Browsing by Author "Universite de Kinshasa"

Filter results by typing the first few letters
Now showing 1 - 10 of 10
  • No Thumbnail Available
    PublicationMetadata only
    The cardiovascular effects of amodiaquine and structurally related antimalarials: An individual patient data meta-analysis
    (2021-09-01) Xin Hui S. Chan; Ilsa L. Haeusler; Yan Naung Win; James Pike; Borimas Hanboonkunupakarn; Maryam Hanafiah; Sue J. Lee; Abdoulaye Djimdé; Caterina I. Fanello; Jean René Kiechel; Marcus V.G. Lacerda; Bernhards Ogutu; Marie A. Onyamboko; André M. Siqueira; Elizabeth A. Ashley; Walter R.J. Taylor; Nicholas J. White; Faculty of Tropical Medicine, Mahidol University; Universite de Kinshasa; Kenya Medical Research Institute; Instituto Nacional de Infectologia Evandro Chagas (INI); Fiocruz Amazônia; UCL Great Ormond Street Institute of Child Health; Nuffield Department of Medicine; Health and Diseases Control Unit; Drugs for Neglected Diseases Initiative; University of Sciences Techniques and Technologies of Bamako; Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
    Background AU Amodiaquine: Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly is a 4-aminoquinoline antimalarial similar to chloroquine : that is used extensively for the treatment and prevention of malaria. Data on the cardiovascular effects of amodiaquine are scarce, although transient effects on cardiac electrophysiology (electrocardiographic QT interval prolongation and sinus bradycardia) have been observed. We conducted an individual patient data meta-analysis to characterise the cardiovascular effects of amodiaquine and thereby support development of risk minimisation measures to improve the safety of this important antimalarial. Methods and findings Studies of amodiaquine for the treatment or prevention of malaria were identified from a systematic review. Heart rates and QT intervals with study-specific heart rate correction (QTcS) were compared within studies and individual patient data pooled for multivariable linear mixed effects regression. The meta-analysis included 2,681 patients from 4 randomised controlled trials evaluating artemisinin-based combination therapies (ACTs) containing amodiaquine (n = 725), lumefantrine (n = 499), piperaquine (n = 716), and pyronaridine (n = 566), as well as monotherapy with chloroquine (n = 175) for uncomplicated malaria. Amodiaquine prolonged QTcS (mean = 16.9 ms, 95% CI: 15.0 to 18.8) less than chloroquine (21.9 ms, 18.3 to 25.6, p = 0.0069) and piperaquine (19.2 ms, 15.8 to 20.5, p = 0.0495), but more than lumefantrine (5.6 ms, 2.9 to 8.2, p < 0.001) and pyronaridine (−1.2 ms, −3.6 to +1.3, p < 0.001). In individuals aged >12 years, amodiaquine reduced heart rate (mean reduction = 15.2 beats per minute [bAU pm],: 95% PleasenotethatbpmhasbeendefinedasbeatsperminuteinthesentenceInindividualsaged CI: 13.4 to 17.0) more than piperaquine (10.5 bpm, 7.7 to 13.3, p = < 0.0013), lumefantrine (9.3 bpm, 6.4 to 12.2, p < 0.001), pyronaridine (6.6 bpm, 4.0 to 9.3, p < 0.001), and chloroquine (5.9 bpm, 3.2 to 8.5, p < 0.001) and was associated with a higher risk of potentially symptomatic sinus bradycardia (>50 bpm) than lumefantrine (risk difference: 14.8%, 95% CI: 5.4 to 24.3, p = 0.0021) and chloroquine (risk difference: 8.0%, 95% CI: 4.0 to 12.0, p < 0.001). The effect of amodiaquine on the heart rate of children aged <12 years compared with other antimalarials was not clinically significant. Study limitations include the unavailability of individual patient-level adverse event data for most included participants, but no serious complications were documented. Conclusions While caution is advised in the use of amodiaquine in patients aged >12 years with concompiledforthoseusedthroughoutthetext:Pleaseverifythatallentriesarecorrect: itant use of heart rate–reducing medications, serious cardiac conduction disorders, or risk factors for torsade de pointes, there have been no serious cardiovascular events reported after amodiaquine in widespread use over 7 decades. Amodiaquine and structurally related antimalarials at the World Health Organization (WHO)-recommended doses alone or in ACTs are safe for the treatment and prevention of malaria.
  • No Thumbnail Available
    PublicationMetadata only
    Defining surrogate endpoints for clinical trials in severe falciparum malaria
    (2017-01-01) Atthanee Jeeyapant; Hugh W. Kingston; Katherine Plewes; Richard J. Maude; Josh Hanson; M. Trent Herdman; Stije J. Leopold; Thatsanun Ngernseng; Prakaykaew Charunwatthana; Nguyen Hoan Phu; Aniruddha Ghose; M. Mahtab Uddin Hasan; Caterina I. Fanello; Md Abul Faiz; Tran Tinh Hien; Nicholas P.J. Day; Nicholas J. White; Arjen M. Dondorp; Mahidol University; Charles Darwin University; Nuffield Department of Clinical Medicine; Menzies School of Health Research; UCL; Chittagong Medical College Hospital; Universite de Kinshasa; Dev Care Foundation
    © 2017 Jeeyapant et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Clinical trials in severe falciparum malaria require a large sample size to detect clinically meaningful differences in mortality. This means few interventions can be evaluated at any time. Using a validated surrogate endpoint for mortality would provide a useful alternative allowing a smaller sample size. Here we evaluate changes in coma score and plasma lactate as surrogate endpoints for mortality in severe falciparum malaria. Methods Three datasets of clinical studies in severe malaria were re-evaluated: studies from Chittagong, Bangladesh (adults), the African 'AQUAMAT' trial comparing artesunate and quinine (children), and the Vietnamese 'AQ' study (adults) comparing artemether with quinine. The absolute change, relative change, slope of the normalization over time, and time to normalization were derived from sequential measurements of plasma lactate and coma score, and validated for their use as surrogate endpoint, including the proportion of treatment effect on mortality explained (PTE) by these surrogate measures. Results Improvements in lactate concentration or coma scores over the first 24 hours of admission, were strongly prognostic for survival in all datasets. In hyperlactataemic patients in the AQ study (n = 173), lower mortality with artemether compared to quinine closely correlated with faster reduction in plasma lactate concentration, with a high PTE of the relative change in plasma lactate at 8 and 12 hours of 0.81 and 0.75, respectively. In paediatric patients enrolled in the 'AQUAMAT' study with cerebral malaria (n = 785), mortality was lower with artesunate compared to quinine, but this was not associated with faster coma recovery. Conclusions The relative changes in plasma lactate concentration assessed at 8 or 12 hours after admission are valid surrogate endpoints for severe malaria studies on antimalarial drugs or adjuvant treatments aiming at improving the microcirculation. Measures of coma recovery are not valid surrogate endpoints for mortality.
  • No Thumbnail Available
    PublicationMetadata only
    Factors affecting COVID-19 vaccine acceptance: an international survey among low-and middle-income countries
    (2021-05-01) Suzanna Awang Bono; Edlaine Faria de Moura Villela; Ching Sin Siau; Won Sun Chen; Supa Pengpid; M. Tasdik Hasan; Philippe Sessou; John D. Ditekemena; Bob Omoda Amodan; Mina C. Hosseinipour; Housseini Dolo; Joseph Nelson Siewe Fodjo; Wah Yun Low; Robert Colebunders; Universite de Kinshasa; UNC Project-Malawi; University of Abomey-Calavi; University of Bamako Faculty of Medicine, Pharmacy and Odonto-Stomatology; Swinburne University of Technology; Universiti Malaya; Universidade Federal de Goiás; University of Liverpool; UNC School of Medicine; Universiteit Antwerpen; Mahidol University; Universiti Kebangsaan Malaysia; Universiti Sains Malaysia; Uganda Public Health Fellowship Program; Brain Research Africa Initiative (BRAIN); Public Health Foundation; Health State Agency of São Paulo
    Vaccination is fast becoming a key intervention against the ongoing COVID-19 pandemic. We conducted cross-sectional online surveys to investigate COVID-19 vaccine acceptance across nine Low-and Middle-Income Countries (LMICs; N = 10,183), assuming vaccine effectiveness at 90% and 95%. The prevalence of vaccine acceptance increased from 76.4% (90% effectiveness) to 88.8% (95% effectiveness). Considering a 90% effective vaccine, Malaysia, Thailand, Bangladesh, and five African countries (Democratic Republic of Congo, Benin, Uganda, Malawi, and Mali) had lower acceptance odds compared to Brazil. Individuals who perceived taking the vaccine as important to protect themselves had the highest acceptance odds (aOR 2.49) at 95% effectiveness.Vaccine acceptance was also positively associated with COVID-19 knowledge, worry/fear regarding COVID-19, higher income, younger age, and testing negative for COVID-19. However, chronic disease and female gender reduced the odds for vaccine acceptance. The main reasons underpinning vaccine refusal were fear of side effects (41.2%) and lack of confidence in vaccine effectiveness (15.1%). Further research is needed to identify country-specific reasons for vaccine hesitancy in order to develop mitigation strategies that would ensure high and equitable vaccination coverage across LMICs.
  • No Thumbnail Available
    PublicationMetadata only
    Genetic surveillance in the greater mekong subregion and south asia to support malaria control and elimination
    (2021-01-01) Christopher G. Jacob; Nguyen Thuy-Nhien; Mayfong Mayxay; Richard J. Maude; Huynh Hong Quang; Bouasy Hongvanthong; Viengxay Vanisaveth; Thang Ngo Duc; Huy Rekol; Rob van der Pluijm; Lorenz von Seidlein; Rick Fairhurst; François Nosten; Md Amir Hossain; Naomi Park; Scott Goodwin; Pascal Ringwald; Keobouphaphone Chindavongsa; Paul Newton; Elizabeth Ashley; Sonexay Phalivong; Rapeephan Maude; Rithea Leang; Cheah Huch; Le Thanh Dong; Kim Tuyen Nguyen; Tran Minh Nhat; Tran Tinh Hien; Hoa Nguyen; Nicole Zdrojewski; Sara Canavati; Abdullah Abu Sayeed; Didar Uddin; Caroline Buckee; Caterina I. Fanello; Marie Onyamboko; Thomas Peto; Rupam Tripura; Chanaki Amaratunga; Aung Myint Thu; Gilles Delmas; Jordi Landier; Daniel M. Parker; Nguyen Hoang Chau; Dysoley Lek; Seila Suon; James Callery; Podjanee Jittamala; Borimas Hanboonkunupakarn; Sasithon Pukrittayakamee; Aung Pyae Phyo; Frank Smithuis; Khin Lin; Myo Thant; Tin Maung Hlaing; Parthasarathi Satpathi; Sanghamitra Satpathi; Prativa K. Behera; Amar Tripura; Subrata Baidya; Neena Valecha; Anupkumar R. Anvikar; Akhter Ul Islam; Abul Faiz; Chanon Kunasol; Eleanor Drury; Mihir Kekre; Mozam Ali; Katie Love; Shavanthi Rajatileka; Anna E. Jeffreys; Kate Rowlands; Christina S. Hubbart; Mehul Dhorda; Ranitha Vongpromek; Namfon Kotanan; Phrutsamon Wongnak; Jacob Almagro Garcia; Richard D. Pearson; Cristina V. Ariani; Thanat Chookajorn; Cinzia Malangone; T. Nguyen; Jim Stalker; Ben Jeffery; Jonathan Keatley; Kimberly J. Johnson; Dawn Muddyman; Xin Hui S. Chan; John Sillitoe; Roberto Amato; Victoria Simpson; Sonia Gonçalves; Kirk Rockett; Nicholas P. Day; Arjen M. Dondorp; Dominic P. Kwiatkowski; Olivo Miotto; Ramathibodi Hospital; Faculty of Tropical Medicine, Mahidol University; Oxford University Clinical Research Unit; Sciences Economiques et Sociales de la Santé et Traitement de l'Information Médicale; The Wellcome Centre for Human Genetics; Ministry of Health Laos; Universite de Kinshasa; National Institute of Malariology, Parasitology and Entomology Hanoi; Ispat General Hospital; Shoklo Malaria Research Unit; Harvard T.H. Chan School of Public Health; Organisation Mondiale de la Santé; National Institute of Malaria Research India; Mahosot Hospital, Lao; Mahidol University; Chittagong Medical College Hospital; Nuffield Department of Medicine; University of California, Irvine; National Institutes of Health (NIH); Wellcome Sanger Institute; Midnapore Medical College; Vysnova Partners Inc; Myanmar Oxford Clinical Research Unit; Asia Regional Centre; Ramu Upazila Health Complex; Malaria Research Group and Dev Care Foundation; Institute of Malariology; Defence Services Medical Academy; Entomology; Agartala Medical College; Royal Society of Thailand; Institute of Malariology
    Background: National Malaria Control Programmes (NMCPs) currently make limited use of parasite genetic data. We have developed GenRe-Mekong, a platform for genetic surveillance of malaria in the Greater Mekong Subregion (GMS) that enables NMCPs to implement large-scale surveillance projects by integrating simple sample collection procedures in routine public health procedures. Methods: Samples from symptomatic patients are processed by SpotMalaria, a high-throughput system that produces a comprehensive set of genotypes comprising several drug resistance markers, species markers and a genomic barcode. GenRe-Mekong delivers Genetic Report Cards, a compendium of genotypes and phenotype predictions used to map prevalence of resistance to multiple drugs. Results: GenRe-Mekong has worked with NMCPs and research projects in eight countries, processing 9623 samples from clinical cases. Monitoring resistance markers has been valuable for tracking the rapid spread of parasites resistant to the dihydroartemisinin-piperaquine combination therapy. In Vietnam and Laos, GenRe-Mekong data have provided novel knowledge about the spread of these resistant strains into previously unaffected provinces, informing decision-making by NMCPs. Conclusions: GenRe-Mekong provides detailed knowledge about drug resistance at a local level, and facilitates data sharing at a regional level, enabling cross-border resistance monitoring and providing the public health community with valuable insights. The project provides a rich open data resource to benefit the entire malaria community.
  • No Thumbnail Available
    PublicationMetadata only
    Genomic epidemiology of artemisinin resistant malaria
    (2016-03-04) Roberto Amato; Olivo Miotto; Charles J. Woodrow; Jacob Almagro-Garcia; Ipsita Sinha; Susana Campino; Daniel Mead; Eleanor Drury; Mihir Kekre; Mandy Sanders; Alfred Amambua-Ngwa; Chanaki Amaratunga; Lucas Amenga-Etego; Voahangy Andrianaranjaka; Tobias Apinjoh; Elizabeth Ashley; Sarah Auburn; Gordon A. Awandare; Vito Baraka; Alyssa Barry; Maciej F. Boni; Steffen Borrmann; Teun Bousema; Oralee Branch; Peter C. Bull; Kesinee Chotivanich; David J. Conway; Alister Craig; Nicholas P. Day; Abdoulaye Djimdé; Christiane Dolecek; Arjen M. Dondorp; Chris Drakeley; Patrick Duffy; Diego F. Echeverry; Thomas G. Egwang; Rick M. Fairhurst; Abul Faiz; Caterina I. Fanello; Tran Tinh Hien; Abraham Hodgson; Mallika Imwong; Deus Ishengoma; Pharath Lim; Chanthap Lon; Jutta Marfurt; Kevin Marsh; Mayfong Mayxay; Pascal Michon; Victor Mobegi; Olugbenga A. Mokuolu; Jacqui Montgomery; Ivo Mueller; Myat Phone Kyaw; Paul N. Newton; Francois Nosten; Rintis Noviyanti; Alexis Nzila; Harold Ocholla; Abraham Oduro; Marie Onyamboko; Jean Bosco Ouedraogo; Aung Pyae P. Phyo; Christopher Plowe; Ric N. Price; Sasithon Pukrittayakamee; Milijaona Randrianarivelojosia; Pascal Ringwald; Lastenia Ruiz; David Saunders; Alex Shayo; Peter Siba; Shannon Takala-Harrison; Thuy Nhien N. Thanh; Vandana Thathy; Federica Verra; Jason Wendler; Wellcome Trust Sanger Institute; Wellcome Trust Centre for Human Genetics; Mahidol University; Nuffield Department of Clinical Medicine; Medical Research Council Laboratories Gambia; National Institute of Allergy and Infectious Diseases; Navrongo Health Research Center; Institut Pasteur de Madagascar; University of Buea; Menzies School of Health Research; University of Ghana; National Institute for Medical Research Tanga; Universiteit Antwerpen; Walter and Eliza Hall Institute of Medical Research; University of Melbourne; University of Oxford; Kenya Medical Research Institute; Universität Tübingen; London School of Hygiene & Tropical Medicine; NYU School of Medicine; Liverpool School of Tropical Medicine; University of Bamako; Oxford University Clinical Research Unit; Purdue University; Centro Internacional de Entrenamiento e Investigaciones Medicas; Med Biotech Laboratories Uganda; Malaria Research Group and Dev Care Foundation; National Centre for Parasitology, Entomology and Malaria Control; Armed Forces Research Institute of Medical Sciences, Thailand; Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU); University of Health Sciences; Divine Word University; University of Ilorin; Pennsylvania State University; Ministry of Health; Shoklo Malaria Research Unit; Eijkman Institute for Molecular Biology; King Fahd University of Petroleum and Minerals; Malawi-Liverpool-Wellcome Trust; Universite de Kinshasa; Institut de Recherche en Sciences de la Santé; University of Maryland School of Medicine; Organisation Mondiale de la Sante; Universidad Nacional de la Amazonia Peruana, Iquitos; University of Dodoma; Papua New Guinea Institute of Medical Research
    © 2016, eLife Sciences Publications Ltd. All rights reserved. The current epidemic of artemisinin resistant Plasmodium falciparum in Southeast Asia is the result of a soft selective sweep involving at least 20 independent kelch13 mutations. In a large global survey, we find that kelch13 mutations which cause resistance in Southeast Asia are present at low frequency in Africa. We show that African kelch13 mutations have originated locally, and that kelch13 shows a normal variation pattern relative to other genes in Africa, whereas in Southeast Asia there is a great excess of non-synonymous mutations, many of which cause radical amino-acid changes. Thus, kelch13 is not currently undergoing strong selection in Africa, despite a deep reservoir of variations that could potentially allow resistance to emerge rapidly. The practical implications are that public health surveillance for artemisinin resistance should not rely on kelch13 data alone, and interventions to prevent resistance must account for local evolutionary conditions, shown by genomic epidemiology to differ greatly between geographical regions.
  • No Thumbnail Available
    PublicationMetadata only
    Mass masking as a way to contain COVID-19 and exit lockdown in low- and middle-income countries
    (2020-09-01) Joseph Nelson Siewe Fodjo; Supa Pengpid; Edlaine Faria de Moura Villela; Vo Van Thang; Mohammed Ahmed; John Ditekemena; Bernardo Vega Crespo; Rhoda K. Wanyenze; Janeth Dula; Takashi Watanabe; Christopher Delgado-Ratto; Koen Vanden Driessche; Rafael Van den Bergh; Robert Colebunders; Elizabeth Glaser Pediatric AIDS Foundation; University Medicine and Pharmacy, Hue University; Universidad Peruana Cayetano Heredia, Instituto de Medicina Tropical Alexander von Humboldt; Universite de Kinshasa; Instituto Nacional de Saude Maputo; University of Cuenca; Makerere University; Universitair Ziekenhuis Antwerpen; Universiteit Antwerpen; Mahidol University; Radboud University Nijmegen Medical Centre; Mogadishu University; Federal University of Jataí
    © 2020 The British Infection Association In new guidelines published on June 5th 2020, the World Health Organization (WHO) recommends that in areas with ongoing COVID-19 community transmission, governments should encourage the general public to wear face masks in specific situations and settings as part of a comprehensive approach to suppress COVID-19 transmission. Recent online surveys in 206,729 persons residing in nine low- and middle-income countries showed that 32.7%-99.7% of respondents used face masks with significant differences across age groups and sexes. Targeted health promotion strategies and government support are required to increase mask use by the general population.
  • No Thumbnail Available
    PublicationMetadata only
    Pharmacokinetic study of rectal artesunate in children with severe Malaria in Africa
    (2021-04-01) Caterina Fanello; Richard M. Hoglund; Sue J. Lee; Daddy Kayembe; Pauline Ndjowo; Charlie Kabedi; Benjamin B. Badjanga; Phettree Niamyim; Joel Tarning; Charles Woodrow; Melba Gomes; Nick P. Day; Nicholas J. White; Marie A. Onyamboko; Faculty of Tropical Medicine, Mahidol University; Universite de Kinshasa; Organisation Mondiale de la Santé; Nuffield Department of Medicine
    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 falciparum 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 in vivo IC50 and IC90 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 IC50 and IC90 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 (P = 0.49). Despite large interindividual variability, rectal artesunate can initiate and sustain rapid parasiticidal activity in most children with severe falciparum malaria while they are transferred to a facility where parenteral artesunate is available. (This study has been registered at ClinicalTrials.gov under identifier NCT02492178.)
  • No Thumbnail Available
    PublicationMetadata only
    Randomized comparison of the efficacies and tolerabilities of three artemisinin-based combination treatments for children with acute Plasmodium falciparum malaria in the Democratic Republic of the Congo
    (2014-01-01) M. A. Onyamboko; C. I. Fanello; K. Wongsaen; J. Tarning; P. Y. Cheah; K. A. Tshefu; A. M. Dondorp; F. Nosten; N. J. White; N. P.J. Day; Mahidol University; Nuffield Department of Clinical Medicine; Universite de Kinshasa
    An open-label, randomized controlled trial was carried out in 2011-2012 in the Democratic Republic of the Congo to test the efficacy, safety, and tolerability of the artemisinin-based combination treatments dihydroartemisinin-piperaquine, amodiaquine-artesunate, and artemether- lumefantrine. Six hundred eighty-four children aged 3 to 59 months with uncomplicated Plasmodium falciparum malaria were randomly allocated to each study arm. Children were hospitalized for 3 days, given supervised treatment, and followed up weekly for 42 days. All regimens were well tolerated and rapidly effective. The median parasitemia clearance half-life was 2.2 h, and half-lives were similar between arms (P = 0.19). The PCR-uncorrected cure rates by day 42 were 73.0% for amodiaquine-artesunate, 70.2% for artemether-lumefantrine, and 86.3% for dihydroartemisinin-piperaquine (P = 0.001). Early treatment failure occurred in three patients (0.5%), one in each arm. The PCR-corrected cure rates were 93.4% for amodiaquine-artesunate, 92.7% for artemether-lumefantrine, and 94.3% for dihydroartemisinin-piperaquine (P = 0.78). The last provided a longer posttreatment prophylactic effect than did the other two treatments. The day 7 plasma concentration of piperaquine was below 30 ng/ml in 47% of the children treated with dihydroartemisinin-piperaquine, and the day 7 lumefantrine concentration was below 280 ng/ml in 37.0% of children who received artemether-lumefantrine. Thus, although cure rates were all satisfactory, they could be improved by increasing the dose. (This study has been registered with the International Standard Randomized Controlled Trial Number Register [www.isrctn.org] under registration no. ISRCTN20984426.) Copyright © 2014 Onyamboko et al.
  • No Thumbnail Available
    PublicationMetadata only
    A randomized controlled trial of three-versus five-day artemether-lumefantrine regimens for treatment of uncomplicated Plasmodium falciparum Malaria in Pregnancy in Africa
    (2020-01-01) Marie A. Onyamboko; Richard M. Hoglund; Sue J. Lee; Charlie Kabedi; Daddy Kayembe; Benjamin B. Badjanga; Gareth D.H. Turner; Nikky V. Jackson; Joel Tarning; Rose McGready; Francois Nosten; Nicholas J. White; Nicholas P.J. Day; Caterina Fanello; Universite de Kinshasa; NHS Foundation Trust; University of Oxford; Mahidol University; Nuffield Department of Clinical Medicine
    Copyright © 2020 Onyamboko et al. Artemether-lumefantrine antimalarial efficacy in pregnancy could be compromised by reduced drug exposure. Population-based simulations suggested that therapeutic efficacy would be improved if the treatment duration was increased. We assessed the efficacy, tolerability, and pharmacokinetics of an extended 5-day regimen of artemether-lumefantrine compared to the standard 3-day treatment in 48 pregnant women and 48 nonpregnant women with uncomplicated falciparum malaria in an open-label, randomized clinical trial. Babies were assessed at birth and 1, 3, 6, and 12 months. Nonlinear mixed-effects modeling was used to characterize the plasma concentration-time profiles of artemether and lumefantrine and their metabolites. Both regimens were highly efficacious (100% PCR-corrected cure rates) and well tolerated. Babies followed up to 1 year had normal development. Parasite clearance half-lives were longer in pregnant women (median [range], 3.30 h [1.39 to 7.83 h]) than in nonpregnant women (2.43 h [1.05 to 6.00 h]) (P=0.005). Pregnant women had lower exposures to artemether and dihydroartemisinin than nonpregnant women, resulting in 1.2% decreased exposure for each additional week of gestational age. By term, these exposures were reduced by 48% compared to nonpregnant patients. The overall exposure to lumefantrine was improved with the extended regimen, with no significant differences in exposures to lumefantrine or desbutyl-lumefantrine between pregnant and nonpregnant women. The extended artemether-lumefantrine regimen was well tolerated and safe and increased the overall antimalarial drug exposure and so could be a promising treatment option in pregnancy in areas with lower rates of malaria transmission and/or emerging drug resistance.
  • No Thumbnail Available
    PublicationMetadata only
    Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria - a proposed model-derived age-based regimen for sub-Saharan Africa
    (2018-01-18) W. Robert Taylor; Htee Khu Naw; Kathryn Maitland; Thomas N. Williams; Melissa Kapulu; Umberto D'Alessandro; James A. Berkley; Philip Bejon; Joseph Okebe; Jane Achan; Alfred Ngwa Amambua; Muna Affara; Davis Nwakanma; Jean Pierre van Geertruyden; Muhindo Mavoko; Pascal Lutumba; Junior Matangila; Philipe Brasseur; Patrice Piola; Rindra Randremanana; Estrella Lasry; Caterina Fanello; Marie Onyamboko; Birgit Schramm; Zolia Yah; Joel Jones; Rick M. Fairhurst; Mahamadou Diakite; Grace Malenga; Malcolm Molyneux; Claude Rwagacondo; Charles Obonyo; Endalamaw Gadisa; Abraham Aseffa; Mores Loolpapit; Marie Claire Henry; Grant Dorsey; Chandy John; Sodiomon B. Sirima; Karen I. Barnes; Peter Kremsner; Nicholas P. Day; Nicholas J. White; Mavuto Mukaka; Unité de Recherche sur les Maladies Infectieuses et Tropicales émergentes; Universite de Kinshasa; Queen Elizabeth Central Hospital Malawi; Malawi-Liverpool-Wellcome Trust Clinical Research Programme; Institut Pasteur de Madagascar; Centre de Recherche Entomologique de Cotonou; Medical Research Council Laboratories Gambia; Armauer Hansen Research Institute; Kenya Medical Research Institute; Wellcome Trust Research Laboratories Nairobi; African Medical Research Foundation Nairobi; London School of Hygiene & Tropical Medicine; Indiana University-Purdue University Indianapolis; University of California, San Francisco; Wellcome Trust; National Institute of Allergy and Infectious Diseases; Universität Tübingen; Universiteit Antwerpen; Epicentre; Mahidol University; Hôpitaux universitaires de Genève; Nuffield Department of Clinical Medicine; Medecins Sans Frontieres; University of Cape Town; Kinshasa Mahidol Oxford Research Unit; USTTB; National Malaria Control Programme; Groupe de Recherche Action en Santé (GRAS); National Malaria Control Program; Kinshasa School of Public Health; Centre National de Recherche et de Formation sur le Paludisme
    © 2018 The Author(s). Background: In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa. Methods: Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia, and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectively defined therapeutic-dose ranges of 0.15-0.4 mg PQ base/kg for children aged 1-5 years and 0.15-0.5 mg PQ base/kg for individuals aged ≥6 years (therapeutic indices 2.7 and 3.3, respectively). We chose 1.25 mg PQ base for infants aged 6-11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA. We modelled an anthropometric database of 661,979 African individuals aged ≥6 months (549,127 healthy individuals, 28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box-Cox transformation power exponential and tested PQ doses of 1-15 mg base, selecting dosing groups based on calculated mg/kg PQ doses. Results: From the Box-Cox transformation power exponential model, five age categories were selected: (i) 6-11 months (n = 39,886, 6.03%), (ii) 1-5 years (n = 261,036, 45.46%), (iii) 6-9 years (n = 20,770, 3.14%), (iv) 10-14 years (n = 12,155, 1.84%) and (v) ≥15 years (n = 328,132, 49.57%) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and 99th centiles) mg/kg PQ base of: (i) 0.16 (0.12-0.25), (ii) 0.21 (0.13-0.37), (iii) 0.25 (0.16-0.38), (iv) 0.26 (0.15-0.38) and (v) 0.27 (0.17-0.40). The proportions of individuals predicted to receive optimal therapeutic PQ doses were: 73.2 (29,180/39,886), 93.7 (244,537/261,036), 99.6 (20,690/20,770), 99.4 (12,086/12,155) and 99.8% (327,620/328,132), respectively. Conclusions: We plan to test the safety of this age-based dosing regimen in a large randomised placebo-controlled trial (ISRCTN11594437) of uncomplicated falciparum malaria in G6PDd African children aged 0.5 - 11 years. If the regimen is safe and demonstrates adequate pharmacokinetics, it should be used to support malaria elimination.