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Improving cascade outcomes for active TB: A global systematic review and meta-analysis of TB interventions [1]

['Gifty Marley', 'Dermatology Hospital Of Southern Medical University', 'Guangzhou', 'University Of North Carolina Project-China', 'Xia Zou', 'Global Health Research Center', 'Guangdong Provincial People S Hospital', 'Guangdong Academy Of Medical Sciences', 'Southern Medical University', 'Juan Nie']

Date: 2023-01

Abstract Background To inform policy and implementation that can enhance prevention and improve tuberculosis (TB) care cascade outcomes, this review aimed to summarize the impact of various interventions on care cascade outcomes for active TB. Methods and findings In this systematic review and meta-analysis, we retrieved English articles with comparator arms (like randomized controlled trials (RCTs) and before and after intervention studies) that evaluated TB interventions published from January 1970 to September 30, 2022, from Embase, CINAHL, PubMed, and the Cochrane library. Commentaries, qualitative studies, conference abstracts, studies without standard of care comparator arms, and studies that did not report quantitative results for TB care cascade outcomes were excluded. Data from studies with similar comparator arms were pooled in a random effects model, and outcomes were reported as odds ratio (OR) with 95% confidence interval (CI) and number of studies (k). The quality of evidence was appraised using GRADE, and the study was registered on PROSPERO (CRD42018103331). Of 21,548 deduplicated studies, 144 eligible studies were included. Of 144 studies, 128 were from low/middle-income countries, 84 were RCTs, and 25 integrated TB and HIV care. Counselling and education was significantly associated with testing (OR = 8.82, 95% CI:1.71 to 45.43; I2 = 99.9%, k = 7), diagnosis (OR = 1.44, 95% CI:1.08 to 1.92; I2 = 97.6%, k = 9), linkage to care (OR = 3.10, 95% CI = 1.97 to 4.86; I2 = 0%, k = 1), cure (OR = 2.08, 95% CI:1.11 to 3.88; I2 = 76.7%, k = 4), treatment completion (OR = 1.48, 95% CI: 1.07 to 2.03; I2 = 73.1%, k = 8), and treatment success (OR = 3.24, 95% CI: 1.88 to 5.55; I2 = 75.9%, k = 5) outcomes compared to standard-of-care. Incentives, multisector collaborations, and community-based interventions were associated with at least three TB care cascade outcomes; digital interventions and mixed interventions were associated with an increased likelihood of two cascade outcomes each. These findings remained salient when studies were limited to RCTs only. Also, our study does not cover the entire care cascade as we did not measure gaps in pre-testing, pretreatment, and post-treatment outcomes (like loss to follow-up and TB recurrence). Conclusions Among TB interventions, education and counseling, incentives, community-based interventions, and mixed interventions were associated with multiple active TB care cascade outcomes. However, cost-effectiveness and local-setting contexts should be considered when choosing such strategies due to their high heterogeneity.

Author summary Why was this study done? Developing new and innovative interventions to improve tuberculosis (TB) care services use and successful treatment are essential to the global efforts to end TB.

There is a limited scope on the overall impact of these interventions because most studies focus on interventions’ capacity to enhance specific TB care outcomes.

Evaluating existing evidence to ascertain the effect TB interventions on overall care cascade outcomes is paramount to informing holistic TB control strategies What did the researchers do and find? We systematically reviewed and meta-analyzed evidence on TB interventions and their effects on the TB care cascade for active TB from 144 peer-reviewed studies.

In this study, the 5 out of 12 identified TB interventions associated with multiple care cascade outcomes were education and counseling, incentives, digital interventions, community-based, multisector collaborations, and mixed interventions.

Among LMIC studies, education and counseling, incentives, community-based interventions, and multisector collaborations were the interventions associated with at least three TB care cascade outcomes. What do these findings mean? A wide range of relatively simple interventions could substantially improve TB care outcomes.

Multistep efficient interventions like education and counseling, incentives, and mixed interventions should be keenly considered in expanding active TB control programs.

Researchers should revise multistage effective interventions to incorporate local context needs due to their high heterogeneity.

Citation: Marley G, Zou X, Nie J, Cheng W, Xie Y, Liao H, et al. (2023) Improving cascade outcomes for active TB: A global systematic review and meta-analysis of TB interventions. PLoS Med 20(1): e1004091. https://doi.org/10.1371/journal.pmed.1004091 Academic Editor: Claudia M. Denkinger, UniversitatsKlinikum Heidelberg, GERMANY Received: August 10, 2022; Accepted: December 13, 2022; Published: January 3, 2023 Copyright: © 2023 Marley et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: All relevant data are within the manuscript and its Supporting Information files. Funding: This work was supported by the National Institute of Health (R34MH119963 to WT), the Key Technologies Research and Development Program (2022YFC2304900-4 to WT), National Nature Science Foundation of China (81903371 to WT), and CRDF Global (G-202104-67775 to WT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Abbreviations: CI, confidence interval; DOTS, directly observed therapy short-course; EPHPP, Effective Public Health Practice Project; GRADE, Grading Recommendations, Assessment, Development, and Evaluation; HICs, high-income countries; HIV, human immunodeficiency virus; LMICs, lower/middle-income countries; MDR, multidrug-resistant TB; NAAT, nucleic acid amplification test; OR, odds ratio; PLWH, persons living with HIV; RCT, randomized controlled trial; TB, tuberculosis; WHO, World Health Organization

Introduction Tuberculosis (TB) affected an estimated 10.6 million people and caused 1.6 million deaths in 2021 [1]. The United Nations Sustainable Development Goals and World Health Organization (WHO)’s End TB Strategy set ambitious global targets for significant reductions in the global TB burden by 2030 [2]. Summarizing the existing evidence is essential in planning future TB control programs, as additional efforts are strongly needed to attain the goal. The TB care cascade comprises six fundamental steps: testing, diagnosis, linkage-to-care, cure, treatment completion, and treatment success [3,4]. Programmatic intervention refers to any public health intervention that seeks to prevent, promote health, or reduce the TB disease burden within a given population [5]. Many interventions like public education, staff training, mobile testing, and point-of-care testing have proven effective in enhancing TB services across the care cascade [6,7]. However, most intervention evaluations have focused on single TB care cascade outcomes, despite some affecting multiple care cascade outcomes. Moreover, previous reviews have mainly focused on synthesizing evidence of interventions on single care cascade outcomes—per our knowledge [8,9]. This limited scope is likely due to most studies focusing on interventions’ capacity to enhance specific care outcomes [10–13]. Recent studies have sought to assess intervention effects on multiple care cascade outcomes [14–16]. Yet, no current review has assessed the impacts of interventions across the whole TB care cascade. Evaluating existing evidence to ascertain the multistep effects capacity of TB care interventions across the care cascade is paramount to inform holistic prevention and control strategies for achieving the global End TB targets. This global systematic review and meta-analysis aimed to synthesize evidence on TB interventions and their effects on the TB care cascade for active TB.

Discussion Ensuring the delivery of quality person-centered service to all people living with TB is a global TB control priority and crucial to ending the TB pandemic [117,118]. This review synthesized existing evidence on the effects of various TB interventions in optimizing care cascade outcomes from a global perspective. Our findings extend the literature by summarizing evidence on how the intervention impacts TB care cascade outcomes to inform holistic TB control strategies. Among TB interventions, education and counseling were associated with an increased likelihood of TB testing, diagnosis, cure, treatment completion, and treatment success compared to standard-of-care. Mixed interventions, community-based interventions, and incentives were each associated with multiple care cascade outcomes, and digital interventions were significantly associated with two care cascade outcomes. Per our findings, community-based interventions, incentives, and multisector collaborations were the interventions associated an increased likelihood of outcomes for at least three care cased stages in LMICs. The evidence quality ranged from low to moderate certainty GRADE assessment. This is consistent with results in the literature on community-based interventions associated with testing, linkage-to-care, and treatment adherence [119–123]. Our sub-analysis findings showed that community-based interventions increased the likelihood of testing, especially in LMICs, where TB is estimated to be more prevalent. Community-based interventions and multisector collaborations may have worked well in LMICs due to the fragile and fragmented healthcare systems and limited resources of many LMICs [124,125]. More research is needed on how best to implement and fund community-based TB care to improve overall outcomes in the settings. The overall and RCTs-only sub-analysis showed that education and counseling increased the likelihood of all TB care cascade outcomes with an average moderate certainty. Mitigating public misconceptions and stigma that hinder TB services utilization through education and counseling may explain this observation. Similar to our findings, a previous review found that patient counseling at diagnosis improved linkage-to-care and treatment completion among TB patients [126]. Another review and Ethiopian study found that education and counseling engaged TB patients in the active self-management of their TB infection, which was essential to cure, treatment success, and the reduction of self-stigma [127,128]. We, therefore, emphasize that education and counseling should be valued and incorporated as a necessary component of ending TB strategies, especially for newly diagnosed TB patients. Mixed interventions and incentives were associated with an increased likelihood of multiple care cascade outcomes with low to moderate evidence quality. Some studies combined two or more interventions and reported the effect of this tailored intervention on TB care. However, it is worth noting that various factors (including where binding constraints are on the cascade, the overall effectiveness of interventions mixed at each point, and the relative costs of different interventions) influence the impact of mixed interventions. Therefore, researchers should consider mixing interventions with multiple outcome effects or efficient single-step strategies that span all six steps of the care cascade when designing mixed interventions. Also, resource availability, existing structures, local settings, and long-term sustainability should be well thought-out when adopting methods like incentives in limited resources settings. Overall, digital intervention only increased the likelihood of testing and linkage to care. This finding conforms with a previous review’s results that evidence of digital technologies improving TB care is contradictory and limited [129]. However, digital interventions have significantly improved healthcare services delivery and uptake for other infectious diseases like HIV [130]. New digital tools like smartphone-based diagnostics are cost-effective for rapid diagnostics in point-of-care testing and could enable real-time remote patient monitoring [131,132]. Thus, the roles of digital interventions in decentralizing and expanding healthcare could be tailored for efficient use in TB care and should be further researched. To be noted, the interventions identified in this review were highly diverse. The pooled effects of these interventions on TB care cascade were highly heterogenous. Results from our meta-regression analysis showed that the study design, year of publication, and region of study were the major sources of heterogeneity. This was not surprising as we observed wide diversification in how interventions were designed, the duration and intensity of implementation and variations in how the interventions were implemented. The variations in settings (rural communities versus urban slums) and target populations (general populations versus prisoners or ex-convicts) and approach to implementation for each intervention contributed to heterogeneity. For example, a study adapted “staff training + recruited and trained lay workers + active case finding” as a comprehensive care approach, while another study implemented “peer training + patient counseling and education +onsite sputum collection + expediated treatment initiation” to improve case detection and treatment outcomes [133,134]. Therefore, attention should be paid to local setting needs and cultural context when choosing to adopt any of the interventions with multistage effects to improve TB care cascade outcomes. We observed some evidence of publication bias per the funnel plots among the studies assessing interventions in TB diagnosis and treatment completion. This suggests that the effect size of certain interventions found in under this outcome may have been affected by missing small-size or negative finding studies. The reluctance of academic journals to publish studies with negative findings and our exclusion of case reports and short research reports may have contributed to this bias. Therefore, our reported effects of interventions on multiple care cascade outcomes should be interpreted with caution and within context. However, we corrected this bias by adjusting the plot using the trim-and-fill method. Therefore, our drawn conclusions based on the meta-analysis results remain salient. Our study has implementation, policy, and research implications. First, our findings reiterate the WHO recommendation that education and counseling should form part of comprehensive TB care strategies [135]. Thus, countries without patient counseling guidelines should consider establishing policies to incorporate counseling into routine TB care. Secondly, merging or concurrently implementing intervention with multiple outcomes effect could improve global TB control significantly. Therefore, researchers should consider revising mixed TB interventions to incorporate more such interventions or effective single-step strategies that span the entire care cascade. Also, programs to upscale evidence-based approaches should consider local context variations and adjust strategies to reach national TB goals. Finally, digital health is the cornerstone of modern healthcare but have unclear impact on TB care cascade outcomes. Therefore, future research should further explore potential roles of digital intervention in optimizing TB care. Our study has some limitations. First, the interventions were highly heterogeneous due to many factors, and the differences in implementation approaches like intensity, coverage, local context settings, and resource availability may have contributed to their effectiveness. Second, we did not evaluate the cost of implementing these interventions. Hence, our findings should be interpreted with attention to cost and feasibility. We also excluded non-English studies, which may have impacted the capture of literature from bibliographic databases of non-anglophone countries and biased our findings. However, our findings can be generalized because many of the interventions reviewed targeted diverse populations like PLWH, children, and migrants in both HIC and LMIC settings. Third, our study does not cover the entire TB care cascade as gaps in the early stages (focusing on testing or pretreatment loss to follow-up) and post-treatment outcomes (like TB recurrence and death) were not outcomes of interest and were not assessed in this review. Future reviews should consider examining these gaps and other key distinctions (like drug susceptibility or different forms of TB) and their effects on TB care outcomes to help inform strategies and policy adoption. Fourth, our funnel plots and meta-regression results showed the existence of publication bias. Nonetheless, our findings remain relevant to informing TB intervention programming if interpreted with caution and within context.

Conclusions Our study shows the existence of a wide range of relatively simple interventions that could substantially improve TB care outcomes. Nonetheless, high fidelity along the care cascade would become increasingly important as the rate of TB drug resistance increases. Therefore, multistep efficient interventions like education and counseling, incentives, and mixed interventions should be keenly considered in expanding active TB control programs. But factors like differences in implementation intensity, resource availability, and local setting contexts should be well thought-out when choosing strategies to strengthen holistic TB care as the interventions were sufficiently heterogeneous.

Acknowledgments We appreciate Dr. Madhu Pai, Dr. Liu Wei, and Miss. Jiayu He for serving as scientific advisors during this study. We also thank Miss Shamen Susan Chauma for assisting with screening articles and extracting data.

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[1] Url: https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004091

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