating consciousness. Hide abstract
Optimizing Malaria Elimination in Vietnam through Individual-based Microsimulation
In 2007, the Bill and Melinda Gates foundation declared malaria eradication as one of their primary goals. Since then, hundreds of research projects and public health initiatives have been funded by this effort, and many of these have successfully increased adoption of artemisinin-combination therapies (ACTs), helped disseminate diagnostic tests, and improved surveillance efforts, case detection, case management, and mosquito control. Regional elimination efforts have been prioritized in some ...