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Background Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level. Methods We systematically searched MEDLINE, Embase and Web of Science (1990–2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration–time curve from 0 to 24 h post-dose (AUC0–24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0–24 and Cmax were assessed with linear mixed-effects models. Results Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0–24 were summarised for isoniazid (18.7 (95% CI 15.5–22.6) h·mg·L−1), rifampicin (34.4 (95% CI 29.4–40.3) h·mg·L−1), pyrazinamide (375.0 (95% CI 339.9–413.7) h·mg·L−1) and ethambutol (8.0 (95% CI 6.4–10.0) h·mg·L−1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0–24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0–24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0–24 and slow acetylators had higher isoniazid AUC0–24 than intermediate acetylators. Determinants of Cmax were generally similar to those for AUC0–24. Conclusions This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualis

Background: Many evidence-based health interventions, particularly in low-income settings, have failed to deliver the expected impact. We designed an Adaptive Diseases Control Expert Programme in Tanzania (ADEPT) to address systemic challenges in health care delivery and examined the feasibility, acceptability and effectiveness of the model using tuberculosis (TB) and diabetes mellitus (DM) as a prototype. Methods: This was an effectiveness-implementation hybrid type-3 design that was implemented in Dar es Salaam, Iringa and Kilimanjaro regions. The strategy included a stepwise training approach with web-based platforms adapting the Gibbs' reflective cycle. Health facilities with TB services were supplemented with DM diagnostics, including glycated haemoglobin A1c (HbA1c). The clinical audit was deployed as a measure of fidelity. Retrospective and cross-sectional designs were used to assess the fidelity, acceptability and feasibility of the model. Results: From 2019-2021, the clinical audit showed that ADEPT intervention health facilities more often identified median 8 (IQR 6-19) individuals with dual TB and DM, compared with control health facilities, median of 1 (IQR 0-3) ( p = 0.02). Likewise, the clinical utility of HbA1c on intervention sites was 63% (IQR:35-75%) in TB/DM individuals compared to none in the control sites at all levels, whereas other components of the standard of clinical management of patients with dual TB and DM did not significantly differ. The health facilities showed no difference in screening for additional comorbidities such as hypertension and malnutrition. The stepwise training enrolled a total of 46 nurse officers and medical doctors/specialists for web-based training and 40 (87%) attended the workshop. Thirty-one (67%), 18 nurse officers and 13 medical doctors/specialists, implemented the second step of training others and yielded a total of 519 additional front-line health care workers trained: 371 nurses and 148 clinicians. Over

BACKGROUND: Poor glycemic control during tuberculosis (TB) treatment is challenging, as the optimum treatment strategy remains unclear. We assessed hyperglycemia severity using glycated hemoglobin (HbA1c) test and predictors of severe hyperglycemia at the time of TB diagnosis in three resources-diverse regions in Tanzania.METHODS: This was a substudy from a large cohort study implemented in three regions of Tanzania. TB individuals with diabetes mellitus (DM) (prior history of DM or newly diagnosed DM) were assessed for hyperglycemic levels using HbA1c test and stratified as mild (<53 mmol/mol), moderate (≥53-<86 mmol/mol), and severe (≥86 mmo/mol).RESULTS: From October 2019 to September 2020, 1344 confirmed TB individuals were screened for DM and 105 (7.8%) individuals had dual TB/DM and were assessed for glycemic levels. Of these, 69 (67.7%) had a prior history of DM and 26 (24.8%) were living with human immunodeficiency virus. Their mean age was 49.0 (±15.0) years and 56.2% were male. The majority (77.1%) had pulmonary TB, and 96.2% were newly diagnosed TB individuals. HbA1c test identified 41(39.0%), 37 (35.2%), and 27 (25.7%) individuals with severe, moderate, and mild the hyperglycaemia respectively. Female sex (odds ratio [OR]: 3.55, 95% confidence interval [CI]: 1.06-11.92, P = 0.040) and previous history of DM (OR: 3.71, 95% CI: 1.33-10.33, P = 0.013) were independent risk factors for severe hyperglycemic at the time of TB diagnosis.CONCLUSION: By integrating early HbA1c testing, a substantial proportion of individuals with severe hyperglycemia were identified. HbA1c testing can be recommended to identify and triage patients requiring personalized intensified DM management in resource-limited programmatic settings.

Temesgen Sidamo,1 Prakruti S Rao,2 Eleni Aklillu,3 Workineh Shibeshi,1 Yumi Park,4,5 Yong-soon Cho,4,5 Jae-Gook Shin,4,5 Scott K Heysell,2 Stellah G Mpagama,6 Ephrem Engidawork1 1Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia; 2Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA; 3Department of Laboratory of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; 4Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea; 5Center for Personalized Precision Medicine of Tuberculosis (cPMTb), Inje University College of Medicine, Busan, Republic of Korea; 6Kibong’oto Infectious Diseases Hospital, Sanya Juu, TanzaniaCorrespondence: Ephrem Engidawork, Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Sciences, Addis Ababa University, P.O. Box 9086, Addis Ababa, Ethiopia, Email ephrem.engidawork@aau.edu.etObjective: This study aimed to explore the population pharmacokinetic modeling (PopPK) of levofloxacin (LFX) and moxifloxacin (MXF), as well as the percent probability of target attainment (PTA) as defined by the ratio of the area under the plasma concentration-time curve over 24 h and the in vitro minimum inhibitory concentration (AUC0-24/MIC) in Ethiopian multidrug resistant tuberculosis (MDR-TB) patients.Methods: Steady state-plasma concentration of the drugs in MDR-TB patients were determined using optimized liquid chromatography-tandem mass spectrometry. PopPK and simulations were run at various doses, and pharmacokinetic parameters were estimated. The effect of covariates on the PK parameters and PTA for maximum mycobacterial kill and resistance prevention was also investigated.Results: LFX and MXF both fit in a one-compartment model with adjustments. Serum-creatinine (Cr)

Objective Diabetes mellitus (DM) has been known to compromise tuberculosis (TB) treatment outcomes. Association data are limited for early hyperglycaemia detection and TB treatment outcomes. Thus, we assessed treatment outcomes including time to sputum conversion and death in TB participants with or without hyperglycaemia. Methods A prospective cohort study recruited TB participants receiving anti-TB treatment at health facilities in Tanzania between October 2019 and September 2020. Hyperglycaemia was defined as having pre-existing DM or pre-treatment random blood glucose of >= 7.8 mmol/L, in combination categorised as impaired glucose regulation (IGR). Those with IGR were further screened for hyperglycaemia severity using glycated haemoglobin. In case of unknown status, participants were tested for HIV. Time to death was determined at 6 months of TB treatment. Results Of 1344 participants, 187 (13.9%) had IGR, of whom 44 (23.5%) were HIV co-infected. Overall treatment success was 1206 (89.7%), and was similar among participants with or without IGR (p > 0.05). Time to death for participants with and without IGR was 18 versus 28 days (p = 0.870), respectively. Age >= 40 years (p = 0.038), bacteriological positive (p = 0.039), HIV (p = 0.009), or recurrent TB (p = 0.017) predicted death or treatment success during TB treatment in adjusted multivariable models. Conclusion IGR did not influence clinical outcomes in TB patients with or without IGR in a programme of early IGR diagnosis and integration TB, HIV and DM care. Early detection and co-management of multi-morbidities among people diagnosed with TB may reduce likelihood of poor treatment outcomes in a programmatic setting.

Objective: To assess the current Tanzania health facilities readiness in integrating clinical management of dual Tuberculosis (TB) and Diabetes Mellitus (DM) by using the Service Availability and Readiness Assessment (SARA) manual of the World Health Organization prior to implementing an integrated service model. Study design: Cross-sectional study. Methods: A needs assessment survey was conducted at varying levels of health care facilities. The SARA manual evaluated the service delivery outcomes in terms of availability of guidelines, medicines and diagnostic equipment, training of healthcare workers in providing TB and DM care, and patient record review. Data were analyzed using Statistical Package for Social Science version 26. Results: Among 29 health facilities selected, three were regional referral hospitals, eight were district hospitals and eighteen were health centers. Baseline investigations revealed that GeneXpert MTB/RIF machines were present in 10 (34.5%) facilities, and glycated hemoglobin devices were present in two (6.9%) facilities, while all health facilities had a glucometer. The presence of an attending medical doctor in 19 (65.5%) facilities and the presence of operating biochemistry analyzers in 15 (51.7%) facilities were two mandatory variables used to assess readiness. Among the various guidelines observed, none of the facilities had the 2016 DM guidelines. Overall, 15 (51.7%) health facilities were ready to integrate dual TB and DM services. Conclusion: Integrative TB/DM screening and management activities can be achieved only if integration initiatives are prioritized at all levels of health facilities and among health policy makers in Tanzania. At least half of the health facilities were prepared to integrate the management of dual TB/DM. However, there is an urgent need to mobilize significant resources to improve the integration in these facilities, such as management guidelines and diagnostics.

INTRODUCTION: Most sub-Saharan African countries endure a high burden of communicable infections but also face a rise of non-communicable diseases (NCDs). Interventions targeting particular epidemics are often executed within vertical programmes. We establish an Adaptive Diseases control Expert Programme in Tanzania (ADEPT) model with three domains; stepwise training approach, integration of communicable and NCDs and a learning system. The model aims to shift traditional vertical programmes to an adaptive diseases management approach through integrating communicable and NCDs using the tuberculosis (TB) and diabetes mellitus (DM) dual epidemic as a case study. We aim to describe the ADEPT protocol with underpinned implementation and operational research on TB/DM.METHODS AND ANALYSIS: The model implement a collaborative TB and DM services protocol as endorsed by WHO in Tanzania. Evaluation of the process and outcomes will follow the logic framework. A mixed research design with both qualitative and quantitative approaches will be used in applied research action. Anticipated implementation research outcomes include at the health facilities level for organising TB/DM services, pathways of patients with TB/DM seeking care in different health facilities, factors in service delivery that need deimplementation and the ADEPT model implementation feasibility, acceptability and fidelity. Expected operational research outcomes include additional identified patients with dual TB/DM, the prevalence of comorbidities like hypertension in patients with TB/DM and final treatment outcomes of TB/DM including treatment-related complications. Findings will inform the future policies and practices for integrating communicable and NCDs services.ETHICS AND DISSEMINATION: Ethical approval was granted by The National Research Health Ethical Committee (Ref-No. NIMR/HQ/R.8a/Vol.IX/2988) and the implementation endorsed by the government authorities. Findings will be proactively

Background: Diagnosis of tuberculosis (TB) in patients co-infected with HIV poses an important challenge because of the low sensitivity and specificity of microscopy, the standard diagnostic method. This study aimed to evaluate the performance of the XpertMTB/RIF tool for TB diagnosis among TB-HIV co-infected patients. Methods: This was a cross-sectional analytical study conducted at Kibong’oto Infectious Disease Hospital in northern Tanzania and involved 69 patients. The performance of the XpertMTB/RIF and microscopy using LJ culture were determined and compared. Demographic, clinical, laboratory and radiological data were collected. Results: XpertMTB/RIF had a higher sensitivity (100%), specificity (100%), positive predictive value (79.2%) and negative predictive value (98.9%) as compared to microscopy. There was a strong correlation between XpertMTB/RIF, microscopy and Löwenstein–Jensen (LJ) culture in terms of their sensitivity and specificity. Conclusion: While using TB symptoms screening tool alone in HIV infected individuals may result into overtreatment, relying on microscopy alone has the potential of TB under-diagnosing, miss-diagnosing and delayed treatment. Our results show XpertMTB/RIF to be highly sensitive and specific to detect all culture positive TB cases among HIV patients. We recommend the adoption of XpertMTB/RIF as an early TB diagnosis tool among HIV patients for early detection of TB among HIV patients.