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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., Author(s): Mohammad S. Hossain 1,2,3,4, Robert J. Commons 1,2,5, Nicholas M. Douglas 2,3, Kamala Thriemer 2, Bereket H. Alemayehu 6, Chanaki Amaratunga 7, Anupkumar R. Anvikar 8, Elizabeth A. Ashley [...]

Background Artemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax. Methods and findings Clinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0%, 95% confidence interval [CI] 38.7-49.8) compared with the 812 patients treated with DP alone (9.3%, 95% CI 7.1-12.2): adjusted hazard ratio (AHR) 12.63 (95% CI 6.40-24.92), p < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95% CI) for every 5-mg/kg increase 0.63 (0.48-0.84), p = 0.0013 and 0.83 (0.73-0.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95% CI 0.99-1.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95% CI 0.01-0.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95% CI 0.10-0.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95% CI 0.01-0.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups. Conclusions In this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis., Author(s): Robert J. Commons 1,2,*, Julie A. Simpson 3, Kamala Thriemer 1, Tesfay Abreha 4, Ishag Adam 5, Nicholas M. Anstey 1, Ashenafi Assefa 6, Ghulam R. Awab 7,8, J. [...]

Background The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations. Methods and findings A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing Conclusions Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment., Author(s): Frank Kloprogge 1,2,3, Lesley Workman 4,5, Steffen Borrmann 6,7, Mamadou Tékété 7,8, Gilbert Lefèvre 9, Kamal Hamed 10, Patrice Piola 11, Johan Ursing 12,13,14, Poul Erik Kofoed 14,15, Andreas [...]

Background and Aims: A relationship between diabetes, glucose and COVID‐19 outcomes has been reported in international cohorts. This study aimed to assess the relationship between diabetes, hyperglycaemia and patient outcomes in those hospitalised with COVID‐19 during the first year of the Victorian pandemic prior to novel variants and vaccinations. Design, setting: Retrospective cohort study from March to November 2020 across five public health services in Melbourne, Australia. Participants: All consecutive adult patients admitted to acute wards of participating institutions during the study period with a diagnosis of COVID‐19, comprising a large proportion of patients from residential care facilities and following dexamethasone becoming standard‐of‐care. Admissions in patients without known diabetes and without inpatient glucose testing were excluded. Results: The DINGO COVID‐19 cohort comprised 840 admissions. In 438 admissions (52%), there was no known diabetes or in‐hospital hyperglycaemia, in 298 (35%) patients had known diabetes, and in 104 (12%) patients had hyperglycaemia without known diabetes. ICU admission was more common in those with diabetes (20%) and hyperglycaemia without diabetes (49%) than those with neither (11%, P < 0.001 for all comparisons). Mortality was higher in those with diabetes (24%) than those without diabetes or hyperglycaemia (16%, P = 0.02) but no difference between those with in‐hospital hyperglycaemia and either of the other groups. On multivariable analysis, hyperglycaemia was associated with increased ICU admission (adjusted odds ratio (aOR) 6.7, 95% confidence interval (95% CI) 4.0–12, P < 0.001) and longer length of stay (aOR 173, 95% CI 11–2793, P < 0.001), while diabetes was associated with reduced ICU admission (aOR 0.55, 95% CI 0.33–0.94, P = 0.03). Neither diabetes nor hyperglycaemia was independently associated with in‐hospital mortality. Conclusions: During the first year of the COVID‐19 pandemic, in‐hospital hyperglycaemia and known diabetes were not associated with in‐hospital mortality, contrasting with published international experiences. This likely mainly relates to hyperglycaemia indicating receipt of mortality‐reducing dexamethasone therapy. These differences in published experiences underscore the importance of understanding population and clinical treatment factors affecting glycaemia and COVID‐19 morbidity within both local and global contexts. [ABSTRACT FROM AUTHOR]

Objective To compare the cost-effectiveness of conventional antimalarial therapy with that of three artemisinin combination treatment regimens in children from Papua New Guinea aged 6 to 60 months. Methods An incremental cost-effectiveness analysis was performed using data from 656 children with Plasmodium falciparum and/or P. vivaxmalaria who participated in a large intervention trial in two clinics in northern Papua New Guinea. The children were randomized to one of the following groups: (i) conventional treatment with chloroquine plus sulfadoxine plus pyrimethamine (CQ+S+P); (ii) artesunate plus S plus P; (iii) dihydroartemisinin plus piperaquine (DHA+PQ); and (iv) artemether plus lumefantrine (A+L). For treatment outcomes, World Health Organization definitions were used. The cost of transport between home and the clinic plus direct health- care costs served as a basis for determining each regimen's incremental cost per incremental treatment success relative to CQ+S+P by day 42 and its cost per life year saved. Findings A+L proved to be the most effective regimen against R falciparum malaria and was highly cost-effective at 6.97 United States dollars (USS) per treatment success (about USS 58 per life year saved). DHA+PQ was the most effective regimen against P. vivax malaria and was more cost-effective than CQ+S+R Conclusion A+L and DHA+PQ are highly cost-effective regimens for the treatment of paediatric P. falciparum and R vivax malaria, respectively, in parts of Papua New Guinea. Future research will be required to determine if these findings hold true for other territories in Asia and Oceania with similar malaria epidemiology. Objectif Comparer le rapport cout -efficacite de la therapie antipaludeenne conventionnelle avec le rapport respectif de trois regimes de traitement associe a base d'artemisinine chez des enfants de Papouasie-NouvelleGuinee ages de 6 a 60 mois. Methodes Une analyse differentielle de cout-efficacite a ete realisee l'aide des donnees de 656 enfants souffrant de Plasmodium falciparum et/ ou de paludisme a P. vivax ayant participe a un vaste essai d'intervention sur le littoral nord-occidental de la Papouasie-Nouvelle-Guinee. Les enfants, qui ont ete presentes dans deux cliniques, ont fait I'objet d'une randomisation vers I'un des regimes therapeutiques suivants : (i) traitement conventionnel avec chloroquine et sulfadoxine-pyrimethamine; (ii) artesunate plus sulfadoxine-pyrimethamine; (iii) dihydroartemisininepiperaquine (DHA+PQ); et (iv) artemether-lumefantrine (A+L). Les resultats des traitements ont ete etablis conformement aux definitions standard de l'Organisation mondiale de la Sante. Le cout du transport entre le domicile et la clinique, ainsi que les frais directs lies aux soins de sante dispenses, ont ete calcules comme base determinante du cout differentiel de chaque regime par traitement reussi au jour 42, et son cout par annee de vie sauvee. Resultats A+L s'est revele comme le regime le plus efficace du point de vue clinique dans le traitement du paludisme a P. falciparum et representait un excellent rapport cout-efficacite a 6,97 dollars par traitement reussi (environ 58 dollars par annee de vie sauvee). DHA+PQ representait l'association de traitement la plus efficace dans la lutte contre le paludisme a P. vivax, et etait d'un meilleur rapport cout-efficacite que le traitement conventionnel contre le paludisme. Conclusion A+L et DHA+PQ sont des regimes tres rentables pour traiter, respectivement, le paludisme pediatrique a P. falciparum et a P vivax, dans les regions de la Papouasie-Nouvelle-Guinee. Des recherches futures seront necessaires arin de determiner si ces resultats se confirment dans d'autres territoires d'Asie et d'Oceanie presentant une epidemiologie de paludisme similaire. Objetivo Comparar la rentabilidad del tratamiento antipaludico convencional respecto a la de los tres tratamientos combinados con artemisinina en ninos de entre 6 y 60 meses de Papua Nueva Guinea. Metodos Se realizo un analisis incremental de la rentabilidad con los datos procedentes de 656 ninos con malaria por Plasmodium falciparum y/o por R vivax que participaron en un ensayo intervencionista a gran escala en la costa Norte de Papua Nueva Guinea. A los ninos que acudieron a dos consultorios, se les asigno aleatoriamente uno de los siguientes tratamientos: (a) tratamiento tradicional con cloroquina, sulfadoxina y pirimetamina; (b) artesunato, sulfadoxina y pirimetamina; (c) dihidroartemisinina y piperaquina (DHA+PQ); y (d) artemeter y lumefantrina (A+L). Se definieron los resultados terapeuticos siguiendo las definiciones normalizadas de la Organizacion Mundial de la Salud. Como base para la determinacion de los costes incrementales por cada logro terapeutico alcanzado a los 42 dias y su coste por ano de vida salvado, se calculo el coste del transporte entre el hogar y el centro de salud, junto con los gastos directos ocasionados por la asistencia sanitaria proporcionada. Resultados Desde el punto de vista clinico, el tratamiento mas eficaz contra la malaria por R falciparum fue el A+L, con una rentabilidad muy elevada de 6,97 dolares norteamericanos (USS) por logro terapeutico (unos 58 USS por ano de vida salvado). La combinacion terapeutica mas eficaz contra la malaria producida por R vivaxfue la DHA+PQ y resulto ser mas rentable que el tratamiento antipaludico habitual. Conclusion En algunas zonas de Papua Nueva Guinea, les tratamientos A+L y DHA+PQ resultan muy rentables en el tratamiento pediatrico contra la malaria por R falciparum y R vivax, respectivamente. Es preciso que se investigue mas en profundidad para determinar si estos resultados tambien son validos para otras regiones de Asia y Oceania que presenten una epidemiologia de malaria similar., Introduction Recent estimates show that Plasmodium falciparum causes 225 to 500 million cases of malaria and nearly one million malaria-related deaths worldwide each year. (1-3) Of these deaths, 96% take [...]

A research conducted to find the pharmacokinetics, efficiency and safety of rectally administered artesunate, artemisinin, dihydroartemisinin and artemether for the treatmet of malaria is presented.