Impact of Intrapartum Azithromycin on the Carriage and Antibiotic Resistance of Escherichia coli and Klebsiella pneumoniae in Mothers and their Newborns: a sub-study of a Randomized Double-Blind Trial Conducted in The Gambia and Burkina Faso.

BACKGROUND: Limited data exists on effects of intrapartum azithromycin on prevalence of carriage and antibiotic resistance of Enterobacterales. METHODS: We conducted a randomized trial in Gambia and Burkina Faso where women received intrapartum azithromycin (2g) or placebo. We determined impact of treatment on prevalence of carriage and antibiotic resistance of Escherichia coli and Klebsiella pneumoniae by analysing rectal swabs (RS), nasopharyngeal swabs (NPS), breast milk and recto-vaginal swabs (RVS). Bacteria were isolated microbiologically; antibiotic susceptibility was confirmed with an E-test. Prevalence ratios (PR) with 95% confidence intervals (CI's) were used for comparison between arms. RESULTS: In infants, E. coli carriage in RS was lower in the intervention than placebo arm at days 6 (63.0% vs. 75.2%, PR, 0.84; CI, 0.75-0.95) and 28 (52.7% vs. 70.4%, 0.75; 0.64-0.87) post-intervention. Prevalence of azithromycin-resistant E. coli was higher in the azithromycin arm at days 6 (13.4% vs. 3.6%, 3.75; 1.83-7.69) and 28 (16.4% vs. 9.6%, 1.71; 1.05-2.79). For K. pneumoniae, carriage in RS was higher in the intervention than placebo arm at days 6 (49.6% vs. 37.2%, 1.33; 1.08-1.64) and 28 (53.6% vs. 32.9%, 1.63; 1.31-2.03). Prevalence of azithromycin-resistant K. pneumoniae was higher in the azithromycin arm at day 28 (7.3% vs. 2.1%, 3.49; 1.30-9.37). No differences were observed for other sample types. CONCLUSION: Intrapartum azithromycin decreased E. coli carriage but increased both K. pneumoniae carriage and azithromycin resistance in both bacteria. These data need to be considered together with efficacy results to balance the potential short- and long-term impact of the intervention. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov: NCT03199547.

Risk factors for non-participation in ivermectin and dihydroartemisinin-piperaquine mass drug administration for malaria control in the MASSIV trial.

BACKGROUND: Mass Drug Administration (MDA) has become a mainstay for the control of several diseases over the last two decades. Successful implementation of MDA programmes requires community participation and can be threatened by systematic non-participation. Such concerns are particularly pertinent for MDA programmes against malaria, as they require multi-day treatment over several consecutive months. Factors associated with non-participation to the MDA campaign with ivermectin (IVM) and dihydroartemisinin-piperaquine (DHP) implemented within the MASSIV cluster randomized trial were determined. METHODS: Coverage data was extracted from the MASSIV trial study database, with every datapoint being a directly observed therapy (DOT). A complete month of MDA was classified as receiving all three daily doses of treatment. For both ivermectin and DHP, ordinal logistic regression was used to identify individual and household level variables associated with non-participation. RESULTS: For ivermectin, 51.5% of eligible participants received all 3 months of treatment while 30.7% received either one or two complete months. For DHP, 56.7% of eligible participants received all 3 months of treatment and 30.5% received either one or two complete months. Children aged 5-15 years and adults aged more than 50 years were more likely to receive at least one complete month of MDA than working age adults, both for ivermectin (aOR 4.3, 95% CI 3.51-5.28 and aOR of 2.26, 95% CI 1.75-2.95) and DHP (aOR 2.47, 95%CI 2.02-3.02 and aOR 1.33, 95%CI 1.01-1.35), respectively. Members of households where the head received a complete month of MDA were more likely to themselves have received a complete month of MDA, both for ivermectin (aOR 1.71, 95%CI 1.35-2.14) and for DHP (aOR 1.64, 95%CI 1.33-2.04). CONCLUSION: Personal and household-level variables were associated with participation in the MDA programme for malaria control. Specific strategies to (increase participation amongst some groups may be important to ensure maximum impact of MDA strategies in achieving malaria elimination. TRIAL REGISTRATION: The MASSIV trial is registered under NCT03576313.

The effect of physical barriers under a raised house on mosquito entry: an experimental study in rural Gambia.

BACKGROUND: Anopheles gambiae, the major malaria mosquito in sub-Saharan Africa, feed largely indoors at night. Raising a house off the ground with no barriers underneath reduces mosquito-house entry. This experiment tested whether walling off the space under an elevated hut affects mosquito-hut entry. METHODS: Four inhabited experimental huts, each of which could be moved up and down, were used in rural Gambia. Nightly collections of mosquitoes were made using light traps and temperature and carbon dioxide levels monitored indoors and outdoors using loggers. Each night, a reference hut was kept at ground level and three huts raised 2 m above the ground; with the space under the hut left open, walled with air-permeable walls or solid walls. Treatments were rotated every four nights using a randomized block design. The experiment was conducted for 32 nights. Primary measurements were mosquito numbers and indoor temperature in each hut. RESULTS: A total of 1,259 female Anopheles gambiae sensu lato were collected in the hut at ground level, 655 in the hut with an open ground floor, 981 in the hut with air-permeable walls underneath and 873 in the hut with solid walls underneath. Multivariate analysis, adjusting for confounders, showed that a raised hut open underneath had 53% fewer mosquitoes (95% CI 47-58%), those with air-permeable walls underneath 24% fewer (95% CI 9-36%) and huts with solid walls underneath 31% fewer (95% CI 24-37%) compared with a hut on the ground. Similar results were found for Mansonia spp. and total number of female mosquitoes, but not for Culex mosquitoes where hut entry was unaffected by height or barriers. Indoor temperature and carbon dioxide levels were similar in all huts. CONCLUSION: Raising a house 2 m from the ground reduces the entry of An. gambiae and Mansonia mosquitoes, but not Culex species. The protective effect of height is reduced if the space underneath the hut is walled off.

Asymptomatic Plasmodium falciparum carriage at the end of the dry season is associated with subsequent infection and clinical malaria in Eastern Gambia.

BACKGROUND: Chronic carriage of asymptomatic low-density Plasmodium falciparum parasitaemia in the dry season may support maintenance of acquired immunity that protects against clinical malaria. However, the relationship between chronic low-density infections and subsequent risk of clinical malaria episodes remains unclear. METHODS: In a 2-years study (December 2014 to December 2016) in eastern Gambia, nine cross-sectional surveys using molecular parasite detection were performed in the dry and wet season. During the 2016 malaria transmission season, passive case detection identified episodes of clinical malaria. RESULTS: Among the 5256 samples collected, 444 (8.4%) were positive for P. falciparum. A multivariate model identified village of residence, male sex, age ≥ 5 years old, anaemia, and fever as independent factors associated with P. falciparum parasite carriage. Infections did not cluster over time within the same households or recurred among neighbouring households. Asymptomatic parasite carriage at the end of dry season was associated with a higher risk of infection (Hazard Ratio, HR = 3.0, p < 0.0001) and clinical malaria (HR = 1.561, p = 0.057) during the following transmission season. Age and village of residence were additional predictors of infection and clinical malaria during the transmission season. CONCLUSION: Chronic parasite carriage during the dry season is associated with an increased risk of malaria infection and clinical malaria. It is unclear whether this is due to environmental exposure or to other factors.

Treat All versus targeted strategies to select HBV-infected people for antiviral therapy in The Gambia, west Africa: a cost-effectiveness analysis.

BACKGROUND: Global elimination of hepatitis B virus (HBV) requires expanded uptake of antiviral therapy, potentially by simplifying testing algorithms, especially in resource-limited countries. We evaluated the effectiveness, cost-effectiveness, and budget impact of three strategies that determine eligibility for anti-HBV treatment, as compared with the WHO 2015 treatment eligibility criteria, in The Gambia. METHODS: We developed a microsimulation model of natural history using data from the Prevention of Liver Fibrosis and Cancer in Africa programme (known as PROLIFICA) in The Gambia, for an HBV-infected cohort of individuals aged 20 years. The algorithms included in the model were a conventional strategy using the European Association for the Study of the Liver (EASL) 2017 criteria, a simplified algorithm using hepatitis B e antigen and alanine aminotransferase (the Treatment Eligibility in Africa for the Hepatitis B Virus [TREAT-B] score), a Treat All approach for all HBV-infected individuals, and the WHO 2015 criteria. Outcomes to measure effectiveness were disability-adjusted life years (DALYs) and years of life saved (YLS), which were used to calculate incremental cost-effectiveness ratios (ICERs) with the WHO 2015 criteria as the base-case scenario. Costs were assessed from a modified social perspective. A budget impact analysis was also done. We tested the robustness of results with a range of sensitiviy analyses including probabilistic sensitivity analysis. FINDINGS: Compared with the WHO criteria, TREAT-B resulted in 4877 DALYs averted and Treat All resulted in 9352 DALYs averted, whereas the EASL criteria led to an excess of 795 DALYs. TREAT-B was cost-saving, whereas the ICER for Treat All (US$2149 per DALY averted) was higher than the cost-effectiveness threshold for The Gambia (0·5 times the country's gross domestic product per capita: $352). These patterns did not change when YLS was the outcome. In a modelled cohort of 5000 adults (aged 20 years) with chronic HBV infection from The Gambia, the 5-year budget impact was $1·14 million for Treat All, $0·66 million for TREAT-B, $1·03 million for the WHO criteria, and $1·16 million for the EASL criteria. Probabilistic sensitivity analysis indicated that among the Treat All, EASL, and TREAT-B algorithms, Treat All would become the most preferred strategy only with a willingness-to-pay threshold exceeding approximately $72 000 per DALY averted or $110 000 per YLS. INTERPRETATION: Although the Treat All strategy might be the most effective, it is unlikely to be cost-effective in The Gambia. A simplified strategy such as TREAT-B might be a cost-saving alternative. FUNDING: UK Research and Innovation (Medical Research Council). TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Practical Guidelines for Standardised Resolution of Important Protocol Deviations in Clinical Trials Conducted in Sub-Saharan Africa.

A clinical trial is any research on human subjects that involves an investigational medicinal product or device. Investigational medicinal products include unlicensed drugs or drugs used outside the product license (e.g. for a new indication) (ICH-GCP). As per the internationally accepted ICH-GCP guidelines, clinical trials should be conducted strictly per the approved protocol. However, during the lifecycle of a trial, protocol deviations may occur. Under ICH efficacy guidelines, protocol deviations are divided into non-important (minor) or important (major), and the latter can jeopardise the participant's rights, safety or the quality of data generated by the study. Existing guidelines on protocol deviation management do not detail or standardise actions to be taken for participants, investigational products, data or samples as part of a holistic management of important protocol deviations. Herein, we propose guidelines to address the current literature gap and promote the standardisation of actions to address important protocol deviations in clinical trials. The advised actions should complement the existing local institutional review board and national regulatory authority requirements.

Mosquitocidal effect of ivermectin-treated nettings and sprayed walls on Anopheles gambiae s.s.

Ivermectin (IVM) has been proposed as a new tool for malaria control as it is toxic on vectors feeding on treated humans or cattle. Nevertheless, IVM may have a direct mosquitocidal effect when applied on bed nets or sprayed walls. The potential for IVM application as a new insecticide for long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) was tested in this proof-of-concept study in a laboratory and semi-field environment. Laboratory-reared, insecticide-susceptible Kisumu Anopheles gambiae were exposed to IVM on impregnated netting materials and sprayed plastered- and mud walls using cone bioassays. The results showed a direct mosquitocidal effect of IVM on this mosquito strain as all mosquitoes died by 24 h after exposure to IVM. The effect was slower on the IVM-sprayed walls compared to the treated nettings. Further work to evaluate possibility of IVM as a new insecticide formulation in LLINs and IRS will be required.

Household-level effects of seasonal malaria chemoprevention in the Gambia.

BACKGROUND: In 2022 the WHO recommended the discretionary expansion of the eligible age range for seasonal malaria chemoprevention (SMC) to children older than 4 years. Older children are at lower risk of clinical disease and severe malaria so there has been uncertainty about the cost-benefit for national control programmes. However, emerging evidence from laboratory studies suggests protecting school-age children reduces the infectious reservoir for malaria and may significantly impact on transmission. This study aimed to assess whether these effects were detectable in the context of a routinely delivered SMC programme. METHODS: In 2021 the Gambia extended the maximum eligible age for SMC from 4 to 9 years. We conducted a prospective population cohort study over the 2021 malaria transmission season covering 2210 inhabitants of 10 communities in the Upper River Region, and used a household-level mixed modelling approach to quantify impacts of SMC on malaria transmission. RESULTS: We demonstrate that the hazard of clinical malaria in older participants aged 10+ years ineligible for SMC decreases by 20% for each additional SMC round per child 0-9 years in the same household. Older inhabitants also benefit from reduced risk of asymptomatic infections in high SMC coverage households. Spatial autoregression tests show impacts are highly localised, with no detectable spillover from nearby households. CONCLUSIONS: Evidence for the transmission-reducing effects of extended-age SMC from routine programmes implemented at scale has been previously limited. Here we demonstrate benefits to the entire household, indicating such programmes may be more cost-effective than previously estimated.

Seasonal malaria chemoprevention (SMC) is the provision of monthly, preventative, anti-malaria medication to young children at times when they are most at risk of severe disease. Recently the World Health Organisation recommended expanding SMC to children older than 4 years. Older children with malaria typically remain symptomless so the advantages were unclear. However, laboratory evidence suggests this group continues to transmit malaria to others. We conducted a population study in 2021 in 10 communities in the Gambia where SMC was extended to all children up to 9 years of age for the first time. We found household members aged over 9 years were less likely to get clinical disease when most young children in the same household did receive SMC. This suggests an added protection of SMC for those who do not receive it, potentially increasing cost-effectiveness.

The Enterics for Global Health (EFGH) Shigella Surveillance Study in The Gambia.

Background: The Gambia, located in West Africa, is one of 7 country sites conducting the Enterics for Global Health (EFGH) Shigella Surveillance Study to establish incidence and consequence of Shigella-associated medically attended diarrhea among children 6-35 months old. Methods: Here we describe the study site and research experience, sociodemographic characteristics of the study catchment area, facilities of recruitment for diarrhea case surveillance, and known care-seeking behavior for diarrheal illness. We also describe The Gambia's healthcare system and financing, current vaccine schedule and Shigella vaccine adaptation, local diarrhea management guidelines and challenges, and antibiotic resistance patterns in the region. Conclusions: The EFGH study in The Gambia will contribute to the multisite network of Shigella surveillance study and prepare the site for future vaccine trials. In addition, the data produced will inform policy makers about prevention strategies and upcoming Shigella vaccine studies among children in this setting.

Tobacco smoking clusters in households affected by tuberculosis in an individual participant data meta-analysis of national tuberculosis prevalence surveys: Time for household-wide interventions?

Tuberculosis (TB) and non-communicable diseases (NCD) share predisposing risk factors. TB-associated NCD might cluster within households affected with TB requiring shared prevention and care strategies. We conducted an individual participant data meta-analysis of national TB prevalence surveys to determine whether NCD cluster in members of households with TB. We identified eligible surveys that reported at least one NCD or NCD risk factor through the archive maintained by the World Health Organization and searching in Medline and Embase from 1 January 2000 to 10 August 2021, which was updated on 23 March 2023. We compared the prevalence of NCD and their risk factors between people who do not have TB living in households with at least one person with TB (members of households with TB), and members of households without TB. We included 16 surveys (n = 740,815) from Asia and Africa. In a multivariable model adjusted for age and gender, the odds of smoking was higher among members of households with TB (adjusted odds ratio (aOR) 1.23; 95% CI: 1.11-1.38), compared with members of households without TB. The analysis did not find a significant difference in the prevalence of alcohol drinking, diabetes, hypertension, or BMI between members of households with and without TB. Studies evaluating household-wide interventions for smoking to reduce its dual impact on TB and NCD may be warranted. Systematically screening for NCD using objective diagnostic methods is needed to understand the actual burden of NCD and inform comprehensive interventions.

A Perspective on the Strategy for Advancing ETVAX®, An Anti-ETEC Diarrheal Disease Vaccine, into a Field Efficacy Trial in Gambian Children: Rationale, Challenges, Lessons Learned, and Future Directions.

For the first time in over 20 years, an Enterotoxigenic Escherichia coli (ETEC) vaccine candidate, ETVAX®, has advanced into a phase 2b field efficacy trial for children 6-18 months of age in a low-income country. ETVAX® is an inactivated whole cell vaccine that has gone through a series of clinical trials to provide a rationale for the design elements of the Phase 2b trial. This trial is now underway in The Gambia and will be a precursor to an upcoming pivotal phase 3 trial. To reach this point, numerous findings were brought together to define factors such as safe and immunogenic doses for children, and the possible benefit of a mucosal adjuvant, double mutant labile toxin (dmLT). Considering the promising but still underexplored potential of inactivated whole cells in oral vaccination, we present a perspective compiling key observations from past ETVAX® trials that informed The Gambian trial design. This report will update the trial's status and explore future directions for ETEC vaccine trials. Our aim is to provide not only an update on the most advanced ETEC vaccine candidate but also to offer insights beneficial for the development of other much-needed oral whole-cell vaccines against enteric and other pathogens.

The PRECISE-DYAD Neurodevelopmental substudy protocol: neurodevelopmental risk in children of mothers with pregnancy complications.

Background: Over 250 million children are not reaching their developmental potential globally. The impact of prenatal factors and their interplay with postnatal environmental factors on child neurodevelopment, is still unclear-particularly in low- and middle-income settings. This study aims to understand the impact of pregnancy complications as well as environmental, psychosocial, and biological predictors on neurodevelopmental trajectories. Methods: This is an observational cohort study of female and male children (≈3,950) born to women (≈4,200) with and without pregnancy complications (pregnancy-induced hypertension, foetal growth restriction, and premature birth) previously recruited into PREgnancy Care Integrating Translational Science, Everywhere study with detailed biological data collected in intrapartum and post-partum periods. Children will be assessed at six weeks to 6 months, 11-13 months, 23-25 months and 35-37 months in rural and semi-urban Gambia (Farafenni, Illiasa, and Ngayen Sanjal) and Kenya (Mariakani and Rabai). We will assess children's neurodevelopment using Prechtls General Movement Assessment, the Malawi Development Assessment Tool (primary outcome), Observation of Maternal-Child Interaction, the Neurodevelopmental Disorder Screening Tool, and the Epilepsy Screening tool. Children screening positive will be assessed with Cardiff cards (vision), Modified Checklist for Autism in Toddlers Revised, and Pediatric Quality of Life Inventory Family Impact. We will use multivariate logistic regression analysis to investigate the impact of pregnancy complications on neurodevelopment and conduct structural equation modelling using latent class growth to study trajectories and relationships between biological, environmental, and psychosocial factors on child development. Conclusions: We aim to provide information regarding the neurodevelopment of infants and children born to women with and without pregnancy complications at multiple time points during the first three years of life in two low-resource African communities. A detailed evaluation of developmental trajectories and their predictors will provide information on the most strategic points of intervention to prevent and reduce the incidence of neurodevelopmental impairments.

The PRECISE-DYAD protocol: linking maternal and infant health trajectories in sub-Saharan Africa.

Background: PRECISE-DYAD is an observational cohort study of mother-child dyads running in urban and rural communities in The Gambia and Kenya. The cohort is being followed for two years and includes uncomplicated pregnancies and those that suffered pregnancy hypertension, fetal growth restriction, preterm birth, and/or stillbirth. Methods: The PRECISE-DYAD study will follow up ~4200 women and their children recruited into the original PRECISE study. The study will add to the detailed pregnancy information and samples in PRECISE, collecting additional biological samples and clinical information on both the maternal and child health.Women will be asked about both their and their child's health, their diets as well as undertaking a basic cardiology assessment. Using a case-control approach, some mothers will be asked about their mental health, their experiences of care during labour in the healthcare facility. In a sub-group, data on financial expenditure during antenatal, intrapartum, and postnatal periods will also be collected. Child development will be assessed using a range of tools, including neurodevelopment assessments, and evaluating their home environment and quality of life. In the event developmental milestones are not met, additional assessments to assess vision and their risk of autism spectrum disorders will be conducted. Finally, a personal environmental exposure model for the full cohort will be created based on air and water quality data, combined with geographical, demographic, and behavioural variables. Conclusions: The PRECISE-DYAD study will provide a greater epidemiological and mechanistic understanding of health and disease pathways in two sub-Saharan African countries, following healthy and complicated pregnancies. We are seeking additional funding to maintain this cohort and to gain an understanding of the effects of pregnancies outcome on longer-term health trajectories in mothers and their children.