Understanding barriers to tuberculosis diagnosis and treatment completion in a low-resource setting: A mixed-methods study in the Kingdom of Lesotho.

BACKGROUND: Lesotho is one of the 30 countries with the highest tuberculosis incidence rates in the world, estimated at 650 per 100,000 population. Tuberculosis case detection is extremely low, particularly with the rapid spread of COVID-19, dropping from an estimated 51% in 2020 to 33% in 2021. The aim of this study is to understand the barriers to tuberculosis diagnosis and treatment completion. METHODS: We used a convergent mixed methods study design. We collected data on the number of clients reporting symptoms upon tuberculosis screening, their sputum test results, the number of clients diagnosed, and the number of clients who started treatment from one district hospital and one health center in Berea district, Lesotho. We conducted in-depth interviews and focus group discussions with 53 health workers and patients. We used a content analysis approach to analyze qualitative data and integrated quantitative and qualitative findings in a joint display. FINDINGS: During March-August, 2019, 218 clients at the hospital and 292 clients at the health center reported tuberculosis symptoms. The full diagnostic testing process was completed for 66% of clients at the hospital and 68% at the health center. Among clients who initiated tuberculosis treatment, 68% (61/90) at the hospital and 74% (32/43) at the health center completed treatment. The main barriers to testing and treatment completion were challenges at sample collection, lack of decentralized diagnostic services, and socioeconomic factors such as food insecurity and high patient movement to search for jobs. CONCLUSIONS: Tuberculosis diagnosis could be improved through the effective decentralization of laboratory services at the health facility level, and treatment completion could be improved by providing food and other forms of social support to patients.

Sensitivity of Various Case Detection Algorithms for Community-based Tuberculosis Screening.

Using data from 388 people diagnosed with tuberculosis through a community-based screening program in Lima, Peru, we estimated that cough screening followed by sputum smear microscopy would have detected only 23% of cases found using an algorithm of radiographic screening followed by rapid nucleic acid amplification testing and clinical evaluation.

Geospatial analysis of reported activity locations to identify sites for tuberculosis screening.

Mobile screening units can help close tuberculosis case detection gaps. Placing screening units where people at high risk for undiagnosed tuberculosis preferentially spend time could make screening more resource-effective. We conducted a case-control study in Lima, Peru to identify locations where people with tuberculosis were more likely to spend time than community controls. We surveyed participants about activity locations over the past 6 months. We used density-based clustering to assess how patient and control activity locations differed, and logistic regression to compare location-based exposures. We included 109 tuberculosis patients and 79 controls. In density-based clustering analysis, the two groups had similar patterns of living locations, but their work locations clustered in distinct areas. Both groups were similarly likely to use public transit, but patients predominantly used buses and were less likely to use rapid transit (adjusted odds ratio [aOR] 0.31, 95% confidence interval [CI] 0.10-0.96) or taxis (aOR 0.42, 95% CI 0.21-0.85). Patients were more likely to have spent time in prison (aOR 11.55, 95% CI 1.48-90.13). Placing mobile screening units at bus terminals serving locations where tuberculosis patients have worked and within and around prisons could help reach people with undiagnosed tuberculosis.

Geographic accessibility to health facilities predicts uptake of community-based tuberculosis screening in an urban setting.

OBJECTIVES: Annually, more than 30% of individuals with tuberculosis (TB) remain undiagnosed. We aimed to assess whether geographic accessibility measures can identify neighborhoods that would benefit from TB screening services targeted toward closing the diagnosis gap. METHODS: We used data from a community-based mobile TB screening program in Carabayllo district, Lima, Peru. We constructed four accessibility measures from the geographic center of neighborhoods to health facilities. We used logistic regression to assess the association between these measures and screening uptake in one's residential neighborhood versus elsewhere, with quasi-information criterion values to assess the association. RESULTS: We analyzed the screening locations for 25,000 Carabayllo residents from 49 neighborhoods. Pedestrian walk time was preferable to Euclidean distance or vehicular time in our models. For each additional 12 minutes walking time between the neighborhood and the health facility, the odds of residents using TB screening units located in their neighborhoods increased by 50% (95% CI: 26%-78%). Females had 9% (95% CI: 3%-16%) increased odds versus males of using a screening unit in their own neighborhood. CONCLUSION: Placing mobile TB screening units in neighborhoods with longer pedestrian time to access health facilities could benefit individuals who face more acute access barriers to health care.

A role for community-level socioeconomic indicators in targeting tuberculosis screening interventions.

Tuberculosis screening programs commonly target areas with high case notification rates. However, this may exacerbate disparities by excluding areas that already face barriers to accessing diagnostic services. We compared historic case notification rates, demographic, and socioeconomic indicators as predictors of neighborhood-level tuberculosis screening yield during a mobile screening program in 74 neighborhoods in Lima, Peru. We used logistic regression and Classification and Regression Tree (CART) analysis to identify predictors of screening yield. During February 7, 2019-February 6, 2020, the program screened 29,619 people and diagnosed 147 tuberculosis cases. Historic case notification rate was not associated with screening yield in any analysis. In regression analysis, screening yield decreased as the percent of vehicle ownership increased (odds ratio [OR]: 0.76 per 10% increase in vehicle ownership; 95% confidence interval [CI]: 0.58-0.99). CART analysis identified the percent of blender ownership (≤ 83.1% vs > 83.1%; OR: 1.7; 95% CI: 1.2-2.6) and the percent of TB patients with a prior tuberculosis episode (> 10.6% vs ≤ 10.6%; OR: 3.6; 95% CI: 1.0-12.7) as optimal predictors of screening yield. Overall, socioeconomic indicators were better predictors of tuberculosis screening yield than historic case notification rates. Considering community-level socioeconomic characteristics could help identify high-yield locations for screening interventions.

Mobile Surgical Scouts Increase Surgical Access for Patients with Cleft Lip and Palate in Nepal.

Background: In Nepal's remote regions, challenging topography prevents patients with cleft lip and palate (CLP) from seeking care. Objective: To measure the effect of a mobile surgical scout program on CLP surgical care in remote regions of Nepal. Methods: Forty-four lay people were trained as mobile surgical scouts and over 5 months traversed remote districts of Nepal on foot to detect and refer CLP patients for surgical care. Surgical patients from remote districts were compared with matched time periods in the year before intervention. Diagnostic accuracy of the surgical scouts was assessed. Findings: Mobile surgical scouts accurately diagnosed (90%) and referred (82%) patients for cleft surgery. Before the intervention, CLP surgeries from remote districts represented 3.5% of cleft surgeries performed. With mobile surgical scouting, patients from remote districts comprised 8.2% of all cleft surgeries (p = 0.007). When transportation and accompaniment was provided in addition to mobile surgical scouts, patients from remote districts represented 13.5% (p ≤ 0.001) of all cleft surgeries. Conclusion: Task-shifting the surgical screening process to trained scouts resulted in accurate diagnoses, referrals, and increased access to cleft surgery in remote districts of Nepal.

Closing delivery gaps in the treatment of tuberculosis infection: Lessons from implementation research in Peru.

BACKGROUND: Targeted testing and treatment of TB infection to prevent disease is a pillar of TB elimination. Despite recent global commitments to greatly expand access to preventive treatment for TB infection, there remains a lack of research on how best to expand preventive treatment programs in settings with high TB burdens. METHODS: We conducted implementation research in Lima, Peru, around a multifaceted intervention to deliver TB preventive treatment to close contacts of all ages, health care workers, and people in congregate settings. Key interventions included use of the interferon gamma release assay (IGRA), specialist support for generalist physicians at primary-level health facilities, and treatment support by community health workers. We applied a convergent mixed methods approach to evaluate feasibility and acceptability based on a care cascade framework. FINDINGS: During April 2019-January 2020, we enrolled 1,002 household contacts, 148 non-household contacts, 107 residents and staff of congregate settings, and 357 health care workers. Cumulative completion of the TB preventive care cascade was 34% for contacts <5 years old, 28% for contacts 5-19 years old, 18% for contacts ≥20 years old, 0% for people in congregate settings, and 4% of health care workers. IGRA testing was acceptable to adults exposed to TB. Preventive treatment was acceptable to contacts, but less acceptable to physicians, who frequently had doubts about prescribing preventive treatment for adults. Community-based treatment support was both acceptable and feasible, and periodic home-visits or calls were identified as facilitators of adherence. CONCLUSIONS: We attempted to close the gap in TB preventive treatment in Peru by expanding preventive services to adult contacts and other risk groups. While suboptimal, care cascade completion for adult contacts was consistent with what has been observed in high-income settings. The major losses in the care cascade occurred in completing evaluations and having doctors prescribe preventive treatment.

Cost of Delivering 12-Dose Isoniazid and Rifapentine Versus 6 Months of Isoniazid for Tuberculosis Infection in a High-Burden Setting.

BACKGROUND: Successful delivery and completion of tuberculosis preventive treatment are necessary for tuberculosis elimination. Shorter preventive treatment regimens currently have higher medication costs, but patients spend less time in care and are more likely to complete treatment. It is unknown how economic costs of successful delivery differ between longer and shorter regimens in high-tuberculosis-burden settings. METHODS: We developed survey instruments to collect costs from program and patient sources, considering costs incurred from when household contacts first entered the health system. We compared the cost per completed course of preventive treatment with either 6 months of daily isoniazid (6H) or 3 months of weekly isoniazid and rifapentine (3HP), delivered by the Indus Health Network tuberculosis program in Karachi, Pakistan, between October 2016 and February 2018. RESULTS: During this period, 459 individuals initiated 6H and 643 initiated 3HP; 39% and 61% completed treatment, respectively. Considering costs to both the program and care recipients, the cost per completed course was 394 US dollars (USD) for 6H and 333 USD for 3HP. Using a new 2020 price for rifapentine reduced the cost per completed course of 3HP to 290 USD. Under varying assumptions about drug prices and costs incurred by care recipients, the cost per completed course was lower for 3HP in all scenarios, and the largest cost drivers were the salaries of clinical staff. CONCLUSIONS: In a high-burden setting, the cost of successful delivery of 3HP was lower than that of 6H, driven by higher completion.

High yield of new HIV diagnoses during active case-finding for tuberculosis.

OBJECTIVE: To evaluate the utility of a broad and nonspecific symptom screen for identifying people with undiagnosed HIV infection. DESIGN: Secondary analysis of operational data collected during implementation of a cluster-randomized trial for tuberculosis case detection. METHODS: As part of the trial, adults reporting cough, fever, night sweats, weight loss, or difficulty breathing for any duration in the past month were identified in health facilities and community-based mobile screening units in western Kenya. Adults reporting any symptom were offered HIV testing. We analysed the HIV testing data from this study, using modified Poisson regression, to identify predictors of new HIV diagnoses among adults with symptoms and initially unknown HIV status. RESULTS: We identified 3818 symptomatic adults, referred 1424 (37%) for testing, of whom 1065 (75%) accepted, and 107 (10%) were newly diagnosed with HIV. The prevalence of new HIV diagnoses was 21% [95% confidence interval (CI) 17-25%] among those tested in health facilities and 5% (95% CI 4-7%) among those tested in mobile units. More men were diagnosed with HIV than women, despite fewer men being screened. People who reported 4-5 symptoms were over twice as likely to be diagnosed with HIV compared to those reporting 1-3 symptoms (adjusted prevalence ratio in health facilities = 2.58, 95% CI 1.65-4.05; adjusted prevalence ratio in mobile units = 2.63, 95% CI 1.37-5.03). CONCLUSION: We observed a high yield of new HIV diagnoses among adults identified by active application of a broad symptom screen. Use of integrated tuberculosis and HIV screening could help close the detection gap for both conditions.

Turning off the tap: stopping tuberculosis transmission through active case-finding and prompt effective treatment.

To halt the global tuberculosis epidemic, transmission must be stopped to prevent new infections and new cases. Identification of individuals with tuberculosis and prompt initiation of effective treatment to rapidly render them non-infectious is crucial to this task. However, in settings of high tuberculosis burden, active case-finding is often not implemented, resulting in long delays in diagnosis and treatment. A range of strategies to find cases and ensure prompt and correct treatment have been shown to be effective in high tuberculosis-burden settings. The population-level effect of targeted active case-finding on reducing tuberculosis incidence has been shown by studies and projected by mathematical modelling. The inclusion of targeted active case-finding in a comprehensive epidemic-control strategy for tuberculosis should contribute substantially to a decrease in tuberculosis incidence.

Control of transcription factor activity and osteoblast differentiation in mammalian cells using an evolved small-molecule-dependent intein.

Inteins are naturally occurring protein elements that catalyze their own excision from within a larger protein together with the ligation of the flanking "extein" sequences. Previously we reported the directed evolution of an intein-based molecular switch in which intein splicing in yeast cells was made dependent on the cell-permeable small molecule 4-hydroxytamoxifen (4-HT). Here we show that these evolved inteins are effective means of rendering protein function and biological signaling pathway activation dependent on 4-HT in mammalian cells. We have characterized the generality, speed, and dose dependence of ligand-induced protein splicing in murine NIH3T3 cells and in human HEK293 cells. Evolved inteins were used to control in mammalian cells the function of Gli1 and a truncated form of Gli3, two transcriptional mediators of the Hedgehog signaling pathway. Finally, we show that a complex biological process such as osteoblast differentiation can be made dependent on 4-HT using the evolved intein system. Our findings suggest that evolved small-molecule-dependent inteins may serve as a general means of achieving gene-specific, dose-dependent, post-translational, and small-molecule-induced control over protein activity in mammalian systems.