Evaluation of Segmentation, Rotation, and Geographic Delivery Approaches for Deployment of Multiple First-Line Treatment (MFT) to Respond to Antimalarial Drug Resistance in Africa: A Qualitative Study in Seven Sub-Sahara Countries.

BACKGROUND: Several studies recently confirmed the emergence of resistance to antimalarial drugs in sub-Saharan Africa. Multiple first-line treatment (MFT) is one of the measures envisaged to respond to the emergence and spread of this resistance. The aim of this study was to identify the perceived advantages and disadvantages of several MFT deployment strategies and to better understand potential implementation drivers and barriers. METHODS: A qualitative survey was conducted in seven sub-Saharan countries amongst key opinion leaders, national decision makers, and end users. A total of 200 individual interviews were conducted and findings were analyzed following a thematic inductive approach. RESULTS: From a policy perspective, the new MFT intervention would require endorsement at the global, national, and regional levels to ensure its inclusion in guidelines. Funding of the MFT intervention could be a bottleneck due to costs associated with additional training of healthcare workers, adaptation of drug delivery mechanisms, and higher costs of drugs. Concerning the MFT deployment strategies, a slight preference for the segmentation strategy was expressed over the rotation and geographic approaches, due to the perception that a segmentation approach is already in place at country level. CONCLUSIONS: The findings highlighted the need for a collective approach to MFT deployment through the engagement of stakeholders at all levels of malaria management.

Minimally invasive versus open distal pancreatectomy for resectable pancreatic neuroendocrine tumors: A propensity score matched multicentric comparative French study.

BACKGROUND: Minimally invasive surgery has gained momentum for left pancreatic resections. However, debate remains about whether it has any advantage over open surgery for distal pancreatectomy for pancreatic neuroendocrine tumors. METHODS: This retrospective review examined pancreatectomies performed for resectable pancreatic neuroendocrine tumors at 21 centers in France between January 2014 and December 2018. Short and long-term outcomes were compared before and after propensity score matching based on tumor size, sex, age, body mass index, center, and method of pancreatic transection. RESULTS: During the period study, 274 patients underwent left pancreatic resection for pancreatic neuroendocrine tumors [109 underwent distal splenopancreatectomy, and 165 underwent spleen-preserving distal pancreatectomy [(splenic vessel preservation (n = 97; 58.7%)/splenic vessel resection (n = 68; 41.3%)]. Before propensity score matching, minimally invasive surgery was associated with a lower rate of major morbidity (P = .004), lower rate of postoperative delayed gastric emptying (P = .04), and higher rate of "textbook" outcomes (P = .04). After propensity score matching, there were 2 groups of 54 patients (n = 30 distal splenopancreatectomy; n = 78 spleen-preserving distal pancreatectomy). Minimally invasive surgery was associated with less blood loss (P = .05), decreased rate of major morbidity (6% vs. 24%; P = .02), less delayed gastric emptying (P = .05) despite similar rates of postoperative fistula, hemorrhage, and reoperation (P > .05). The 5-year overall survival (79% vs. 75%; P = .74) and recurrence-free survival (10% vs 17%; P = .39) were similar. CONCLUSION: Minimally invasive surgery for left pancreatic resection can be safely proposed for patients with resectable left pancreatic neuroendocrine tumors. Minimally invasive surgery decreases the rate of major complications while providing comparable long-term oncologic outcomes.

Malaria risk mapping among children under five in Togo.

Malaria is a major health threat in sub-Sahara Africa, especially for children under five. However, there is considerable heterogeneity between areas in malaria risk reported, associated with environmental and climatic. We used data from Togo to explore spatial patterns of malaria incidence. Geospatial covariate datasets, including climatic and environmental variables from the 2017 Malaria Indicator Survey in Togo, were used for this study. The association between malaria incidence and ecological predictors was assessed using three regression techniques, namely the Ordinary Least Squares (OLS), spatial lag model (SLM), and spatial error model (SEM). A total of 171 clusters were included in the survey and provided data on environmental and climate variables. Spatial autocorrelation showed that the distribution of malaria incidence was not random and revealed significant spatial clustering. Mean temperature, precipitation, aridity and proximity to water bodies showed a significant and direct association with malaria incidence rate in the SLM model, which best fitted the data according to AIC. Five malaria incidence hotspots were identified. Malaria incidence is spatially clustered in Togo associated with climatic and environmental factors. The results can contribute to the development of specific malaria control plans taking geographical variation into consideration and targeting transmission hotspots.

Design and selection of drug properties to increase the public health impact of next-generation seasonal malaria chemoprevention: a modelling study.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is recommended for disease control in settings with moderate to high Plasmodium falciparum transmission and currently depends on the administration of sulfadoxine-pyrimethamine plus amodiaquine. However, poor regimen adherence and the increased frequency of parasite mutations conferring sulfadoxine-pyrimethamine resistance might threaten the effectiveness of SMC. Guidance is needed to de-risk the development of drug compounds for malaria prevention. We aimed to provide guidance for the early prioritisation of new and alternative SMC drugs and their target product profiles. METHODS: In this modelling study, we combined an individual-based malaria transmission model that has explicit parasite growth with drug pharmacokinetic and pharmacodynamic models. We modelled SMC drug attributes for several possible modes of action, linked to their potential public health impact. Global sensitivity analyses identified trade-offs between drug elimination half-life, maximum parasite killing effect, and SMC coverage, and optimisation identified minimum requirements to maximise malaria burden reductions. FINDINGS: Model predictions show that preventing infection for the entire period between SMC cycles is more important than drug curative efficacy for clinical disease effectiveness outcomes, but similarly important for impact on prevalence. When children younger than 5 years receive four SMC cycles with high levels of coverage (ie, 69% of children receiving all cycles), drug candidates require a duration of protection half-life higher than 23 days (elimination half-life >10 days) to achieve reductions higher than 75% in clinical incidence and severe disease (measured over the intervention period in the target population, compared with no intervention across a range of modelled scenarios). High coverage is crucial to achieve these targets, requiring more than 60% of children to receive all SMC cycles and more than 90% of children to receive at least one cycle regardless of the protection duration of the drug. INTERPRETATION: Although efficacy is crucial for malaria prevalence reductions, chemoprevention development should select drug candidates for their duration of protection to maximise burden reductions, with the duration half-life determining cycle timing. Explicitly designing or selecting drug properties to increase community uptake is paramount. FUNDING: Bill & Melinda Gates Foundation and the Swiss National Science Foundation.

Safety and efficacy of dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in pregnant women with HIV from Gabon and Mozambique: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The cornerstone of malaria prevention in pregnancy, intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine, is contraindicated in women with HIV who are receiving co-trimoxazole prophylaxis. We assessed whether IPTp with dihydroartemisinin-piperaquine is safe and effective in reducing the risk of malaria infection in women with HIV receiving co-trimoxazole prophylaxis and antiretroviral drugs. METHODS: For this randomised, double-blind, placebo-controlled clinical trial, women with HIV attending the first antenatal care clinic visit, resident in the study area, and with a gestational age up to 28 weeks were enrolled at five sites in Gabon and Mozambique. Participants were randomly assigned (1:1) to receive either IPTp with dihydroartemisinin-piperaquine at each scheduled antenatal care visit plus daily co-trimoxazole (intervention group) or placebo at each scheduled antenatal care visit plus daily co-trimoxazole (control group). Randomisation was done centrally via block randomisation (block sizes of eight), stratified by country. IPTp was given over 3 days under direct observation by masked study personnel. The number of daily IPTp tablets was based on bodyweight and according to the treatment guidelines set by WHO (target dose of 4 mg/kg per day [range 2-10 mg/kg per day] of dihydroartemisinin and 18 mg/kg per day [range 16-27 mg/kg per day] of piperaquine given once a day for 3 days). At enrolment, all participants received co-trimoxazole (fixed combination drug containing 800 mg trimethoprim and 160 mg sulfamethoxazole) for daily intake. The primary study outcome was prevalence of peripheral parasitaemia detected by microscopy at delivery. The modified intention-to-treat population included all randomly assigned women who had data for the primary outcome. Secondary outcomes included frequency of adverse events, incidence of clinical malaria during pregnancy, and frequency of poor pregnancy outcomes. All study personnel, investigators, outcome assessors, data analysts, and participants were masked to treatment assignment. This study is registered with ClinicalTrials.gov, NCT03671109. FINDINGS: From Sept 18, 2019, to Nov 26, 2021, 666 women (mean age 28·5 years [SD 6·4]) were enrolled and randomly assigned to the intervention (n=332) and control (n=334) groups. 294 women in the intervention group and 308 women in the control group had peripheral blood samples taken at delivery and were included in the primary analysis. Peripheral parasitaemia at delivery was detected in one (<1%) of 294 women in the intervention group and none of 308 women in the control group. The incidence of clinical malaria during pregnancy was lower in the intervention group than in the control group (one episode in the intervention group vs six in the control group; relative risk [RR] 0·12, 95% CI 0·03-0·52, p=0·045). In a post-hoc analysis, the composite outcome of overall malaria infection (detected by any diagnostic test during pregnancy or delivery) was lower in the intervention group than in the control group (14 [5%] of 311 women vs 31 [10%] of 320 women; RR 0·48, 95% CI 0·27-0·84, p=0·010). The frequency of serious adverse events and poor pregnancy outcomes (such as miscarriages, stillbirths, premature births, and congenital malformations) did not differ between groups. The most frequently reported drug-related adverse events were gastrointestinal disorder (reported in less than 4% of participants) and headache (reported in less than 2% of participants), with no differences between study groups. INTERPRETATION: In the context of low malaria transmission, the addition of IPTp with dihydroartemisinin-piperaquine to co-trimoxazole prophylaxis in pregnant women with HIV did not reduce peripheral parasitaemia at delivery. However, the intervention was safe and associated with a decreased risk of clinical malaria and overall Plasmodium falciparum infection, so it should be considered as a strategy to protect pregnant women with HIV from malaria. FUNDING: European and Developing Countries Clinical Trials Partnership 2 (EDCTP2) and Medicines for Malaria Venture. TRANSLATIONS: For the Portuguese and French translations of the abstract see Supplementary Materials section.