Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus.

BACKGROUND: The appropriate antibiotic treatment for severe scrub typhus, a neglected but widespread reemerging zoonotic infection, is unclear. METHODS: In this multicenter, double-blind, randomized, controlled trial, we compared the efficacy of intravenous doxycycline, azithromycin, or a combination of both in treating severe scrub typhus. Patients who were 15 years of age or older with severe scrub typhus with at least one organ involvement were enrolled. The patients were assigned to receive a 7-day course of intravenous doxycycline, azithromycin, or both (combination therapy). The primary outcome was a composite of death from any cause at day 28, persistent complications at day 7, and persistent fever at day 5. RESULTS: Among 794 patients (median age, 48 years) who were included in the modified intention-to-treat analysis, complications included those that were respiratory (in 62%), hepatic (in 54%), cardiovascular (in 42%), renal (in 30%), and neurologic (in 20%). The use of combination therapy resulted in a lower incidence of the composite primary outcome than the use of doxycycline (33% and 47%, respectively), for a risk difference of -13.3 percentage points (95% confidence interval [CI], -21.6 to -5.1; P = 0.002). The incidence with combination therapy was also lower than that with azithromycin (48%), for a risk difference of -14.8 percentage points (95% CI, -23.1 to -6.5; P<0.001). No significant difference was seen between the azithromycin and doxycycline groups (risk difference, 1.5 percentage points; 95% CI, -7.0 to 10.0; P = 0.73). The results in the per-protocol analysis were similar to those in the primary analysis. Adverse events and 28-day mortality were similar in the three groups. CONCLUSIONS: Combination therapy with intravenous doxycycline and azithromycin was a better therapeutic option for the treatment of severe scrub typhus than monotherapy with either drug alone. (Funded by the India Alliance and Wellcome Trust; INTREST Clinical Trials Registry-India number, CTRI/2018/08/015159.).

The heterogeneity of symptom reporting across study sites: a secondary analysis of a randomised placebo-controlled multicentre antimalarial trial.

INTRODUCTION: Symptoms reported following the administration of investigational drugs play an important role in decisions for registration and treatment guidelines. However, symptoms are subjective, and interview methods to quantify them are difficult to standardise. We explored differences in symptom reporting across study sites of a multicentre antimalarial trial, with the aim of informing trial design and the interpretation of safety and tolerability data. METHODS: Data were derived from the IMPROV trial, a randomised, placebo-controlled double blinded trial of high dose primaquine to prevent Plasmodium vivax recurrence conducted in eight study sites in Afghanistan, Ethiopia, Indonesia and Vietnam. At each follow up visit a 13-point symptom questionnaire was completed. The number and percentage of patients with clinically relevant symptoms following the administration of primaquine or placebo, were reported by study site including vomiting, diarrhoea, anorexia, nausea, abdominal pain and dizziness. Multivariable logistic regression was used to estimate the confounder-adjusted site-specific proportion of each symptom. RESULTS: A total of 2,336 patients were included. The greatest variation between sites in the proportion of patients reporting symptoms was for anorexia between day 0 and day 13: 97.3% (361/371) of patients in Arba Minch, Ethiopia, reported the symptom compared with 4.7% (5/106) of patients in Krong Pa, Vietnam. Differences attenuated slightly after adjusting for treatment arm, age, sex, day 0 parasite density and fever; with the adjusted proportion for anorexia ranging from 4.8% to 97.0%. Differences between sites were greater for symptoms graded as mild or moderate compared to those rated as severe. Differences in symptom reporting were greater between study sites than between treatment arms within the same study site. CONCLUSION: Despite standardised training, there was large variation in symptom reporting across trial sites. The reporting of severe symptoms was less skewed compared to mild and moderate symptoms, which are likely to be more subjective. Trialists should clearly distinguish between safety and tolerability outcomes. Differences between trial arms were much less variable across sites, suggesting that the relative difference in reported symptoms between intervention and control group is more relevant than absolute numbers and should be reported when possible. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01814683; March 20th, 2013.

Fever and health-seeking behaviour among migrants living along the Thai-Myanmar border: a mixed-methods study.

BACKGROUND: Fever is a common reason to seek healthcare in Southeast Asia, and the decline of malaria has complexified how is perceived, and what actions are taken towards it. We investigated the concept of fever and the determinants influencing health-seeking behaviours among migrants on the Thai-Myanmar border, where rapid economic development collides with precarious political and socio-economic conditions. METHODS: We implemented a mixed-methods study between August to December 2019. Phase I used a qualitative approach, with in-depth interviews and focus group discussions. Phase II used a quantitative approach with a close-ended questionnaire based on Phase I findings. A conditional inference tree (CIT) model first identified geographic and socio-demographic determinants, which were then tested using a logistic regression model. RESULTS: Fever corresponded to a high diversity of conceptions, symptoms and believed causes. Self-medication was the commonest behaviour at fever onset. If fever persisted, migrants primarily sought care in humanitarian cost-free clinics (45.5%, 92/202), followed by private clinics (43.1%, 87/202), health posts (36.1%, 73/202), public hospitals (33.7%, 68/202) and primary care units (30, 14.9%). The qualitative analysis identified distance and legal status as key barriers for accessing health care. The quantitative analysis further investigated determinants influencing health-seeking behaviour: living near a town where a cost-free clinic operated was inversely associated with seeking care at health posts (adjusted odds ratio [aOR], 0.40, 95% confidence interval [95% CI] [0.19-0.86]), and public hospital attendance (aOR 0.31, 95% CI [0.14-0.67]). Living further away from the nearest town was associated with health posts attendance (aOR 1.05, 95% CI [1.00-1.10] per 1 km). Having legal status was inversely associated with cost-free clinics attendance (aOR 0.27, 95% CI [0.10-0.71]), and positively associated with private clinic and public hospital attendance (aOR 2.56, 95% CI [1.00-6.54] and 5.15, 95% CI [1.80-14.71], respectively). CONCLUSIONS: Fever conception and believed causes are context-specific and should be investigated prior to any intervention. Distance to care and legal status were key determinants influencing health-seeking behaviour. Current economic upheavals are accelerating the unregulated flow of undocumented migrants from Myanmar to Thailand, warranting further inclusiveness and investments in the public health system.

Experiences, coping strategies and perspectives of people in Malaysia during the COVID-19 pandemic.

BACKGROUND: A nationwide Movement Control Order (MCO) was enforced in Malaysia on 18 March 2020 in view of the global COVID-19 pandemic. Malaysia implemented various public health measures and later raced against time to administer COVID-19 vaccines when they became available. As a result of various public health measures to curb the spread of the virus, people in Malaysia faced unprecedented circumstances and new challenges. This study addressed the knowledge gap in our understanding the experiences, coping strategies and perspectives of the people in Malaysia about infection countermeasures by investigating their experiences during the COVID-19 pandemic. METHODS: A sequential mixed method approach was used to conduct an online survey and in-depth interviews among residents in Malaysia. A total of 827 respondents participated in the online survey from 1st May to 30th June 2020. Nineteen in-depth interviews were conducted online and by phone with key informants and members of the public, who were selected through maximum variation purposive sampling between 2nd May 2020 to 20th December 2021. The semi-structured interviews employed a phenomenological approach and transcripts were analysed using thematic analysis. The survey data were analysed using descriptive statistics in Stata 15.0. RESULTS: The survey reflected significant economic impacts of the pandemic, the maximum number of days that people could cope during the MCO, and their coping strategies, which generally entailed changes in lifestyle. The internet and social media were vital platforms to mitigate against the impact of public health measures. Thematic analysis of the interview data revealed participant experiences and perceptions of COVID-19 and public health measures in four main themes: (1) work and business; (2) emotional impact (3) coping with change and (4) the COVID-19 vaccine. CONCLUSIONS: This study provides insights into the experiences, coping strategies and perspectives of people in Malaysia living through the first-ever MCO during the COVID-19 pandemic. Such insights into COVID-19-related public health measures are pertinent for successfully planning and implementing future responses to pandemics.

Facilitating Safe Discharge Through Predicting Disease Progression in Moderate Coronavirus Disease 2019 (COVID-19): A Prospective Cohort Study to Develop and Validate a Clinical Prediction Model in Resource-Limited Settings.

BACKGROUND: In locations where few people have received coronavirus disease 2019 (COVID-19) vaccines, health systems remain vulnerable to surges in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Tools to identify patients suitable for community-based management are urgently needed. METHODS: We prospectively recruited adults presenting to 2 hospitals in India with moderate symptoms of laboratory-confirmed COVID-19 to develop and validate a clinical prediction model to rule out progression to supplemental oxygen requirement. The primary outcome was defined as any of the following: SpO2 < 94%; respiratory rate > 30 BPM; SpO2/FiO2 < 400; or death. We specified a priori that each model would contain three clinical parameters (age, sex, and SpO2) and 1 of 7 shortlisted biochemical biomarkers measurable using commercially available rapid tests (C-reactive protein [CRP], D-dimer, interleukin 6 [IL-6], neutrophil-to-lymphocyte ratio [NLR], procalcitonin [PCT], soluble triggering receptor expressed on myeloid cell-1 [sTREM-1], or soluble urokinase plasminogen activator receptor [suPAR]), to ensure the models would be suitable for resource-limited settings. We evaluated discrimination, calibration, and clinical utility of the models in a held-out temporal external validation cohort. RESULTS: In total, 426 participants were recruited, of whom 89 (21.0%) met the primary outcome; 257 participants comprised the development cohort, and 166 comprised the validation cohort. The 3 models containing NLR, suPAR, or IL-6 demonstrated promising discrimination (c-statistics: 0.72-0.74) and calibration (calibration slopes: 1.01-1.05) in the validation cohort and provided greater utility than a model containing the clinical parameters alone. CONCLUSIONS: We present 3 clinical prediction models that could help clinicians identify patients with moderate COVID-19 suitable for community-based management. The models are readily implementable and of particular relevance for locations with limited resources.

Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial.

BACKGROUND: Artemisinin and partner-drug resistance in Plasmodium falciparum are major threats to malaria control and elimination. Triple artemisinin-based combination therapies (TACTs), which combine existing co-formulated ACTs with a second partner drug that is slowly eliminated, might provide effective treatment and delay emergence of antimalarial drug resistance. METHODS: In this multicentre, open-label, randomised trial, we recruited patients with uncomplicated P falciparum malaria at 18 hospitals and health clinics in eight countries. Eligible patients were aged 2-65 years, with acute, uncomplicated P falciparum malaria alone or mixed with non-falciparum species, and a temperature of 37·5°C or higher, or a history of fever in the past 24 h. Patients were randomly assigned (1:1) to one of two treatments using block randomisation, depending on their location: in Thailand, Cambodia, Vietnam, and Myanmar patients were assigned to either dihydroartemisinin-piperaquine or dihydroartemisinin-piperaquine plus mefloquine; at three sites in Cambodia they were assigned to either artesunate-mefloquine or dihydroartemisinin-piperaquine plus mefloquine; and in Laos, Myanmar, Bangladesh, India, and the Democratic Republic of the Congo they were assigned to either artemether-lumefantrine or artemether-lumefantrine plus amodiaquine. All drugs were administered orally and doses varied by drug combination and site. Patients were followed-up weekly for 42 days. The primary endpoint was efficacy, defined by 42-day PCR-corrected adequate clinical and parasitological response. Primary analysis was by intention to treat. A detailed assessment of safety and tolerability of the study drugs was done in all patients randomly assigned to treatment. This study is registered at ClinicalTrials.gov, NCT02453308, and is complete. FINDINGS: Between Aug 7, 2015, and Feb 8, 2018, 1100 patients were given either dihydroartemisinin-piperaquine (183 [17%]), dihydroartemisinin-piperaquine plus mefloquine (269 [24%]), artesunate-mefloquine (73 [7%]), artemether-lumefantrine (289 [26%]), or artemether-lumefantrine plus amodiaquine (286 [26%]). The median age was 23 years (IQR 13 to 34) and 854 (78%) of 1100 patients were male. In Cambodia, Thailand, and Vietnam the 42-day PCR-corrected efficacy after dihydroartemisinin-piperaquine plus mefloquine was 98% (149 of 152; 95% CI 94 to 100) and after dihydroartemisinin-piperaquine was 48% (67 of 141; 95% CI 39 to 56; risk difference 51%, 95% CI 42 to 59; p<0·0001). Efficacy of dihydroartemisinin-piperaquine plus mefloquine in the three sites in Myanmar was 91% (42 of 46; 95% CI 79 to 98) versus 100% (42 of 42; 95% CI 92 to 100) after dihydroartemisinin-piperaquine (risk difference 9%, 95% CI 1 to 17; p=0·12). The 42-day PCR corrected efficacy of dihydroartemisinin-piperaquine plus mefloquine (96% [68 of 71; 95% CI 88 to 99]) was non-inferior to that of artesunate-mefloquine (95% [69 of 73; 95% CI 87 to 99]) in three sites in Cambodia (risk difference 1%; 95% CI -6 to 8; p=1·00). The overall 42-day PCR-corrected efficacy of artemether-lumefantrine plus amodiaquine (98% [281 of 286; 95% CI 97 to 99]) was similar to that of artemether-lumefantrine (97% [279 of 289; 95% CI 94 to 98]; risk difference 2%, 95% CI -1 to 4; p=0·30). Both TACTs were well tolerated, although early vomiting (within 1 h) was more frequent after dihydroartemisinin-piperaquine plus mefloquine (30 [3·8%] of 794) than after dihydroartemisinin-piperaquine (eight [1·5%] of 543; p=0·012). Vomiting after artemether-lumefantrine plus amodiaquine (22 [1·3%] of 1703) and artemether-lumefantrine (11 [0·6%] of 1721) was infrequent. Adding amodiaquine to artemether-lumefantrine extended the electrocardiogram corrected QT interval (mean increase at 52 h compared with baseline of 8·8 ms [SD 18·6] vs 0·9 ms [16·1]; p<0·01) but adding mefloquine to dihydroartemisinin-piperaquine did not (mean increase of 22·1 ms [SD 19·2] for dihydroartemisinin-piperaquine vs 20·8 ms [SD 17·8] for dihydroartemisinin-piperaquine plus mefloquine; p=0·50). INTERPRETATION: Dihydroartemisinin-piperaquine plus mefloquine and artemether-lumefantrine plus amodiaquine TACTs are efficacious, well tolerated, and safe treatments of uncomplicated P falciparum malaria, including in areas with artemisinin and ACT partner-drug resistance. FUNDING: UK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and US National Institutes of Health.

Short-course primaquine for the radical cure of Plasmodium vivax malaria: a multicentre, randomised, placebo-controlled non-inferiority trial.

BACKGROUND: Primaquine is the only widely used drug that prevents Plasmodium vivax malaria relapses, but adherence to the standard 14-day regimen is poor. We aimed to assess the efficacy of a shorter course (7 days) of primaquine for radical cure of vivax malaria. METHODS: We did a randomised, double-blind, placebo-controlled, non-inferiority trial in eight health-care clinics (two each in Afghanistan, Ethiopia, Indonesia, and Vietnam). Patients (aged ≥6 months) with normal glucose-6-phosphate dehydrogenase (G6PD) and presenting with uncomplicated vivax malaria were enrolled. Patients were given standard blood schizontocidal treatment and randomly assigned (2:2:1) to receive 7 days of supervised primaquine (1·0 mg/kg per day), 14 days of supervised primaquine (0·5 mg/kg per day), or placebo. The primary endpoint was the incidence rate of symptomatic P vivax parasitaemia during the 12-month follow-up period, assessed in the intention-to-treat population. A margin of 0·07 recurrences per person-year was used to establish non-inferiority of the 7-day regimen compared with the 14-day regimen. This trial is registered at ClinicalTrials.gov (NCT01814683). FINDINGS: Between July 20, 2014, and Nov 25, 2017, 2336 patients were enrolled. The incidence rate of symptomatic recurrent P vivax malaria was 0·18 (95% CI 0·15 to 0·21) recurrences per person-year for 935 patients in the 7-day primaquine group and 0·16 (0·13 to 0·18) for 937 patients in the 14-day primaquine group, a difference of 0·02 (-0·02 to 0·05, p=0·3405). The incidence rate for 464 patients in the placebo group was 0·96 (95% CI 0·83 to 1·08) recurrences per person-year. Potentially drug-related serious adverse events within 42 days of starting treatment were reported in nine (1·0%) of 935 patients in the 7-day group, one (0·1%) of 937 in the 14-day group and none of 464 in the control arm. Four of the serious adverse events were significant haemolysis (three in the 7-day group and one in the 14-day group). INTERPRETATION: In patients with normal G6PD, 7-day primaquine was well tolerated and non-inferior to 14-day primaquine. The short-course regimen might improve adherence and therefore the effectiveness of primaquine for radical cure of P vivax malaria. FUNDING: UK Department for International Development, UK Medical Research Council, UK National Institute for Health Research, and the Wellcome Trust through the Joint Global Health Trials Scheme (MR/K007424/1) and the Bill & Melinda Gates Foundation (OPP1054404).

Sequential Open-Label Study of the Safety, Tolerability, and Pharmacokinetic Interactions between Dihydroartemisinin-Piperaquine and Mefloquine in Healthy Thai Adults.

Artemisinin-based combination therapies (ACTs) have contributed substantially to the global decline in Plasmodium falciparum morbidity and mortality, but resistance to artemisinins and their partner drugs is increasing in Southeast Asia, threatening malaria control. New antimalarial compounds will not be generally available soon. Combining three existing antimalarials in the form of triple ACTs, including dihydroartemisinin (DHA)-piperaquine + mefloquine, is a potential treatment option for multidrug-resistant Plasmodium falciparum malaria. In a sequential open-label study, healthy Thai volunteers were treated with DHA-piperaquine (120 to 960 mg), mefloquine (500 mg), and DHA-piperaquine + mefloquine (120 to 960 mg + 500 mg), and serial symptom questionnaires, biochemistry, full blood counts, pharmacokinetic profiles, and electrocardiographic measurements were performed. Fifteen healthy subjects were enrolled. There was no difference in the incidence or severity of adverse events between the three treatment arms. The slight prolongation in QTc (QT interval corrected for heart rate) associated with DHA-piperaquine administration did not increase after administration of DHA-piperaquine + mefloquine. The addition of mefloquine had no significant effect on the pharmacokinetic properties of piperaquine. However, coadministration of mefloquine significantly reduced the exposures to dihydroartemisinin for area under the concentration-time curve (-22.6%; 90% confidence interval [CI], -33.1, -10.4; P = 0.0039) and maximum concentration of drug in serum (-29.0%; 90% CI, -40.6, -15.1; P = 0.0079). Mefloquine can be added safely to dihydroartemisinin-piperaquine in malaria treatment. (This study has been registered at ClinicalTrials.gov under identifier NCT02324738.).

Data management and sharing policy: the first step towards promoting data sharing.

BACKGROUND: Health-related research funders, regulators and journals expect that de-identified individual-level health data be shared widely, with as few restrictions as possible; yet, in reality, the volume of shared data remains low. MAIN BODY: Health researchers and other data producers are reluctant to share their data unless they are confident that their datasets are of high quality and reliable, and that they are used in accordance with the values and aims of their institutions. We argue that having an institutional, departmental or group data management and sharing policy is the first step towards encouraging researchers and healthcare professionals to share their data more widely. Our paper outlines the elements of a data management and sharing policy, which should include aims consistent with those of the institution as well as with data management procedures, models of data sharing, request procedures, consent models and cost recovery mechanisms. A policy would help an institution, department or group maximise the use of its data and protect the interests of the institution and its members. We base our recommendations on our experience collecting and curating data for large clinical trials conducted in low- and middle-income countries, facilitating the sharing of datasets with secondary users, whilst teaching data management and conducting empirical research on data sharing. Although the fundamentals of a policy are general, the paper is focused on the low- and middle-income country context. CONCLUSION: We argue that having an institutional, departmental or group data management and sharing policy is the first step in promoting data sharing.

Defining the hidden burden of disease in rural communities in Bangladesh, Cambodia and Thailand: a cross-sectional household health survey protocol.

INTRODUCTION: In low-income and middle-income countries in Southeast Asia, the burden of diseases among rural population remains poorly understood, posing a challenge for effective healthcare prioritisation and resource allocation. Addressing this knowledge gap, the South and Southeast Asia Community-based Trials Network (SEACTN) will undertake a survey that aims to determine the prevalence of a wide range of non-communicable and communicable diseases, as one of the key initiatives of its first project-the Rural Febrile Illness project (RFI). This survey, alongside other RFI studies that explore fever aetiology, leading causes of mortality, and establishing village and health facility maps and profiles, will provide an updated epidemiological background of the rural areas where the network is operational. METHODS AND ANALYSIS: During 2022-2023, a cross-sectional household survey will be conducted across three SEACTN sites in Bangladesh, Cambodia and Thailand. Using a two-stage cluster-sampling approach, we will employ a probability-proportional-to-size sample method for village, and a simple random sample for household, selection, enrolling all members from the selected households. Approximately 1500 participants will be enrolled per country. Participants will undergo questionnaire interview, physical examination and haemoglobin point-of-care testing. Blood samples will be collected and sent to central laboratories to test for chronic and acute infections, and biomarkers associated with cardiovascular disease, and diabetes. Prevalences will be presented as an overall estimate by country, and stratified and compared across sites and participants' sociodemographic characteristics. Associations between disease status, risk factors and other characteristics will be explored. ETHICS AND DISSEMINATION: This study protocol has been approved by the Oxford Tropical Research Ethics Committee, National Research Ethics Committee of Bangladesh Medical Research Council, the Cambodian National Ethics Committee for Health Research, the Chiang Rai Provincial Public Health Research Ethical Committee. The results will be disseminated via the local health authorities and partners, peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: NCT05389540.

Investigating the Secondary Use of Clinical Research Data: Protocol for a Mixed Methods Study.

BACKGROUND: The increasing emphasis to share patient data from clinical research has resulted in substantial investments in data repositories and infrastructure. However, it is unclear how shared data are used and whether anticipated benefits are being realized. OBJECTIVE: The purpose of our study is to examine the current utilization of shared clinical research data sets and assess the effects on both scientific research and public health outcomes. Additionally, the study seeks to identify the factors that hinder or facilitate the ethical and efficient use of existing data based on the perspectives of data users. METHODS: The study will utilize a mixed methods design, incorporating a cross-sectional survey and in-depth interviews. The survey will involve at least 400 clinical researchers, while the in-depth interviews will include 20 to 40 participants who have utilized data from repositories or institutional data access committees. The survey will target a global sample, while the in-depth interviews will focus on individuals who have used data collected from low- and middle-income countries. Quantitative data will be summarized by using descriptive statistics, while multivariable analyses will be used to assess the relationships between variables. Qualitative data will be analyzed through thematic analysis, and the findings will be reported in accordance with the COREQ (Consolidated Criteria for Reporting Qualitative Research) guidelines. The study received ethical approval from the Oxford Tropical Research Ethics Committee in 2020 (reference number: 568-20). RESULTS: The results of the analysis, including both quantitative data and qualitative data, will be available in 2023. CONCLUSIONS: The outcomes of our study will offer crucial understanding into the current status of data reuse in clinical research, serving as a basis for guiding future endeavors to enhance the utilization of shared data for the betterment of public health outcomes and for scientific progress. TRIAL REGISTRATION: Thai Clinical Trials Registry TCTR20210301006; https://tinyurl.com/2p9atzhr. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/44875.

Prevalence and Risk Factors of Neonatal Hyperbilirubinemia in a Semi-Rural Area of the Democratic Republic of Congo: A Cohort Study.

Neonatal hyperbilirubinemia (NH) is a frequent condition that, if left untreated, can lead to neurological disability and death. We assessed the prevalence of NH and associated neonatal and maternal risk factors in 362 mothers and 365 newborns in a semi-rural area of the Democratic Republic of Congo. In addition, we explored the knowledge and practices of mothers regarding this condition. We collected demographic data, anthropometric data, and obstetric and medical anamneses. We examined newborns at birth and at 24, 48, and 72 hours and measured bilirubin at birth in umbilical cord and capillary blood and thereafter in capillary blood. Hemoglobin, hematocrit, ABO group, Rhesus factor, glucose-6-phosphate dehydrogenase (G6PD) deficiency, Hemoglobin S (HbS), and malaria were assessed in mothers and newborns. Among 296 newborns (all time points available), 5.7% developed NH (95% CI: 3.4-9.0) between 24 and 72 hours according to National Institute for Health and Care Excellence (NICE) UK guidelines. There was a significantly higher risk in newborns with G6PD deficiency (homo- and hemizygous adjusted Odd Ratio [aOR]: 21.0, 95% CI: 4.1-105.9), preterm births (aOR: 6.1, 95% CI: 1.4-26.9), newborns with excessive birth weight loss (aOR: 5.8, 95% CI: 1.4-23.2), and hyperbilirubinemia at birth (aOR: 14.8, 95% CI: 2.7-79.6). Newborns with feto-maternal ABO incompatibility and G6PD deficiency had significantly higher bilirubin at birth than others. More than 60% of mothers had adequate knowledge of NH, but compliance with phototherapy in the absence of symptoms was low. Although risk factors for NH are common in this area, prevalence was not high, suggesting a need for better case definition. Implementation of point-of-care devices for diagnosis and awareness programs on risk prevention could help reduce neonatal morbidity and mortality associated with hyperbilirubinemia in these areas.

Safety of age-dosed, single low-dose primaquine in children with glucose-6-phosphate dehydrogenase deficiency who are infected with Plasmodium falciparum in Uganda and the Democratic Republic of the Congo: a randomised, double-blind, placebo-controlled, non-inferiority trial.

BACKGROUND: WHO recommends gametocytocidal, single low-dose primaquine for blocking the transmission of Plasmodium falciparum; however, safety concerns have hampered the implementation of this strategy in sub-Saharan Africa. We aimed to investigate the safety of age-dosed, single low-dose primaquine in children from Uganda and the Democratic Republic of the Congo. METHODS: We conducted this randomised, double-blind, placebo-controlled, non-inferiority trial at the Mbale Regional Referral Hospital, Mbale, Uganda, and the Kinshasa Mahidol Oxford Research Unit, Kinshasa, Democratic Republic of the Congo. Children aged between 6 months and 11 years with acute uncomplicated P falciparum infection and haemoglobin concentrations of at least 6 g/dL were enrolled. Patients were excluded if they had a comorbid illness requiring inpatient treatment, were taking haemolysing drugs for glucose-6-phosphate dehydrogenase (G6PD) deficiency, were allergic to the study drugs, or were enrolled in another clinical trial. G6PD status was defined by genotyping for the G6PD c.202T allele, the cause of the G6PD-deficient A- variant. Participants were randomly assigned (1:1) to receive single low-dose primaquine combined with either artemether-lumefantrine or dihydroartemisinin-piperaquine, dosed by bodyweight. Randomisation was stratified by age and G6PD status. The primary endpoint was the development of profound (haemoglobin <4 g/dL) or severe (haemoglobin <5 g/dL) anaemia with severity features, within 21 days of treatment. Analysis was by intention to treat. The sample size assumed an incidence of 1·5% in the placebo group and a 3% non-inferiority margin. The trial is registered at ISRCTN, 11594437, and is closed to new participants. FINDINGS: Participants were recruited at the Mbale Regional Referral Hospital between Dec 18, 2017, and Oct 7, 2019, and at the Kinshasa Mahidol Oxford Research Unit between July 17, 2017, and Oct 5, 2019. 4620 patients were assessed for eligibility. 3483 participants were excluded, most owing to negative rapid diagnostic test or negative malaria slide (n=2982). 1137 children with a median age of 5 years were enrolled and randomly assigned (286 to the artemether-lumefantrine plus single low-dose primaquine group, 286 to the artemether-lumefantrine plus placebo group, 283 to the dihydroartemisinin-piperaquine plus single low-dose primaquine group, and 282 to the dihydroartemisinin-piperaquine plus placebo group). Genotyping of G6PD identified 239 G6PD-c.202T hemizygous males and 45 G6PD-c.202T homozygous females (defining the G6PD-deficient group), 119 heterozygous females, 418 G6PD-c.202C normal males and 299 G6PD-c.202C normal females (defining the non-G6PD-deficient group), and 17 children of unknown status. 67 patients were lost to follow-up and four patients withdrew during the study-these numbers were similar between groups. No participants developed profound anaemia and three developed severe anaemia: from the G6PD-deficient group, none (0%) of 133 patients who received placebo and one (0·66%) of 151 patients who received primaquine (difference -0·66%, 95% CI -1·96 to 0·63; p=0·35); and from the non-G6PD-deficient group, one (0·23%) of 430 patients who received placebo and one (0·25%) of 407 patients who received primaquine (-0·014%, -0·68 to 0·65; p=0·97). INTERPRETATION: Gametocytocidal, age-dosed, single low-dose primaquine was well tolerated in children from Uganda and the Democratic Republic of the Congo who were infected with P falciparum, and the safety profile of this treatment was similar to that of the placebo. These data support the wider implementation of single low-dose primaquine in Africa. FUNDING: UK Government Department for International Development, UK Medical Research Council, UK National Institute for Health Research, and the Wellcome Trust Joint Global Health Trials Scheme.

Antimalarial chemoprophylaxis for forest goers in southeast Asia: an open-label, individually randomised controlled trial.

BACKGROUND: Malaria in the eastern Greater Mekong subregion has declined to historic lows. Countries in the Greater Mekong subregion are accelerating malaria elimination in the context of increasing antimalarial drug resistance. Infections are now increasingly concentrated in remote, forested foci. No intervention has yet shown satisfactory efficacy against forest-acquired malaria. The aim of this study was to assess the efficacy of malaria chemoprophylaxis among forest goers in Cambodia. METHODS: We conducted an open-label, individually randomised controlled trial in Cambodia, which recruited participants aged 16-65 years staying overnight in forests. Participants were randomly allocated 1:1 to antimalarial chemoprophylaxis, a 3-day course of twice-daily artemether-lumefantrine followed by the same daily dosing once a week while travelling in the forest and for a further 4 weeks after leaving the forest (four tablets per dose; 20 mg of artemether and 120 mg of lumefantrine per tablet), or a multivitamin with no antimalarial activity. Allocations were done according to a computer-generated randomisation schedule, and randomisation was in permuted blocks of size ten and stratified by village. Investigators and participants were not masked to drug allocation, but laboratory investigations were done without knowledge of allocation. The primary outcome was a composite endpoint of either clinical malaria with any Plasmodium species within 1-28, 29-56, or 57-84 days, or subclinical infection detected by PCR on days 28, 56, or 84 using complete-case analysis of the intention-to-treat population. Adherence to study drug was assessed primarily by self-reporting during follow-up visits. Adverse events were assessed in the intention-to-treat population as a secondary endpoint from self-reporting at any time, plus a physical examination and symptom questionnaire at follow-up. This trial is registered at ClinicalTrials.gov (NCT04041973) and is complete. FINDINGS: Between March 11 and Nov 20, 2020, 1480 individuals were enrolled, of whom 738 were randomly assigned to artemether-lumefantrine and 742 to the multivitamin. 713 participants in the artemether-lumefantrine group and 714 in the multivitamin group had a PCR result or confirmed clinical malaria by rapid diagnostic test during follow-up. During follow-up, 19 (3%, 95% CI 2-4) of 713 participants had parasitaemia or clinical malaria in the artemether-lumefantrine group and 123 (17%, 15-20) of 714 in the multivitamin group (absolute risk difference 15%, 95% CI 12-18; p<0·0001). During follow-up, there were 166 malaria episodes caused by Plasmodium vivax, 14 by Plasmodium falciparum, and five with other or mixed species infections. The numbers of participants with P vivax were 18 (3%, 95% CI 2-4) in the artemether-lumefantrine group versus 112 (16%, 13-19) in the multivitamin group (absolute risk difference 13%, 95% CI 10-16; p<0·0001). The numbers of participants with P falciparum were two (0·3%, 95% CI 0·03-1·01) in the artemether-lumefantrine group versus 12 (1·7%, 0·9-2·9) in the multivitamin group (absolute risk difference 1·4%, 95% CI 0·4-2·4; p=0·013). Overall reported adherence to the full course of medication was 97% (95% CI 96-98; 1797 completed courses out of 1854 courses started) in the artemether-lumefantrine group and 98% (97-98; 1842 completed courses in 1885 courses started) in the multivitamin group. Overall prevalence of adverse events was 1·9% (355 events in 18 806 doses) in the artemether-lumefantrine group and 1·1% (207 events in 19 132 doses) in the multivitamin group (p<0·0001). INTERPRETATION: Antimalarial chemoprophylaxis with artemether-lumefantrine was acceptable and well tolerated and substantially reduced the risk of malaria. Malaria chemoprophylaxis among high-risk groups such as forest workers could be a valuable tool for accelerating elimination in the Greater Mekong subregion. FUNDING: The Global Fund to Fight AIDS, Tuberculosis and Malaria; Wellcome Trust.

BurkHostGEN: a study protocol for evaluating variations in the Burkholderia pseudomallei and host genomes associated with melioidosis infection.

Background: Melioidosis is a frequently fatal disease caused by an environmental bacterium Burkholderia pseudomallei. The disease is prevalent in northeast Thailand, particularly among rice field farmers who are at risk of bacterial exposure through contact with contaminated soil and water. However, not all exposure results in disease, and infection can manifest diverse outcomes. We postulate that genetic factors, whether from the bacterium, the host or the combination of both, may influence disease outcomes. To address this hypothesis, we aim to collect, sequence, and analyse genetic data from melioidosis patients and controls, along with isolates of B. pseudomallei obtained from patients. Additionally, we will study the metagenomics of the household water supply for both patients and controls, including the presence of B. pseudomallei. Methods: BurkHostGEN is an ongoing observational study being conducted at Sunpasitthiprasong Hospital, Ubon Ratchathani, Thailand. We are obtaining consent from 600 melioidosis patients and 700 controls, spanning both sexes, to collect 1 mL of blood for host DNA analysis, 3 mL of blood for RNA analysis, as well as 5 L of household water supply for metagenomic analysis. Additionally, we are isolating B. pseudomallei from the melioidosis patients to obtain bacterial DNA. This comprehensive approach will allow us to identify B. pseudomallei and their paired host genetic factors associated with disease acquisition and severity. Ethical approvals have been obtained for BurkHostGEN. Host and bacterial genetic data will be uploaded to European Genome-Phenome Archive (EGA) and European Nucleotide Archive (ENA), respectively. Conclusions: BurkHostGEN holds the potential to discover bacterial and host genetic factors associated with melioidosis infection and severity of illness. It can also support various study designs, including biomarker validation, disease pathogenesis, and epidemiological analysis not only for melioidosis but also for other infectious diseases.

Weekly primaquine for radical cure of patients with Plasmodium vivax malaria and glucose-6-phosphate dehydrogenase deficiency.

BACKGROUND: The World Health Organization recommends that primaquine should be given once weekly for 8-weeks to patients with Plasmodium vivax malaria and glucose-6-phosphate dehydrogenase (G6PD) deficiency, but data on its antirelapse efficacy and safety are limited. METHODS: Within the context of a multicentre, randomised clinical trial of two primaquine regimens in P. vivax malaria, patients with G6PD deficiency were excluded and enrolled into a separate 12-month observational study. They were treated with a weekly dose of 0.75 mg/kg primaquine for 8 weeks (PQ8W) plus dihydroartemisinin piperaquine (Indonesia) or chloroquine (Afghanistan, Ethiopia, Vietnam). G6PD status was diagnosed using the fluorescent spot test and confirmed by genotyping for locally prevalent G6PD variants. The risk of P. vivax recurrence following PQ8W and the consequent haematological recovery were characterized in all patients and in patients with genotypically confirmed G6PD variants, and compared with the patients enrolled in the main randomised control trial. RESULTS: Between July 2014 and November 2017, 42 male and 8 female patients were enrolled in Afghanistan (6), Ethiopia (5), Indonesia (19), and Vietnam (20). G6PD deficiency was confirmed by genotyping in 31 patients: Viangchan (14), Mediterranean (4), 357A-G (3), Canton (2), Kaiping (2), and one each for A-, Chatham, Gaohe, Ludhiana, Orissa, and Vanua Lava. Two patients had recurrent P. vivax parasitaemia (days 68 and 207). The overall 12-month cumulative risk of recurrent P. vivax malaria was 5.1% (95% CI: 1.3-18.9) and the incidence rate of recurrence was 46.8 per 1000 person-years (95% CI: 11.7-187.1). The risk of P. vivax recurrence was lower in G6PD deficient patients treated with PQ8W compared to G6PD normal patients in all treatment arms of the randomised controlled trial. Two of the 26 confirmed hemizygous males had a significant fall in haemoglobin (>5g/dl) after the first dose but were able to complete their 8 week regimen. CONCLUSIONS: PQ8W was highly effective in preventing P. vivax recurrences. Whilst PQ8W was well tolerated in most patients across a range of different G6PD variants, significant falls in haemoglobin may occur after the first dose and require clinical monitoring. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (NCT01814683).

Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria.

BACKGROUND: There are no pharmacokinetic data of single low dose primaquine (SLDPQ) as transmission blocking in African children with acute Plasmodium falciparum and glucose-6-phosphate dehydrogenase deficiency (G6PDd). METHODS: Primaquine pharmacokinetics of age-dosed SLDPQ (shown previously to be gametocytocidal with similar tolerability as placebo) were characterised in falciparum-infected Ugandan and Congolese children aged 6 months to 11 years, treated on admission with standard 3-day dihydroartemisinin-piperaquine or artemether-lumefantrine plus SLDPQ: 6 m-<1 y: 1.25 mg, 1-5 y: 2.5 mg, 6-9 y: 5 mg, 10-11 y: 7.5 mg. LC-MS/MS-measured plasma primaquine and carboxyprimaquine (baseline, 1, 1.5, 2, 4, 8, 12, 24 h) were analysed by noncompartmental analysis. Multivariable linear regression modelled associations between covariates, including cytochrome-P450 2D6 metaboliser status, and outcomes. FINDINGS: 258 children (median age 5 [interquartile range (IQR) 3-7]) were sampled; 8 (3.1%) with early vomiting were excluded. Primaquine doses of 0.10-0.40 (median 0.21, IQR 0.16-0.25) mg base/kg resulted in primaquine maximum plasma concentrations (Cmax) of 2.3-447 (median 103.0, IQR 72.1-140.0) ng/mL between 1.0 and 8.0 (median 2) hours (Tmax) and median areas under the drug concentration curves (AUC0-last) 730.2 (6 m-<1 y, n = 12), 582.8 (1-5 y, n = 126), 871.1 (6-9 y, n = 80), and 931.0 (10-11 y, n = 32) ng∗h/mL. Median elimination half-live (T½) was 4.7 (IQR 3.8-5.6) hours. Primaquine clearance/kg peaked at 18 months, plateauing at 4 y. Increasing CYP2D6 metaboliser activity score [poor (3/250), intermediate (52/250), normal (150/250), ultrarapid (5/250), indeterminate (40/250)] and baseline haemoglobin were significantly associated with a lower primaquine AUC0-last,which increased with increasing mg/kg dose and age but was independent of the artemisinin treatment used. INTERPRETATION: Age-dosed SLDPQ resulted in variable primaquine exposure that depended on bodyweight-adjusted dose, age, baseline haemoglobin and CYP2D6 metaboliser status, but not on dihydroartemisinin-piperaquine or artemether-lumefantrine. These data support age-dosed SLDPQ for transmission blocking in sub-Saharan Africa. FUNDING: This work was cofunded by the UK Medical Research Council, Wellcome Trust, and UK Aid through the Global Health Trials (grant reference MR/P006973/1). The funders had no role in the study design, execution, and analysis and decisions regarding publication.

ACORN (A Clinically-Oriented Antimicrobial Resistance Surveillance Network) II: protocol for case based antimicrobial resistance surveillance.

Background: Antimicrobial resistance surveillance is essential for empiric antibiotic prescribing, infection prevention and control policies and to drive novel antibiotic discovery. However, most existing surveillance systems are isolate-based without supporting patient-based clinical data, and not widely implemented especially in low- and middle-income countries (LMICs). Methods: A Clinically-Oriented Antimicrobial Resistance Surveillance Network (ACORN) II is a large-scale multicentre protocol which builds on the WHO Global Antimicrobial Resistance and Use Surveillance System to estimate syndromic and pathogen outcomes along with associated health economic costs. ACORN-healthcare associated infection (ACORN-HAI) is an extension study which focuses on healthcare-associated bloodstream infections and ventilator-associated pneumonia. Our main aim is to implement an efficient clinically-oriented antimicrobial resistance surveillance system, which can be incorporated as part of routine workflow in hospitals in LMICs. These surveillance systems include hospitalised patients of any age with clinically compatible acute community-acquired or healthcare-associated bacterial infection syndromes, and who were prescribed parenteral antibiotics. Diagnostic stewardship activities will be implemented to optimise microbiology culture specimen collection practices. Basic patient characteristics, clinician diagnosis, empiric treatment, infection severity and risk factors for HAI are recorded on enrolment and during 28-day follow-up. An R Shiny application can be used offline and online for merging clinical and microbiology data, and generating collated reports to inform local antibiotic stewardship and infection control policies. Discussion: ACORN II is a comprehensive antimicrobial resistance surveillance activity which advocates pragmatic implementation and prioritises improving local diagnostic and antibiotic prescribing practices through patient-centred data collection. These data can be rapidly communicated to local physicians and infection prevention and control teams. Relative ease of data collection promotes sustainability and maximises participation and scalability. With ACORN-HAI as an example, ACORN II has the capacity to accommodate extensions to investigate further specific questions of interest.

Triple therapy with artemether-lumefantrine plus amodiaquine versus artemether-lumefantrine alone for artemisinin-resistant, uncomplicated falciparum malaria: an open-label, randomised, multicentre trial.

BACKGROUND: Late treatment failures after artemisinin-based combination therapies (ACTs) for falciparum malaria have increased in the Greater Mekong subregion in southeast Asia. Addition of amodiaquine to artemether-lumefantrine could provide an efficacious treatment for multidrug-resistant infections. METHODS: We conducted an open-label, randomised trial at five hospitals or health centres in three locations (western Cambodia, eastern Cambodia, and Vietnam). Eligible participants were male and female patients aged 2-65 years with uncomplicated Plasmodium falciparum malaria. Patients were randomly allocated (1:1 in blocks of eight to 12) to either artemether-lumefantrine alone (dosed according to WHO guidelines) or artemether-lumefantrine plus amodiaquine (10 mg base per kg/day), both given orally as six doses over 3 days. All received a single dose of primaquine (0·25 mg/kg) 24 h after the start of study treatment to limit transmission of the parasite. Parasites were genotyped, identifying artemisinin resistance. The primary outcome was Kaplan-Meier 42-day PCR-corrected efficacy against recrudescence of the original parasite, assessed by intent-to-treat. Safety was a secondary outcome. This completed trial is registered at ClinicalTrials.gov (NCT03355664). FINDINGS: Between March 18, 2018, and Jan 30, 2020, 310 patients received randomly allocated treatment; 154 received artemether-lumefantrine alone and 156 received artemether-lumefantrine plus amodiaquine. Parasites from 305 of these patients were genotyped. 42-day PCR-corrected treatment efficacy was noted in 151 (97%, 95% CI 92-99) of 156 patients with artemether-lumefantrine plus amodiaquine versus 146 (95%, 89-97) of 154 patients with artemether-lumefantrine alone; hazard ratio (HR) for recrudescence 0·6 (95% CI 0·2-1·9, p=0·38). Of the 13 recrudescences, 12 were in 174 (57%) of 305 infections with pfkelch13 mutations indicating artemisinin resistance, for which 42-day efficacy was noted in 89 (96%) of 93 infections with artemether-lumefantrine plus amodiaquine versus 73 (90%) of 81 infections with artemether-lumefantrine alone; HR for recrudescence 0·44 (95% CI 0·14-1·40, p=0·17). Artemether-lumefantrine plus amodiaquine was generally well tolerated, but the number of mild (grade 1-2) adverse events, mainly gastrointestinal, was greater in this group compared with artemether-lumefantrine alone (vomiting, 12 [8%] with artemether-lumefantrine plus amodiaquine vs three [2%] with artemether-lumefantrine alone, p=0·03; and nausea, 11 [7%] with artemether-lumefantrine plus amodiaquine vs three [2%] with artemether-lumefantrine alone, p=0·05). Early vomiting within 1 h of treatment, requiring retreatment, occurred in no patients of 154 with artemether-lumefantrine alone versus five (3%) of 156 with artemether-lumefantrine plus amodiaquine, p=0·06. Bradycardia (≤54 beats/min) of any grade was noted in 59 (38%) of 154 patients with artemether-lumefantrine alone and 95 (61%) of 156 with artemether-lumefantrine plus amodiaquine, p=0·0001. INTERPRETATION: Artemether-lumefantrine plus amodiaquine provides an alternative to artemether-lumefantrine alone as first-line treatment for multidrug-resistant P falciparum malaria in the Greater Mekong subregion, and could prolong the therapeutic lifetime of artemether-lumefantrine in malaria-endemic populations. FUNDING: Bill & Melinda Gates Foundation, Wellcome Trust.

A Clinically Oriented antimicrobial Resistance surveillance Network (ACORN): pilot implementation in three countries in Southeast Asia, 2019-2020.

Background: Case-based surveillance of antimicrobial resistance (AMR) provides more actionable data than isolate- or sample-based surveillance. We developed A Clinically Oriented antimicrobial Resistance surveillance Network (ACORN) as a lightweight but comprehensive platform, in which we combine clinical data collection with diagnostic stewardship, microbiological data collection and visualisation of the linked clinical-microbiology dataset. Data are compatible with WHO GLASS surveillance and can be stratified by syndrome and other metadata. Summary metrics can be visualised and fed back directly for clinical decision-making and to inform local treatment guidelines and national policy. Methods: An ACORN pilot was implemented in three hospitals in Southeast Asia (1 paediatric, 2 general) to collect clinical and microbiological data from patients with community- or hospital-acquired pneumonia, sepsis, or meningitis. The implementation package included tools to capture site and laboratory capacity information, guidelines on diagnostic stewardship, and a web-based data visualisation and analysis platform. Results: Between December 2019 and October 2020, 2294 patients were enrolled with 2464 discrete infection episodes (1786 community-acquired, 518 healthcare-associated and 160 hospital-acquired). Overall, 28-day mortality was 8.7%. Third generation cephalosporin resistance was identified in 54.2% (39/72) of E. coli and 38.7% (12/31) of K. pneumoniae isolates . Almost a quarter of S. aureus isolates were methicillin resistant (23.0%, 14/61). 290/2464 episodes could be linked to a pathogen, highlighting the level of enrolment required to achieve an acceptable volume of isolate data. However, the combination with clinical metadata allowed for more nuanced interpretation and immediate feedback of results. Conclusions: ACORN was technically feasible to implement and acceptable at site level. With minor changes from lessons learned during the pilot ACORN is now being scaled up and implemented in 15 hospitals in 9 low- and middle-income countries to generate sufficient case-based data to determine incidence, outcomes, and susceptibility of target pathogens among patients with infectious syndromes.