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Author: White, Nicholas J.

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    PublicationOpen Access
    Genetic marker suitable for identification and genotyping of Plasmodium ovale curtisi and Plasmodium ovale wallikeri.
    (2013-12) Naowarat Tanomsing; เนาวรัตน์ ถนอมสิงห์; Mallika Imwong; มัลลิกา อิ่มวงศ์; Sutherland, Colin J.; Dolecek,Christiane; Hien,Tran Tinh; Nosten, Francois; Day, Nicholas P. J.; White, Nicholas J.; Snounouh, Georges; Mallika Imwong; Mahidol University. Faculty of Tropical Medicine. Department of Molecular Tropical Medicine and Genetics.; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Tropical Medicine Research Unit.; Mahidol University. Faculty of Tropical Medicine. Shoklo Malaria Research Unit.
    We present a seminested PCR method that specifically discriminates between Plasmodium ovale curtisi and P. ovale wallikeri with high sensitivity. The test is based on species-specific amplification of a size-polymorphic fragment of the tryptophan-rich antigen gene, potra, which also permits discrimination of intraspecific sequence variants at this locus.
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    PublicationOpen Access
    Genetic diversity of Plasmodium vivax in Kolkata, India.
    (2006-08-14) Kim, Jung-Ryong; Mallika Imwong; มัลลิกา อิ่มวงศ์; Nandy, Amitabha; Kesinee Chotivanich; เกศินี โชติวานิช; Apichart Nontprasert; อภิชาต นนท์ประเสริฐ; Naowarat Tonomsing; Maji, Ardhendu; Addy, Manjulika; Day, Nick P.J.; White, Nicholas J.; Sasithon Pukrittayakamee; ศศิธร ผู้กฤตยาคามี; Mallika Imwong; Mahidol University. Faculty of Tropical Medicine. Department of Clinical Tropical Medicine
    . The genotyping protocols used in this study may be useful for differentiating re-infection from relapse and recrudescence in studies assessing of malarial drug efficacy in vivax malaria.
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    PublicationOpen Access
    Practical PCR genotyping protocols for Plasmodium vivax using Pvcs and Pvmsp1.
    (2005-04-27) Mallika Imwong; มัลลิกา อิ่มวงศ์; Sasithon Pukrittayakamee; Grüner, Anne Charlotte; Rénia, Laurent; Letourneur, Frank; Sornchai Looareesuwan; ศรชัย หลูอารีย์สุวรรณ; White, Nicholas J.; Snounou, Georges; Mallika Imwong; Mahidol University. Faculty of Tropical Medicine. Department of Clinical Tropical Medicine.
    BACKGROUND: The use of antimalarial drug combinations with artemisinin derivatives is recommended to overcome drug resistance in Plasmodium falciparum. The fixed combination of oral artemether-lumefantrine, an artemisinin combination therapy (ACT) is highly effective and well tolerated. It is the only registered fixed combination containing an artemisinin. The trial presented here was conducted to monitor the efficacy of the six-dose regimen of artemether-lumefantrine (ALN) in an area of multi-drug resistance, along the Thai-Myanmar border. METHODS: The trial was an open-label, two-arm, randomized study comparing artemether-lumefantrine and mefloquine-artesunate for the treatment of uncomplicated falciparum malaria with 42 days of follow up. Parasite genotyping by polymerase chain reaction (PCR) was used to distinguish recrudescent from newly acquired P. falciparum infections. The PCR adjusted cure rates were evaluated by survival analysis. RESULTS: In 2001-2002 a total of 490 patients with slide confirmed uncomplicated P. falciparum malaria were randomly assigned to receive artemether-lumefantrine (n = 245) or artesunate and mefloquine (n = 245) and were followed for 42 days. All patients had rapid initial clinical and parasitological responses. In both groups, the PCR adjusted cure rates by day 42 were high: 98.8% (95% CI 96.4, 99.6%) for artemether-lumefantrine and 96.3% (95% CI 93.1, 98.0%) for artesunate-mefloquine. Both regimens were very well tolerated with no serious adverse events observed attributable to either combination. CONCLUSION: Overall, this study confirms that these two artemisinin-based combinations remain highly effective and result in equivalent therapeutic responses in the treatment of highly drug-resistant falciparum malaria.
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    PublicationOpen Access
    Population genetic analysis of Plasmodium falciparum parasites using a customized Illumina GoldenGate genotyping assay.
    (2011) Campino, Susana; Auburn, Sarah; Kivinen, Katja; Zongo, Issaka; Ouedraogo, Jean-Bosco; Mangano, Valentina; Djimde, Abdoulaye; Doumbo, Ogobara K.; Kiara, Steven M.; Nzila, Alexis; Borrmann, Steffen; Marsh, Kevin; Michon, Pascal; Mueller, Ivo; Siba, Peter; Jiang, Hongying; Su, Xin-Zhuan; Chanaki Amaratunga; Socheat, Duong; Fairhurst, Rick M.; Mallika Imwong; มัลลิกา อิ่มวงศ์; Anderson, Timothy; Nosten, Francois; White, Nicholas J.; Gwilliam, Rhian; Deloukas, Panos; MacInnis, Bronwyn; Newbold, Christopher I.; Rockett, Kirk; Clark, Taane G.; Kwiatkowski, Dominic P.; Campino, Susana; Fitzgerald, J. Ross; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford University Research Unit.; Mahidol University. Faculty of Tropical Medicine. Department of Clinical Tropical Medicine.; Mahidol University. Faculty of Tropical Medicine. Department of Molecular Tropical Medicine and Genetics.
    The diversity in the Plasmodium falciparum genome can be used to explore parasite population dynamics, with practical applications to malaria control. The ability to identify the geographic origin and trace the migratory patterns of parasites with clinically important phenotypes such as drug resistance is particularly relevant. With increasing single-nucleotide polymorphism (SNP) discovery from ongoing Plasmodium genome sequencing projects, a demand for high SNP and sample throughput genotyping platforms for large-scale population genetic studies is required. Low parasitaemias and multiple clone infections present a number of challenges to genotyping P. falciparum. We addressed some of these issues using a custom 384-SNP Illumina GoldenGate assay on P. falciparum DNA from laboratory clones (long-term cultured adapted parasite clones), short-term cultured parasite isolates and clinical (non-cultured isolates) samples from East and West Africa, Southeast Asia and Oceania. Eighty percent of the SNPs (n = 306) produced reliable genotype calls on samples containing as little as 2 ng of total genomic DNA and on whole genome amplified DNA. Analysis of artificial mixtures of laboratory clones demonstrated high genotype calling specificity and moderate sensitivity to call minor frequency alleles. Clear resolution of geographically distinct populations was demonstrated using Principal Components Analysis (PCA), and global patterns of population genetic diversity were consistent with previous reports. These results validate the utility of the platform in performing population genetic studies of P. falciparum.
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    PublicationOpen Access
    High-throughput ultrasensitive molecular techniques for quantifying low-density malaria parasitemias.
    (2014-09) Mallika Imwong; มัลลิกา อิ่มวงศ์; Sarun Hanchana; Malleret, Benoit; Rénia, Laurent; Day, Nicholas P. J.; Dondorp, Arjen; Nosten, Francois; Snounou, Georges; White, Nicholas J.; Mallika Imwong; Mahidol University. Faculty of Tropical Medicine. Department of Molecular Tropical Medicine and Genetics.; Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Research Unit.; Mahidol University. Faculty of Tropical Medicine. Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit.
    The epidemiology of malaria in "low-transmission" areas has been underestimated. Molecular detection methods have revealed higher prevalences of malaria than conventional microscopy or rapid diagnostic tests, but these typically evaluate finger-prick capillary blood samples (∼5 μl) and therefore cannot detect parasite densities of <200/ml. Their use underestimates true parasite carriage rates. To characterize the epidemiology of malaria in low-transmission settings and plan elimination strategies, more sensitive quantitative PCR (qPCR) is needed to identify and quantify low-density malaria parasitemias. A highly sensitive "high-volume" quantitative PCR (qPCR) method based on Plasmodium sp. 18S RNA was adapted for blood sample volumes of ≥250 μl and scaled for high throughput. The methods were validated by assessment of the analytical sensitivity and specificity, diagnostic sensitivity, and specificity, efficiency, precision, analytical and diagnostic accuracies, limit of detection, root cause analysis of false positives, and robustness. The high-volume qPCR method based on Plasmodium sp. 18S RNA gave high PCR efficiency of 90 to 105%. Concentrations of parasite DNA from large volumes of blood gave a consistent analytical detection limit (LOD) of 22 parasites/ml (95% CI, 21.79 to 74.9), which is some 2,500 times more sensitive than conventional microscopy and 50 times more sensitive than currently used PCR methods from filter paper blood spots. The diagnostic specificity was 99.75%. Using automated procedures it was possible to process 700 blood samples per week. A very sensitive and specific high-throughput high-volume qPCR method for the detection of low-density parasitemias (>20 parasites/ml) was developed and validated.
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    PublicationOpen Access
    Efficacy of artemether-lumefantrine, the nationally-recommended artemisinin combination for the treatment of uncomplicated falciparum malaria, in southern Laos.
    (2012-06-8) Mayfong Mayxay; Maniphone Khanthavong; Odai Chanthongthip; Mallika Imwong; มัลลิกา อิ่มวงศ์; Tiengkham Pongvongsa; Bouasy Hongvanthong; Samalane Phompida; Viengxay Vanisaveth; White, Nicholas J.; Newton, Paul N; Mayfong Mayxay; Mahidol University. Faculty of Tropical Medicine. Department of Molecular Tropical Medicine and Genetics
    malaria. RESULTS: Of 630 patients with P. falciparum enrolled in the trial of thiamin treatment, 549 (87%, 357 children ≤15 years and 192 adults) were included in this study. The per protocol 42-day cure rates were 97% (524/541) [96% (337/352
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    PublicationOpen Access
    In vivo susceptibility of Plasmodium falciparum to artesunate in Binh Phuoc Province, Vietnam.
    (2012-10-26) Hien, Tran Tinh; Thuy-Nhien, Nguyen Thanh; Phu, Nguyen Hoan; Boni, Maciej F.; Thanh, Ngo Viet; Nha-Ca, Nguyen Thuy; Thai, Le Hong; Thai, Cao Quang; Toi, Pham Van; Thuan, Phung Duc; Long, Le Thanh; Dong, Le Thanh; Merson, Laura; Dolecek, Christiane; Stepniewska, Kasia; Ringwald, Pascal; White, Nicholas J.; Farrar, Jeremy; Wolbers, Marcel; Hien, Tran Tinh; Mahidol University. Faculty of Tropical Medicine
    BACKGROUND: By 2009, there were worrying signs from western Cambodia that parasitological responses to artesunate-containing treatment regimens for uncomplicated Plasmodium falciparum malaria were slower than elsewhere which suggested the emergence of artemisinin resistance. Vietnam shares a long land border with Cambodia with a large number of migrants crossing it on a daily basis. Therefore, there is an urgent need to investigate whether there is any evidence of a change in the parasitological response to the artemisinin derivatives in Vietnam. METHODS: From August 2010 to May 2011, a randomized controlled clinical trial in uncomplicated falciparum malaria was conducted to compare two doses of artesunate (AS) (2mg/kg/day versus 4 mg/kg/day for three days) followed by dihydroartemisinin-piperaquine (DHA-PPQ) and a control arm of DHA-PPQ. The goal was characterization of the current efficacy of artesunate in southern Vietnam. The primary endpoint of this study was the parasite clearance half-life; secondary endpoints included the parasite reduction ratios at 24 and 48 hours and the parasite clearance time. RESULTS: 166 patients were recruited into the study. The median parasite clearance half-lives were 3.54 (AS 2mg/kg), 2.72 (AS 4mg/kg), and 2.98 hours (DHA-PPQ) (p=0.19). The median parasite-reduction ratio at 24 hours was 48 in the AS 2mg/kg group compared with 212 and 113 in the other two groups, respectively (p=0.02). The proportions of patients with a parasite clearance time of >72 hours for AS 2mg/kg, AS 4mg/kg and DHA-PPQ were 27%, 27%, and 22%, respectively. Early treatment failure occurred in two (4%) and late clinical failure occurred in one (2%) of the 55 patients in the AS 2mg/kg group, as compared with none in the other two study arms. The PCR-corrected adequate clinical and parasitological response (APCR) rates in the three groups were 94%, 100%, and 100% (p=0.04). CONCLUSIONS: This study demonstrated faster P. falciparum parasite clearance in southern Vietnam than in western Cambodia but slower clearance in comparison with historical data from Vietnam. Further studies to determine whether this represents the emergence of artemisinin resistance in this area are needed. Currently, the therapeutic response to DHA-PPQ remains satisfactory in southern Vietnam.
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    PublicationOpen Access
    Persistent Plasmodium falciparum and Plasmodium vivax infections in a western Cambodian population: implications for prevention, treatment and elimination strategies
    (2016) Rupam Tripura; Peto, Thomas J.; Jeremy Chalk; Lee, Sue J.; Pasathorn Sirithiranont; Chea Nguon; Mehul Dhorda; Seidlein, Lorenz von; Maude, Richard J.; Day, Nicholas P. J.; Mallika Imwong; White, Nicholas J.; Dondorp, Arjen M.; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Tropical Medicine Research Unit
    Background: Subclinical Plasmodium parasitaemia is an important reservoir for the transmission and persistence of malaria, particularly in low transmission areas. Methods: Using ultrasensitive quantitative PCR (uPCR) for the detection of parasitaemia, the entire population of three Cambodian villages in Pailin province were followed for 1 year at three-monthly intervals. A cohort of adult participants found initially to have asymptomatic malaria parasitaemia was followed monthly over the same period. Results: The initial cross sectional survey in June 2013 (M0) of 1447 asymptomatic residents found that 32 (2.2 %) had Plasmodium falciparum, 48 (3.3 %) had P. vivax, 4 (0.3 %) had mixed infections and in 142/1447 (9.8 %) malaria was detected but there was insufficient DNA to identify the species (Plasmodium. species). Polymorphisms in the ‘K13-propeller’ associated with reduced susceptibility to artemisinin derivatives (C580Y) were found in 17/32 (51 %) P. falciparum strains. Monthly follow-up without treatment of 24 adult participants with asymptomatic mono or mixed P. falciparum infections found that 3/24 (13 %) remained parasitaemic for 2–4 months, whereas the remaining 21/24 (87 %) participants had cleared their parasitaemia after 1 month. In contrast, 12/34 (35 %) adult participants with P. vivax mono-infection at M0 had malaria parasites (P. vivax or P. sp.) during four or more of the following 11 monthly surveys. Conclusions: This longitudinal survey in a low transmission setting shows limited duration of P. falciparum carriage, but prolonged carriage of P. vivax infections. Radical treatment of P. vivax infections by 8-aminoquinoline regimens may be required to eliminate all malaria from Cambodia. Trial registration ClinicalTrials.gov NCT01872702
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    PublicationOpen Access
    Parasite clearance rates in Upper Myanmar indicate a distinctive artemisinin resistance phenotype: a therapeutic efficacy study
    (2016) Tun, Kyaw Myo; Atthanee Jeeyapant; Mallika Imwong; Min Thein; Sai Soe Moe Aung; Hlaing, Tin Maung; Prayoon Yuentrakul; Cholrawee Promnarate; Mehul Dhorda; Woodrow, Charles J.; Dondorp, Arjen M.; Ashley, Elizabeth A.; Smithuis, Frank M.; White, Nicholas J.; Day, Nicholas P. J.; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Tropical Medicine Research Unit
    Background: Artemisinin resistance in Plasmodium falciparum extends across Southeast Asia where it is associated with worsening partner drug resistance and a decline in the efficacy of frontline artemisinin-based combination therapy. Dihydroartemisinin-piperaquine (DP) is an essential component of preventive and curative treatment in the region, but its therapeutic efficacy has fallen in Cambodia. Methods: A prospective clinical and parasitological evaluation of DP was conducted at two sites in Upper Myanmar between August 2013 and December 2014, enrolling 116 patients with acute uncomplicated falciparum malaria. Patients received DP orally for 3 days together with primaquine 0.25 mg/kg on admission. Parasite clearance half-lives based on 6 hourly blood smears, and day 42 therapeutic responses were assessed as well as parasite K13 genotypes. Results: Median parasite clearance half-life was prolonged, and clearance half-life was greater than 5 h in 21 % of patients. Delayed parasite clearance was significantly associated with mutations in the propeller region of the parasite k13 gene. The k13 F446I mutation was found in 25.4 % of infections and was associated with a median clearance halflife of 4.7 h compared with 2.7 h for infections without k13 mutations (p < 0.001). There were no failures after 42 days of follow-up, although 18 % of patients had persistent parasitaemia on day 3. Conclusion: The dominant k13 mutation observed in Upper Myanmar, F446I, appears to be associated with an intermediate rate of parasite clearance compared to other common mutations described elsewhere in the Greater Mekong Subregion. Discerning this phenotype requires relatively detailed clearance measurements, highlighting the importance of methodology in assessing artemisinin resistance.
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    PublicationOpen Access
    World Antimalarial Resistance Network (WARN) IV: clinical pharmacology
    (2007-09-06) Barnes, Karen I.; Lindegardh, Niklas; Ogundahunsi, Olumide; Olliaro, Piero; Plowe, Christopher V.; Randrianarivelojosia, Milijaona; Gbotosho, Grace O; Watkins, William M.; Sibley, Carol H.; White, Nicholas J.; Barnes, Karen I.; Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Tropical Medicine Research Unit (MORU).
    A World Antimalarial Resistance Network (WARN) database has the potential to improve the treatment of malaria, through informing current drug selection and use and providing a prompt warning of when treatment policies need changing. This manuscript outlines the contribution and structure of the clinical pharmacology component of this database. The determinants of treatment response are multi-factorial, but clearly providing adequate blood concentrations is pivotal to curing malaria. The ability of available antimalarial pharmacokinetic data to inform optimal dosing is constrained by the small number of patients studied, with even fewer (if any) studies conducted in the most vulnerable populations. There are even less data relating blood concentration data to the therapeutic response (pharmacodynamics). By pooling all available pharmacokinetic data, while paying careful attention to the analytical methodologies used, the limitations of small (and thus underpowered) individual studies may be overcome and factors that contribute to inter-individual variability in pharmacokinetic parameters defined. Key variables for pharmacokinetic studies are defined in terms of patient (or study subject) characteristics, the formulation and route of administration of the antimalarial studied, the sampling and assay methodology, and the approach taken to data analysis. Better defining these information needs and criteria of acceptability of pharmacokinetic-pharmacodynamic (PK-PD) studies should contribute to improving the quantity, relevance and quality of these studies. A better understanding of the pharmacokinetic properties of antimalarials and a more clear definition of what constitutes "therapeutic drug levels" would allow more precise use of the term "antimalarial resistance", as it would indicate when treatment failure is not caused by intrinsic parasite resistance but is instead the result of inadequate drug levels. The clinical pharmacology component of the WARN database can play a pivotal role in monitoring accurately for true antimalarial drug resistance and promptly correcting sub-optimal dosage regimens to prevent these contributing to the emergence and spread of antimalarial resistance.