Integrating pediatric TB services into child healthcare services in Africa: study protocol for the INPUT cluster-randomized stepped wedge trial

Background Tuberculosis is among the top-10 causes of mortality in children with more than 1 million children suffering from TB disease annually worldwide. The main challenge in young children is the difficulty in establishing an accurate diagnosis of active TB. The INPUT study is a stepped-wedge cluster-randomized intervention study aiming to assess the effectiveness of integrating TB services into child healthcare services on TB diagnosis capacities in children under 5 years of age. Methods Two strategies will be compared: i) The standard of care, offering pediatric TB services based on national standard of care; ii) The intervention, with pediatric TB services integrated into child healthcare services: it consists of a package of training, supportive supervision, job aids, and logistical support to the integration of TB screening and diagnosis activities into pediatric services. The design is a cluster-randomized stepped-wedge of 12 study clusters in Cameroon and Kenya. The sites start enrolling participants under standard-of-care and will transition to the intervention at randomly assigned time points. We enroll children aged less than 5 years with a presumptive diagnosis of TB after obtaining caregiver written informed consent. The participants are followed through TB diagnosis and treatment, with clinical information prospectively abstracted from their medical records. The primary outcome is the proportion of TB cases diagnosed among children < 5 years old attending the child healthcare services. Secondary outcomes include: number of children screened for presumptive active TB; diagnosed; initiated on TB treatment; and completing treatment. We will also assess the cost-effectiveness of the intervention, its acceptability among health care providers and users, and fidelity of implementation. Discussion Study enrolments started in May 2019, enrolments will be completed in October 2020 and follow up will be completed by June 2021. The study findings will be disseminated to national, regional and international audiences and will inform innovative approaches to integration of TB screening, diagnosis, and treatment initiation into child health care services.publishedVersio

Research priorities for accelerating the achievement of three 95 HIV goals in Cameroon: a consensus statement from the Cameroon HIV Research Forum (CAM-HERO)

Introduction:&nbsp;the Treat-All remains the globally endorsed approach to attain the 95-95-95 targets and end the AIDS pandemic by 2030, but requires some country-level contextualization. In Cameroon, the specific research agenda to inform strategies for improving HIV policy was yet to be defined. Methods:&nbsp;under the patronage of the Cameroon Ministry of health, researchers, policy makers, implementing partners, and clinicians from 13 institutions, used the Delphi method to arrive at a consensus of HIV research priorities. The process had five steps: 1) independent literature scan by 5 working groups; 2) review of the initial priority list; 3) appraisal of priorities list in a larger group; 4) refinement and consolidation by a consensus group; 5) rating of top research priorities. Results:&nbsp;five research priorities and corresponding research approaches, resulted from the process. These include: 1) effectiveness, safety and active toxicity monitoring of new and old antiretrovirals; 2) outcomes of Antiretroviral Therapy (ART) with focus in children and adolescents; 3) impact of HIV and ART on aging and major chronic diseases; 4) ART dispensation models and impact on adherence and retention; 5) evaluations of HIV treatment and prevention programs. Conclusion:&nbsp;the research priorities resulted from a consensus amongst a multidisciplinary team and were based on current data about the pandemic and science to prevent, treat, and ultimately cure HIV. These priorities highlighted critical areas of investigation with potential relevance for the country, funders, and regulatory bodies

Outcomes of the first meeting of the CAMEROON HIV RESEARCH FORUM (CAM-HERO)

Research is a vital component for the development of any country. In Cameroon, HIV Operational research is rapidly growing, however, it faces some intractable problems which can only be solved through an urgent, strategic, efficient, and collaborative approach involving key stakeholders. The Kribi meeting (09 and 10th&nbsp;December 2020) brought together under the auspices of the Ministry of Public Health leading HIV research organisations and connected HIV researchers and actors from different sectors. These actors disseminated and discussed recent research findings and worked out mechanisms to advance HIV research development, developed new ideas and identified priority research areas, with emphasis on translational research. The official launching and consolidation of Cam-HERO was a critical step and it is hoped that these synergistic efforts will catalyse attainment of the 95-95-95 goals in Cameroon

Evidence for an enhanced HIV/AIDS policy and care in Cameroon: proceedings of the second Cameroon HIV Research Forum (CAM-HERO) 2021

To achieve the Sustainable Development Goal of zero hunger, multi-sectoral strategies to improve nutrition are necessary. Building towards this goal, the food and agriculture sector must be considered when designing nutritional interventions. Nevertheless, most frameworks designed to guide nutritional interventions do not adequately capture opportunities for integrating nutrition interventions within the food and agriculture sector. This paper aims to highlight how deeply connected the food and agriculture sector is to underlying causes of malnutrition and identify opportunities to better integrate the food and agriculture sector and nutrition in low and middle income countries. In particular, this paper: (1) expands on the UNICEF conceptual framework for undernutrition to integrate the food and agriculture sector and nutrition outcomes, (2) identifies how nutritional outcomes and agriculture are linked in six important ways by defining evidence-based food and agriculture system components within these pathways: as a source of food, as a source of income, through food prices, women’s empowerment, women’s utilization of time, and women’s health and nutritional status, and (3) shows that the food and agriculture sector facilitates interventions through production, processing and consumption, as well as through farmer practices and behavior. Current frameworks used to guide nutrition interventions are designed from a health sector paradigm, leaving agricultural aspects not sufficiently leveraged. This paper concludes by proposing intervention opportunities to rectify the missed opportunities generated by this approach. Program design should consider the ways that the food and agriculture sector is linked to other critical sectors to comprehensively address malnutrition. This framework is designed to help the user to begin to identify intervention sites that may be considered when planning and implementing multi-sectoral nutrition program

Research Questions and Priorities for Pediatric Tuberculosis: A Survey of Published Systematic Reviews and Meta-Analyses

Background. Advancing a research agenda designed to meet the specific needs of children is critical to ending pediatric TB epidemic. Systematic reviews are increasingly informing policies in pediatric tuberculosis (TB) care and control. However, there is a paucity of information on pediatric TB research priorities. Methodology. We searched MEDLINE, EMBASE, Web of Science, and the Cochrane Library for systematic reviews and meta-analyses on any aspect related to pediatric TB published between 2015 and 2021. We used the UK Health Research Classification System (HRCS) to help us classify the research questions and priorities. Findings. In total, 29 systematic reviews, with 84 research questions, were included in this review. The four most common research topics in the area of detection were 43.33% screening and diagnosis of TB, 23.33% evaluation of treatments and therapeutic interventions, 13.34% TB etiology and risk factors, and 13.34% prevention of disease and conditions and promotion of well-being. The research priorities focused mainly on evaluating TB diagnosis by improving yield through enhanced in specimen collection or preparation and evaluating of bacteriological TB diagnostic tests. Other topics of future research were developing a treatment for TB in children, assessing the use of IPT in reducing TB-associated morbidity, evaluating the prioritization of an IPT-friendly healthcare environment, and providing additional guidance for the use of isoniazid in the prevention of TB in HIV-infected children. Conclusion. There is a need for more systematic reviews on pediatric TB. The review identified several key priorities for future pediatric TB research mainly in the domain of (1) “Detection, screening and diagnosis,” “Development of Treatments and Therapeutic Interventions,” and “Prevention of Disease and Conditions, and Promotion of Well-Being.” These domains are very relevant in the research component of the roadmap towards ending TB in children. It also will serve as an additional action in the WHO End TB strategy

Increased risk of late-onset, immune-mediated, adverse reactions related to dermal fillers in patients bearing HLA-B*08 and DRB1*03 haplotypes

Even though manufacturers claim that the dermal fillers are nontoxic and nonimmunogenic, adverse events may occur. Clinically and histologically, most of the late onset adverse events present as an inflammatory response. To assess whether HLA polymorphisms are associated with late-onset inflammatory adverse events related to dermal fillers. A total of 211 patients were included, of whom 129 experienced late-onset inflammatory adverse events to different fillers (Inflammation group) and 82 who did not (Reference group). Patients completed a standardized questionnaire and provided a blood sample or oral swap for HLA testing. The study population consisted of 188 (89%) women and 23 (11%) men. The two study groups were similar in the distributions of filler type, location of injecting, allergy, autoimmune disease, gender, age, ethnicity, and smoking status. Of the 211 patients in the sample, 25 had the combination of HLA subtype-B*08 and HLA subtype-DRB1*03. This was 16.3% of the inflammatory group and 4.9% of the reference group. This combination of HLA subtypes was associated with an almost 4-fold increase in the odds of developing immune mediated adverse events (odds ratio = 3.79, 95% CI 1.25-11.48). Genetic polymorphisms such as HLA combinations may identify patients at risk of developing late onset immune mediated adverse events to dermal fillers

Household costs incurred under community- and facility-based service-delivery models of tuberculosis preventive therapy for children: a survey in Cameroon and Uganda

# Background Tuberculosis preventive treatment (TPT) in child household contacts is recommended by World Health Organization (WHO) but limited data has been reported on the costs experienced by households with children receiving TPT. # Methods We evaluated the economic impact on households with children receiving TPT within a service-delivery model cluster-randomised controlled trial in Cameroon and Uganda. The intervention included community health worker-led home-based child-contact screening, TPT initiation and monitoring, and referral of children with presumptive tuberculosis or side effects, and was compared with each country's facility-based standard of care (control). We used a retrospective cross-sectional survey adapted from the WHO Global task force on tuberculosis patient cost surveys. All costs were collected between February 2021 and March 2021 and are presented in 2021 US\$. # Results The median household costs estimated using the human capital approach were higher in the control arm (\$62.96 $$interquartile range, IQR; \$19.78-239.74$$ in Cameroon and \$35.95 $$IQR; \$29.03-91.26$$ in Uganda) compared to the intervention arm (\$2.73 $$IQR; \$2.73-14.18$$ in Cameroon and \$4.55 $$IQR; \$3.03-6.06$$ in Uganda). Using a threshold of 20% of annual household income, 15% (95%CI; 5-31%) of households in Cameroon and 14% (95%CI; 4-26%) in Uganda experienced catastrophic costs in the control compared to 3% (95%CI; 1- 8%) in Cameroon and 3% (95%CI; 1-8%) in Uganda in the intervention. Using the output-based approach to estimate income losses increased costs by 14-32% in the control and 13-19% in the intervention across the two countries. The proportion of participants experiencing any dissaving was higher in the control, 53% (95%CI; 36-71%) in Cameroon and 50% (95%CI; 31-69%) in Uganda, compared to 18% (95%CI; 10-29%) in Cameroon and 17% (95%CI; 8-28%) in Uganda in the intervention. # Conclusions Households with child contacts initiated on TPT under a facility-based model incur significant costs. Community-based interventions help to reduce these costs but do not eliminate catastrophic expenditures. \ **Registration** https://clinicaltrials.gov/ct2/show/NCT03832023

Integrating pediatric TB services into child healthcare services in Africa: study protocol for the INPUT cluster-randomized stepped wedge trial

Background Tuberculosis is among the top-10 causes of mortality in children with more than 1 million children suffering from TB disease annually worldwide. The main challenge in young children is the difficulty in establishing an accurate diagnosis of active TB. The INPUT study is a stepped-wedge cluster-randomized intervention study aiming to assess the effectiveness of integrating TB services into child healthcare services on TB diagnosis capacities in children under 5 years of age. Methods Two strategies will be compared: i) The standard of care, offering pediatric TB services based on national standard of care; ii) The intervention, with pediatric TB services integrated into child healthcare services: it consists of a package of training, supportive supervision, job aids, and logistical support to the integration of TB screening and diagnosis activities into pediatric services. The design is a cluster-randomized stepped-wedge of 12 study clusters in Cameroon and Kenya. The sites start enrolling participants under standard-of-care and will transition to the intervention at randomly assigned time points. We enroll children aged less than 5 years with a presumptive diagnosis of TB after obtaining caregiver written informed consent. The participants are followed through TB diagnosis and treatment, with clinical information prospectively abstracted from their medical records. The primary outcome is the proportion of TB cases diagnosed among children < 5 years old attending the child healthcare services. Secondary outcomes include: number of children screened for presumptive active TB; diagnosed; initiated on TB treatment; and completing treatment. We will also assess the cost-effectiveness of the intervention, its acceptability among health care providers and users, and fidelity of implementation. Discussion Study enrolments started in May 2019, enrolments will be completed in October 2020 and follow up will be completed by June 2021. The study findings will be disseminated to national, regional and international audiences and will inform innovative approaches to integration of TB screening, diagnosis, and treatment initiation into child health care services

Effectiveness of a community-based approach for the investigation and management of children with household tuberculosis contact in Cameroon and Uganda: a cluster-randomised trial.

BACKGROUND: Globally, the uptake of tuberculosis-preventive treatment (TPT) among children with household tuberculosis contact remains low, partly due to the necessity of bringing children to health facilities for investigations. This study aimed to evaluate the effect on TPT initiation and completion of community-based approaches to tuberculosis contact investigations in Cameroon and Uganda. METHODS: We did a parallel, cluster-randomised, controlled trial across 20 clusters (consisting of 25 district hospitals and primary health centres) in Cameroon and Uganda, which were randomised (1:1) to receive a community-based approach (intervention group) or standard-of-care facility-based approach to contact screening and management (control group). The community-based approach consisted of symptom-based tuberculosis screening of all household contacts by community health workers at the household, with referral of symptomatic contacts to local facilities for investigations. Initiation of TPT (3-month course of rifampicin-isoniazid) was done by a nurse in the household, and home visits for TPT follow-up were done by community health workers. Index patients were people aged 15 years or older with bacteriologically confirmed, drug-susceptible, pulmonary tuberculosis diagnosed less than 1 month before inclusion and who declared at least one child or young adolescent (aged 0-14 years) household contact. The primary endpoint was the proportion of declared child contacts in the TPT target group (those aged 2 months) and ten in the control group. Between Oct 14, 2019 and Jan 13, 2022, 2894 child contacts were declared by 899 index patients with bacteriologically confirmed tuberculosis. Among all child contacts declared, 1548 (81·9%) of 1889 in the intervention group and 475 (47·3%) of 1005 in the control group were screened for tuberculosis. 1400 (48·4%) child contacts were considered to be in the TPT target group: 941 (49·8%) of 1889 in the intervention group and 459 (45·7%) of 1005 in the control group. In the TPT target group, TPT was commenced and completed in 752 (79·9%) of 941 child contacts in the intervention group and 283 (61·7%) of 459 in the control group (odds ratio 3·06 [95% CI 1·24-7·53]). INTERPRETATION: A community-based approach using community health workers can significantly increase contact investigation coverage and TPT completion among eligible child contacts in a tuberculosis-endemic setting. FUNDING: Unitaid. TRANSLATION: For the French translation of the abstract see Supplementary Materials section

Improving COVID-19 contact tracing and testing of exposed individuals in Cameroon using digital health technology: a cluster randomised trialResearch in context

Summary: Background: Contact tracing was described as a key strategy to contribute to controlling the spread of severe acute respiratory syndrome of Coronavirus 2 (SARS-CoV-2) but implementing it can be a challenge. Digitalisation of contact tracing is among the proposed solutions being explored in sub-Saharan African settings. We assessed the effectiveness of a digital tool to expand SARS-CoV-2 testing in exposed individuals in Cameroon. Methods: We conducted a cluster-randomised (1:1) trial in eight health districts, including 22 facilities and SARS-CoV-2 testing units, randomly assigned to a digital (intervention) or standard (control) contact tracing approach. The intervention consisted of a contact tracing module added to the digital platform “Mamal PRO” used for monitoring and coordination of Coronavirus Disease 2019 pandemic response in Cameroon. The primary outcome was the proportion of contacts declared by SAR-CoV-2 index patients who were successfully traced and tested for SARS-CoV-2 evaluated with a Poisson regression model with cluster adjustment. This study is registered with ClinicalTrials.gov (NCT05684887). Findings: Between October 18, 2022, and March 31, 2023, we enrolled 164 index patients in the intervention arm and 149 in the control arm, who identified 854 and 849 contacts, respectively. In the intervention arm, 93.8% (801/854) of identified contacts were successfully reached by the tracing unit versus 54.5% (463/849) in the control arm. The intervention significantly increased the likelihood of successfully tracing contacts (adjusted relative risks (RR) 1.72 [95% CI: 1.00–2.95], p = 0.049). The median (interquartile range, IQR) time to successfully tracing contacts was 0 days [IQR: 0, 1] in the intervention and 1 day [IQR: 0, 2] in the control arm. In the intervention arm, 21.3% (182/854) of identified contacts received SARS-CoV-2 testing compared to 14.5% (123/849) in the control arm (adjusted RR 1.47 [95% CI: 0.44–4.90], p = 0.530). Interpretation: Digitalising the contact tracing process improved exposure notification and facilitated the tracing of a greater number of contacts of individuals infected with SARS-CoV-2 in resource-limited settings. Funding: The study was funded by FIND, United Kingdom (FCDO 40105983), Switzerland (81066910), Netherlands (SDD 4000004160), Canada (DFATD 7429348), The Kingdom of Saudi Arabia (FIND—ACT-A DX PARTNERSHIP 20.08.2020), The Rockefeller Foundation (2020 HTH 059), Germany (BMZ Covid-19 Diagnostic and Surveillance Response 27.07.2021), Australia (DFAT 76442), Kuwait (M239/2020), The Government of Portugal and Partners (ANF, BCP, CGF, APIFARMA) and The BlackRock Foundation (Grant Agreement as of April 20, 2022)