Evaluation of a Bayesian hierarchical pharmacokinetic-pharmacodynamic model for predicting parasitological outcomes in Phase 2 studies of new antimalarial drugs.

The rise of multidrug-resistant malaria requires accelerated development of novel antimalarial drugs. Pharmacokinetic-pharmacodynamic (PK-PD) models relate blood antimalarial drug concentrations with the parasite-time profile to inform dosing regimens. We performed a simulation study to assess the utility of a Bayesian hierarchical mechanistic PK-PD model for predicting parasite-time profiles for a Phase 2 study of a new antimalarial drug, cipargamin. We simulated cipargamin concentration- and malaria parasite-profiles based on a Phase 2 study of eight volunteers who received cipargamin 7 days after inoculation with malaria parasites. The cipargamin profiles were generated from a two-compartment PK model and parasite profiles from a previously published biologically informed PD model. One thousand PK-PD data sets of eight patients were simulated, following the sampling intervals of the Phase 2 study. The mechanistic PK-PD model was incorporated in a Bayesian hierarchical framework, and the parameters were estimated. Population PK model parameters describing absorption, distribution, and clearance were estimated with minimal bias (mean relative bias ranged from 1.7% to 8.4%). The PD model was fitted to the parasitaemia profiles in each simulated data set using the estimated PK parameters. Posterior predictive checks demonstrate that our PK-PD model adequately captures the simulated PD profiles. The bias of the estimated population average PD parameters was low-moderate in magnitude. This simulation study demonstrates the viability of our PK-PD model to predict parasitological outcomes in Phase 2 volunteer infection studies. This work will inform the dose-effect relationship of cipargamin, guiding decisions on dosing regimens to be evaluated in Phase 3 trials.

The Asymptomatic Proportion of SARS-CoV-2 Omicron Variant Infections in Households: A Systematic Review.

Understanding the clinical spectrum of SARS-CoV-2 infection, including the asymptomatic fraction, is important as asymptomatic individuals are still able to infect other individuals and contribute to ongoing transmission. The WHO Unity Household transmission investigation (HHTI) protocol provides a platform for the prospective and systematic collection of high-quality clinical, epidemiological, serological and virological data from SARS-CoV-2 confirmed cases and their household contacts. These data can be used to understand key severity and transmissibility parameters-including the asymptomatic proportion-in relation to local epidemic context and help inform public health response. We aimed to estimate the asymptomatic proportion of SARS-CoV-2 Omicron variant infections in Unity-aligned HHTIs. We conducted a systematic review and meta-analysis in alignment with the PRISMA 2020 guidelines and registered our systematic review on PROSPERO (CRD42022378648). We searched EMBASE, Web of Science, MEDLINE and bioRxiv and medRxiv from 1 November 2021 to 22 August 2023. We identified 8368 records, of which 98 underwent full text review. We identified only three studies for data extraction, with substantial variation in study design and corresponding estimates of the asymptomatic proportion. As a result, we did not generate a pooled estimate or I2 metric. The limited number of quality studies that we identified highlights the need for improved preparedness and response capabilities to facilitate robust HHTI implementation, analysis and reporting, to better inform national, regional and global risk assessments and policymaking.

Characterising HIV-1 transmission in Victoria, Australia: a molecular epidemiological study.

Background: In Australia the incidence of HIV has declined steadily, yet sustained reduction of HIV transmission in this setting requires improved public health responses. As enhanced public health responses and prioritisation of resources may be guided by molecular epidemiological data, here we aimed to assess the applicability of these approaches in Victoria, Australia. Methods: A comprehensive collection of HIV-1 pol sequences from individuals diagnosed with HIV in Victoria, Australia, between January 1st 2000 and December 31st 2020 were deidentified and used as the basis of our assessment. These sequences were subtyped and surveillance drug resistance mutations (SDRMs) identified, before definition of transmission groups was performed using HIV-TRACE (0.4.4). Phylodynamic methods were applied using BEAST (2.6.6), assessing effective reproductive numbers for large groups, and additional demographic data were integrated to provide a high resolution view of HIV transmission in Victoria on a decadal time scale. Findings: Based on standard settings for HIV-TRACE, 70% (2438/3507) of analysed HIV-1 pol sequences were readily assigned to a transmission group. Individuals in transmission groups were more commonly males (aOR 1.50), those born in Australia (aOR 2.13), those with probable place of acquisition as Victoria (aOR 6.73), and/or those reporting injectable drug use (aOR 2.13). SDRMs were identified in 375 patients (10.7%), with sustained transmission of these limited to a subset of smaller groups. Informative patterns of epidemic growth, stabilisation, and decline were observed; many transmission groups showed effective reproductive numbers (R e ) values reaching greater than 4.0, representing considerable epidemic growth, while others maintained low R e values. Interpretation: This study provides a high resolution view of HIV transmission in Victoria, Australia, and highlights the potential of molecular epidemiology to guide and enhance public health responses in this setting. This informs ongoing discussions with community groups on the acceptability and place of molecular epidemiological approaches in Australia. Funding: National Health and Medical Research Council, Australian Research Council.

Opportunities to strengthen respiratory virus surveillance systems in Australia: lessons learned from the COVID-19 response.

Abstract: Disease surveillance data was critical in supporting public health decisions throughout the coronavirus disease 2019 (COVID-19) pandemic. At the same time, the unprecedented circumstances of the pandemic revealed many shortcomings of surveillance systems for viral respiratory pathogens. Strengthening of surveillance systems was identified as a priority for the recently established Australian Centre for Disease Control, which represents a critical opportunity to review pre-pandemic and pandemic surveillance practices, and to decide on future priorities, during both pandemic and inter-pandemic periods. On 20 October 2022, we ran a workshop with experts from the academic and government sectors who had contributed to the COVID-19 response in Australia on 'The role of surveillance in epidemic response', at the University of New South Wales, Sydney, Australia. Following the workshop, we developed five recommendations to strengthen respiratory virus surveillance systems in Australia, which we present here. Our recommendations are not intended to be exhaustive. We instead chose to focus on data types that are highly valuable yet typically overlooked by surveillance planners. Three of the recommendations focus on data collection activities that support the monitoring and prediction of disease impact and the effectiveness of interventions (what to measure) and two focus on surveillance methods and capabilities (how to measure). Implementation of our recommendations would enable more robust, timely, and impactful epidemic analysis.

Immune imprinting in early life shapes cross-reactivity to influenza B virus haemagglutinin.

Influenza exposures early in life are believed to shape future susceptibility to influenza infections by imprinting immunological biases that affect cross-reactivity to future influenza viruses. However, direct serological evidence linked to susceptibility is limited. Here we analysed haemagglutination-inhibition titres in 1,451 cross-sectional samples collected between 1992 and 2020, from individuals born between 1917 and 2008, against influenza B virus (IBV) isolates from 1940 to 2021. We included testing of 'future' isolates that circulated after sample collection. We show that immunological biases are conferred by early life IBV infection and result in lineage-specific cross-reactivity of a birth cohort towards future IBV isolates. This translates into differential estimates of susceptibility between birth cohorts towards the B/Yamagata and B/Victoria lineages, predicting lineage-specific birth-cohort distributions of observed medically attended IBV infections. Our data suggest that immunological measurements of imprinting could be important in modelling and predicting virus epidemiology.

Intermittent preventive treatment with sulphadoxine-pyrimethamine but not dihydroartemisinin-piperaquine modulates the relationship between inflammatory markers and adverse pregnancy outcomes in Malawi.

Women in malaria-endemic areas receive sulphadoxine-pyrimethamine (SP) as Intermittent Preventive Treatment in Pregnancy (IPTp) to reduce malaria. While dihydroartemisinin-piperaquine (DP) has superior antimalarial properties as IPTp, SP is associated with superior fetal growth. As maternal inflammation influences fetal growth, we investigated whether SP alters the relationship between inflammation and birth outcomes. We measured C-reactive protein (CRP) and alpha-1-acid glycoprotein (AGP) at enrollment (16-28 gestation weeks (gw)), visit 3 (24-36 gw) and delivery in 1319 Malawian women randomized to receive monthly SP, DP, or DP and single-dose azithromycin (AZ) in the IMPROVE trial (NCT03208179). Logistic regression was used to assess the relationship between adverse outcomes, inflammation, and treatment arm. Elevated AGP at enrollment was associated with adverse birth outcome (aRR 1.40, 95% CI: 1.15, 1.70), with similar associations observed across treatment arms, exceptions being that elevated AGP was associated with low maternal weight gain in SP recipients (aRR 1.94, 95% CI: 1.36, 2.76) and with small for gestational age in DP+AZ recepients (aRR 1.49, 95% CI 1.02, 2.17). At visit 3 there were few associations between inflammation andoutcomes. At delivery, women with elevated AGP receiving either DP or DP+AZ had an increased risk of adverse birth outcomes (aRR 1.60, 95% CI: 1.28, 2.00), including low birth weight, pre-term birth and foetal loss, this was not seen in women receiving SP (aRR 0.82, 95% CI: 0.54, 1.26). The risk of an association between elevated AGP and adverse birth outcome was higher in those receiving DP or DP+AZ compared to those receiving SP (aRR 1.95, 95% CI: 1.21, 3.13). No clear associations between CRP and adverse outcomes were observed. AGP identified women at risk of adverse pregnancy outcomes. SP modifies the relationship between inflammatory biomarkers and adverse outcomes. Our findings provide insights into potential mechanisms by which SP may improve pregnancy outcomes.

Erratum to "Learnings from the Australian first few X household transmission project for COVID-19" [The Lancet Regional Health - Western Pacific 28 (2022) 100573].

[This corrects the article DOI: 10.1016/j.lanwpc.2022.100573.].

Combination of Antistaphylococcal ß-Lactam With Standard Therapy Compared to Standard Therapy Alone for the Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia: A Post Hoc Analysis of the CAMERA2 Trial Using a Desirability of Outcome Ranking Approach.

Background: Desirability of outcome ranking (DOOR) is an emerging approach to clinical trial outcome measurement using an ordinal scale to incorporate efficacy and safety endpoints. Methods: We applied a previously validated DOOR endpoint to a cohort of CAMERA2 trial participants with methicillin-resistant Staphylococcus aureus bacteremia (MRSAB). Participants were randomly assigned to standard therapy, or to standard therapy plus an antistaphylococcal ß-lactam (combination therapy). Each participant was assigned a DOOR category, within which they were further ranked according to their hospital length of stay (LOS) and duration of intravenous antibiotic treatment. We calculated the probability and the generalized odds ratio of participants receiving combination therapy having worse outcomes than those receiving standard therapy. Results: Participants assigned combination therapy had a 54.5% (95% confidence interval [CI], 48.9%-60.1%; P = .11) probability and a 1.2-fold odds (95% CI, .95-1.50; P = .12) of having a worse outcome than participants on standard therapy. When further ranked according to LOS and duration of antibiotic treatment, participants in the combination group had a 55.6% (95% CI, 49.5%-61.7%) and 55.3% (95% CI, 49.2%-61.4%) probability of having a worse outcome than participants in the standard treatment group, respectively. Conclusions: When considering both efficacy and safety, treatment of MRSAB with a combination of standard therapy and a ß-lactam likely results in a worse clinical outcome than standard therapy. However, a small benefit of combination therapy cannot be excluded. Most likely the toxicity of combination therapy outweighed any benefit from faster clearance of bacteremia.

Overlapping Streptococcus pyogenes and Streptococcus dysgalactiae subspecies equisimilis household transmission and mobile genetic element exchange.

Streptococcus dysgalactiae subspecies equisimilis (SDSE) and Streptococcus pyogenes share skin and throat niches with extensive genomic homology and horizontal gene transfer (HGT) possibly underlying shared disease phenotypes. It is unknown if cross-species transmission interaction occurs. Here, we conduct a genomic analysis of a longitudinal household survey in remote Australian First Nations communities for patterns of cross-species transmission interaction and HGT. Collected from 4547 person-consultations, we analyse 294 SDSE and 315 S. pyogenes genomes. We find SDSE and S. pyogenes transmission intersects extensively among households and show that patterns of co-occurrence and transmission links are consistent with independent transmission without inter-species interference. We identify at least one of three near-identical cross-species mobile genetic elements (MGEs) carrying antimicrobial resistance or streptodornase virulence genes in 55 (19%) SDSE and 23 (7%) S. pyogenes isolates. These findings demonstrate co-circulation of both pathogens and HGT in communities with a high burden of streptococcal disease, supporting a need to integrate SDSE and S. pyogenes surveillance and control efforts.

Burden of antimicrobial prescribing in primary care attributable to sore throat: a retrospective cohort study of patient record data.

BACKGROUND: Reducing antibiotic use in Australia, and the subsequent impact on antimicrobial resistance, requires multiple, sustained approaches with appropriate resources and support. Additional strategies to reduce antibiotic prescribing include effective vaccines, against pathogens such as Streptococcus pyogenes, the most common bacterial cause of sore throat. As part of efforts towards assessing the benefits of introducing new strategies to reduce antimicrobial prescribing, we aimed to determine the burden of antimicrobial prescribing for sore throat in general practice. METHODS: General practice activity data from 2013 - 2017 derived from the first 8 practices participating in the 'Primary Care Audit, Teaching and Research Open Network' (Patron) program were analysed according to reason for visit (upper respiratory tract infection, URTI, or sore throat) and antibiotic prescription. The main outcome measures were percentage of sore throat or URTI presentations with antibiotic prescription by age. RESULTS: A total of 722,339 visits to general practice were made by 65,449 patients; 5.7% of visits were for URTI with 0.8% meeting the more specific criteria for sore throat. 66.1% of sore throat visits and 36.2% of URTI visits resulted in antibiotic prescription. Penicillin, the recommended antibiotic for sore throat when indicated, was the antibiotic of choice in only 52.9% of sore throat cases prescribed antibiotics. Broader spectrum antibiotics were prescribed more frequently in older age groups. CONCLUSIONS: Frequency of antibiotic prescribing for sore throat is high and broad, despite Australian Therapeutic guideline recommendations. Multiple, sustained interventions to reduce prescribing, including availability of effective S. pyogenes vaccines that could reduce the incidence of streptococcal pharyngitis, could obviate the need to prescribe antibiotics and support ongoing efforts to promote antimicrobial stewardship.

Mosquitoes provide a transmission route between possums and humans for Buruli ulcer in southeastern Australia.

Buruli ulcer, a chronic subcutaneous infection caused by Mycobacterium ulcerans, is increasing in prevalence in southeastern Australia. Possums are a local wildlife reservoir for M. ulcerans and, although mosquitoes have been implicated in transmission, it remains unclear how humans acquire infection. We conducted extensive field survey analyses of M. ulcerans prevalence among mosquitoes in the Mornington Peninsula region of southeastern Australia. PCR screening of trapped mosquitoes revealed a significant association between M. ulcerans and Aedes notoscriptus. Spatial scanning statistics revealed overlap between clusters of M. ulcerans-positive Ae. notoscriptus, M. ulcerans-positive possum excreta and Buruli ulcer cases, and metabarcoding analyses showed individual mosquitoes had fed on humans and possums. Bacterial genomic analysis confirmed shared single-nucleotide-polymorphism profiles for M. ulcerans detected in mosquitoes, possum excreta and humans. These findings indicate Ae. notoscriptus probably transmit M. ulcerans in southeastern Australia and highlight mosquito control as a Buruli ulcer prevention measure.

A multi-criteria framework for disease surveillance site selection: case study for Plasmodium knowlesi malaria in Indonesia.

Disease surveillance aims to collect data at different times or locations, to assist public health authorities to respond appropriately. Surveillance of the simian malaria parasite, Plasmodium knowlesi, is sparse in some endemic areas and the spatial extent of transmission is uncertain. Zoonotic transmission of Plasmodium knowlesi has been demonstrated throughout Southeast Asia and represents a major hurdle to regional malaria elimination efforts. Given an arbitrary spatial prediction of relative disease risk, we develop a flexible framework for surveillance site selection, drawing on principles from multi-criteria decision-making. To demonstrate the utility of our framework, we apply it to the case study of Plasmodium knowlesi malaria surveillance site selection in western Indonesia. We demonstrate how statistical predictions of relative disease risk can be quantitatively incorporated into public health decision-making, with specific application to active human surveillance of zoonotic malaria. This approach can be used in other contexts to extend the utility of modelling outputs.

Updating estimates of Plasmodium knowlesi malaria risk in response to changing land use patterns across Southeast Asia.

BACKGROUND: Plasmodium knowlesi is a zoonotic parasite that causes malaria in humans. The pathogen has a natural host reservoir in certain macaque species and is transmitted to humans via mosquitoes of the Anopheles Leucosphyrus Group. The risk of human P. knowlesi infection varies across Southeast Asia and is dependent upon environmental factors. Understanding this geographic variation in risk is important both for enabling appropriate diagnosis and treatment of the disease and for improving the planning and evaluation of malaria elimination. However, the data available on P. knowlesi occurrence are biased towards regions with greater surveillance and sampling effort. Predicting the spatial variation in risk of P. knowlesi malaria requires methods that can both incorporate environmental risk factors and account for spatial bias in detection. METHODS & RESULTS: We extend and apply an environmental niche modelling framework as implemented by a previous mapping study of P. knowlesi transmission risk which included data up to 2015. We reviewed the literature from October 2015 through to March 2020 and identified 264 new records of P. knowlesi, with a total of 524 occurrences included in the current study following consolidation with the 2015 study. The modelling framework used in the 2015 study was extended, with changes including the addition of new covariates to capture the effect of deforestation and urbanisation on P. knowlesi transmission. DISCUSSION: Our map of P. knowlesi relative transmission suitability estimates that the risk posed by the pathogen is highest in Malaysia and Indonesia, with localised areas of high risk also predicted in the Greater Mekong Subregion, The Philippines and Northeast India. These results highlight areas of priority for P. knowlesi surveillance and prospective sampling to address the challenge the disease poses to malaria elimination planning.

Tafenoquine following G6PD screening versus primaquine for the treatment of vivax malaria in Brazil: A cost-effectiveness analysis using a transmission model.

BACKGROUND: Malaria transmission modelling has demonstrated the potential impact of semiquantitative glucose-6-phosphate dehydrogenase (G6PD) testing and treatment with single-dose tafenoquine for Plasmodium vivax radical cure but has not investigated the associated costs. This study evaluated the cost-effectiveness of P. vivax treatment with tafenoquine after G6PD testing using a transmission model. METHODS AND FINDINGS: We explored the cost-effectiveness of using tafenoquine after G6PD screening as compared to usual practice (7-day low-dose primaquine (0.5 mg/kg/day) without G6PD screening) in Brazil using a 10-year time horizon with 5% discounting considering 4 scenarios: (1) tafenoquine for adults only assuming 66.7% primaquine treatment adherence; (2) tafenoquine for adults and children aged >2 years assuming 66.7% primaquine adherence; (3) tafenoquine for adults only assuming 90% primaquine adherence; and (4) tafenoquine for adults only assuming 30% primaquine adherence. The incremental cost-effectiveness ratios (ICERs) were estimated by dividing the incremental costs by the disability-adjusted life years (DALYs) averted. These were compared to a willingness to pay (WTP) threshold of US$7,800 for Brazil, and one-way and probabilistic sensitivity analyses were performed. All 4 scenarios were cost-effective in the base case analysis using this WTP threshold with ICERs ranging from US$154 to US$1,836. One-way sensitivity analyses showed that the results were most sensitive to severity and mortality due to vivax malaria, the lifetime and number of semiquantitative G6PD analysers needed, cost per malaria episode and per G6PD test strips, and life expectancy. All scenarios had a 100% likelihood of being cost-effective at the WTP threshold. The main limitations of this study are due to parameter uncertainty around our cost estimates for low transmission settings, the costs of G6PD screening, and the severity of vivax malaria. CONCLUSIONS: In our modelling study that incorporated impact on transmission, tafenoquine prescribed after a semiquantitative G6PD testing was highly likely to be cost-effective in Brazil. These results demonstrate the potential health and economic importance of ensuring safe and effective radical cure.

A blueprint for a multi-disease, multi-domain Bayesian adaptive platform trial incorporating adult and paediatric subgroups: the Staphylococcus aureus Network Adaptive Platform trial.

The Staphylococcus aureus Network Adaptive Platform (SNAP) trial is a multifactorial Bayesian adaptive platform trial that aims to improve the way that S. aureus bloodstream infection, a globally common and severe infectious disease, is treated. In a world first, the SNAP trial will simultaneously investigate the effects of multiple intervention modalities within multiple groups of participants with different forms of S. aureus bloodstream infection. Here, we formalise the trial structure, modelling approach, and decision rules that will be used for the SNAP trial. By summarising the statistical principles governing the design, our hope is that the SNAP trial will serve as an adaptable template that can be used to improve comparative effectiveness research efficiency in other disease areas.Trial registration NCT05137119 . Registered on 30 November 2021.

Transmissibility and severity of COVID-19 in a humanitarian setting: First few X investigation of cases and contacts in Juba, South Sudan, 2020.

BACKGROUND: The first few 'X' (FFX) studies provide evidence to guide public health decision-making and resource allocation. The adapted WHO Unity FFX protocol for COVID-19 was implemented to gain an understanding of the clinical, epidemiological, virological and household transmission dynamics of the first cases of COVID-19 infection detected in Juba, South Sudan. METHODS: Laboratory-confirmed COVID-19 cases were identified through the national surveillance system, and an initial visit was conducted with eligible cases to identify all close contacts. Consenting cases and close contacts were enrolled between June 2020 and December 2020. Demographic, clinical information and biological samples were taken at enrollment and 14-21 days post-enrollment for all participants. RESULTS: Twenty-nine primary cases and 82 contacts were included in the analyses. Most primary cases (n = 23/29, 79.3%) and contacts (n = 61/82, 74.4%) were male. Many primary cases (n = 18/29, 62.1%) and contacts (n = 51/82, 62.2%) were seropositive for SARS-CoV-2 at baseline. The secondary attack rate among susceptible contacts was 12.9% (4/31; 95% CI: 4.9%-29.7%). All secondary cases and most (72%) primary cases were asymptomatic. Reported symptoms included coughing (n = 6/29, 20.7%), fever or history of fever (n = 4/29, 13.8%), headache (n = 3/29, 10.3%) and shortness of breath (n = 3/29, 10.3%). Of 38 cases, two were hospitalised (5.3%) and one died (2.6%). CONCLUSIONS: These findings were used to develop the South Sudanese Ministry of Health surveillance and contract tracing protocols, informing local COVID-19 case definitions, follow-up protocols and data management systems. This investigation demonstrates that rapid FFX implementation is critical in understanding the emerging disease and informing response priorities.

Effect of high dose vitamin D3 on the HIV-1 reservoir: A pilot randomised controlled trial.

Introduction: Antiretroviral therapy for people living with HIV-1 must be taken lifelong due to the persistence of latent virus in long-lived and proliferating CD4+ T cells. Vitamin D3 is a steroidal gene transcription regulator which exerts diverse effects on immune and epithelial cells including reductions in CD4+ T cell proliferation and improvement in gut barrier integrity. We hypothesised that a high dose of vitamin D3 would reduce the size of the HIV-1 reservoir by reducing CD4+ T cell proliferation. Methods: We performed a randomised placebo-controlled trial evaluating the effect of 24 weeks of vitamin D3 (10,000 international units per day) on the HIV-1 reservoir and immunologic parameters in 30 adults on antiretroviral therapy; participants were followed for 12 weeks post-treatment. The primary endpoint was the effect on total HIV-1 DNA at week 24. Parameters were assessed using mixed-effects models. Results: We found no effect of vitamin D3 on the change in total HIV-1 DNA from week 0 to week 24 relative to placebo. There were also no changes in integrated HIV-1 DNA, 2-long-terminal repeat (2-LTR) circles or cell-associated HIV-1 RNA. Vitamin D3 induced a significant increase in the proportion of central memory CD4+ and CD8+ T cells, a reduction in the proportion of senescent CD8+ T cells and a reduction in the natural killer cell frequency at all time points including week 36, 12 weeks after the study drug cessation. At week 36, there was a significant reduction in total HIV-1 DNA relative to placebo and persistently elevated 25-hydroxyvitamin D levels. No significant safety issues were identified. Conclusions: Vitamin D3 administration had a significant impact on the T cell differentiation but overall effects on the HIV-1 reservoir were limited and a reduction in HIV-1 DNA was only seen following cessation of the study drug. Additional studies are required to determine whether the dose and duration of vitamin D3 can be optimised to promote a continued depletion of the HIV-1 reservoir over time. Trial registration: ClinicalTrials.gov NCT03426592.

Evidence Based Optimal Dosing of Intravenous Artesunate in Children with Severe Falciparum Malaria.

The majority of deaths from malaria are in young African children. Parenteral artesunate (ARS) is the first-line treatment for severe falciparum malaria. Since 2015, the World Health Organization has recommended individual doses of 3 mg/kg for children weighing < 20 kg. Recently, the US Food and Drug Administration (FDA) has challenged this recommendation, based on a simulated pediatric population, and argued for a lower dose in younger children (2.4 mg/kg). In this study, we performed population pharmacokinetic (PK) modeling of plasma concentration data from 80 children with severe falciparum malaria in the Democratic Republic of Congo who were given 2.4 mg/kg of ARS intravenously. Bayesian hierarchical modeling and a two-compartment parent drug-metabolite PK model for ARS were used to describe the population PKs of ARS and its main biologically active metabolite dihydroartemisinin. We then generated a virtual population representative of the target population in which the drug is used and simulated the total first-dose exposures. Our study shows that the majority of younger children given the lower 2.4 mg/kg dose of intravenous ARS do not reach the same drug exposures as older children above 20 kg. This finding supports withdrawal of the FDA's recent lower ARS dose recommendation as parenteral ARS is an extremely safe and well-tolerated drug and there is potential for harm from underdosing in this rapidly lethal infection.