Defining a malaria diagnostic pathway from innovation to adoption: Stakeholder perspectives on data and evidence gaps.

Malaria, a major global health concern, requires effective diagnostic tools for patient care, disease control, and elimination. The pathway from concept to the adoption of diagnostic products is complex, involving multiple steps and stakeholders. To map this process, our study introduces a malaria-specific diagnostic pathway, synthesising existing frameworks with expert insights. Comprising six major stages and 31 related activities, the pathway retains the core stages from existing frameworks and integrates essential malaria diagnostic activities, such as WHO prequalification processes, global stakeholder involvement, and broader health systems considerations. To understand the scope and availability of evidence guiding the activities along this pathway, we conducted an online survey with 113 participants from various stages of the malaria diagnostic pathway. The survey assessed perceptions on four critical attributes of evidence: clear requirements, alignment with user needs, accuracy and reliability, and public and free availability. It also explored the types of evidence used and the challenges and potential solutions related to evidence generation and use. Respondents reported using a broad range of formal and informal data sources. Findings indicated differing levels of agreement on the attributes across pathway stages, with notable challenges in the Approvals and Manufacturing stage and consistent concerns regarding the public availability of data/evidence. The study offers valuable insights for optimising evidence generation and utilisation across the malaria diagnostic pathway. It highlights the need for enhanced stakeholder collaboration, improved data availability, and increased funding to support effective evidence generation, sharing, and use. We propose actionable solutions, including the use of public data repositories, progressive data sharing policies, open-access publishing, capacity-building initiatives, stakeholder engagement forums, and innovative funding solutions. The developed framework and study insights have broader applications, offering a model adaptable for other diseases, particularly for neglected tropical diseases, which face similar diagnostic challenges.

Rapid diagnostic tests for dengue would reduce hospitalizations, healthcare costs and antibiotic prescriptions in Spain: A cost-effectiveness analysis.

BACKGROUND: Current gold standard diagnostic techniques for dengue are expensive and time-consuming. Rapid diagnostic tests (RDTs) have been proposed as alternatives, although data about their potential impact in non-endemic areas is scarce. METHODS: We performed a cost-effectiveness analysis comparing the costs of dengue RDTs to the current standard of care for the management of febrile returning travelers in Spain. Effectiveness was measured in terms of potential averted hospital admissions and reduction of empirical antibiotics, based on 2015-2020 dengue admissions at Hospital Clinic Barcelona (Spain). RESULTS: Dengue RDTs were associated with 53.6% (95% CI: 33.9-72.5) reduction of hospital admissions and were estimated to save 289.08-389.31€ per traveler tested. Moreover, RDTs would have avoided the use of antibiotics in 46.4% (95% CI: 27.5-66.1) of dengue patients. DISCUSSION: Implementation of dengue RDTs for the management of febrile travelers is a cost-saving strategy that would lead to a reduction of half of dengue admissions and a reduction of inappropriate antibiotics in Spain.

The contribution of risk perception and social norms to reported preventive behaviour against selected vector-borne diseases in Guyana.

Preventing vector-borne diseases (VBDs) mainly relies on effective vector control tools and strategies, which in turn depend on population acceptance and adherence. Inspired by the abundant recent literature on SARS-COV-2, we investigate the relationship between risk perception and preventive behaviour for selected VBDs and the extent to which risk perception is determined by social norms. We use cross-sectional data collected from 497 individuals in four regions of Guyana in 2017. We use a conditional mixed process estimator with multilevel coefficients, estimated through a Generalized Linear Model (GLM) framework, applying a simultaneous equation structure. We find robust results on malaria: risk perception was significantly influenced by the risk perception of the reference group across different definitions of the reference group, hinting at the existence of social norms. Risk perception significantly increased the likelihood of passive behaviour by 4.48%. Less clear-cut results were found for dengue. This study applies quantitative social science methods to public health issues in the context of VBDs. Our findings point to the relevance of tailoring communications on health risks for VBDs to groups defined at the intersection of socio-economic and demographic characteristics. Such tailored strategies are expected to align risk perception among reference groups and boost preventive behaviour.

Female genital schistosomiasis, human papilloma virus infection, and cervical cancer in rural Madagascar: a cross sectional study.

BACKGROUND: Women's health in resource-limited settings can benefit from the integrated management of high-burden diseases, such as female genital schistosomiasis (FGS) and human papilloma virus (HPV)-related cervical cancer. In schistosomiasis-endemic countries such as Madagascar, data on FGS and HPV prevalence are lacking as well as preventive measures for both conditions. This study aims to estimate the prevalence of FGS and HPV in rural Madagascar, and to examine associated risk factors to identify opportunities for improving women's health. METHODS: After initial community outreach activities, interested women aged 18-49 years were recruited consecutively in 2021 at three primary health care centers in the district of Marovoay. FGS was detected by colposcopy. Colposcopy images were double-blind reviewed by two independent specialists. A Luminex bead-based assay was performed on cervical vaginal lavage specimens for HPV typing. Crude (CPR) and adjusted prevalence ratios (APR) of associations between selected factors and FGS and HPV positivity were estimated using univariable and multivariable binary Poisson regression with 95% confidence intervals (CIs). RESULTS: Among 500 women enrolled, 302 had complete information on FGS and HPV diagnosis, and were thus eligible for analysis. Within the sample, 189 (62.6%, 95% CI: 56.9-68.1) cases of FGS were detected. A total of 129 women (42.7%, 95% CI: 37.1-48.5) tested positive for HPV. In total, 80 women (26.5%, 95% CI: 21.6-31.8]) tested positive for both conditions. No association was observed between FGS and HPV positivity, while previous pregnancy (APR = 0.65, 95% CI: 0.43-0.78) and older age (APR = 0.59, 95% CI: 0.42-0.81) are showing a negative association with HPV infection compared to no previous pregnancy and younger age groups. CONCLUSIONS: The results of the study show that FGS and HPV are highly prevalent in rural Madagascar. The concurrent prevalence of these two conditions requires urgent adaptations of public health strategies to improve women's health, such as integrated services at primary level of care.

Cost-effectiveness of community-based distribution of intermittent preventive treatment of malaria in pregnancy in Madagascar, Mozambique, Nigeria, and the Democratic Republic of Congo.

INTRODUCTION: Malaria in pregnancy is a major driver of maternal and infant mortality in sub-Saharan Africa. The WHO recommends the administration of intermittent preventive treatment with sulfadoxine pyrimethamine (IPTp-SP) at antenatal care (ANC) visits. Despite being a highly cost-effective strategy, IPTp-SP coverage and uptake remains low. A pilot project was conducted to assess the cost-effectiveness (CE) of community-based delivery of IPTp (C-IPTp) in addition to ANC delivery to increase IPTp uptake in the Democratic Republic of Congo (DRC), Madagascar (MDG), Mozambique (MOZ) and Nigeria (NGA). METHODS: Costs and CE estimates of C-IPTp were calculated according to two scenarios: (1) costs in 'programmatic mode' (ie, costs if C-IPTp was to be implemented by national health systems) and (2) costs from the pilot project. The effectiveness of C-IPTp was obtained through estimates of the averted disability-adjusted life-years (DALYs) associated with maternal clinical malaria and anaemia, low birth weight and neonatal mortality. RESULTS: Net incremental costs of C-IPTp ranged between US$6138-US$47 177 (DRC), US$5552-US$31 552 (MDG), US$10 202-US$53 221 (MOZ) and US$667-US$28 645 (NGA) per 1000 pregnant women, under scenarios (1) and (2), respectively. Incremental cost-effectiveness ratios (ICERs) ranged between US$15-US$119 in DRC, US$9-US$53 in MDG, US$104-US$543 in MOZ and US$2-US$66 in NGA per DALY averted, under scenarios (1) and (2), respectively. ICERs fall below the WHO recommended CE threshold based on the gross domestic product per capita. CONCLUSION: Findings suggest that C-IPTp is a highly cost-effective intervention. Results can inform policy decisions on adopting and optimising effective interventions for preventing malaria in pregnancy.

The economic costs of malaria in pregnancy: evidence from four sub-Saharan countries.

Background Malaria in pregnancy is a major public health problem in sub-Saharan Africa (SSA), which imposes a significant economic burden. We provide evidence on the costs of malaria care in pregnancy to households and the health system in four high-burden countries in SSA.  Methods Household and health system economic costs associated with malaria control in pregnancy were estimated in selected areas of the Democratic Republic of Congo (DRC), Madagascar (MDG), Mozambique (MOZ) and Nigeria (NGA). An exit survey was administered to 2,031 pregnant women when leaving the antenatal care (ANC) clinic from October 2020 to June 2021. Women reported the direct and indirect costs associated to malaria prevention and treatment in pregnancy. To estimate health system costs, we interviewed health workers from 133 randomly selected health facilities. Costs were estimated using an ingredients-based approach. Results Average household costs of malaria prevention per pregnancy were USD6.33 in DRC, USD10.06 in MDG, USD15.03 in MOZ and USD13.33 in NGA. Household costs of treating an episode of uncomplicated/complicated malaria were USD22.78/USD46 in DRC, USD16.65/USD35.65 in MDG, USD30.54/USD61.25 in MOZ and USD18.92/USD44.71 in NGA, respectively. Average health system costs of malaria prevention per pregnancy were USD10.74 in DRC, USD16.95 in MDG, USD11.17 in MOZ and USD15.64 in NGA. Health system costs associated with treating an episode of uncomplicated/complicated malaria were USD4.69/USD101.41 in DRC, USD3.61/USD63.33 in MDG, USD4.68/USD83.70 in MOZ and USD4.09/USD92.64 in NGA. These estimates resulted in societal costs of malaria prevention and treatment per pregnancy of USD31.72 in DRC, USD29.77 in MDG, USD31.98 in MOZ and USD46.16 in NGA. Conclusions Malaria in pregnancy imposes a high economic burden on households and the health system. Findings emphasize the importance of investing in effective strategies that improve access to malaria control and reduce the burden of the infection in pregnancy.

Development of vaccines for Chagas disease (CRUZIVAX): stakeholders' preferences and potential impacts on healthcare.

A vaccine for Chagas disease does not currently exist. This study aims to inform the development of two vaccines for the prevention and treatment of Trypanosoma cruzi infection, and guide their pre-clinical phase up to clinical phase I. The three main objectives are: 1) to explore patients' and policy makers' preferences on the candidate vaccines in Argentina and Spain; 2) to investigate health-related quality of life of patients affected by Chagas disease; and 3) to assess the potential health provider savings associated with the vaccines, in terms of resource use and health care costs. Discrete choice experiments will be employed to estimate and characterize the theoretical demand for the vaccines and investigate patients' and policy makers' preferences. Health-related quality of life will be assessed using the EQ-5D-3L questionnaire. Resources use and costs associated with Chagas disease will be investigated using information from the databases of the Hospital Clínic of Barcelona.

Phase 3 evaluation of an innovative simple molecular test for the diagnosis of malaria in different endemic and health settings in sub-Saharan Africa (DIAGMAL).

BACKGROUND: Rapid Diagnostic Tests (RDTs) have become the cornerstone for the management of malaria in many endemic settings, but their use is constrained for several reasons: (i) persistent malaria antigen (histidine-rich protein 2; HRP2) leading to false positive test results; (ii) hrp2 deletions leading to false negative PfHRP2 results; and (iii) limited sensitivity with a detection threshold of around 100 parasites/µl blood (pLDH- and HRP2-based) leading to false negative tests. Microscopy is still the gold standard for malaria diagnosis, and allows for species determination and quantitation, but requires trained microscopists, maintained microscopes and has detection limit issues. Consequently, there is a pressing need to develop and evaluate more sensitive and accurate diagnostic tests. To address this need we have developed a direct on blood mini PCR-NALFIA test that combines the benefits of molecular biology with low infrastructural requirements and extensive training. METHODS: This is a Phase 3 diagnostic evaluation in 5 African countries. Study sites (Sudan, Ethiopia, Burkina, Kenya and Namibia) were selected to ensure wide geographical coverage of Africa and to address various malaria epidemiological contexts ranging from high transmission to near elimination settings with different clinical scenarios and diagnostic challenges. Study participants will be enrolled at the study health facilities after obtaining written informed consent. Diagnostic accuracy will be assessed following the WHO/TDR guidelines for the evaluation of diagnostics and reported according to STARD principles. Due to the lack of a 100% specific and sensitive standard diagnostic test for malaria, the sensitivity and specificity of the new test will be compared to the available diagnostic practices in place at the selected sites and to quantitative PCR as the reference test. DISCUSSION: This phase 3 study is designed to validate the clinical performance and feasibility of implementing a new diagnostic tool for the detection of malaria in real clinical settings. If successful, the proposed technology will improve the diagnosis of malaria. Enrolment started in November 2022 (Kenya) with assessment of long term outcome to be completed by 2023 at all recruitment sites. TRIAL REGISTRATION: Pan African Clinical Trial Registry (www.pactr.org) PACTR202202766889963 on 01/02/2022 and ISCRTN (www.isrctn.com/) ISRCTN13334317 on 22/02/2022.

Costs and cost-effectiveness of HIV counselling and testing modalities in Southern Mozambique.

OBJECTIVE: Despite the high HIV associated burden, Mozambique lacks data on HIV counselling and testing (HCT) costs. To help guide national HIV/AIDS programs, we estimated the cost per test for voluntary counselling and testing (VCT) from the patient's perspective and the costs per person tested and per HIV-positive individual linked to care to the healthcare provider for VCT, provider-initiated counselling and testing (PICT) and home-based testing (HBT). We also assessed the cost-effectiveness of these strategies for linking patients to care. METHODS: Data from a cohort study conducted in the Manhiça District were used to derive costs and linkage-to-care outcomes of the three HCT strategies. A decision tree was used to model HCT costs according to the likelihood of HCT linking individuals to care and to obtain the incremental cost-effectiveness ratios (ICERs) of PICT and HBT with VCT as the comparator. Sensitivity analyses were performed to assess robustness of base-case findings. FINDINGS: Based on costs and valuations in 2015, average and median VCT costs to the patient per individual tested were US$1.34 and US$1.08, respectively. Costs per individual tested were greatest for HBT (US$11.07), followed by VCT (US$7.79), and PICT (US$7.14). The costs per HIV-positive individual linked to care followed a similar trend. PICT was not cost-effective in comparison with VCT at a willingness-to-accept threshold of US$4.53, but only marginally given a corresponding base-case ICER of US$4.15, while HBT was dominated, with higher costs and lower impact than VCT. Base-case results for the comparison between PICT and VCT presented great uncertainty, whereas findings for HBT were robust. CONCLUSION: PICT and VCT are likely equally cost-effective in Manhiça. We recommend that VCT be offered as the predominant HCT strategy in Mozambique, but expansion of PICT could be considered in limited-resource areas. HBT without facilitated linkage or reduced costs is unlikely to be cost-effective.

Household costs associated with seeking malaria treatment during pregnancy: evidence from Burkina Faso and The Gambia.

BACKGROUND: Malaria in pregnancy remains a major health threat in sub-Saharan Africa to both expectant mothers and their unborn children. To date, there have been very few studies focused on the out of pocket costs associated with seeking treatment for malaria during pregnancy. METHODS: A cross-sectional survey was undertaken in Burkina Faso and The Gambia to estimate the direct and indirect costs associated with outpatient consultations (OP) and inpatient admissions (IP). Direct costs were broken down into medical (admission fees, drug charges, and laboratory fees), and non-medical (transportation and food). Indirect costs reflected time lost due to illness. In total, 220 pregnant women in Burkina Faso and 263 in The Gambia were interviewed about their treatment seeking decisions, expenditure, time use and financial support associated with each malaria episode. RESULTS: In Burkina Faso 6.7% sought treatment elsewhere before their OP visits, and 27.1% before their IP visits. This compares to 1.3% for OP and 25.92% for IP in The Gambia. Once at the facility, the average direct costs (out of pocket) were 3.91US$ for an OP visit and 15.38US$ of an IP visit in Burkina Faso, and 0.80US$ for an OP visit and 9.19US$ for an IP visit in The Gambia. Inpatient direct costs were driven by drug costs (9.27US$) and transportation costs (2.72US$) in Burkina Faso and drug costs (3.44 US$) and food costs (3.44 US$) in The Gambia. Indirect costs of IP visits, valued as the opportunity cost of time lost due to the illness, were estimated at 11.85US$ in Burkina Faso and 4.07US$ in The Gambia. The difference across the two countries was mainly due to the longer time of hospitalization in Burkina Faso compared to The Gambia. In The Gambia, the vast majority of pregnant women reported receiving financial support from family members living abroad, most commonly siblings (65%). CONCLUSIONS: High malaria treatment costs are incurred by pregnant women in Burkina Faso and The Gambia. Beyond the medical costs of fees and drugs, costs in terms of transport, food and time are significant drivers. The role of remittances, particularly their effect on accessing health care, needs further investigation.

The Impact of the Priority Review Voucher on Research and Development for Tropical Diseases.

BACKGROUND: In 2007, the priority review voucher (PRV) was implemented in the US to incentivize research and development (R&D) for tropical diseases. The PRV is issued by the US FDA and grants a quicker review to manufacturers upon successful development of a product for a disease eligible for the program. OBJECTIVE: The objective of this analysis was to assess whether the PRV has incentivized R&D (measured as clinical trial activity) for the intended tropical diseases. METHOD: We used a difference-in-difference-in-differences (DDD) strategy by exploiting variation in its implementation across diseases and registries around the world. Clinical trials were retrieved from the World Health Organization International Clinical Trials Registry Platform for the years 2005-2019. RESULTS: We found a positive, but not statistically significant, effect of the PRV on stimulating R&D activity. Delayed effects of the policy could not be found. CONCLUSION: Our findings, which were robust across a series of robustness tests, suggest that the PRV program is not associated with a trigger in innovation for neglected diseases and therefore should not be considered as a stand-alone solution. It should be supplemented with other government measures to incentivize R&D activity. To increase the value of the program, we recommend that the PRV only be awarded to novel products and not to products that have already been licensed outside the US. Doing so would restrict the number of vouchers awarded and slow down their ongoing market depreciation. Finally, we propose that product sponsors be required to submit an access plan for PRV-awarded products.

The impact of a malaria elimination initiative on school outcomes: Evidence from Southern Mozambique.

Despite the significant improvements achieved over the last ten years, primary education attainment in Mozambique is still low. Potential reasons acting from the demand perspective include ill health, among other factors. In Mozambique, ill health is still largely linked to malaria, which is a leading cause of outpatient contacts, hospital admissions and death, particularly among under-five and school-aged children. Despite this, in Mozambique and more generally, in malaria endemic countries, the identification and measurement of how improved malaria indicators may contribute to better school outcomes remains largely unknown. In particular, there is a low understanding of the extent to which better health translates immediately into school indicators, such as absenteeism and grades. In this study, we exploit the first year of a malaria elimination initiative implemented in Magude district (Southern Mozambique) that started in 2015, as a quasi-experiment to estimate the impact of malaria on selected primary school outcomes. While malaria was not eliminated, its incidence drastically dropped. We use as control a neighbouring district (Manhiça) with similar socio-economic and epidemiological characteristics. By employing a difference-in-differences (DiD) approach, we examine whether the positive health shock translated into improved school outcomes. Using information from school registers, we generated a dataset on school attendance and grades for 9,848 primary-school students from 9 schools (4 in the treated district and 5 in the control district). In our main specification, a repeated cross-section analysis, we find that the elimination initiative led to a 28% decrease in school absenteeism and a 2% increase in students' grades. Our results are robust across different specifications, including a panel DiD individual fixed effects estimate on a sub-sample of students. These findings provide evidence on the negative impact of malaria on primary education attainment and suggest remarkable economic benefits consequent to its elimination.

Funding patterns for biomedical research and infectious diseases burden in Gabon.

BACKGROUND: Biomedical research plays an important role in improving health. There seems to exist a negative correlation between the amount of biomedical research funding and disease burden from all Sub-Saharan African countries. In this study, we describe funding patterns for biomedical research, explore the correlation between funding and burden of diseases, and quantify inequalities in funds distribution across diseases in Gabon over the period 2005-2015. METHODS: Data on medical research funds from 2005 to 2015 were retrieved through a structured questionnaire distributed to Gabonese biomedical research institutions and by consulting online databases. Data on the burden of diseases were gathered from the World Health Organization and the Institute for Health Metrics and Evaluation. We used Kendall rank correlation coefficient to explore the correlation between cumulative funds over time and the burden of disease. The inequality distribution of funding across diseases was assessed through Gini coefficient and Lorenz curve. RESULTS: Biomedical research funding was characterized by a remarkable growth from 2005 to 2010 and a decline from 2010 to 2014. Funds were mostly from external sources and from partnerships. There was inequality in research funds allocation across diseases and malaria was far the most funded disease. There was a significant negative correlation between cumulative funding and the burden of HIV, tuberculosis, and of Helminthiasis (from 2006 to 2010) suggesting that research may be contributing to the management of such diseases. A positive, although not significant, correlation was found between cumulative funds and malaria burden. CONCLUSIONS: The negative correlation between HIV and tuberculosis cumulative funding and burden suggests that research may be contributing to the management of such diseases but further research is needed to assess the causal direction of such as relationship. As the burden of non-communicable diseases is increasing, more research funds should be focused on those. While research partnerships have been and will remain fundamental, Gabon should increase the amount of national funds to overcome periods of reduced research funding flows from abroad.

A cluster randomized controlled trial for assessing POC-CCA test based praziquantel treatment for schistosomiasis control in pregnant women and their young children: study protocol of the freeBILy clinical trial in Madagascar.

BACKGROUND: Mass drug administration (MDA) of praziquantel is one of the main control measures against human schistosomiasis. Although there are claims for including pregnant women, infants and children under the age of 5 years in high-endemic regions in MDA campaigns, they are usually not treated without a diagnosis. Diagnostic tools identifying infections at the primary health care centre (PHCC) level could therefore help to integrate these vulnerable groups into control programmes. freeBILy (fast and reliable easy-to-use-diagnostics for eliminating bilharzia in young children and mothers) is an international consortium focused on implementing and evaluating new schistosomiasis diagnostic strategies. In Madagascar, the study aims to determine the effectiveness of a test-based schistosomiasis treatment (TBST) strategy for pregnant women and their infants and children up until the age of 2 years. METHODS: A two-armed, cluster-randomized, controlled phase III trial including 5200 women and their offspring assesses the impact of TBST on child growth and maternal haemoglobin in areas of medium to high endemicity of Schistosoma mansoni. The participants are being tested with the point of care-circulating cathodic antigen (POC-CCA) test, a commercially available urine-based non-invasive rapid diagnostic test for schistosomiasis. In the intervention arm, a POC-CCA-TBST strategy is offered to women during pregnancy and 9 months after delivery, for their infants at 9 months of age. In the control arm, study visit procedures are the same, but without the POC-CCA-TBST procedure. All participants are being offered the POC-CCA-TBST 24 months after delivery. This trial is being integrated into the routine maternal and child primary health care programmes at 40 different PHCC in Madagascar's highlands. The purpose of the trial is to assess the effectiveness of the POC-CCA-TBST for controlling schistosomiasis in young children and mothers. DISCUSSION: This trial assesses a strategy to integrate pregnant women and their children under the age of 2 years into schistosomiasis control programmes using rapid diagnostic tests. It includes local capacity building for clinical trials and large-scale intervention research. TRIAL REGISTRATION: Pan-African Clinical Trial Register PACTR201905784271304. Retrospectively registered on 15 May 2019.

The short-term impact of a malaria elimination initiative in Southern Mozambique: Application of the synthetic control method to routine surveillance data.

In public health epidemiology, quasi-experimental methods are widely used to estimate the causal impacts of interventions. In this paper, we demonstrate the contribution the synthetic control method (SCM) can make in evaluating public health interventions, when routine surveillance data are available and the validity of other quasi-experimental approaches may be in question. In our application, we evaluate the short-term effects of a large-scale Mass Drug Administration (MDA) based malaria elimination initiative in Southern Mozambique. We apply the SCM to district level weekly malaria incidence data and compare the observed reduction in age group specific malaria incidence. Between August 2015 and April 2017, a total of 13,322 (78%) cases of malaria were averted relative to the synthetic control. During the peak malaria seasons, the elimination initiative resulted in an 87% reduction in Year 1 (December 2015-April 2016), and 79% reduction in Year 2 (December 2016-April 2017). Comparison with an interrupted time series approach shows the SCM accounts for pre-intervention trends in the data and post-intervention weather events influencing malaria cases. We conclude MDA brought about a drastic reduction in malaria burden and can be a useful addition to existing (or new) vector control strategies and tools in accelerating towards elimination.

Improved housing versus usual practice for additional protection against clinical malaria in The Gambia (RooPfs): a household-randomised controlled trial.

BACKGROUND: In malaria-endemic areas, residents of modern houses have less malaria than those living in traditional houses. We aimed to assess whether children in The Gambia received an incremental benefit from improved housing, where current best practice of insecticide-treated nets, indoor residual spraying, seasonal malaria chemoprevention in children younger than 5 years, and prompt treatment against clinical malaria was in place. METHODS: In this randomised controlled study, 800 households with traditional thatched-roofed houses were randomly selected from 91 villages in the Upper River Region of The Gambia. Within each village, equal numbers of houses were randomly allocated to the control and intervention groups using a sampling frame. Houses in the intervention group were modified with metal roofs and screened doors and windows, whereas houses in the control group received no modifications. In each group, clinical malaria in children aged 6 months to 13 years was monitored by active case detection over 2 years (2016-17). We did monthly collections from indoor light traps to estimate vector densities. Primary endpoints were the incidence of clinical malaria in study children with more than 50% of observations each year and household vector density. The trial is registered at ISRCTN02622179. FINDINGS: In June, 2016, 785 houses had one child each recruited into the study (398 in unmodified houses and 402 in modified houses). 26 children in unmodified houses and 28 children in modified houses did not have at least 50% of visits in a year and so were excluded from analysis. 38 children in unmodified houses were recruited after study commencement, as were 21 children in modified houses, meaning 410 children in unmodified houses and 395 in modified houses were included in the parasitological analyses. At the end of the study, 659 (94%) of 702 children were reported to have slept under an insecticide-treated net; 662 (88%) of 755 children lived in houses that received indoor residual spraying; and 151 (90%) of 168 children younger than 5 years had seasonal malaria chemoprevention. Incidence of clinical malaria was 0·12 episodes per child-year in children in the unmodified houses and 0·20 episodes per child-year in the modified houses (unadjusted incidence rate ratio [RR] 1·68 [95% CI 1·11-2·55], p=0·014). Household vector density was 3·30 Anopheles gambiae per house per night in the unmodified houses compared with 3·60 in modified houses (unadjusted RR 1·28 [0·87-1·89], p=0·21). INTERPRETATION: Improved housing did not provide protection against clinical malaria in this area of low seasonal transmission with high coverage of insecticide-treated nets, indoor residual spraying, and seasonal malaria chemoprevention. FUNDING: Global Health Trials funded by Medical Research Council, UK Department for International Development, and Wellcome Trust.

Cost-effectiveness of district-wide seasonal malaria chemoprevention when implemented through routine malaria control programme in Kita, Mali using fixed point distribution.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a strategy for malaria control recommended by the World Health Organization (WHO) since 2012 for Sahelian countries. The Mali National Malaria Control Programme adopted a plan for pilot implementation and nationwide scale-up by 2016. Given that SMC is a relatively new approach, there is an urgent need to assess the costs and cost effectiveness of SMC when implemented through the routine health system to inform decisions on resource allocation. METHODS: Cost data were collected from pilot implementation of SMC in Kita district, which targeted 77,497 children aged 3-59 months. Starting in August 2014, SMC was delivered by fixed point distribution in villages with the first dose observed each month. Treatment consisted of sulfadoxine-pyrimethamine and amodiaquine once a month for four consecutive months, or rounds. Economic and financial costs were collected from the provider perspective using an ingredients approach. Effectiveness estimates were based upon a published mathematical transmission model calibrated to local epidemiology, rainfall patterns and scale-up of interventions. Incremental cost effectiveness ratios were calculated for the cost per malaria episode averted, cost per disability adjusted life years (DALYs) averted, and cost per death averted. RESULTS: The total economic cost of the intervention in the district of Kita was US $357,494. Drug costs and personnel costs accounted for 34% and 31%, respectively. Incentives (payment other than salary for efforts beyond routine activities) accounted for 25% of total implementation costs. Average financial and economic unit costs per child per round were US $0.73 and US $0.86, respectively; total annual financial and economic costs per child receiving SMC were US $2.92 and US $3.43, respectively. Accounting for coverage, the economic cost per child fully adherent (receiving all four rounds) was US $6.38 and US $4.69, if weighted highly adherent, (receiving 3 or 4 rounds of SMC). When costs were combined with modelled effects, the economic cost per malaria episode averted in children was US $4.26 (uncertainty bound 2.83-7.17), US $144 (135-153) per DALY averted and US $ 14,503 (13,604-15,402) per death averted. CONCLUSIONS: When implemented at fixed point distribution through the routine health system in Mali, SMC was highly cost-effective. As in previous SMC implementation studies, financial incentives were a large cost component.

Investment Case for a Comprehensive Package of Interventions Against Hepatitis B in China: Applied Modeling to Help National Strategy Planning.

BACKGROUND: In 2016, the first global viral hepatitis elimination targets were endorsed. An estimated one-third of the world's population of individuals with chronic hepatitis B virus (HBV) infection live in China and liver cancer is the sixth leading cause of mortality, but coverage of first-line antiviral treatment was low. In 2015, China was one of the first countries to initiate a consultative process for a renewed approach to viral hepatitis. We present the investment case for the scale-up of a comprehensive package of HBV interventions. METHODS: A dynamic simulation model of HBV was developed and used to simulate the Chinese HBV epidemic. We evaluated the impact, costs, and return on investment of a comprehensive package of prevention and treatment interventions from a societal perspective, incorporating costs of management of end-stage liver disease and lost productivity costs. RESULTS: Despite the successes of historical vaccination scale-up since 1992, there will be a projected 60 million people still living with HBV in 2030 and 10 million HBV-related deaths, including 5.7 million HBV-related cancer deaths between 2015 and 2030. This could be reduced by 2.1 million by highly active case-finding and optimal antiviral treatment regimens. The package of interventions is likely to have a positive return on investment to society of US$1.57 per US dollar invested. CONCLUSIONS: Increases in HBV-related deaths for the next few decades pose a major public health threat in China. Active case-finding and access to optimal antiviral treatment are required to mitigate this risk. This investment case approach provides a real-world example of how applied modeling can support national dialog and inform policy planning.