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BackgroundIn locations where few people have received COVID-19 vaccines, health systems remain vulnerable to surges in SARS-CoV-2 infections. Tools to identify patients suitable for community-based management are urgently needed.MethodsWe prospectively recruited adults presenting to two hospitals in India with moderate symptoms of laboratory-confirmed COVID-19 in order 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 one of seven shortlisted biochemical biomarkers measurable using near-patient tests (CRP, D-dimer, IL-6, NLR, PCT, sTREM-1 or suPAR), to ensure the models would be suitable for resource-limited settings. We evaluated discrimination, calibration and clinical utility of the models in a temporal external validation cohort.Findings426 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 three models containing NLR, suPAR or IL-6 demonstrated promising discrimination (c-statistics: 0·72 to 0·74) and calibration (calibration slopes: 1·01 to 1·05) in the validation cohort, and provided greater utility than a model containing the clinical parameters alone.InterpretationWe present three 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.FundingMédecins Sans Frontières, India.RESEARCH IN CONTEXTEvidence before this studyA living systematic review by Wynants et al. identified 137 COVID-19 prediction models, 47 of which were derived to predict whether patients with COVID-19 will have an adverse outcome. Most lacked external validation, relied on retrospective data, did not focus on patients with moderate disease, were at high risk of bias, and were not practical for use in resource-limited settings. To identify promising biochemical biomarkers which may have been evaluated independently of a prediction model and therefore not captured by this review, we searched PubMed on 1 June 2020 using synonyms of “SARS-CoV-2” AND [“biomarker” OR “prognosis”]. We identified 1,214 studies evaluating biochemical biomarkers of potential value in the prognostication of COVID-19 illness. In consultation with FIND (Geneva, Switzerland) we shortlisted seven candidates for evaluation in this study, all of which are measurable using near-patient tests which are either currently available or in late-stage development.Added value of this studyWe followed the TRIPOD guidelines to develop and validate three promising clinical prediction models to help clinicians identify which patients presenting with moderate COVID-19 can be safely managed in the community. Each model contains three easily ascertained clinical parameters (age, sex, and SpO2) and one biochemical biomarker (NLR, suPAR or IL-6), and would be practical for implementation in high-patient-throughput low resource settings. The models showed promising discrimination and calibration in the validation cohort. The inclusion of a biomarker test improved prognostication compared to a model containing the clinical parameters alone, and extended the range of contexts in which such a tool might provide utility to include situations when bed pressures are less critical, for example at earlier points in a COVID-19 surge.Implications of all the available evidencePrognostic models should be developed for clearly-defined clinical use-cases. We report the development and temporal validation of three clinical prediction models to rule-out progression to supplemental oxygen requirement amongst patients presenting with moderate COVID-19. The models are readily implementable and should prove useful in triage and resource allocation. We provide our full models to enable independent validation.

INTRODUCTION In locations where few people have received Covid-19 vaccines, health systems remain vulnerable to spikes in SARS-CoV-2 infections. Triage tools, which could include biomarkers, to identify patients with moderate Covid-19 infection suitable for community-based management would be useful in the event of surges. In consultation with FIND (Geneva, Switzerland) we shortlisted seven biomarkers for evaluation, all measurable using point-of-care tests, and either currently available or in late-stage development. METHODS We prospectively recruited unvaccinated adults with laboratory-confirmed Covid-19 presenting to two hospitals in India with moderate symptoms, in order to develop and validate a clinical prediction model to rule-out progression to supplemental oxygen requirement. Moderate disease was defined as oxygen saturation (SpO2) ≥ 94% and respiratory rate < 30 breaths per minute (bpm), in the context of systemic symptoms (breathlessness or fever and chest pain, abdominal pain, diarrhoea, or severe myalgia). All patients had clinical observations and blood collected at presentation, and were followed up for 14 days for the primary outcome, defined as any of the following: SpO2 < 94%; respiratory rate > 30 bpm; SpO2/fraction of inspired oxygen (FiO2) < 400; or death. We specified a priori that each model would contain three easily ascertained clinical parameters (age, sex, and SpO2) and one of the seven biomarkers (C-reactive protein (CRP), D-dimer, interleukin-6 (IL-6), neutrophil-to-lymphocyte ratio (NLR), procalcitonin (PCT), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), or soluble urokinase plasminogen activator receptor (suPAR)), to ensure the models would be implementable in high patient-throughput, low-resource settings. We evaluated the models’ discrimination, calibration, and clinical utility in a held-out external temporal validation cohort. ETHICS Ethical approval was given by the ethics committees of AIIMS and CMC, India, the Oxford Tropical Research Ethics Committee, UK; and by the MSF Ethics Review Board. ClinicalTrials.gov number, NCT04441372. RESULTS 426 participants were recruited, of which 89 (21.0%) met the primary outcome. 257 participants comprised the development, and 166 the validation, cohorts. The three models containing NLR, suPAR, or IL-6 demonstrated promising discrimination (c-statistics: 0.72 to 0.74) and calibration (calibration slopes: 1.01 to 1.05) in the held-out validation cohort. Furthermore, they provided greater utility than a model containing the clinical parameters alone (c-statistic = 0.66; calibration slope = 0.68). The inclusion of either NLR or suPAR improved predictive performance such that the ratio of correctly to incorrectly discharged patients increased from 10:1 to 23:1 or 25:1 respectively. Including IL-6 resulted in a similar proportion (~21%) of correctly discharged patients as the clinical model, but without missing any patients requiring supplemental oxygen. CONCLUSION We present three clinical prediction models that could help clinicians identify patients with moderate Covid-19 suitable for community-based management. These models are readily implementable and, if validated, could be of particular relevance for resource-limited settings. CONFLICTS OF INTEREST None declared.

Background: Typhoid and paratyphoid fever (enteric fever) is a common cause of non-specific febrile infection in adults and children presenting to health care facilities in low resource settings such as the South Asia. A 7-day course of a single oral antimicrobial such as ciprofloxacin, cefixime, or azithromycin is commonly used for its treatment. Increasing antimicrobial resistance threatens the effectiveness of these treatment choices. We hypothesize that combined treatment with azithromycin (active mainly intracellularly) and cefixime (active mainly extracellularly) will be a better option for the treatment of clinically suspected and culture-confirmed typhoid fever in South Asia.\ud \ud Methods: This is a phase IV, international multi-center, multi-country, comparative participant-and observer-blind, 1:1 randomised clinical trial. Patients with suspected uncomplicated typhoid fever will be randomized to one of the two interventions: Arm A: azithromycin 20mg/kg/day oral dose once daily (maximum 1gm/day) and cefixime 20mg/kg/day oral dose in two divided doses (maximum 400mg bd) for 7 days, Arm B: azithromycin 20mg/kg/day oral dose once daily (max 1gm/day) for 7 days AND cefixime-matched placebo for 7 days. We will recruit 1500 patients across sites in Bangladesh, India, Nepal, and Pakistan. We will assess whether treatment outcomes are better with the combination after one week of treatment and at one- and three-months follow-up.\ud \ud Discussion: Combined treatment may limit the emergence of resistance if one of the components is active against resistant sub-populations not covered by the other antimicrobial activity. If the combined treatment is better than the single antimicrobial treatment, this will be an important result for patients across South Asia and other typhoid endemic areas.\ud \ud Clinicaltrials.gov registration: NCT04349826 (16/04/2020)

Summary 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).

Pharyngitis is usually caused by a viral infection for which antibiotics are often unnecessarily prescribed, adding to the burden of antimicrobial resistance. Identifying who needs antibiotics is challenging; microbiological confirmation and clinical scores are used but have limitations. In a cross-sectional study nested within a randomized controlled trial, we estimated the prevalence and antibiotic susceptibility profiles of group A Streptococcus (GAS) in patients presenting to primary care with a sore throat and fever in northern Thailand. We then evaluated the use of C-reactive protein (CRP) and clinical scores (Centor and FeverPAIN) to identify the presence of GAS. One hundred sixty-nine patients were enrolled, of whom 35 (20.7%) had β-hemolytic Streptococci (BHS) isolated from throat swab culture, and 11 (6.5%) had GAS. All GAS isolates were sensitive to penicillin G. The median CRP of those without BHS isolation was 10 mg/L (interquartile range [IQR] £ 8–18), compared with 18 mg/L (IQR 9–71, P = 0.0302) for those with GAS and 14 mg/L (IQR £ 8–38, P = 0.0516) for those with any BHS isolated. However, there were no significant relationships between CRP > 8 mg/L (P = 0.112), Centor ³ 3 (P = 0.212), and FeverPAIN ³ 4 (P = 1.000), and the diagnosis of GAS compared with no BHS isolation. Identifying who requires antibiotics for pharyngitis remains challenging and necessitates further larger studies. C-reactive protein testing alone, although imperfect, can reduce prescribing compared with routine care. Targeted CRP testing through clinical scoring may be the most cost-effective approach to ruling out GAS infection.

Background Melioidosis is a frequently fatal disease requiring specific treatment. The yield of Burkholderia pseudomallei from sites with a normal flora is increased by culture using selective, differential media such as Ashdown’s agar and selective broth. However, since melioidosis mainly affects people in resource-poor countries, the cost effectiveness of selective culture has been questioned. We therefore retrospectively evaluated this in two laboratories in southeast Asia. Methodology/Principal findings The results of all cultures in the microbiology laboratories of Mahosot Hospital, Vientiane, Laos and Angkor Hospital for Children, Siem Reap, Cambodia, in 2017 were reviewed. We identified patients with melioidosis who were only diagnosed as a result of culture of non-sterile sites and established the total number of such samples cultured using selective media and the associated costs in each laboratory. We then conducted a rudimentary cost-effectiveness analysis by determining the incremental cost-effectiveness ratio (ICER) per DALY averted and compared this against the 2017 GDP per capita in each country. Overall, 29 patients in Vientiane and 9 in Siem Reap (20% and 16.9% of all culture-positive patients respectively) would not have been diagnosed without the use of selective media, the majority of whom (18 and 8 respectively) were diagnosed by throat swab culture. The cost per additional patient detected by selective culture was approximately $100 in Vientiane and $39 in Siem Reap. Despite the different patient populations (all ages in Vientiane vs. only children in Siem Reap) and testing strategies (all samples in Vientiane vs. based on clinical suspicion in Siem Reap), selective B. pseudomallei culture proved highly cost effective in both settings, with an ICER of ~$170 and ~$28 in Vientiane and Siem Reap, respectively. Conclusions/Significance Selective culture for B. pseudomallei should be considered by all laboratories in melioidosis-endemic areas. However, the appropriate strategy for implementation should be decided locally., Author summary Melioidosis is a frequently fatal disease caused by a soil bacterium called Burkholderia pseudomallei, that is widespread in the rural tropics. Because staff are often not familiar with it and because it may be hidden if it is outgrown by other bacteria, special culture media can help laboratories diagnose the disease. However, this costs more money so it is not always done even in areas where the disease is known to be present. We have looked at the results of a year’s bacterial cultures in two different laboratories in southeast Asia to identify how many patients were only identified using these special culture techniques, how much it cost, and whether the investment was considered worthwhile in terms of the gain in healthy life years in these patients who might otherwise have died had the disease not been diagnosed. Even though the laboratories adopted very different strategies for using the special media and served very different populations, in both places the use of the special techniques was very cost effective in terms not just of lives saved, but on purely financial grounds when compared with the GDP of each country.

Background The emergence and spread of multidrug-resistant Plasmodium falciparum in the Greater Mekong Subregion (GMS) threatens global malaria elimination efforts. Mass drug administration (MDA), the presumptive antimalarial treatment of an entire population to clear the subclinical parasite reservoir, is a strategy to accelerate malaria elimination. We report a cluster randomised trial to assess the effectiveness of dihydroartemisinin-piperaquine (DP) MDA in reducing falciparum malaria incidence and prevalence in 16 remote village populations in Myanmar, Vietnam, Cambodia, and the Lao People’s Democratic Republic, where artemisinin resistance is prevalent. Methods and findings After establishing vector control and community-based case management and following intensive community engagement, we used restricted randomisation within village pairs to select 8 villages to receive early DP MDA and 8 villages as controls for 12 months, after which the control villages received deferred DP MDA. The MDA comprised 3 monthly rounds of 3 daily doses of DP and, except in Cambodia, a single low dose of primaquine. We conducted exhaustive cross-sectional surveys of the entire population of each village at quarterly intervals using ultrasensitive quantitative PCR to detect Plasmodium infections. The study was conducted between May 2013 and July 2017. The investigators randomised 16 villages that had a total of 8,445 residents at the start of the study. Of these 8,445 residents, 4,135 (49%) residents living in 8 villages, plus an additional 288 newcomers to the villages, were randomised to receive early MDA; 3,790 out of the 4,423 (86%) participated in at least 1 MDA round, and 2,520 out of the 4,423 (57%) participated in all 3 rounds. The primary outcome, P. falciparum prevalence by month 3 (M3), fell by 92% (from 5.1% [171/3,340] to 0.4% [12/2,828]) in early MDA villages and by 29% (from 7.2% [246/3,405] to 5.1% [155/3,057]) in control villages. Over the following 9 months, the P. falciparum prevalence increased to 3.3% (96/2,881) in early MDA villages and to 6.1% (128/2,101) in control villages (adjusted incidence rate ratio 0.41 [95% CI 0.20 to 0.84]; p = 0.015). Individual protection was proportional to the number of completed MDA rounds. Of 221 participants with subclinical P. falciparum infections who participated in MDA and could be followed up, 207 (94%) cleared their infections, including 9 of 10 with artemisinin- and piperaquine-resistant infections. The DP MDAs were well tolerated; 6 severe adverse events were detected during the follow-up period, but none was attributable to the intervention. Conclusions Added to community-based basic malaria control measures, 3 monthly rounds of DP MDA reduced the incidence and prevalence of falciparum malaria over a 1-year period in areas affected by artemisinin resistance. P. falciparum infections returned during the follow-up period as the remaining infections spread and malaria was reintroduced from surrounding areas. Limitations of this study include a relatively small sample of villages, heterogeneity between villages, and mobility of villagers that may have limited the impact of the intervention. These results suggest that, if used as part of a comprehensive, well-organised, and well-resourced elimination programme, DP MDA can be a useful additional tool to accelerate malaria elimination. Trial registration ClinicalTrials.gov NCT01872702, In a cluster-randomized trial, Lorenz von Seidlin & colleagues investigate whether mass drug administration can accelerate malaria elimination in the Greater Mekong Subregion., Author summary Why was this study done? The emergence and spread of multidrug resistance in the Greater Mekong Subregion (GMS) threaten regional and global malaria control. Mass drug administrations (MDAs) are controversial but could be useful in the control and elimination of malaria. We wanted to know whether well-resourced MDAs can accelerate malaria elimination in the GMS. What did the researchers do and find? We randomised 16 villages (clusters) to receive MDAs with antimalarial drugs (dihydroartemisinin-piperaquine [DP] plus low-dose primaquine) either in year 1 or year 2 of the study. The entire village population (except pregnant women and children under the age of 6 months) was invited to take 3 consecutive daily doses of antimalarial drugs 3 times at monthly intervals. Everyone was followed up for 1 year; all malaria cases were recorded, and quarterly malaria surveys were conducted using highly sensitive high-volume PCR detection. Most (87%) of the villagers completed at least 1 round of the antimalarial drugs, which were well tolerated. The intervention had a substantial impact on the prevalence of P. falciparum infections by month 3 after the start of the MDAs. Over the subsequent 9 months, P. falciparum infections returned but stayed below baseline levels. What do these findings mean? MDAs might be a useful tool to accelerate falciparum malaria elimination in low-endemicity settings. The effectiveness of MDAs depends on continued support for village health workers, adequate drug efficacy, high levels of community participation, and carefully planned roll out to minimise the risk of malaria reintroduction.

Background Context matters for the successful implementation of medical interventions, but its role remains surprisingly understudied. Against the backdrop of antimicrobial resistance, a global health priority, we investigated the introduction of a rapid diagnostic biomarker test (C-reactive protein, or CRP) to guide antibiotic prescriptions in outpatient settings and asked, “Which factors account for cross-country variations in the effectiveness of CRP biomarker test interventions?” Methods We conducted a cross-case comparison of CRP point-of-care test trials across Yangon (Myanmar), Chiang Rai (Thailand), and Hanoi (Vietnam). Cross-sectional qualitative data were originally collected as part of each clinical trial to broaden their evidence base and help explain their respective results. We synthesised these data and developed a large qualitative data set comprising 130 interview and focus group participants (healthcare workers and patients) and nearly one million words worth of transcripts and interview notes. Inductive thematic analysis was used to identify contextual factors and compare them across the three case studies. As clinical trial outcomes, we considered patients’ and healthcare workers’ adherence to the biomarker test results, and patient exclusion to gauge the potential “impact” of CRP point-of-care testing on the population level. Results We identified three principal domains of contextual influences on intervention effectiveness. First, perceived risks from infectious diseases influenced the adherence of the clinical users (nurses, doctors). Second, the health system context related to all three intervention outcomes (via the health policy and antibiotic policy environment, and via health system structures and the ensuing utilisation patterns). Third, the demand-side context influenced the patient adherence to CRP point-of-care tests and exclusion from the intervention through variations in local healthcare-seeking behaviours, popular conceptions of illness and medicine, and the resulting utilisation of the health system. Conclusions Our study underscored the importance of contextual variation for the interpretation of clinical trial findings. Further research should investigate the range and magnitude of contextual effects on trial outcomes through meta-analyses of large sets of clinical trials. For this to be possible, clinical trials should collect qualitative and quantitative contextual information for instance on their disease, health system, and demand-side environment. Trial registration ClinicalTrials.gov, NCT02758821 registered on 3 May 2016 and NCT01918579 registered on 7 August 2013. Electronic supplementary material The online version of this article (10.1186/s13063-019-3215-9) contains supplementary material, which is available to authorized users.

Summary: Background: In southeast Asia, antibiotic prescription in febrile patients attending primary care is common, and a probable contributor to the high burden of antimicrobial resistance. The objective of this trial was to explore whether C-reactive protein (CRP) testing at point of care could rationalise antibiotic prescription in primary care, comparing two proposed thresholds to classify CRP concentrations as low or high to guide antibiotic treatment. Methods: We did a multicentre, open-label, randomised, controlled trial in participants aged at least 1 year with a documented fever or a chief complaint of fever (regardless of previous antibiotic intake and comorbidities other than malignancies) recruited from six public primary care units in Thailand and three primary care clinics and one outpatient department in Myanmar. Individuals were randomly assigned using a computer-based randomisation system at a ratio of 1:1:1 to either the control group or one of two CRP testing groups, which used thresholds of 20 mg/L (group A) or 40 mg/L CRP (group B) to guide antibiotic prescription. Health-care providers were masked to allocation between the two intervention groups but not to the control group. The primary outcome was the prescription of any antibiotic from day 0 to day 5 and the proportion of patients who were prescribed an antibiotic when CRP concentrations were above and below the 20 mg/L or 40 mg/L thresholds. The primary outcome was analysed in the intention-to-treat and per-protocol populations. The trial is registered with ClinicalTrials.gov, number NCT02758821, and is now completed. Findings: Between June 8, 2016, and Aug 25, 2017, we recruited 2410 patients, of whom 803 patients were randomly assigned to CRP group A, 800 to CRP group B, and 807 to the control group. 598 patients in CRP group A, 593 in CRP group B, and 767 in the control group had follow-up data for both day 5 and day 14 and had been prescribed antibiotics (or not) in accordance with test results (per-protocol population). During the trial, 318 (39%) of 807 patients in the control group were prescribed an antibiotic by day 5, compared with 290 (36%) of 803 patients in CRP group A and 275 (34%) of 800 in CRP group B. The adjusted odds ratio (aOR) of 0·80 (95% CI 0·65–0·98) and risk difference of −5·0 percentage points (95% CI −9·7 to −0·3) between group B and the control group were significant, although lower than anticipated, whereas the reduction in prescribing in group A compared with the control group was not significant (aOR 0·86 [0·70–1·06]; risk difference −3·3 percentage points [–8·0 to 1·4]). Patients with high CRP concentrations in both intervention groups were more likely to be prescribed an antibiotic than in the control group (CRP ≥20 mg/L: group A vs control group, p

Aim We assess the cost-benefit implications of C-reactive protein (CRP) testing in reducing antibiotic prescription for acute respiratory infection in Viet Nam by comparing the incremental costs of CRP testing with the economic costs of antimicrobial resistance averted due to lower antibiotic prescribing. Findings Patients in the CRP group and the controls incurred similar costs in managing their illness, excluding the costs of the quantitative CRP tests, provided free of charge in the trial context. Assuming a unit cost of $1 per test, the incremental cost of CRP testing was $0.93 per patient. Based on a previous modelling analysis, the 20 percentage point reduction in prescribing observed in the trial implies a societal benefit of $0.82 per patient. With the low levels of adherence to the test results observed in the trial, CRP testing would not be cost-beneficial. The sensitivity analyses showed, however, that with higher adherence to test results their use would be cost-beneficial. Electronic supplementary material The online version of this article (10.1186/s13756-018-0414-1) contains supplementary material, which is available to authorized users.

Contains fulltext : 193552.pdf (Publisher’s version ) (Open Access) Background: Antimicrobial resistance (AMR) is a global health priority. Leading UK and global strategy papers to fight AMR recognise its social and behavioural dimensions, but current policy responses to improve the popular use of antimicrobials (eg, antibiotics) are limited to education and awareness-raising campaigns. In response to conceptual, methodological and empirical weaknesses of this approach, we study people's antibiotic-related health behaviour through three research questions.RQ1: What are the manifestations and determinants of problematic antibiotic use in patients' healthcare-seeking pathways?RQ2: Will people's exposure to antibiotic awareness activities entail changed behaviours that diffuse or dissipate within a network of competing healthcare practices?RQ3: Which proxy indicators facilitate the detection of problematic antibiotic behaviours across and within communities? Methods: We apply an interdisciplinary analytical framework that draws on the public health, medical anthropology, sociology and development economics literature. Our research involves social surveys of treatment-seeking behaviour among rural dwellers in northern Thailand (Chiang Rai) and southern Lao PDR (Salavan). We sample approximately 4800 adults to produce district-level representative and social network data. Additional 60 cognitive interviews facilitate survey instrument development and data interpretation. Our survey data analysis techniques include event sequence analysis (RQ1), multilevel regression (RQ1-3), social network analysis (RQ2) and latent class analysis (RQ3). Discussion: Social research in AMR is nascent, but our unprecedentedly detailed data on microlevel treatment-seeking behaviour can contribute an understanding of behaviour beyond awareness and free choice, highlighting, for example, decision-making constraints, problems of marginalisation and lacking access to healthcare and competing ideas about desirable behaviour. Trial registration number: NCT03241316; Pre-results.

In an era marked by the worldwide decline of malaria, fever remains the most frequent reason for seeking health care in the tropics. Non-malarial pathogens are mainly studied among hospitalised patients, while evidence in primary care is scarce. In addition to the limited evidence on the local epidemiology, prescribers routinely face difficulty in identifying patients who really need an antibiotic. This translates into high antibiotic prescription, fuelling the worldwide spread of antimicrobial resistance. C-reactive protein (CRP) is one of the most studied host-response biomarkers for guiding the management of acutely febrile patients, although evidence mainly originates from hospitals in high-income countries, implying that findings may not be applicable in primary care in low-to-middle-income countries (LMICs). My thesis aims to explore the bacteria and viruses driving acute fever in primary care in Southeast Asia, as well as the potential utility of CRP in identifying patients who need an antibiotic. To this end, we designed an individually randomised controlled trial of CRP-guided treatment in all febrile children and adults, ‘the CRP Study’. We also collected blood and respiratory specimens to ascertain the causes of fever in these patients. We found a significant antibiotic reduction of 7.8 percentage-points using CRP at a 40 mg/L threshold compared to routine practice, without differences in clinical outcome. Routine prescription levels were lower than prior to study implementation, suggesting that future studies should adopt a cluster rather than individual randomised design. Influenza virus type A, dengue virus and respiratory syncytial virus were the key pathogens among our primary care patients, although ascertaining causality was challenging due to lack of acontrol group, especially in nasopharyngeal swabs. Most bacterial infections showed low inflammatory levels and recovered without antibiotics, questioning the interpretation of microbiological findings among non-severe patients. CRP performance in distinguishing bacterial from viral pathogens was limited, suggesting that CRP may rather discriminate self-limiting from serious infections. We also evaluated the performance of CRP in a cohort of febrile patients in Tanzania. Here CRP showed a high sensitivity for detecting bacterial bloodstream infection, indicating that prospective evaluations on its effect on antibiotic prescriptions could be envisaged. The detection of bacterial zoonotic pathogens was of lower accuracy, warranting further evaluations for various levels of healthcare settings and age categories.

This thesis is composed of two economic evaluations: one trial-based study and one model-based study. In a recent study published in Clinical Infectious Diseases in 2011, a team of OUCRU investigators found that immediate antiretroviral therapy (ART) was not associated with improved 9-month survival in HIV-associated TBM patients (HR, 1.12; 95% CI, .81 to–1.55; P = .50). An economic evaluation of this clinical trial was conducted to examine the cost-effectiveness of immediate ART (initiate ART within 1 week of study entry) versus deferred ART (initiate ART after 2 months of TB treatment) in HIV-associated TBM patients. Over 9 months, immediate ART was not different from deferred ART in terms of costs and QALYs gained. Late initiation of ART during TB and HIV treatment for HIV-positive TBM patients proved to be the most cost-effective strategy. Increasing resistance of Plasmodium falciparum malaria to artemisinin is posing a major threat to the global effort to eliminate malaria. Artesmisinin combination therapies (ACT) are currently known as the most efficacious first-line therapies to treat uncomplicated malaria. However, resistance to both artemisinin and partner drugs is developing and this could result in increasing morbidity, mortality, and economic costs. One strategy advocated for delaying the development of resistance to the ACTs is the wide-scale deployment of multiple first-line therapies. A previous modeling study examined that the use of multiple first-line therapies (MFT) reduced the long-term treatment failures compared with strategies in which a single first-line ACT was recommended. Motivated by observed results of the published modelling study in the Lancet, the cost-effectiveness of the MFT versus the single first-line therapies was assessed in settings of different transmission intensities, treatment coverages and fitness cost of resistance using a previously developed model of the dynamics of malaria and a literature –based cost estimate of changing antimalarial drug policy at national level. This study demonstrates that the MFT strategies outperform the single first-line strategies in terms of costs and benefits across the wide range of epidemiological and economic scenarios considered. The second analysis of the thesis is not only internationally relevant but also with a focus towards healthcare practice in Vietnam. These two studies add significant new cost-effectiveness evidence in Vietnam. This thesis presents the first trial-based economic evaluation in Vietnam considers patient-health outcome measures as the participants have cognitive limitations (tuberculous meningitis), dealing with missing data along with the potential ways to handle this common problem by the use of multiple imputation, and the issues of censored costs data. Having identified these issues would support the decision makers or stakeholders including the pharmaceutical industry to devise a new guideline on how to implement a well-design trial-based economic evaluation in Vietnam in the future. Another novelty of this thesis is the introduction of the detailed of costing of drug regimens change in which the economic evaluations considering the drug policy change often do not include. This cost could be substantial to the healthcare system for retraining the staff and publishing the new guidelines. This thesis will document the costs incurred by the Vietnamese government by changing the first-line treatment of malaria, from single first-line therapy (ACT) to multiple first-line therapies.

[This corrects the article DOI: 10.1371/journal.pone.0283405.]., (Copyright: © 2024 Betrian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)