Same-day versus rapid ART initiation in HIV-positive individuals presenting with symptoms of tuberculosis: Protocol for an open-label randomized non-inferiority trial in Lesotho and Malawi.

BACKGROUND: In absence of contraindications, same-day initiation (SDI) of antiretroviral therapy (ART) is recommended for people testing HIV-positive who are ready to start treatment. Until 2021, World Health Organization (WHO) guidelines considered the presence of TB symptoms (presumptive TB) a contraindication to SDI due to the risk of TB-immune reconstitution inflammatory syndrome (TB-IRIS). To reduce TB-IRIS risk, ART initiation was recommended to be postponed until results of TB investigations were available, and TB treatment initiated if active TB was confirmed. In 2021, the WHO guidelines changed to recommending SDI even in the presence of TB symptoms without awaiting results of TB investigations based on the assumption that TB investigations often unnecessarily delay ART initiation, increasing the risk for pre-ART attrition from care, and noting that the clinical relevance of TB-IRIS outside the central nervous system remains unclear. However, this guideline change was not based on conclusive evidence, and it remains unclear whether SDI of ART or TB test results should be prioritized in people with HIV (PWH) and presumptive TB. DESIGN AND METHODS: SaDAPT is an open-label, pragmatic, parallel, 1:1 individually randomized, non-inferiority trial comparing two strategies for the timing of ART initiation in PWH with presumptive TB ("ART first" versus "TB results first"). PWH in Lesotho and Malawi, aged 12 years and older (re)initiating ART who have at least one TB symptom (cough, fever, night sweats or weight loss) and no signs of intracranial infection are eligible. After a baseline assessment, participants in the "ART first" arm will be offered SDI of ART, while those in the "TB results first" arm will be offered ART only after active TB has been confirmed or refuted. We hypothesize that the "ART first" approach is safe and non-inferior to the "TB results first" approach with regard to HIV viral suppression (<400 copies/ml) six months after enrolment. Secondary outcomes include retention in care and adverse events consistent with TB-IRIS. EXPECTED OUTCOMES: SaDAPT will provide evidence on the safety and effects of SDI of ART in PWH with presumptive TB in a pragmatic clinical trial setting. TRIAL REGISTRATION: The trial has been registered on clinicaltrials.gov (NCT05452616; July 11 2022).

Community-based type 2 diabetes care by lay village health workers in rural Lesotho: protocol for a cluster-randomized trial within the ComBaCaL cohort study (ComBaCaL T2D TwiC).

BACKGROUND: Type 2 diabetes (T2D) poses a growing public health burden, especially in low- and middle-income countries (LMICs). Task-shifting to lay village health workers (VHWs) and the use of digital clinical decision support systems (CDSS) are promising approaches to tackle the current T2D care gap in LMICs. However, evidence on the effectiveness of lay worker-led T2D care models, in which VHWs initiate and monitor drug treatment in addition to community-based screening and referral services, is lacking. METHODS: We are conducting a cluster-randomized trial nested within the Community-Based Chronic Disease Care Lesotho (ComBaCaL) cohort study (NCT05596773) using the trial within cohort (TwiC) design to assess the effectiveness of a VHW-led, CDSS-assisted T2D care model in rural Lesotho. Participants are non-pregnant members of the ComBaCaL cohort study with T2D. The ComBaCaL cohort study is conducted in approximately 100 villages in two rural districts in Lesotho and is managed by trained and supervised VHWs. In intervention villages, VHWs offer a community-based T2D care package including lifestyle counselling, first-line oral antidiabetic, lipid-lowering, and antiplatelet treatment guided by a tablet-based CDSS to participants who are clinically eligible, as well as treatment support to participants who prefer or clinically require facility-based T2D care. In control clusters, all participants will be referred to a health facility for T2D management. The primary endpoint is the mean glycosylated haemoglobin (HbA1c) 12 months after enrolment. Secondary endpoints include the 10-year risk for cardiovascular events estimated using the World Health Organization risk prediction tool. DISCUSSION: The trial was launched on May 13, 2023, and has enrolled 226 participants at the date of submission (October 6, 2023). To our knowledge, the trial is the first to assess task-shifting of T2D care to VHWs at the community level, including the prescription of first-line antidiabetic, lipid-lowering, and antiplatelet medication in sub-Saharan Africa, and will thus provide the missing evidence on the effectiveness of such a T2D care model in this setting. The study is operating within the established Lesotho VHW programme. Similar community health worker programmes which exist across sub-Saharan Africa may benefit from the findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT05743387. Registered on February 24 2023.

High Rates of Undiagnosed Target Organ Damage Among Adults with Elevated Blood Pressure or Diabetes Mellitus in a Community-Based Survey in Lesotho.

INTRODUCTION: Prevalence of elevated blood pressure (BP) and diabetes mellitus (DM) is increasing in sub-Saharan Africa. Data on target organ damage such as retinopathy, left ventricular hypertrophy (LVH), renal impairment and peripheral neuropathy (PN) among persons with elevated BP and/or DM in sub-Saharan Africa remain scarce. AIM: To determine at community-level the prevalence of retinopathy, LVH, renal impairment, and PN among adults with elevated BP and/or DM, and assess the association of elevated BP and/or DM with target organ damage in Lesotho. METHODS: During a household-based survey, a sub-sample of adults with elevated BP (≥ 140/90 mmHg) and/or DM (glycosylated hemoglobin ≥ 6.5%), as well as comparators (BP < 140/90 mmHg, HbA1c < 6.5%) were screened for retinopathy, LVH, renal impairment, and PN. We used multivariable logistic regression for inferential analysis. RESULTS: Out of 6108 participants screened during the survey, 420 with elevated BP only, 80 with DM only, 61 with elevated BP and DM, and 360 comparators were assessed for target organ damage. Among those with elevated BP, and among those with DM with or without elevated BP, prevalence of retinopathy was 34.6% (89/257) and 14.4% (15/104); renal impairment was 45.0% (156/347) and 42.4% (56/132), respectively. Among those with elevated BP, 2.3% (7/300) and 65.7% (224/341) had LVH and left ventricular concentric remodeling, respectively. PN, only assessed among those with DM, was present in 32.6% (42/129). Elevated BP was associated with increased odds of retinopathy (aOR, 19.13; 95% CI, 8.52-42.94; P < 0.001) and renal impairment (aOR, 1.80; 95% CI, 1.27-2.55; P = 0.001). Presence of both elevated BP and DM was associated with an increased odds of retinopathy (aOR, 16.30; 95%CI, 5.69-46.68; P < 0.001), renal impairment (aOR, 2.55; 95% CI, 1.35-4.81; P = 0.004), and PN (aOR, 2.13; 95% CI, 1.04-4.38; P = 0.040). CONCLUSION: We found a high prevalence of undiagnosed target organ damage among adults with elevated BP and/or DM during community-based screening. These findings emphasize the importance of regular prevention and screening activities in this setting.

Barriers to climate change and health research in India: a qualitative study.

OBJECTIVES: Almost a quarter of the global burden of disease and mortalities is attributable to environmental causes, the magnitude of which is projected to increase in the near future. However, in many low- and middle-income settings, there remains a large gap in the synthesis of evidence on climate-sensitive health outcomes. In India, now the world's most populous country, little remains known about the impacts of climate change on various health outcomes. The objective of this study is to better understand the challenges faced in conducting climate change and health research in Puducherry, India. DESIGN AND SETTING: In this study, we employed key informant interviews to deepen the understanding of the perceived research barriers in Puducherry. The findings were analysed using data-driven qualitative thematic analysis to elaborate the major perceived barriers to conducting environmental health research. PARTICIPANTS: This study was conducted among 16 public health professionals, including medical researchers, and professionals involved in environmental policies and planning in Puducherry. RESULTS: We identify three key barriers faced by public health professionals as key stakeholders, namely: (1) political and institutional barriers; (2) education and awareness barriers; and (3) technical research barriers. We show there is a need, from the professionals' perspective, to improve community and political awareness on climate change and health; strengthen technical research capacity and collaboration among researchers; and strengthen health surveillance, resource allocation and access to health data for research. CONCLUSION: Evidence informed policies and interventions are a key element in the adaptation response for countries. In the context of the paucity of data on environmental health from India, despite recognised climate change related health vulnerabilities, these findings could contribute to the development and improvement of relevant interventions conducive to a strong research environment.

Head-to-head comparison of the WHO STEPwise approach with immediate unattended and delayed unattended automated blood pressure measurements during household-based screening: a diagnostic accuracy study in Lesotho.

Background: WHO introduced the STEPwise approach to surveillance (STEPS) to monitor trends in non-communicable diseases. For arterial hypertension, the STEPS protocol takes the average of the last two out of three standard blood pressure measurements (SBPM). This study assesses the diagnostic accuracy of SBPM, same-day and next-day unattended automated measurement (uABP), with 24 h ambulatory measurement (24 h-ABPM) as reference. Methods: This diagnostic accuracy study was done within a population-based household survey on cardiovascular risk factors in two districts in Northern Lesotho. Adults (aged ≥ 18 years) with elevated SBPM (defined as ≥140/90 mmHg), and 2:1 age- and sex-matched participants with normal SBPM during the survey were recruited. Following SBPM, first uABP readings were obtained on survey day. Afterwards, participants received a 24 h-ABPM device. Second uABP readings were taken 24 h later, after retrieval of the 24 h-ABPM. The main outcome was overall diagnostic accuracy of all screening measurements (SBPM, first uABP, and second uABP), determined using area under the receiver operating characteristic curve (AUROC), with 24 h-ABPM as a reference. Findings: Between November 2, 2021 and August 31, 2022, 275 participants (mean age 58 years (SD: 16 years), 163 (59%) female) were enrolled, 183 of whom had elevated and 92 had normal SBPM. Mean difference between systolic daytime 24 h-ABPM and screening measurements was highest for SBPM (mean difference: -13 mmHg; 95% CI: -14 to -11). Mean difference between diastolic daytime 24 h-ABPM and diastolic SBPM was -2 mmHg (95% CI: -4 to -1), whereas no difference was found for mean diastolic first uABP (mean difference: -1 mmHg; 95% CI: -2.0 to 0.3); and mean diastolic second uABP (mean difference: 1.0 mmHg; 95% CI: -0.4 to 2.3). White coat hypertension was highest with SBPM (55 [20%]), followed by first uABP (27 [9.8%]), and second uABP (18 [6.5%]). Using systolic daytime 24 h-ABPM as a reference, the uABPs had higher AUROC (first uABP: 87% [95% CI: 83-91]; second uABP: 88% [95% CI: 84-92]); SBPM: (79% [95% CI: 74-85]). This difference was significant between first uABP and SBPM (P = 0.0024), and between second uABP and SBPM (P = 0.0017). Interpretation: uABP had better diagnostic performance than SBPM. Integration of uABP into STEPS protocol should be considered. Funding: Swiss Agency for Development and Cooperation under the ComBaCaL project, and the World Diabetes Foundation.

Prevalence and determinants of cardiovascular risk factors in Lesotho: a population-based survey.

BACKGROUND: There are no recent data on the prevalence of cardiovascular risk factors (CVDRFs) in Lesotho. This study aims to assess the prevalence of CVDRFs and their determinants. METHODS: We conducted a household-based, cross-sectional survey among adults ≥18 y of age in 120 randomly sampled clusters in two districts. RESULTS: Among 6061 participants, 52.2% were female and their median age was 39 y (interquartile range 27-58). The overall prevalence of overweight, diabetes, elevated blood pressure (BP) and tobacco use was 39.9%, 5.3%, 21.6% and 24.9%, respectively. Among participants, 34.6% had none, 45.2% had one and 20.2% had two or more CVDRFs. Women were more likely to have two or more CVDRFs (20.7% vs 12.3%). Overall, 7.5% of participants had elevated total cholesterol, 52.7% had low high-density lipoprotein cholesterol and 1.6% had elevated low-density lipoprotein cholesterol. Among younger participants (18-29 y), 16.1% reported tobacco use, 28.6% were overweight, 1.5% had diabetes and 3.5% had elevated BP. Household wealth positively correlated with the prevalence of elevated BP, overweight and diabetes, whereas tobacco use was higher among people in the lowest three wealth quintiles. CONCLUSIONS: CVDRFs are highly prevalent in Lesotho across age and sex groups, underlining the importance of strengthening prevention and care programs in Lesotho and similar settings in southern Africa.

Understanding diarrhoeal diseases in response to climate variability and drought in Cape Town, South Africa: a mixed methods approach.

BACKGROUND: The climate of southern Africa is expected to become hotter and drier with more frequent severe droughts and the incidence of diarrhoea to increase. From 2015 to 2018, Cape Town, South Africa, experienced a severe drought which resulted in extreme water conservation efforts. We aimed to gain a more holistic understanding of the relationship between diarrhoea in young children and climate variability in a system stressed by water scarcity. METHODS: Using a mixed-methods approach, we explored diarrhoeal disease incidence in children under 5 years between 2010 to 2019 in Cape Town, primarily in the public health system through routinely collected diarrhoeal incidence and weather station data. We developed a negative binomial regression model to understand the relationship between temperature, precipitation, and relative humidity on incidence of diarrhoea with dehydration. We conducted in-depth interviews with stakeholders in the fields of health, environment, and human development on perceptions around diarrhoea and health-related interventions both prior to and over the drought, and analysed them through the framework method. RESULTS: From diarrhoeal incidence data, the diarrhoea with dehydration incidence decreased over the decade studied, e.g. reduction of 64.7% in 2019 [95% confidence interval (CI): 5.5-7.2%] compared to 2010, with no increase during the severe drought period. Over the hot dry diarrhoeal season (November to May), the monthly diarrhoea with dehydration incidence increased by 7.4% (95% CI: 4.5-10.3%) per 1 °C increase in temperature and 2.6% (95% CI: 1.7-3.5%) per 1% increase in relative humidity in the unlagged model. Stakeholder interviews found that extensive and sustained diarrhoeal interventions were perceived to be responsible for the overall reduction in diarrhoeal incidence and mortality over the prior decade. During the drought, as diarrhoeal interventions were maintained, the expected increase in incidence in the public health sector did not occur. CONCLUSIONS: We found that that diarrhoeal incidence has decreased over the last decade and that incidence is strongly influenced by local temperature and humidity, particularly over the hot dry season. While climate change and extreme weather events especially stress systems supporting vulnerable populations such as young children, maintaining strong and consistent public health interventions helps to reduce negative health impacts.

Starting at the community: Treatment-seeking pathways of children with suspected severe malaria in Uganda.

Community health workers (CHW) usually refer children with suspected severe malaria to the nearest public health facility or a designated public referral health facility (RHF). Caregivers do not always follow this recommendation. This study aimed at identifying post-referral treatment-seeking pathways that lead to appropriate antimalarial treatment for children less than five years with suspected severe malaria. An observational study in Uganda enrolled children below five years presenting to CHWs with signs of severe malaria. Children were followed up 28 days after enrolment to assess their condition and treatment-seeking history, including referral advice and provision of antimalarial treatment from visited providers. Of 2211 children included in the analysis, 96% visited a second provider after attending a CHW. The majority of CHWs recommended caregivers to take their child to a designated RHF (65%); however, only 59% followed this recommendation. Many children were brought to a private clinic (33%), even though CHWs rarely recommended this type of provider (3%). Children who were brought to a private clinic were more likely to receive an injection than children brought to a RHF (78% vs 51%, p<0.001) and more likely to receive the second or third-line injectable antimalarial (artemether: 22% vs. 2%, p<0.001, quinine: 12% vs. 3%, p<0.001). Children who only went to non-RHF providers were less likely to receive an artemisinin-based combination therapy (ACT) than children who attended a RHF (odds ratio [OR] = 0.64, 95% CI 0.51-0.79, p<0.001). Children who did not go to any provider after seeing a CHW were the least likely to receive an ACT (OR = 0.21, 95% CI 0.14-0.34, p<0.001). Health policies should recognise local treatment-seeking practices and ensure adequate quality of care at the various public and private sector providers where caregivers of children with suspected severe malaria actually seek care.

Correction: Health worker compliance with severe malaria treatment guidelines in the context of implementing pre-referral rectal artesunate in the Democratic Republic of the Congo, Nigeria, and Uganda: An operational study.

[This corrects the article DOI: 10.1371/journal.pmed.1004189.].

"Climate Change and Health?": Knowledge and Perceptions among Key Stakeholders in Puducherry, India.

Climate change has far-reaching impacts on human health, with low- and middle-income countries, including India, being particularly vulnerable. While there have been several advances in the policy space with the development of adaptation plans, little remains known about how stakeholders who are central to the strengthening and implementation of these plans perceive this topic. We conducted a qualitative study employing key interviews with 16 medical doctors, researchers, environmentalists and government officials working on the climate change agenda from Puducherry, India. The findings were analysed using the framework method, with data-driven thematic analysis. We elucidated that despite elaborating the direct and indirect impacts of climate change on health, there remains a perceived gap in education and knowledge about the topic among participants. Knowledge of the public health burden and vulnerabilities influenced the perceived health risks from climate change, with some level of scepticism on the impacts on non-communicable diseases, such as cardiovascular diseases. There was also a felt need for multi-level awareness and intervention programmes targeting all societal levels along with stakeholder recommendations to fill these gaps. The findings of this study should be taken into consideration for strengthening the region's climate change and health adaptation policy. In light of limited research on this topic, our study provides an improved understanding of how key stakeholders perceive the impacts of climate change on health in India.

Health worker compliance with severe malaria treatment guidelines in the context of implementing pre-referral rectal artesunate in the Democratic Republic of the Congo, Nigeria, and Uganda: An operational study.

BACKGROUND: For a full treatment course of severe malaria, community-administered pre-referral rectal artesunate (RAS) should be completed by post-referral treatment consisting of an injectable antimalarial and oral artemisinin-based combination therapy (ACT). This study aimed to assess compliance with this treatment recommendation in children under 5 years. METHODS AND FINDINGS: This observational study accompanied the implementation of RAS in the Democratic Republic of the Congo (DRC), Nigeria, and Uganda between 2018 and 2020. Antimalarial treatment was assessed during admission in included referral health facilities (RHFs) in children under 5 with a diagnosis of severe malaria. Children were either referred from a community-based provider or directly attending the RHF. RHF data of 7,983 children was analysed for appropriateness of antimalarials; a subsample of 3,449 children was assessed additionally for dosage and method of ACT provision (treatment compliance). A parenteral antimalarial and an ACT were administered to 2.7% (28/1,051) of admitted children in Nigeria, 44.5% (1,211/2,724) in Uganda, and 50.3% (2,117/4,208) in DRC. Children receiving RAS from a community-based provider were more likely to be administered post-referral medication according to the guidelines in DRC (adjusted odds ratio (aOR) = 2.13, 95% CI 1.55 to 2.92, P < 0.001), but less likely in Uganda (aOR = 0.37, 95% CI 0.14 to 0.96, P = 0.04) adjusting for patient, provider, caregiver, and other contextual factors. While in DRC, inpatient ACT administration was common, ACTs were often prescribed at discharge in Nigeria (54.4%, 229/421) and Uganda (53.0%, 715/1,349). Study limitations include the unfeasibility to independently confirm the diagnosis of severe malaria due to the observational nature of the study. CONCLUSIONS: Directly observed treatment was often incomplete, bearing a high risk for partial parasite clearance and disease recrudescence. Parenteral artesunate not followed up with oral ACT constitutes an artemisinin monotherapy and may favour the selection of resistant parasites. In connection with the finding that pre-referral RAS had no beneficial effect on child survival in the 3 study countries, concerns about an effective continuum of care for children with severe malaria seem justified. Stricter compliance with the WHO severe malaria treatment guidelines is critical to effectively manage this disease and further reduce child mortality. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03568344).

Health system readiness and the implementation of rectal artesunate for severe malaria in sub-Saharan Africa: an analysis of real-world costs and constraints.

BACKGROUND: Rectal artesunate, an efficacious pre-referral treatment for severe malaria in children, was deployed at scale in Uganda, Nigeria, and DR Congo. In addition to distributing rectal artesunate, implementation required additional investments in crucial but neglected components in the care for severe malaria. We examined the real-world costs and constraints to rectal artesunate implementation. METHODS: We collected primary data on baseline health system constraints and subsequent rectal artesunate implementation expenditures. We calculated the equivalent annual cost of rectal artesunate implementation per child younger than 5 years at risk of severe malaria, from a health system perspective, separating neglected routine health system components from incremental costs of rectal artesunate introduction. FINDINGS: The largest baseline constraints were irregular health worker supervisions, inadequate referral facility worker training, and inadequate malaria commodity supplies. Health worker training and behaviour change campaigns were the largest startup costs, while supervision and supply chain management accounted for most annual routine costs. The equivalent annual costs of preparing the health system for managing severe malaria with rectal artesunate were US$2·63, $2·20, and $4·19 per child at risk and $322, $219, and $464 per child treated in Uganda, Nigeria, and DR Congo, respectively. Strengthening the neglected, routine health system components accounted for the majority of these costs at 71·5%, 65·4%, and 76·4% of per-child costs, respectively. Incremental rectal artesunate costs accounted for the minority remainder. INTERPRETATION: Although rectal artesunate has been touted as a cost-effective pre-referral treatment for severe malaria in children, its real-world potential is limited by weak and under-financed health system components. Scaling up rectal artesunate or other interventions relying on community health-care providers only makes sense alongside additional, essential health system investments sustained over the long term. FUNDING: Unitaid. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Acceptability of pre-referral rectal artesunate for severe malaria in children under 5 years by health workers and caregivers in the Democratic Republic of the Congo, Nigeria and Uganda.

BACKGROUND: For children below 6 years with suspected severe malaria attending a health care provider unable to provide parenteral malaria treatment, pre-referral rectal artesunate (RAS) is recommended by the World Health Organization to prevent death and disability. A number of African countries are in the process of rolling out quality-assured RAS for pre-referral treatment of severe malaria at community-level. The success of RAS depends, among other factors, on the acceptability of RAS in the communities where it is being rolled-out. Yet to date, there is limited literature on RAS acceptability. This study aimed to determine the acceptability of RAS by health care providers and child caregivers in communities where quality assured RAS was rolled out. This study was nested within the comprehensive multi-country observational research project Community Access to Rectal Artesunate for Malaria (CARAMAL), implemented in the Democratic Republic of the Congo (DRC), Nigeria, and Uganda between 2018 and 2020. Data from three different sources were analysed to understand RAS acceptability: interviews with health workers during three health care provider surveys (N = 341 community health workers and 467 primary health facility workers), with caregivers of children < 5 years of age during three household surveys (N = 9332 caregivers), and with caregivers of children < 5 years of age who were treated with RAS and enrolled in the CARAMAL Patient Surveillance System (N = 3645 caregivers). RESULTS: RAS acceptability was high among all interviewed stakeholders in the three countries. After the roll-out of RAS, 97-100% heath care providers in DRC, 98-100% in Nigeria and 93-100% in Uganda considered RAS as very good or good. Majority of caregivers whose children had received RAS for pre-referral management of severe malaria indicated that they would want to get the medication again, if their child had the same illness (99.8% of caregivers in DRC, 100% in Nigeria and 99.9% in Uganda). In three household surveys, 67-80% of caregivers whose children had not previously received RAS considered the medication as useful. CONCLUSION: RAS was well accepted by health workers and child caregivers in DRC, Nigeria and Uganda. Acceptability is unlikely to be an obstacle to the large-scale roll-out of RAS in the studied settings.

Effectiveness of rectal artesunate as pre-referral treatment for severe malaria in children under 5 years of age: a multi-country observational study.

BACKGROUND: To prevent child deaths from severe malaria, early parenteral treatment is essential. Yet, in remote rural areas, accessing facilities offering parenteral antimalarials may be difficult. A randomised controlled trial found pre-referral treatment with rectal artesunate (RAS) to reduce deaths and disability in children who arrived at a referral facility with delay. This study examined the effectiveness of pre-referral RAS treatment implemented through routine procedures of established community-based health care systems. METHODS: An observational study accompanied the roll-out of RAS in the Democratic Republic of the Congo (DRC), Nigeria and Uganda. Children <5 years of age presenting to a community-based health provider with a positive malaria test and signs of severe malaria were enrolled and followed up during admission and after 28 days to assess their health status and treatment history. The primary outcome was death; covariates of interest included RAS use, referral completion, and post-referral treatment. RESULTS: Post-roll-out, RAS was administered to 88% of patients in DRC, 52% in Nigeria, and 70% in Uganda. The overall case fatality rate (CFR) was 6.7% (135/2011) in DRC, 11.7% (69/589) in Nigeria, and 0.5% (19/3686) in Uganda; 13.8% (865/6286) of patients were sick on day 28. The CFR was higher after RAS roll-out in Nigeria (16.1 vs. 4.2%) and stable in DRC (6.7 vs. 6.6%) and Uganda (0.7 vs. 0.3%). In DRC and Nigeria, children receiving RAS were more likely to die than those not receiving RAS (aOR=3.06, 95% CI 1.35-6.92 and aOR=2.16, 95% CI 1.11-4.21, respectively). Only in Uganda, RAS users were less likely to be dead or sick at follow-up (aOR=0.60, 95% CI 0.45-0.79). Post-referral parenteral antimalarials plus oral artemisinin-based combination therapy (ACT), a proxy for appropriate post-referral treatment, was protective. However, in referral health facilities, ACT was not consistently administered after parenteral treatment (DRC 68.4%, Nigeria 0%, Uganda 70.9%). CONCLUSIONS: Implemented at scale to the recommended target group, pre-referral RAS had no beneficial effect on child survival in three highly malaria-endemic settings. RAS is unlikely to reduce malaria deaths unless health system issues such as referral and quality of care at all levels are addressed. TRIAL REGISTRATION: The study is registered on ClinicalTrials.gov : NCT03568344.

Key factors predicting suspected severe malaria case management and health outcomes: an operational study in the Democratic Republic of the Congo.

BACKGROUND: Evidence suggests that pre-referral Rectal Artesunate (RAS) can be a life-saving intervention for severe malaria in remote settings in Africa. Recognition of danger signs indicative of severe malaria is critical for prompt and appropriate case management. METHODS: This was an observational study conducted in three Health Zones of the Democratic Republic of the Congo to determine the distribution of dangers signs for severe malaria and assess their impact on RAS use, referral completion, injectable treatment and ACT provision, and health outcomes including death. An individual-level analysis was carried out, using multilevel-mixed effects logistic regression models. Severely ill febrile children < 5 years seeking care from community-based healthcare providers were recruited into a patient surveillance system based on the presence of key danger signs. Clinical and case management data were collected comprehensively over a 28 days period. Treatment seeking was elicited and health outcomes assessed during 28 days home visits. RESULTS: Overall, 66.4% of patients had iCCM general danger signs. Age of 2-5 years and iCCM general danger signs predicted RAS use (aOR = 2.77, 95% CI 2.04-3.77). RAS administration positively affected referral completion (aOR = 0.63, 95% CI 0.44-0.92). After RAS rollout, 161 children died (case fatality ratio: 7.1%, 95% CI 6.1-8.2). RAS improved the health status of the children on Day 28 (aOR = 0.64, 95% CI 0.45-0.92) and there was a non-significant trend that mortality was higher in children not receiving RAS (aOR = 1.50, 95% CI 0.86-2.60). Full severe malaria treatment at the RHF including injectable anti-malarial and a course of ACT was highly protective against death (aOR = 0.26, 95% CI 0.09-0.79). CONCLUSIONS: The main findings point towards the fact that danger signs are reasonably well recognized by health provider at the primary care level, and that RAS could influence positively health outcomes of such severe disease episodes and death. Its effectiveness is hampered by the insufficient quality of care at RHF, especially the provision of a full course of ACT following parenteral treatment. These are simple but important findings that requires urgent action by the health system planners and implementers.

Care Seeking and Treatment of Febrile Children with and without Danger Signs of Severe Disease in Northern Uganda: Results from Three Household Surveys (2018-2020).

Identification, stabilization, and prompt referral of children with signs of severe febrile disease (danger signs) in rural communities are crucial for preventing complications and death from severe malaria, pneumonia, and diarrhea. We set out to determine the treatment-seeking practices and treatment patterns for children < 5 years of age with an acute febrile illness, with or without danger signs of severe disease, in a highly malaria-endemic area of northern Uganda. Three household surveys were conducted from November through December each year in 2018, 2019, and 2020. Overall, 30% of the children in the study were reported to have had a WHO-classified danger sign including convulsions, unconsciousness/unusually sleepy, inability to feed or drink, and vomiting everything. Only half of the children in this study sought care from a health provider. However, significantly more children with danger signs of severe disease sought and received treatment and diagnostics from a health provider, compared with those without danger signs (adjusted odds ratio: 1.6, 95% confidence interval: 1.2-2.0; P < 0.01). In the total population studied, care seeking in the public sector was 26% and similar to care seeking in the private sector (24%). Community health workers were used as the first source of care by 12% of the children. Approximately 38% of the children who were reported to have danger signs of severe disease requiring prompt referral and treatment did not seek care from a health provider. Understanding and addressing barriers to accessing healthcare could contribute to better treatment seeking practices.

Prereferral rectal artesunate and referral completion among children with suspected severe malaria in the Democratic Republic of the Congo, Nigeria and Uganda.

INTRODUCTION: Children who receive prereferral rectal artesunate (RAS) require urgent referral to a health facility where appropriate treatment for severe malaria can be provided. However, the rapid improvement of a child's condition after RAS administration may influence a caregiver's decision to follow this recommendation. Currently, the evidence on the effect of RAS on referral completion is limited. METHODS: An observational study accompanied the roll-out of RAS in three malaria endemic settings in the Democratic Republic of the Congo (DRC), Nigeria and Uganda. Community health workers and primary health centres enrolled children under 5 years with suspected severe malaria before and after the roll-out of RAS. All children were followed up 28 days after enrolment to assess their treatment-seeking pathways. RESULTS: Referral completion was 67% (1408/2104) in DRC, 48% (287/600) in Nigeria and 58% (2170/3745) in Uganda. In DRC and Uganda, RAS users were less likely to complete referral than RAS non-users in the pre-roll-out phase (adjusted OR (aOR)=0.48, 95% CI 0.30 to 0.77 and aOR=0.72, 95% CI 0.58 to 0.88, respectively). Among children seeking care from a primary health centre in Nigeria, RAS users were less likely to complete referral compared with RAS non-users in the post-roll-out phase (aOR=0.18, 95% CI 0.05 to 0.71). In Uganda, among children who completed referral, RAS users were significantly more likely to complete referral on time than RAS non-users enrolled in the pre-roll-out phase (aOR=1.81, 95% CI 1.17 to 2.79). CONCLUSIONS: The findings of this study raise legitimate concerns that the roll-out of RAS may lead to lower referral completion in children who were administered prereferral RAS. To ensure that community-based programmes are effectively implemented, barriers to referral completion need to be addressed at all levels. Alternative effective treatment options should be provided to children unable to complete referral. TRIAL REGISTRSTION NUMBER: NCT03568344; ClinicalTrials.gov.

Assessment of a viral load result-triggered automated differentiated service delivery model for people taking ART in Lesotho (the VITAL study): Study protocol of a cluster-randomized trial.

INTRODUCTION: To sustainably provide good quality care to increasing numbers of people living with HIV (PLHIV) receiving antiretroviral therapy (ART) in resource-limited settings, care delivery must shift from a "one-size-fits-all" approach to differentiated service delivery models. Such models should reallocate resources from PLHIV who are doing well to groups of PLHIV who may need more attention, such as those with treatment failure. The VIral load Triggered ART care Lesotho (VITAL) trial assesses a viral load (VL)-, participant's preference-informed, electronic health (eHealth)-supported, automated differentiated service delivery model (VITAL model). With VITAL, we aim to assess if the VITAL model is at least non-inferior to the standard of care in the proportion of participants engaged in care with viral suppression at 24 months follow-up and if it is cost-saving. METHODS: The VITAL trial is a pragmatic, multicenter, cluster-randomized, non-blinded, non-inferiority trial with 1:1 allocation conducted at 18 nurse-led, rural health facilities in two districts of northern Lesotho, enrolling adult PLHIV taking ART. In intervention clinics, providers are trained to implement the VITAL model and are guided by a clinical decision support tool, the VITALapp. VITAL differentiates care according to VL results, clinical characteristics, sub-population and participants' and health care providers' preferences. EXPECTED OUTCOMES: Evidence on the effect of differentiated service delivery for PLHIV on treatment outcomes is still limited. This pragmatic cluster-randomized trial will assess if the VITAL model is at least non-inferior to the standard of care and if it is cost saving. TRIAL REGISTRATION: The study has been registered with clinicaltrials.gov (Registration number NCT04527874; August 27, 2020).