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Background: Antibodies to variant surface antigens (VSAs) such as Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) may vary with malaria severity. The influence of ABO blood group on antibody development is not understood., Methods: Immunoglobulin G antibodies to VSAs in Papua New Guinean children with severe (n = 41) or uncomplicated (n = 30) malaria were measured by flow cytometry using homologous P falciparum isolates. Isolates were incubated with ABO-matched homologous and heterologous acute and convalescent plasma. RNA was used to assess var gene transcription., Results: Antibodies to homologous, but not heterologous, isolates were boosted in convalescence. The relationship between antibody and severity varied by blood group. Antibodies to VSAs were similar in severe and uncomplicated malaria at presentation, higher in severe than uncomplicated malaria in convalescence, and higher in children with blood group O than other children. Six var gene transcripts best distinguished severe from uncomplicated malaria, including UpsA and 2 CIDRα1 domains., Conclusions: ABO blood group may influence antibody acquisition to VSAs and susceptibility to severe malaria. Children in Papua New Guinea showed little evidence of acquisition of cross-reactive antibodies following malaria. Var gene transcripts in Papua New Guinean children with severe malaria were similar to those reported from Africa., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: We aimed to assess safety, tolerability, and Plasmodium vivax relapse rates of ultra-short course (3.5 days) high-dose (1 mg/kg twice daily) primaquine (PQ) for uncomplicated malaria because of any Plasmodium species in children randomized to early- or delayed treatment., Methods: Children aged 0.5 to 12 years with normal glucose-6-phosphate-dehydrogenase (G6PD) activity were enrolled. After artemether-lumefantrine (AL) treatment, children were randomized to receive PQ immediately after (early) or 21 days later (delayed). Primary and secondary endpoints were the appearance of any P. vivax parasitemia within 42 or 84 days, respectively. A non-inferiority margin of 15% was applied (ACTRN12620000855921)., Results: A total of 219 children were recruited, 70% with Plasmodium falciparum and 24% with P. vivax. Abdominal pain (3.7% vs 20.9%, P <0.0001) and vomiting (0.9% vs 9.1%, P = 0.01) were more common in the early group. At day 42, P. vivax parasitemia was observed in 14 (13.2%) and 8 (7.8%) in the early and delayed groups, respectively (difference, -5.4%; 95% confidence interval -13.7 to 2.8). At day 84, P. vivax parasitemia was observed in 36 (34.3%) and 17 (17.5%; difference -16.8%, -28.6 to -6.1)., Conclusion: Ultra-short high-dose PQ was safe and tolerated without severe adverse events. Early treatment was non-inferior to delayed treatment in preventing P. vivax infection at day 42., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2023. Published by Elsevier Ltd.)

Kalimantan is a part of Indonesia, which occupies the southern three-quarters of the island of Borneo, sharing a border with the Malaysian states of Sabah and Sarawak. Although most areas of Kalimantan have low and stable transmission of Plasmodium falciparum and Plasmodium vivax, there are relatively high case numbers in the province of East Kalimantan. Two aspects of malaria endemicity in Kalimantan differentiate it from the rest of Indonesia, namely recent deforestation and potential exposure to the zoonotic malaria caused by Plasmodium knowlesi that occurs in relatively large numbers in adjacent Malaysian Borneo. In the present review, the history of malaria and its current epidemiology in Kalimantan are examined, including control and eradication efforts over the past two centuries, mosquito vector prevalence, anti-malarial use and parasite resistance, and the available data from case reports of knowlesi malaria and the presence of conditions which would support transmission of this zoonotic infection., (© 2022. The Author(s).)

The simian parasite Plasmodium knowlesi is the predominant species causing human malaria infection, including hospitalisations for severe disease and death, in Malaysian Borneo. By contrast, there have been only a few case reports of knowlesi malaria from Indonesian Borneo. This situation seems paradoxical since both regions share the same natural macaque hosts and Anopheles mosquito vectors, and therefore have a similar epidemiologically estimated risk of infection. To determine whether there is a true cross-border disparity in P. knowlesi prevalence, we conducted a community-based malaria screening study using PCR in Kapuas Hulu District, West Kalimantan. Blood samples were taken between April and September 2019 from 1000 people aged 6 months to 85 years attending health care facilities at 27 study sites within or close to jungle areas. There were 16 Plasmodium positive samples by PCR, five human malarias (two Plasmodium vivax, two Plasmodium ovale and one Plasmodium malariae) and 11 in which no species could be definitively identified. These data suggest that, if present, simian malarias including P. knowlesi are rare in the Kapuas Hulu District of West Kalimantan, Indonesian Borneo compared to geographically adjacent areas of Malaysian Borneo. The reason for this discrepancy, if confirmed in other epidemiologically similar regions of Indonesian Borneo, warrants further studies targeting possible cross-border differences in human activities in forested areas, together with more detailed surveys to complement the limited data relating to monkey hosts and Anopheles mosquito vectors in Indonesian Borneo., (© 2022. The Author(s).)

Since there are inconsistent data relating to the effect of haemoglobinopathies on disposition of artemisinin antimalarial combination therapy, and none in sickle cell trait (SCT) or sickle cell disease (SCD), the aim of this study was to characterize the pharmacokinetic properties of artemether-lumefantrine (ARM-LUM) in children with SCD/SCT. Thirty-eight Tanzanian children aged 5-10 years with normal (haemoglobin AA; n = 12), heterozygous (haemoglobin AS; n = 14) or homozygous (haemoglobin SS; n = 12) sickle genotypes received six ARM-LUM doses (1.7 mg/kg plus 10 mg/kg, respectively) over 3 days. Sparse venous and mixed-capillary dried blood spot (DBS) samples were taken over 42 days. Plasma and DBS ARM and LUM, and their active metabolites dihydroartemisinin (DHA) and desbutyl-lumefantrine (DBL), were assayed using validated liquid chromatography-mass spectrometry. Multi-compartmental pharmacokinetic models were developed using a population approach. Plasma but not DBS concentrations of ARM/DHA were assessable. The majority (85%) of the 15 measurable values were within 95% prediction intervals from a published population pharmacokinetic ARM/DHA model in Papua New Guinean children of similar age without SCD/SCT who had uncomplicated malaria, and there was no clear sickle genotype clustering. Plasma (n = 38) and corrected DBS (n = 222) LUM concentrations were analysed using a two-compartment model. The median [inter-quartile range] LUM AUC 0-∞ was 607,296 [426,480-860,773] μg.h/L, within the range in published studies involving different populations, age-groups and malaria status. DBS and plasma DBL concentrations correlated poorly and were not modelled. These data support use of the conventional ARM-LUM treatment regimen for uncomplicated malaria in children with SCT/SCD., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: The aim of this study was to assess the pharmacokinetic properties of artemether, lumefantrine and their active metabolites in Plasmodium knowlesi malaria., Methods: Malaysian adults presenting with uncomplicated P. knowlesi infections received six doses of artemether (1.7 mg/kg) plus lumefantrine (10 mg/kg) over 3 days. Venous blood and dried blood spot (DBS) samples were taken at predetermined time-points over 28 days. Plasma and DBS artemether, dihydroartemisinin, lumefantrine and desbutyl-lumefantrine were measured using liquid chromatography-mass spectrometry. Multi-compartmental population pharmacokinetic models were developed using plasma with or without DBS drug concentrations., Results: Forty-one participants (mean age 45 years, 66% males) were recruited. Artemether-lumefantrine treatment was well tolerated and parasite clearance was prompt. Plasma and DBS lumefantrine concentrations were in close agreement and were used together in pharmacokinetic modelling, but only plasma concentrations of the other analytes were used because of poor correlation with DBS levels. The areas under the concentration-time curve (AUC 0-∞ ) for artemether, dihydroartemisinin and lumefantrine (medians 1626, 1881 and 625 098 μg.h/L, respectively) were similar to those reported in previous pharmacokinetic studies in adults and children. There was evidence of auto-induction of artemether metabolism (mean increase in clearance relative to bioavailability 25.2% for each subsequent dose). The lumefantrine terminal elimination half-life (median 9.5 days) was longer than reported in healthy volunteers and adults with falciparum malaria., Conclusion: The disposition of artemether, dihydroartemisinin and lumefantrine in knowlesi malaria largely parallels that in other human malarias. DBS lumefantrine concentrations can be used in pharmacokinetic studies but DBS technology is currently unreliable for the other analytes., (© 2021 British Pharmacological Society.)

The component drugs in the widely used antimalarial artemisinin combination therapy artemether-lumefantrine are lipophilic, with the possibility that recommended fixed doses in adults may lead to subtherapeutic concentrations and consequent treatment failure in overweight/obese individuals with malaria. The aim of this study was to investigate the pharmacokinetic properties of artemether, lumefantrine and their active metabolites dihydroartemisinin and desbutyl-lumefantrine in 16 normal-weight, overweight and obese healthy male volunteers [body mass index (BMI) categories ≤25 kg/m², >25-≤30 kg/m² and >30 kg/m², respectively; absolute range 19.3-37.2 kg/m²]. Participants received the conventional six doses of artemether-lumefantrine over 3 days, each dose comprising 80 mg artemether plus 480 mg lumefantrine administered with 6.7 g fat, and blood samples were collected at pre-specified time-points over 14 days. Plasma drug/metabolite concentrations were measured using liquid chromatography-mass spectrometry and included in multi-compartmental population pharmacokinetic models. There was a non-significant trend to a lower area under the plasma concentration-time curve with a higher body weight or BMI for dihydroartemisinin and especially artemether which was attenuated when normalized for mg/kg dose, but this relationship was not evident in the case of the more lipophilic lumefantrine and its metabolite desbutyl-lumefantrine. Simulated Day 7 plasma lumefantrine concentrations were >200 µg/L (the threshold at which Plasmodium falciparum recrudescences are minimized) in all participants. These results indicate that there is no need for artemether-lumefantrine dose modification in overweight and obese patients with malaria., (Copyright © 2021 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Plasmodium knowlesi, a simian malaria parasite responsible for all recent indigenous cases of malaria in Malaysia, infects humans throughout Southeast Asia. There are two genetically distinct subpopulations of Plasmodium knowlesi in Malaysian Borneo, one associated with long-tailed macaques (termed cluster 1) and the other with pig-tailed macaques (cluster 2). A prospective study was conducted to determine whether there were any between-subpopulation differences in clinical and laboratory features, as well as in epidemiological characteristics. Over 2 years, 420 adults admitted to Kapit Hospital, Malaysian Borneo with knowlesi malaria were studied. Infections with each subpopulation resulted in mostly uncomplicated malaria. Severe disease was observed in 35/298 (11.7%) of single cluster 1 and 8/115 (7.0%) of single cluster 2 infections (p = 0.208). There was no clinically significant difference in outcome between the two subpopulations. Cluster 1 infections were more likely to be associated with peri-domestic activities while cluster 2 were associated with interior forest activities consistent with the preferred habitats of the respective macaque hosts. Infections with both P. knowlesi subpopulations cause a wide spectrum of disease including potentially life-threatening complications, with no implications for differential patient management., (© 2021. The Author(s).)

We aimed to identify clinical and laboratory predictors of mortality in children from a malaria-endemic area of Papua New Guinea hospitalized for severe illness. Children aged 0.5-10 years presenting with any WHO-defined feature of severe malarial illness were eligible for recruitment. Each child was assessed with a detailed clinical examination, blood film microscopy, malaria rapid diagnostic testing (RDT), a full blood examination, and blood glucose and lactate concentrations. Clinical care was coordinated by local medical staff in accordance with national guidelines. Daily study assessments were conducted until death or discharge. Other biochemical tests and malaria polymerase chain reaction (PCR) tests were performed subsequently. Logistic regression identified independent predictors of death. Of 787 evaluable children with severe illness, 336 had confirmed severe malaria (microscopy and PCR positive) and 58 (6.6%) died during hospitalization. The independent predictors of mortality were hyperlactatemia (adjusted odds ratio [95% CI]: 2.85 [1.24-6.41], P = 0.01), malnutrition (2.92 [1.36-6.23], P = 0.005), renal impairment (3.85 [1.53-9.24], P = 0.002), plasma albumin (0.93 [0.88-0.98] for a 1 g/L increase, P = 0.004), and Blantyre coma score (BCS) ≤ 2 (10.3 [4.77-23.0] versus a normal BCS, P < 0.0001). Confirmed severe malaria (0.11 [0.03-0.30] versus non-malarial severe illness, P < 0.0001) was independently associated with lower mortality. Although established risk factors were evident, malaria was inversely associated with mortality. This highlights the importance of accurate diagnosis through blood film microscopy, RDTs, and, if available, PCR to both guide management and provide valid epidemiological data.

Introduction: Malaria in pregnancy continues to be a significant public health burden globally, with over 100 million women at risk each year. Sulfadoxine-pyrimethamine (SP) is the only antimalarial recommended for intermittent preventive therapy in pregnancy (IPTp) but increasing parasite resistance threatens its viability. There are few other available antimalarial therapies that currently have sufficient evidence of tolerability, safety, and efficacy to replace SP., Areas Covered: Novel antimalarial combinations are under investigation for potential use as chemoprophylaxis and in IPTp regimens. The present review summarizes currently available therapies, emerging candidate combination therapies, and the potential challenges to integrating these into mainstream policy., Expert Opinion: Alternative drugs or combination therapies to SP for IPTp are desperately required. Dihydroartemisinin-piperaquine and azithromycin-based combinations are showing great promise as potential candidates for IPTp but pharmacokinetic data suggest that dose modification may be required to ensure adequate prophylactic efficacy. If a suitable candidate regimen is not identified in the near future, the success of chemopreventive strategies such as IPTp may be in jeopardy.

Plasmodium knowlesi is a simian malaria of primarily the macaque species of South East Asia. While it was known that human infections could be induced during the years of malariotherapy, naturally occurring P. knowlesi human infections were thought to be rare. However, in 2004, knowlesi infections became recognized as an important infection amongst human populations in Sarawak, Malaysian Borneo. Since then, it has become recognized as a disease affecting people living and visiting endemic areas across South East Asia. Over the last 12 years, clinical studies have improved our understanding of this potentially fatal disease. In this review article the current literature is reviewed to give a comprehensive description of the disease and treatment.

Optimal dosing of sulfadoxine-pyrimethamine (SP) as intermittent preventive treatment in pregnancy remains to be established, particularly when coadministered with azithromycin (AZI). To further characterize SP pharmacokinetics in pregnancy, plasma concentration-time data from 45 nonpregnant and 45 pregnant women treated with SP-AZI ( n = 15 in each group) and SP-chloroquine ( n = 30 in each group) were analyzed. Population nonlinear mixed-effect pharmacokinetic models were developed for pyrimethamine (PYR), sulfadoxine (SDOX), and N -acetylsulfadoxine (the SDOX metabolite NASDOX), and potential covariates were included. Pregnancy increased the relative clearance (CL/F) of PYR, SDOX, and NASDOX by 48, 29, and 70%, respectively, as well as the relative volumes of distribution (V/F) of PYR (46 and 99%) and NASDOX (46%). Coadministration of AZI resulted in a greater increase in PYR CL/F (80%) and also increased NASDOX V/F by 76%. Apparent differences between these results and those of published studies of SP disposition may reflect key differences in study design, including the use of an early postpartum follow-up study rather than a nonpregnant comparator group. Simulations based on the final population model demonstrated that, compared to conventional single-dose SP in nonpregnant women, two such doses given 24 h apart should ensure that pregnant women have similar drug exposure, while three daily SP doses may be required if SP is given with AZI. The results of past and ongoing trials using recommended adult SP doses with or without AZI in pregnant women may need to be interpreted in light of these findings and consideration given to using increased doses in future trials., (Copyright © 2017 American Society for Microbiology.)