Malaria Chemoprevention for the Post-Discharge Management of Paediatric Severe Anaemia in Malaria Endemic Areas of Africa

Children hospitalised with severe anaemia in malaria-endemic areas are at high risk of readmission or death within six months post-discharge. No strategy specifically addresses this post-discharge period. This thesis aims to provide evidence of the burden of post-discharge mortality and morbidity among children less than five years of age who are admitted with all-cause severe anaemia and other syndromes and living in malaria-endemic areas of Africa. We also report the results of a malaria chemoprevention trial for the post-discharge management of severe anaemia. In the first study, we conducted a retrospective cohort analysis using data collected between 2008 and 2013 from continuous paediatric in-hospital surveillance and population-based surveillance in western Kenya. During this period, 3,639 hospital admissions involving 4,423 different diagnoses were recorded. Overall, in-hospital mortality was 2.8% and the post-discharge mortality by three, six and twelve months among the 3,538 survivors was 7.6%, 9.4%, and 12.4%, respectively. Admissions with severe acute malnutrition and severe anaemia were associated with the highest post-discharge mortality in the first six months. Severe anaemia was associated with a significantly higher odds of six-month post-discharge mortality than in-hospital mortality (Mantel-Haenszel odds ratio [MHOR]=2.02, 95% CI 1.19-4.05, p=0.011). In the second study, we conducted a systematic review and meta-analysis to determine the pooled risks of morbidity and mortality in the post-discharge period among children admitted with severe anaemia versus other syndromes in malaria-endemic areas in Africa. Children admitted with severe anaemia were found to have higher odds of dying within six months post-discharge than during the in-hospital stay (N=4, MHOR=1.44, 95% CI 1.07-1.92, p<0.0157, I2=0.8%) and they were twice as likely to die by 6 months post-discharge compared with children admitted without severe anaemia (N=4, Relative Risk [RR]=2.80, 95% CI 1.61-4.86, p<0.0001, I2=73.1%). Severe acute malnutrition was also associated with increased post-discharge mortality compared to children admitted without severe anaemia or malnutrition (N=2, RR=4.27, 95% CI 2.42-7.55, p<0.0001, I2=76.8). The risk of readmission was also higher among children admitted with severe anaemia compared to other syndromes (RR=3.05, 95% CI 1.12-8.35, p<0.001, I2=0.0%). The third study was a randomised placebo-controlled trial in nine hospitals in Kenya and Uganda to determine if three months of post-discharge malaria chemoprevention (PMC) with monthly 3-day treatment courses of dihydroartemisinin-piperaquine (DP) reduced the rate of all-cause readmissions and deaths by six months post-discharge (primary outcome). Children aged <5 years with admission haemoglobin of <5g/dL were eligible. A 3-day course with artemether-lumefantrine was given to all children at discharge. Children were then randomised to receive DP or placebo-DP at two, six, and ten weeks post-discharge and followed until week 26 inclusive. There were 184 primary outcome events in the PMC arm and 316 in the placebo arm (HR=0.65, 95% CI 0.54-0.78, p<0.001). The HR was 0.30 (95% CI 0.22-0.42, p<0.001) during the PMC-intervention period (2-14 weeks) and 1.13 (95% CI 0.87-1.47, p=0.35) during the post-intervention period (15-26 weeks), p<0.001). This thesis shows that children admitted with severe anaemia and other acute conditions are at a high risk of post-discharge mortality and morbidity. Admission with all-cause severe anaemia in this setting is associated with a doubling of the risk of post-discharge mortality compared to other acute conditions. Malaria chemoprevention with three monthly courses of DP is a promising tool for post-discharge management of children recently admitted with severe anaemia in malaria-endemic areas

Human Direct Skin Feeding Versus Membrane Feeding to Assess the Mosquitocidal Efficacy of High-Dose Ivermectin (IVERMAL Trial)

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Efficacy and Safety of High-Dose Ivermectin for Reducing Malaria Transmission (IVERMAL): Protocol for a Double-Blind, Randomized, Placebo-Controlled, Dose-Finding Trial in Western Kenya

Background: Innovative approaches are needed to complement existing tools for malaria elimination. Ivermectin is a broad spectrum antiparasitic endectocide clinically used for onchocerciasis and lymphatic filariasis control at single doses of 150‐200 mcg/kg. It also shortens the lifespan of mosquitoes that feed on individuals recently treated with ivermectin. However, the effect after a 150‐200 mcg/kg oral dose is short‐lived (6‐11 days). Modelling suggests higher doses, that prolong the mosquitocidal effects, are needed to make a significant contribution to malaria elimination. Ivermectin has a wide therapeutic index and previous studies have shown doses up to 2,000 mcg/kg, i.e. 10x the US Food and Drug Administration approved dose, are well tolerated and safe; the highest dose used for onchocerciasis is single‐dose 800 mcg/kg. Objective: To determine the safety, tolerability, and efficacy of ivermectin 0, 300, 600 mcg/kg/day for 3 days, when provided with a standard 3‐day course of the antimalarial dihydroartemisinin‐piperaquine, on mosquito survival. Methods: This is a double‐blind, randomised, placebo‐controlled, parallel‐group, 3‐arm, dose‐finding trial in adults with uncomplicated malaria. Monte Carlo simulations based on pharmacokinetic modelling were performed to determine the optimum dosing regimens to be tested. Modelling showed that a 3‐day regimen of 600 mcg/kg/day achieves similar median (5‐95 percentiles) Cmax concentrations of ivermectin to single‐dose of 800 mcg/kg, while increasing the median time above the LC50 (16 ng/mL) from 1.9 days (1.0‐5.7) to 6.8 (3.8‐13.4) days. The 300 mcg/kg/day dose was chosen at 50% of the higher dose to allow evaluation of the dose response. Mosquito survival will be assessed daily up to 28 days in laboratory‐reared Anopheles gambiae s.s. populations fed on patients’ blood taken at days 0, 2 (Cmax), 7 (primary outcome), 10, 14, 21, and 28 after the start of treatment. Safety outcomes include QT‐prolongation and mydriasis. The trial will be conducted in 6 health facilities in western Kenya and requires a sample size of 141 participants (47 per arm). Sub‐studies include: (1) rich pharmacokinetics and (2) direct skin vs membrane feeding assays. Results: Recruitment started July 20th, 2015. Data collection was completed on July 2nd, 2016. Unblinding and analysis will commence once the database has been completed, cleaned and locked. Discussion: High‐dose ivermectin, if found to be safe and well tolerated, might offer a promising new tool for malaria elimination. Trial registration: ClinicalTrials.gov: NCT02511353 (July 15, 2015)

Policy uptake and implementation of the RTS,S/AS01 malaria vaccine in sub-Saharan African countries: status 2 years following the WHO recommendation

In October 2021, the WHO recommended the world’s first malaria vaccine—RTS,S/AS01—to prevent malaria in children living in areas with moderate-to-high transmission in sub-Saharan Africa (SSA). A second malaria vaccine, R21/Matrix-M, was recommended for use in October 2023 and added to the WHO list of prequalified vaccines in December 2023. This study analysis assessed the country status of implementation and delivery strategies for RTS,S/AS01 by searching websites for national malaria policies, guidelines and related documents. Direct contact with individuals working in malaria programmes was made to obtain documents not publicly available. 10 countries had documents with information relating to malaria vaccine implementation, 7 referencing RTS,S/AS01 and 3 (Burkina Faso, Kenya and Nigeria) referencing RTS,S/AS01 and R21/Matrix-M. Five other countries reported plans for malaria vaccine roll-out without specifying which vaccine. Ghana, Kenya and Malawi, which piloted RTS,S/AS01, have now integrated the vaccine into routine immunisation services. Cameroon and Burkina Faso are the first countries outside the pilot countries to incorporate the vaccine into national immunisation services. Uganda plans a phased RTS,S/AS01 introduction, while Guinea plans to first pilot RTS,S/AS01 in five districts. The RTS,S/AS01 schedule varied by country, with the first dose administered at 5 or 6 months in all countries but the fourth dose at either 18, 22 or 24 months. SSA countries have shown widespread interest in rolling out the malaria vaccine, the Global Alliance for Vaccines and Immunization having approved financial support for 20 of 30 countries which applied as of March 2024. Limited availability of RTS,S/AS01 means that some approved countries will not receive the required doses. Vaccine availability and equity must be addressed even as R21/Matrix-M becomes available

Economic evaluation of postdischarge malaria chemoprevention in preschool children treated for severe anaemia in Malawi, Kenya, and Uganda: A cost-effectiveness analysis

Background Children hospitalised with severe anaemia in malaria-endemic areas are at a high risk of dying or being readmitted within six months of discharge. A trial in Kenya and Uganda showed that three months of postdischarge malaria chemoprevention (PDMC) with monthly dihydroartemisinin-piperaquine (DP) substantially reduced this risk. The World Health Organization recently included PDMC in its malaria chemoprevention guidelines. We conducted a cost-effectiveness analysis of community-based PDMC delivery (supplying all three PDMC-DP courses to caregivers at discharge to administer at home), facility-based PDMC delivery (monthly dispensing of PDMC-DP at the hospital), and the standard of care (no PDMC). Methods We combined data from two recently completed trials; one placebo-controlled trial in Kenya and Uganda collecting efficacy data (May 6, 2016 until November 15, 2018; n=1049), and one delivery mechanism trial from Malawi collecting adherence data (March 24, 2016 until October 3, 2018; n=375). Cost data were collected alongside both trials. Three Markov decision models, one each for Malawi, Kenya, and Uganda, were used to compute incremental cost-effectiveness ratios expressed as costs per quality-adjusted life-year (QALY) gained. Deterministic and probabilistic sensitivity analyses were performed to account for uncertainty. Findings Both PDMC strategies were cost-saving in each country, meaning less costly and more effective in increasing health-adjusted life expectancy than the standard of care. The estimated incremental cost savings for community-based PDMC compared to the standard of care were US$ 22·10 (Malawi), 38·52 (Kenya), and 26·23 (Uganda) per child treated. The incremental effectiveness gain using either PDMC strategy varied between 0·3 and 0·4 QALYs. Community-based PDMC was less costly and more effective than facility-based PDMC. These results remained robust in sensitivity analyses. Interpretation PDMC under implementation conditions is cost-saving. Caregivers receiving PDMC at discharge is a cost-effective delivery strategy for implementation in malaria-endemic southeastern African settings

Post-Discharge Risk of Mortality in Children Under Five Years of Age in Western Kenya: A Retrospective Cohort Study

Limited evidence suggests that children in sub-Saharan Africa hospitalized with all-cause severe anemia or severe acute malnutrition (SAM) are at high risk of dying in the first few months post-discharge. We aimed to compare the risks of post-discharge mortality by health condition among hospitalized children in an area with high malaria transmission in western Kenya. We conducted a retrospective cohort study among recently discharged children aged <5 years using mortality data from a Health and Demographic Surveillance System that included household and pediatric in-hospital surveillance. Cox regression was used to compare post-discharge mortality. Between 2008 and 2013, overall, in-hospital mortality was 2∙8% (101/3,639). The mortality by six months post-discharge (primary outcome) was 6.2% (159/2,556) and highest in children with severe acute malnutrition (SAM) (21·6%), followed by severe anemia (15·5%), severe pneumonia (5·6%), ‘other conditions’ (5·6%), and severe malaria (0·7%). Overall, the six-month post-discharge mortality in children hospitalized with SAM (HR=3·95, 2·60-6·00, p<0∙001) or severe anemia (HR=2·55, 1·74-3·71, p<0.001) was significantly higher than in children without these conditions. Severe malaria was associated with lower 6-month post-discharge mortality (HR=0·33, 0·21-0·53, p<0.001). The odds of dying by six months post-discharge tended to be higher than during the in-hospital period for all children, except for those admitted with severe malaria. The first six months post-discharge is a high-risk period for mortality among children admitted with severe anemia and SAM in western Kenya. Strategies to address this risk period are urgently needed

Diagnostic performance of loop-mediated isothermal amplification and ultra-sensitive rapid diagnostic tests for malaria screening among pregnant women in Kenya

Background: Screen-and-treat strategies with sensitive diagnostic tests may reduce malaria-associated adverse pregnancy outcomes. We conducted a diagnostic accuracy study to evaluate new point-of-care tests to screen pregnant women for malaria at their first antenatal visit in western Kenya. Methods: Consecutively women were tested for Plasmodium infection by expert-microscopy, conventional rapid diagnostic test (cRDT), ultra-sensitive RDT (usRDT), and loop-mediated isothermal amplification (LAMP). Photo-induced electron-transfer polymerase-chain-reaction (PET-PCR) served as the reference standard. Diagnostic performance was calculated and modelled at low parasite densities. Results: Between May-September 2018, 172 out of 482 screened participants (35.7%) were PET-PCR positive. Relative to PET-PCR, expert-microscopy was least sensitive (40.1%, 95% CI 32.7-47.9), followed by cRDT (49.4%, 41.7-57.1), usRDT (54.7%, 46.9-62.2), and LAMP (68.6%, 61.1-75.5). Test sensitivities were comparable in febrile women (N=90). Among afebrile women (N=392), the geometric- mean parasite density was 29 parasites/μL and LAMP (sensitivity=61.9%) and usRDT (43.2%) detected 1.74 (1.31-2.30) and 1.21 (0.88-2.21) more infections than cRDT (35.6%). Per our model, tests performed similarly at densities >200 parasites/μL. At 50 parasites/μL, the sensitivities were 45%, 56%, 62% and 74% with expert-microscopy, cRDT, usRDT, and LAMP, respectively. Conclusions: This first-generation usRDT provided moderate improvement in detecting low-density infections in afebrile pregnant women compared to cRDTs

Post-discharge Malaria Chemoprevention in Children Admitted with Severe Anaemia in Malaria-Endemic Settings in Africa: A systematic review and Individual Patient Data meta-analysis of randomised controlled trials

Background: Severe anaemia is associated with high in-hospital mortality among young children. In malaria-endemic areas, surviving children also have an increased risk of mortality or readmission after hospital discharge. We conducted an individual patient data (IPD) meta-analysis to determine the efficacy of monthly post-discharge malaria chemoprevention (PDMC) in children recovering from severe anaemia. Methods: Following PRISMA-IPD guidelines, we searched multiple databases, without time or language restrictions, for randomised controlled trials comparing monthly PDMC with placebo or standard-of-care among children admitted with severe anaemia in malaria-endemic Africa. Trials using daily or weekly malaria prophylaxis were not eligible. Fixed-effects two-stage meta-analysis of risk ratios (RR) was used to generate pooled effect estimates for mortality. Recurrent time-to-event data were analysed using one-stage mixed-effects Prentice-Williams-Peterson Total-Time models to obtain hazard ratios (HRs). This study is registered with PROSPERO-CRD42022308791. Findings: Three double-blind placebo-controlled trials involving 3,663 children with severe anaemia fulfilled the eligibility criteria; 3,507 (95.7%) contributed to the modified intention-to-treat analysis. They received either monthly sulfadoxine-pyrimethamine until the end of the malaria transmission season (average 3.1 courses/child) (N=1,085, the Gambia), monthly artemether-lumefantrine given at the end of the 4th and 8th week post-discharge (N=1,373, Malawi), or monthly dihydroartemisinin-piperaquine given at the end of the 2nd, 6th, and 10th week post-discharge (N=1,049, Uganda and Kenya). During the period of chemoprevention, PDMC was associated with a 77% reduction in mortality (RR=0.23 [95% CI 0.08-0.70], p=0.0094, I2=0%) and a 55% reduction in all-cause readmissions (HR=0.45 [0.36-0.56], p<0.0001). The reductions were not sustained after protective drug levels had waned. The small number of trials limited our ability to assess heterogeneity, its sources and publication bias. Interpretation: In malaria-endemic Africa, PDMC reduces mortality and readmissions in recently discharged children recovering from severe anaemia. PDMC can be a valuable strategy for the post-discharge management of this high-risk group. Future research should focus on methods of PDMC delivery, options to prolong the protection duration, other hospitalised special risk groups, and interventions targeting non-malarial causes of post-discharge morbidity

Implementation of post-discharge malaria chemoprevention (PDMC) in Benin, Kenya, Malawi, and Uganda: stakeholder engagement meeting report

A Stakeholder engagement meeting on the implementation of post-discharge malaria chemoprevention (PDMC) in Benin, Kenya, Malawi, and Uganda was held in Nairobi, Kenya, on 27 September 2023. Representatives from the respective National Malaria Control Programmes, the World Health Organization (WHO) Geneva, Africa Regional and Kenya offices, research partners, non-governmental rganizations, and the Medicines for Malaria Venture participated. PDMC was recommended by the WHO in June 2022 and involves provision of a full anti-malarial treatment course at regular intervals during the post-discharge period in children hospitalized with severe anaemia in areas of moderate-to-high malaria transmission. The WHO recommendation followed evidence from a meta-analysis of three clinical trials and from acceptability, delivery, cost-ffectiveness, and modelling studies. The trials were conducted in The Gambia using monthly sulfadoxine-pyrimethamine during the transmission season, in Malawi using monthly artemether-lumefantrine, and in Kenya and Uganda using monthly dihydroartemisinin-piperaquine, showing a significant reduction in all-cause mortality by 77% (95% CI 30–98) and a 55% (95% CI 44–64) reduction in all-cause hospital readmissions 6 months post-discharge. The recommendation has not yet been implemented in sub-Saharan Africa. There is no established platform for PDMC delivery. The objectives of the meeting were for the participating countries to share country contexts, plans and experiences regarding the adoption and implementation of PDMC and to explore potential delivery platforms in each setting. The meeting served as the beginning of stakeholder engagement within the PDMC Saves Lives project and will be followed by formative and implementation research to evaluate alternative delivery strategies in selected countries. Meeting highlights included country consensus on use of dihydroartemisinin-piperaquine for PDMC and expansion of the target group to "severe anaemia or severe malaria", in addition to identifying country-specific options for PDMC delivery for evaluation in implementation research. Further exploration is needed on whether the age group should be extended to school-age children

Efficacy of Single-Dose Primaquine With Artemisinin Combination Therapy on Plasmodium falciparum Gametocytes and Transmission: An Individual Patient Meta-Analysis

Background Since the World Health Organization recommended single low-dose (0.25mg/kg) primaquine (PQ) in combination with artemisinin-based combination therapies (ACTs) in areas of low transmission or artemisinin-resistant P. falciparum, several single-site studies have been conducted to assess its efficacy. Methods An individual patient meta-analysis to assess the gametocytocidal and transmission-blocking efficacy of PQ used in combination with different ACTs was conducted. Random effects logistic regression was used to quantify PQ effect on (i) gametocyte carriage in the first two weeks post-treatment; (ii) the probability of infecting at least one mosquito or of a mosquito becoming infected. Results In 2,574 participants from fourteen studies, PQ reduced PCR-determined gametocyte carriage on days 7 and 14, most apparently in patients presenting with gametocytaemia on day 0 (Odds Ratio (OR)=0.22; 95%CI 0.17-0.28 and OR=0.12; 95%CI 0.08–0.16, respectively). The rate of decline in gametocyte carriage was faster when PQ was combined with artemether-lumefantrine (AL) compared to dihydroartemisinin-piperaquine (DP) (p=0.010 for day 7). Addition of 0.25mg/kg PQ was associated with near complete prevention of transmission to mosquitoes. Conclusion Primaquine’s transmission-blocking effects are achieved with 0.25 mg/kg PQ. Gametocyte persistence and infectivity are lower when PQ is combined with AL compared to DP