Barriers to engagement by people with active tuberculosis in the care cascade in India: a systematic review of two decades of quantitative research

Background. India has the highest burden of tuberculosis (TB), accounting for more than one-quarter of people with active TB and nearly one-third of TB deaths globally. Most people contracting active TB in India do not successfully navigate all stages of the care cascade to receive treatment and achieve TB recurrence-free survival. Understanding reasons for losses across the care cascade is critical to improve outcomes. In this paper, guided by a PECO (population/exposure/comparison/outcome) framework, we describe quantitative findings of a systematic review aimed at identifying factors contributing to unfavorable outcomes experienced by people with TB at each care cascade gap in India. Methods and findings. We defined care cascade gaps as comprising people with confirmed or presumptive TB who did not: start the TB diagnostic workup (Gap 1), complete the diagnostic workup (Gap 2), start treatment (Gap 3), achieve treatment success (Gap 4), or achieve TB recurrence-free survival (Gap 5). Three systematic searches were conducted to identify 147 unique articles published from 2000 to 2021 that evaluated factors associated with unfavorable outcomes for each gap (reported as odds, relative risk, or hazard ratios) and, among people experiencing unfavorable outcomes, reasons reported for these outcomes (reported as proportions). Findings were organized into patient-, family-, society-, or health system-related factors, using a social-ecological framework. Some factors were common and associated with unfavorable outcomes across multiple care cascade stages. These included male sex, older age (variably defined across studies), a broad array of poverty-related factors, lower symptom severity or duration, undernutrition, alcohol use, smoking, and distrust of (or dissatisfaction with) local government health services. People who had been previously treated for TB were more likely to seek care and engage in the TB diagnostic workup (Gaps 1 and 2) but were also more likely to suffer pretreatment loss to follow-up (Gap 3) and unfavorable outcomes during TB treatment (Gap 4), especially those who had been lost to follow-up during their prior treatment episode. For individual care cascade gaps, multiple studies highlighted the importance of lack of TB knowledge and structural barriers to care (e.g., transport or financial challenges in reaching clinics) in contributing to lack of care-seeking for TB symptoms (Gap 1, 15 studies or analyses); lack of access to diagnostics (e.g., chest X-ray), non-identification of eligible patients for testing, and failure of providers to communicate concern for TB to patients in contributing to non-completion of the diagnostic workup (Gap 2, 20 studies or analyses); TB stigma, poor recording of patient contact information by providers, and early death due to diagnostic delays in contributing to pretreatment loss to follow-up (Gap 3, 25 studies); and medication adverse effects, TB stigma, and lack of TB knowledge in contributing to unfavorable treatment outcomes (Gap 4, 104 studies). Medication nonadherence contributed to unfavorable treatment outcomes (Gap 4) and post-treatment TB recurrence (Gap 5, 15 studies). Conclusions. This extensive systematic review illuminates common patterns of risk that shape outcomes for people with TB in India, while also highlighting gaps in knowledge, particularly with regard to TB care for children or in the private sector, that can help to guide future research. These findings may help inform targeting of additional support services to people with TB who are at higher risk of poor outcomes and inform development of multi-component interventions to close gaps in India′s TB care cascade. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by a Clinical Scientist Development Award from the Doris Duke Foundation (grant 2018095), a Data Sharing Award from the Doris Duke Foundation (grant 2021074), and a grant from the Bill and Melinda Gates Foundation (grant INV-038215). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used (or will use) ONLY openly available human data that were originally located through already published peer-reviewed journal articles or publicly available reports. These data sources were all openly available before the initiation of the study, and all of these peer-reviewed journal articles or publicly available reports can be located using the references included in our study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript or supplemental appendices.