Shoklo Malaria Research Unit

Mae Sot, Thailand

Shoklo Malaria Research Unit

Mae Sot, Thailand
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Rijken M.J.,Shoklo Malaria Research Unit | McGready R.,Shoklo Malaria Research Unit | McGready R.,University of Oxford | McGready R.,Mahidol University | And 9 more authors.
The Lancet Infectious Diseases | Year: 2012

Most pregnant women at risk of for infection with Plasmodium vivax live in the Asia-Pacific region. However, malaria in pregnancy is not recognised as a priority by many governments, policy makers, and donors in this region. Robust data for the true burden of malaria throughout pregnancy are scarce. Nevertheless, when women have little immunity, each infection is potentially fatal to the mother, fetus, or both. WHO recommendations for the control of malaria in pregnancy are largely based on the situation in Africa, but strategies in the Asia-Pacific region are complicated by heterogeneous transmission settings, coexistence of multidrug-resistant Plasmodium falciparum and Plasmodium vivax parasites, and different vectors. Most knowledge of the epidemiology, effect, treatment, and prevention of malaria in pregnancy in the Asia-Pacific region comes from India, Papua New Guinea, and Thailand. Improved estimates of the morbidity and mortality of malaria in pregnancy are urgently needed. When malaria in pregnancy cannot be prevented, accurate diagnosis and prompt treatment are needed to avert dangerous symptomatic disease and to reduce effects on fetuses. © 2012 Elsevier Ltd.


Ch'ng J.-H.,National University of Singapore | Renia L.,Agency for Science, Technology and Research Singapore | Nosten F.,Shoklo Malaria Research Unit | Nosten F.,Center for Clinical Vaccinology and Tropical Medicine | Tan K.S.W.,National University of Singapore
Trends in Parasitology | Year: 2012

Although resistance to chloroquine (CQ) has relegated it from modern chemotherapeutic strategies to treat . Plasmodium falciparum malaria, new evidence suggests that higher doses of the drug may exert a different killing mechanism and offers this drug a new lease of life. Whereas the established antimalarial mechanisms of CQ are usually associated with nanomolar levels of the drug, micromolar levels of CQ trigger a distinct cell death pathway involving the permeabilization of the digestive vacuole of the parasite and a release of hydrolytic enzymes. In this paper, we propose that this pathway is a promising antimalarial strategy and suggest that revising the CQ treatment regimen may elevate blood drug levels to trigger this pathway without increasing the incidence of adverse reactions. © 2012 Elsevier Ltd.


Douglas N.M.,University of Oxford | Anstey N.M.,University of Oxford | Angus B.J.,University of Oxford | Nosten F.,University of Oxford | And 4 more authors.
The Lancet Infectious Diseases | Year: 2010

Early parasitological diagnosis and treatment with artemisinin-based combination therapies (ACTs) are key components of worldwide malaria elimination programmes. In general, use of ACTs has been limited to patients with falciparum malaria whereas blood-stage infections with Plasmodium vivax are mostly still treated with chloroquine. We review the evidence for the relative benefits and disadvantages of the existing separate treatment approach versus a unified ACT-based strategy for treating Plasmodium falciparum and P vivax infections in regions where both species are endemic (co-endemic). The separate treatment scenario is justifiable if P vivax remains sensitive to chloroquine and diagnostic tests reliably distinguish P vivax from P falciparum. However, with the high number of misdiagnoses in routine practice and the rise and spread of chloroquine-resistant P vivax, there might be a compelling rationale for a unified ACT-based strategy for vivax and falciparum malaria in all co-endemic regions. Analyses of the cost-effectiveness of ACTs for both Plasmodium species are needed to assess the role of these drugs in the control and elimination of vivax malaria. © 2010 Elsevier Ltd. All rights reserved.


Price R.N.,University of Oxford | Price R.N.,Charles Darwin University | von Seidlein L.,Charles Darwin University | Valecha N.,National Institute of Malaria Research | And 7 more authors.
The Lancet Infectious Diseases | Year: 2014

Background: Chloroquine is the first-line treatment for Plasmodium vivax malaria in most endemic countries, but resistance is increasing. Monitoring of antimalarial efficacy is essential, but in P vivax infections the assessment of treatment efficacy is confounded by relapse from the dormant liver stages. We systematically reviewed P vivax malaria treatment efficacy studies to establish the global extent of chloroquine resistance. Methods: We searched Medline, Web of Science, Embase, and the Cochrane Database of Systematic Reviews to identify studies published in English between Jan 1, 1960, and April 30, 2014, which investigated antimalarial treatment efficacy in P vivax malaria. We excluded studies that did not include supervised schizonticidal treatment without primaquine. We determined rates of chloroquine resistance according to P vivax malaria recurrence rates by day 28 whole-blood chloroquine concentrations at the time of recurrence and study enrolment criteria. Findings: We identified 129 eligible clinical trials involving 21 694 patients at 179 study sites and 26 case reports describing 54 patients. Chloroquine resistance was present in 58 (53%) of 113 assessable study sites, spread across most countries that are endemic for P vivax. Clearance of parasitaemia assessed by microscopy in 95% of patients by day 2, or all patients by day 3, was 100% predictive of chloroquine sensitivity. Interpretation: Heterogeneity of study design and analysis has confounded global surveillance of chloroquine-resistant P vivax, which is now present across most countries endemic for P vivax. Improved methods for monitoring of drug resistance are needed to inform antimalarial policy in these regions. Funding: Wellcome Trust (UK). © 2014 Price et al. Open Access article distributed under the terms of CC-BY.


Burgoine K.L.,Shoklo Malaria Research Unit | Burgoine K.L.,University of Oxford | Bancone G.,Shoklo Malaria Research Unit | Bancone G.,Mahidol University | And 3 more authors.
Malaria Journal | Year: 2010

Background: Primaquine is currently the only medication used for radical cure of Plasmodium vivax infection. Unfortunately, its use is not without risk. Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency have an increased susceptibility to haemolysis when given primaquine. This potentially fatal clinical syndrome can be avoided if patients are tested for G6PD deficiency and adequately informed before being treated. Case presentation. A 35-year old male presented to our clinic on the Thai-Burmese border with a history and clinical examination consistent with intravascular haemolysis. The patient had been prescribed primaquine and chloroquine four days earlier for a P. vivax infection. The medication instructions had not been given in a language understood by the patient and he had not been tested for G6PD deficiency. The patient was not only G6PD deficient but misunderstood the instructions and took all his primaquine tablets together. With appropriate treatment the patient recovered and was discharged home a week later. Conclusions. Whilst primaquine remains the drug of choice to eradicate hypnozoites and control P. vivax transmission, the risks associated with its use must be minimized during its deployment. In areas where P. vivax exists, patients should be tested for G6PD deficiency and adequately informed before administration of primaquine. © 2010 Burgoine et al; licensee BioMed Central Ltd.


Rueangweerayut R.,Mae Sot General Hospital | Phyo A.P.,Shoklo Malaria Research Unit | Uthaisin C.,Mae Ramat Hospital | Poravuth Y.,National Malaria Center | And 9 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Pyronaridine-artesunate is an artemisinin-based combination therapy under evaluation for the treatment of Plasmodium falciparum and P. vivax malaria. METHODS: We conducted a phase 3, open-label, multicenter, noninferiority trial that included 1271 patients between 3 and 60 years of age from Asia (81.3%) or Africa (18.7%) with microscopically confirmed, uncomplicated P. falciparum malaria. Patients underwent randomization for treatment with a fixed-dose combination of 180 mg of pyronaridine and 60 mg of artesunate or with 250 mg of mefloquine plus 100 mg of artesunate. Doses were calculated according to body weight and administered once daily for 3 days. RESULTS: Pyronaridine-artesunate was noninferior to mefloquine plus artesunate for the primary outcome: adequate clinical and parasitologic response in the per-protocol population on day 28, corrected for reinfection with the use of polymerase-chain-reaction (PCR) genotyping. For this outcome, efficacy in the group receiving pyronaridine-artesunate was 99.2% (743 of 749 patients; 95% confidence interval [CI], 98.3 to 99.7) and that in the group receiving mefloquine plus artesunate was 97.8% (360 of 368 patients; 95% CI, 95.8 to 99.1), with a treatment difference of 1.4 percentage points (95% CI, 0.0 to 3.5; P = 0.05). In the intention-to-treat population, efficacy on day 42 in the group receiving pyronaridine-artesunate was 83.1% (705 of 848 patients; 95% CI, 80.4 to 85.6) and that in the group receiving mefloquine plus artesunate was 83.9% (355 of 423 patients; 95% CI, 80.1 to 87.3). In Cambodia, where there were 211 study patients, the median parasite clearance time was prolonged for both treatments: 64 hours versus 16.0 to 38.9 hours in other countries (P<0.001, on the basis of Kaplan-Meier estimates). Kaplan-Meier estimates of the recrudescence rate in the intention-to-treat population in Cambodia until day 42 were higher with pyronaridine-artesunate than with mefloquine plus artesunate (10.2% [95% CI, 5.4 to 18.6] vs. 0%; P = 0.04 as calculated with the log-rank test), but similar for the other countries combined (4.7% [95% CI, 3.3 to 6.7] and 2.8% [95% CI, 1.5 to 5.3], respectively; P = 0.24). Elevated levels of aminotransferases were observed in those receiving pyronaridine-artesunate. Two patients receiving mefloquine plus artesunate had seizures. CONCLUSIONS: Fixed-dose pyronaridine-artesunate was efficacious in the treatment of uncomplicated P. falciparum malaria. In Cambodia, extended parasite clearance times were suggestive of in vivo resistance to artemisinin. (Funded by Shin Poong Pharmaceutical Company and the Medicines for Malaria Venture; ClinicalTrials.gov number, NCT00403260.) Copyright © 2012 Massachusetts Medical Society.


Nkhoma S.C.,The Texas Institute | Nair S.,The Texas Institute | Al-Saai S.,The Texas Institute | Ashley E.,Mahidol University | And 8 more authors.
Molecular Ecology | Year: 2013

Pathogen control programs provide a valuable, but rarely exploited, opportunity to directly examine the relationship between population decline and population genetics. We investigated the impact of an ~12-fold decline in transmission on the population genetics of Plasmodium falciparum infections (n = 1731) sampled from four clinics on the Thai-Burma border over 10 years and genotyped using 96 genome-wide SNPs. The most striking associated genetic change was a reduction in the frequency of infections containing multiple parasite genotypes from 63% in 2001 to 14% in 2010 (P = 3 × 10-15). Two measures of the clonal composition of populations (genotypic richness and the β-parameter of the Pareto distribution) declined over time as more people were infected by parasites with identical multilocus genotypes, consistent with increased selfing and a reduction in the rate at which multilocus genotypes are broken apart by recombination. We predicted that the reduction in transmission, multiple clone carriage and outbreeding would be mirrored by an increased influence of genetic drift. However, geographical differentiation and expected heterozygosity remained stable across the sampling period. Furthermore, N e estimates derived from allele frequencies fluctuation between years remained high (582 to ∞) and showed no downward trend. These results demonstrate how genetic data can compliment epidemiological assessments of infectious disease control programs. The temporal changes in a single declining population parallel to those seen in comparisons of parasite genetics in regions of differing endemicity, strongly supporting the notion that reduced opportunity for outbreeding is the key driver of these patterns. See also the Perspective by Neafsey © 2012 Blackwell Publishing Ltd.


Rijken M.J.,Shoklo Malaria Research Unit
Malaria journal | Year: 2012

The presence of malaria parasites and histopathological changes in the placenta are associated with a reduction in birth weight, principally due to intrauterine growth restriction. The aim of this study was to examine the feasibility of studying early pregnancy placental volumes using three-dimensional (3D) ultrasound in a malaria endemic area, as a small volume in the second trimester may be an indicator of intra-uterine growth restriction and placental insufficiency. Placenta volumes were acquired using a portable ultrasound machine and a 3D ultrasound transducer and estimated using the Virtual Organ Computer-aided AnaLysis (VOCAL) image analysis software package. Intra-observer reliability and limits of agreement of the placenta volume measurements were calculated. Polynomial regression models for the mean and standard deviation as a function of gestational age for the placental volumes of uninfected women were created and tested. Based on these equations each measurement was converted into a z -score. The z-scores of the placental volumes of malaria infected and uninfected women were then compared. Eighty-four women (uninfected = 65; infected = 19) with a posterior placenta delivered congenitally normal, live born, single babies. The mean placental volumes in the uninfected women were modeled to fit 5th, 10th, 50th, 90th and 95th centiles for 14-24 weeks' gestation. Most placenta volumes in the infected women were below the 50th centile for gestational age; most of those with Plasmodium falciparum were below the 10th centile. The 95% intra-observer limits of agreement for first and second measurements were ± 37.0 mL and ± 25.4 mL at 30 degrees and 15 degrees rotation respectively. The new technique of 3D ultrasound volumetry of the placenta may be useful to improve our understanding of the pathophysiological constraints on foetal growth caused by malaria infection in early pregnancy.


McGready R.,Shoklo Malaria Research Unit | McGready R.,Mahidol Oxford Tropical Medicine Research Unit | McGready R.,University of Oxford | Lee S.J.,Mahidol Oxford Tropical Medicine Research Unit | And 17 more authors.
The Lancet Infectious Diseases | Year: 2012

Background: The effects of malaria and its treatment in the first trimester of pregnancy remain an area of concern. We aimed to assess the outcome of malaria-exposed and malaria-unexposed first-trimester pregnancies of women from the Thai-Burmese border and compare outcomes after chloroquine-based, quinine-based, or artemisinin-based treatments. Methods: We analysed all antenatal records of women in the first trimester of pregnancy attending Shoklo Malaria Research Unit antenatal clinics from May 12, 1986, to Oct 31, 2010. Women without malaria in pregnancy were compared with those who had a single episode of malaria in the first trimester. The association between malaria and miscarriage was estimated using multivariable logistic regression. Findings: Of 48 426 pregnant women, 17 613 (36%) met the inclusion criteria: 16 668 (95%) had no malaria during the pregnancy and 945 (5%) had a single episode in the first trimester. The odds of miscarriage increased in women with asymptomatic malaria (adjusted odds ratio 2·70, 95% CI 2·04-3·59) and symptomatic malaria (3·99, 3·10-5·13), and were similar for Plasmodium falciparum and Plasmodium vivax. Other risk factors for miscarriage included smoking, maternal age, previous miscarriage, and non-malaria febrile illness. In women with malaria, additional risk factors for miscarriage included severe or hyperparasitaemic malaria (adjusted odds ratio 3·63, 95% CI 1·15-11·46) and parasitaemia (1·49, 1·25-1·78 for each ten-fold increase in parasitaemia). Higher gestational age at the time of infection was protective (adjusted odds ratio 0·86, 95% CI 0·81-0·91). The risk of miscarriage was similar for women treated with chloroquine (92 [26%] of 354), quinine (95 [27%) of 355), or artesunate (20 [31%] of 64; p=0·71). Adverse effects related to antimalarial treatment were not observed. Interpretation: A single episode of falciparum or vivax malaria in the first trimester of pregnancy can cause miscarriage. No additional toxic effects associated with artesunate treatment occurred in early pregnancy. Prospective studies should now be done to assess the safety and efficacy of artemisinin combination treatments in early pregnancy. Funding: Wellcome Trust and Bill & Melinda Gates Foundation. © 2012 Elsevier Ltd.


Phyo A.P.,Mahidol University | Phyo A.P.,Shoklo Malaria Research Unit | Nkhoma S.,The Texas Institute | Stepniewska K.,Mahidol University | And 22 more authors.
The Lancet | Year: 2012

Artemisinin-resistant falciparum malaria has arisen in western Cambodia. A concerted international eff ort is underway to contain artemisinin-resistant Plasmodium falciparum, but containment strategies are dependent on whether resistance has emerged elsewhere. We aimed to establish whether artemisinin resistance has spread or emerged on the Thailand-Myanmar (Burma) border. Methods In malaria clinics located along the northwestern border of Thailand, we measured six hourly parasite counts in patients with uncomplicated hyperparasitaemic falciparum malaria (≤4% infected red blood cells) who had been given various oral artesunate-containing regimens since 2001. Parasite clearance half-lives were estimated and parasites were genotyped for 93 single nucleotide polymorphisms. Findings 3202 patients were studied between 2001 and 2010. Parasite clearance half-lives lengthened from a geometric mean of 2·6 h (95% CI 2·5-2·7) in 2001, to 3·7 h (3·6-3·8) in 2010, compared with a mean of 5·5 h (5·2-5·9) in 119 patients in western Cambodia measured between 2007 and 2010. The proportion of slow-clearing infections (half-life ≤6·2 h) increased from 0·6% in 2001, to 20% in 2010, compared with 42% in western Cambodia between 2007 and 2010. Of 1583 infections genotyped, 148 multilocus parasite genotypes were identifi ed, each of which infected between two and 13 patients. The proportion of variation in parasite clearance attributable to parasite genetics increased from 30% between 2001 and 2004, to 66% between 2007 and 2010. Interpretation Genetically determined artemisinin resistance in P falciparum emerged along the Thailand-Myanmar border at least 8 years ago and has since increased substantially. At this rate of increase, resistance will reach rates reported in western Cambodia in 2-6 years.

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