Addressing implementation uncertainty in postdischarge malaria chemoprevention : Determinants of adherence, cost-effectiveness, and the value of further research in Malawi and other malaria-endemic African countries

Postponed access: the file will be accessible after 2025-11-08Bakgrunn: Malaria fortsetter å være en ledende årsak til dødsfall og dødelighet for barn som bor i malaria-endemiske områder i Afrika sør for Sahara. Verdens helseorganisasjon (WHO) anbefaler chemoprevention av malaria for sårbare under-grupper som en strategi for å redusere forekomst av regional stagnerende malaria- og dødelighetsrater. Postdischarge malaria chemo-prevention (PDMC) består av husholdningsbasert oral antimalariabehandling for førskolebarn i endemiske områder i månedene etter recovery/bedring etter mottatt sykehusbehandling for alvorlig anemi. Tre måneder av PDMC reduserte risiko for dødelighet og readmission/gjeninnleggelse på sykehus substansielt. Basert på tilgjengelig bevis/funn/resultater anbefalte nylig WHO at land adopterer PDMC i malaria-endemiske områder. Denne avhandlingen hadde som mål å adressere de resterende kunnskapshull som lovgivere i afrikanske land sør for Sahara møter når de vurderer implementering av PDMC: faktorer for omsorgsgiveres adherence/etterlevelse til PDMC i Malawi, økonomisk evaluering av ulike delivery/leverings? strategier i sørøstlige afrikanske settinger, og verdien av videre informasjon for afrikanske land sør for Sahara ble analysert. Datakilder: Data fra en efficacy trial i Kenya og Uganda (n=1040) og en delivery trial i Malawi (n=375), gjennomført fra 2016 til 2018 ble brukt til de tre analysene og komplimentert med data fra litteraturen. Begge trials brukte tre måneder med månedlig dihydroartemisinin-pipereaquine (DHAP) til PDMC. The efficacy trial/studien sammenlignet PDMC med placebobehandling. The delivery trial sammenlignet community-delivered PDMC, hvor den totale mengden på ni doser av DHAP ble distribuert til omsorgsgivere ved utskriving fra sykehus med ‘facility-delivered’ PDMC, hvor tre månedsdoser ble hentet månedlig fra sykehuset. Metoder: Modified Poisson regresjonsanalyse ble brukt for å forutsi omsorgsgiveres adherence/etterlevelse basert på barn, omsorgsgiver, og husholdningskarakteristikker (predictor analyse, artikkel 1). Resultatene ble rapportert som relativ risiko for komplett etterlevelse. Kost-nytte-analysen (CEA, artikkel 2) brukte Markov decision modell for å sammenligne to leveringsstrategier av PDMC med standard of care for Malawi, Kenya og Uganda. Societal costing perspective ble tatt og resultatene ble rapportert som trinnvis kost-nytte ratio per kvalitets-justert liv-år oppnådd. I en value of information analyse (VOI, artikkel 3) kalkulerte vi per-decision net monetary benefit (NMB) for Kenya, Uganda og Malawi av perfekt og delvis perfekt informasjon for inputvariablene av CEA. Et scenario med halverte etterlevelsesrater for å simulere implementeringsbetingelser fra real-world ble inkludert. Resultatene ble/er rapportert som årlig per land NMB av perfekt informasjon og anvendt til 27 andre afrikanske land sør for Sahara, justert for variasjon i terskel for kjøpekraft og villighet til å betale. Resultater og tolkning: Det ble ikke funnet konkluderende sett av determinants/faktorer? for PDMC etterlevelse. En sosioøkonomisk indeks viste blandet assosiering på tvers av kvintiler med lav etterlevelse. Barn med fire eller fler malariainfeksjoner før innleggelse ble assosiert med redusert etterlevelse. PDMC kombinerer flere faktorer som kompliserer etterlevelsesatferd, og vi foreslår at etablerte spådde faktorer for adherence/etterlevelse av mindre komplekse regimer har svakere eller mer komplekse assosiasjoner med adherence/etterlevelse av PDMC. CEA viste at PDMC var kostnadsbesparende og mer effektivt enn standard of care. Community-delivered PDMC var den kostnadseffektive strategien i alle land, som ble bekreftet med sensitivitetsanalyse. Det robuste resultatet foreslår at PDMC er kostnadseffektivt og at å distribuere en komplett course av PDMC ved utskrivelse er den optimale delivery/leverings? strategien for malaria-endemiske sør-østlige afrikanske settinger. VOI analysen bekreftet dette resultatet ved å identifisere kun to kategorier av modellinput med usikkerheter som hadde en potensiell effekt på avgjørelsen av den optimale delivery/leverings? strategien: den relative dødelighetsraten ved å motta PDMC sammenlignet med standard of care og etterlevelsesraten. Perfekt informasjon ved begge parametere hadde en theoretical årlig verdi på US$1 379, US$7 979 og US$4 840 for henholdsvis Malawi, Kenya og Uganda. Scenarioet med redusert etterlevelsesrater genererte sammenlignbare, generelt lavere verdier av perfekt informasjon. Større forskningsprosjektet for å løse disse usikkerhetsmomentene kan derfor ikke være rettferdiggjøres økonomisk.Background: Malaria continues to be a leading cause of death and morbidity in children living in malaria-endemic areas of sub-Saharan Africa. The WHO recommends chemoprevention of malaria in vulnerable sub-populations as strategy to reduce the regionally stagnating malaria incidence and mortality rates. Postdischarge malaria chemoprevention (PDMC) comprises household-based oral antimalarial treatment of preschool children in endemic areas during the months of recovery after they were treated in hospital for severe anaemia. Three months of PDMC substantially reduce the risk of mortality and hospital readmission. Based on the available evidence, the WHO recently recommended that countries adopted PDMC in malaria-endemic areas. This thesis aimed to address remaining evidence gaps that policy-makers in sub-Saharan countries face when considering PDMC implementation. Namely, the determinants of caregivers’ adherence to PDMC in Malawi, the economic evaluation of different delivery strategies of PDMC in south-eastern African settings, and the value of further information for sub-Saharan Africa were, analysed. Data Sources: Data from an efficacy trial in Kenya and Uganda (n=1 040) and a delivery trial in Malawi (n = 375), conducted from 2016 to 2018, were used for the three analyses, and complemented with data from the literature. Both trials used three months with monthly dihydroartemisinin-piperaquine (DHAP) for PDMC. The efficacy trial compared PDMC to a placebo treatment. The delivery trial compared community-based PDMC delivery, where the full nine doses of DHAP were distributed to caregivers at hospital discharge, to facility-based PDMC delivery, where three monthly doses were collected monthly from the hospital. Methods: Modified Poisson regression analysis was used to predict caregiver adherence based on child, caregiver, and household features (predictor analysis, Paper 1). Results are reported as relative risk for high adherence. The cost-effectiveness analysis (CEA, Paper 2) used Markov decision models to compare the two delivery strategies of PDMC with the standard of care for Malawi, Kenya, and Uganda. A societal costing perspective was assumed and results are reported as incremental cost-effectiveness ratios per quality-adjusted life-year gained. In a value of information analysis (VOI, Paper 3), we calculated the per-decision net monetary benefit (NMB) for Kenya, Uganda, and Malawi, of perfect and partial perfect information for the input variables of the CEA. A scenario with halved adherence rates to simulate real-world implementation conditions was included. Results were reported as per country annual NMB of perfect information, and applied to 27 other sub-Saharan countries, adjusted for variations in purchasing power and willingness to pay thresholds. Results and Interpretation: No conclusive set of determinants for PDMC adherence could be found in the predictor study. A socio-economic index showed mixed associations across quintiles with poor adherence. Children with four or more malaria infections before admission were associated with reduced adherence. PDMC combines multiple factors that complicate adherence behaviour, and we suggest that established predictive factors for adherence to less complex regimens have weaker or more complex associations with adherence to PDMC. The CEA showed that PDMC was cost-saving and more effective than standard of care treatment. Community-based PDMC delivery was the cost-effective strategy in all countries, confirmed in sensitivity analyses. The robust results suggest that PDMC is cost-effective and that distributing a full course of PDMC at discharge is the optimal delivery strategy for malaria-endemic south-eastern African settings. The VOI analysis confirmed this result, identifying only two categories of model input with uncertainties that had a potential impact on the decision for the optimal delivery strategy: the relative mortality rate when receiving PDMC compared to standard of care, and the adherence rates. Perfect information on both parameters had a theoretical annual value of US$1 379, $7 979, and$4 840 for Malawi, Kenya, and Uganda, respectively. The scenario with reduced adherence rates generated comparable, overall lower, values of perfect information. Larger research projects to resolve these uncertainties may, thus, not be economically justifiable.Doktorgradsavhandlin

Predicting adherence to postdischarge malaria chemoprevention in Malawian pre-school children: A prognostic multivariable analysis

Chemoprevention with antimalarials is a key strategy for malaria control in sub-Saharan Africa. Three months of postdischarge malaria chemoprevention (PDMC) reduces malaria-related mortality and morbidity in pre-school children recently discharged from hospital following recovery from severe anemia. Research on adherence to preventive antimalarials in children is scarce. We aimed to investigate the predictors for caregivers’ adherence to three courses of monthly PDMC in Malawi. We used data from a cluster randomized implementation trial of PDMC in Malawi (n = 357). Modified Poisson regression for clustered data was used to obtain relative risks of predictors for full adherence to PDMC. We did not find a conclusive set of predictors for PDMC adherence. The distribution of households across a socio-economic index and caregivers’ education showed mixed associations with poor adherence. Caregivers of children with four or more malaria infections in the past year were associated with reduced adherence. With these results, we cannot confirm the associations established in the literature for caregiver adherence to artemisinin-based combination therapies (ACTs). PDMC combines multiple factors that complicate adherence. Our results may indicate that prevention interventions introduce a distinct complexity to ACT adherence behavior. Until we better understand this relationship, PDMC programs should ensure high program fidelity to sustain adherence by caregivers during implementation

Adherence to community versus facility-based delivery of monthly malaria chemoprevention with dihydroartemisinin-piperaquine for the post-discharge management of severe anemia in Malawian children: A cluster randomized trial

BACKGROUND The provision of post-discharge malaria chemoprevention (PMC) in children recently admitted with severe anemia reduces the risk of death and re-admissions in malaria endemic countries. The main objective of this trial was to identify the most effective method of delivering dihydroartemesinin-piperaquine to children recovering from severe anemia. METHODS This was a 5-arm, cluster-randomized trial among under-5 children hospitalized with severe anemia at Zomba Central Hospital in Southern Malawi. Children were randomized to receive three day treatment doses of dihydroartemesinin-piperaquine monthly either; 1) in the community without a short text reminder; 2) in the community with a short message reminder; 3) in the community with a community health worker reminder; 4) at the facility without a short text reminder; or 5) at the facility with a short message reminder. The primary outcome measure was adherence to all treatment doses of dihydroartemesinin-piperaquine and this was assessed by pill-counts done by field workers during home visits. Poisson regression was utilized for analysis. RESULTS Between March 2016 and October 2018, 1460 clusters were randomized. A total of 667 children were screened and 375 from 329 clusters were eligible and enrolled from the hospital. Adherence was higher in all three community-based compared to the two facility-based delivery (156/221 [70·6%] vs. 78/150 [52·0%], IRR = 1·24,95%CI 1·06-1·44, p = 0·006). This was observed in both the SMS group (IRR = 1·41,1·21-1·64, p<0·001) and in the non-SMS group (IRR = 1·37,1·18-1·61, p<0·001). Although adherence was higher among SMS recipients (98/148 66·2%] vs. non-SMS 82/144 (56·9%), there was no statistical evidence that SMS reminders resulted in greater adherence ([IRR = 1·03,0·88-1·21, p = 0·68). When compared to the facility-based non-SMS arm (control arm), community-based delivery utilizing CHWs resulted in higher adherence [39/76 (51·3%) vs. 54/79 (68·4%), IRR = 1·32, 1·14-1·54, p<0·001]. INTERPRETATION Community-based delivery of dihydroartemesinin-piperaquine for post-discharge malaria chemoprevention in children recovering from severe anemia resulted in higher adherence compared to facility-based methods. TRIAL REGISTRATION NCT02721420; ClinicalTrials.gov

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

A cluster randomised trial to evaluate the effectiveness of household alcohol-based hand rub for the prevention of sepsis, diarrhoea, and pneumonia in Ugandan infants (the BabyGel trial): a study protocol

Background: Infections are one of the leading causes of death in the neonatal period. This trial aims to evaluate if the provision of alcohol-based hand rub (ABHR) to pregnant women for postnatal household use prevents severe infections (including sepsis, diarrhoea, pneumonia, or death) among infants during the first three postnatal months. Methods: Through a cluster-randomised trial in eastern Uganda, 72 clusters are randomised in a 2-arm design with rural villages as units of randomisation. We estimate to include a total of 5932 pregnant women at 34 weeks of gestation. All women and infants in the study are receiving standard antenatal and postnatal care. Women in the intervention group additionally receive six litres of ABHR and training on its use. Research midwives conduct follow-up visits at participants’ homes on days 1, 7, 28, 42, and 90 after birth and telephone calls on days 14, 48, and 60 to assess the mother and infant for study outcomes. Primary analyses will be by intention to treat. Discussion: This study will provide evidence on the effectiveness of a locally available and low-cost intervention in preventing neonatal sepsis and early infant infections. If ABHR is found effective, it could be implemented by adding it to birthing kits. Trial registration: Pan African Clinical Trial Registry, PACTR202004705649428. Registered 1 April 2020, https://pactr.samrc.ac.za/

Projected health impact of post-discharge malaria chemoprevention among children with severe malarial anaemia in Africa.

Children recovering from severe malarial anaemia (SMA) remain at high risk of readmission and death after discharge from hospital. However, a recent trial found that post-discharge malaria chemoprevention (PDMC) with dihydroartemisinin-piperaquine reduces this risk. We developed a mathematical model describing the daily incidence of uncomplicated and severe malaria requiring readmission among 0-5-year old children after hospitalised SMA. We fitted the model to a multicentre clinical PDMC trial using Bayesian methods and modelled the potential impact of PDMC across malaria-endemic African countries. In the 20 highest-burden countries, we estimate that only 2-5 children need to be given PDMC to prevent one hospitalised malaria episode, and less than 100 to prevent one death. If all hospitalised SMA cases access PDMC in moderate-to-high transmission areas, 38,600 (range 16,900-88,400) malaria-associated readmissions could be prevented annually, depending on access to hospital care. We estimate that recurrent SMA post-discharge constitutes 19% of all SMA episodes in moderate-to-high transmission settings

Are we overlooking alcohol use by younger children?

Alcohol use is a leading contributor to the burden of disease among youth. Early-onset use is associated with later life dependency, ill health and poor social functioning. Yet, research on and treatment opportunities for alcohol use among younger children are scarce. Despite knowledge that alcohol intake occurs in childhood, and the fact that children understand alcohol related norms and develop alcohol expectancies from age 4, younger children are rarely included in studies on alcohol use.Patterns of early alcohol use vary greatly across the globe and are part of complex interplays between sociocultural, economic and health-related factors. Family influence has proven important, but genetic factors do not seem to play a crucial role at this age. Stressful circumstances, including mental health problems and sociocultural factors can entice alcohol use to cope with difficult situations. The World Health Organization has developed guidelines for effective strategies to reduce the harmful use of alcohol, including preventative and treatment interventions, but important gaps in implementation remain. An increased focus on research, policy and implementation strategies related to early alcohol use is warranted, granted its wide-ranging implications for public health and social functioning. In this summary of literature on alcohol use among younger children and adolescents, we show that younger children (aged 10 and younger) tend to be systematically overlooked. However, research, interventions and policy implementation strategies need to include younger children to mitigate the global burden of harmful alcohol use more effectively.publishedVersio

Child alcohol use disorder in Eastern Uganda: screening, diagnostics, risk factors and management of children drinking alcohol in Uganda (TREAT CAUD): a mixed-methods research protocol

Background Following a finding of alcohol use among children aged 5–8 years old in Mbale, Uganda, this project investigates the magnitude of alcohol and substance use among children ged 6–13 years old and related household, community, school, health system and clinical factors. Methods The project includes four larger work packages (WPs). WP1 comprises management, WP2 and 3 include the scientific components and WP4 includes integration of results, dissemination, policy and implementation advice. This protocol presents the planned research work in WP 2 and 3. WP2 comprises the adaptation and validation of the alcohol use screening tool Car-Relax-Alone-Forget-Family and Friends-Trouble (CRAFFT) to the age group and setting. WP3 comprises four substudies (SS). SS1 is a cross-sectional community household survey with an estimated sample size of 3500 children aged 6–13 years and their caregivers. We apply cluster sampling and systematic sampling within the clusters. Data collection includes a structured questionnaire for caregiver and child, measuring social and demographic factors, mental health status, alcohol and substance use, nutrition history and anthropometry. Urine samples from children will be collected to measure ethyl glucuronide (EtG), a biological marker of alcohol intake. Further, facilitators, barriers and response mechanisms in the health system (SS2) and the school system (SS3) is explored with surveys and qualitative assessments. SS4 includes qualitative interviews with children. Analysis will apply descriptive statistics for the primary outcome of establishing the magnitude of alcohol drinking and substance use, and associated factors will be assessed using appropriate regression models. The substudies will be analysed independently, as well as inform each other through mixed methods strategies at the stages of design, analysis, and dissemination. Ethics and dissemination Data protection and ethical approvals have been obtained in Uganda and Norway, and referral procedures developed. Dissemination comprises peer-reviewed, open access research papers, policy recommendations and intersectoral dialogues

Adherence to community versus facility-based delivery of monthly malaria chemoprevention with dihydroartemisinin-piperaquine for the post-discharge management of severe anemia in Malawian children: A cluster randomized trial

Background: The provision of post-discharge malaria chemoprevention (PMC) in children recently admitted with severe anemia reduces the risk of death and re-admissions in malaria endemic countries. The main objective of this trial was to identify the most effective method of delivering dihydroartemesinin-piperaquine to children recovering from severe anemia. Methods: This was a 5-arm, cluster-randomized trial among under-5 children hospitalized with severe anemia at Zomba Central Hospital in Southern Malawi. Children were randomized to receive three day treatment doses of dihydroartemesinin-piperaquine monthly either; 1) in the community without a short text reminder; 2) in the community with a short message reminder; 3) in the community with a community health worker reminder; 4) at the facility without a short text reminder; or 5) at the facility with a short message reminder. The primary outcome measure was adherence to all treatment doses of dihydroartemesinin-piperaquine and this was assessed by pill-counts done by field workers during home visits. Poisson regression was utilized for analysis. Results: Between March 2016 and October 2018, 1460 clusters were randomized. A total of 667 children were screened and 375 from 329 clusters were eligible and enrolled from the hospital. Adherence was higher in all three community-based compared to the two facility-based delivery (156/221 [70·6%] vs. 78/150 [52·0%], IRR = 1·24,95%CI 1·06–1·44, p = 0·006). This was observed in both the SMS group (IRR = 1·41,1·21–1·64, p<0·001) and in the non-SMS group (IRR = 1·37,1·18–1·61, p<0·001). Although adherence was higher among SMS recipients (98/148 66·2%] vs. non-SMS 82/144 (56·9%), there was no statistical evidence that SMS reminders resulted in greater adherence ([IRR = 1·03,0·88–1·21, p = 0·68). When compared to the facility-based non-SMS arm (control arm), community-based delivery utilizing CHWs resulted in higher adherence [39/76 (51·3%) vs. 54/79 (68·4%), IRR = 1·32, 1·14–1·54, p<0·001]. Interpretation: Community-based delivery of dihydroartemesinin-piperaquine for post-discharge malaria chemoprevention in children recovering from severe anemia resulted in higher adherence compared to facility-based methods

Projected health impact of post-discharge malaria chemoprevention among children with severe malarial anaemia in Africa

Children recovering from severe malarial anaemia (SMA) remain at high risk of readmission and death after discharge from hospital. However, a recent trial found that post-discharge malaria chemoprevention (PDMC) with dihydroartemisinin-piperaquine reduces this risk. We developed a mathematical model describing the daily incidence of uncomplicated and severe malaria requiring readmission among 0–5-year old children after hospitalised SMA. We fitted the model to a multicentre clinical PDMC trial using Bayesian methods and modelled the potential impact of PDMC across malaria-endemic African countries. In the 20 highest-burden countries, we estimate that only 2–5 children need to be given PDMC to prevent one hospitalised malaria episode, and less than 100 to prevent one death. If all hospitalised SMA cases access PDMC in moderate-to-high transmission areas, 38,600 (range 16,900–88,400) malaria-associated readmissions could be prevented annually, depending on access to hospital care. We estimate that recurrent SMA post-discharge constitutes 19% of all SMA episodes in moderate-to-high transmission settings