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Background: India accounts for about one-quarter of people contracting tuberculosis (TB) disease annually and nearly one-third of TB deaths globally. Many Indians do not navigate all care cascade stages to receive TB treatment and achieve recurrence-free survival. Guided by a population/exposure/comparison/outcomes (PECO) framework, we report findings of a systematic review to identify factors contributing to unfavorable outcomes across each care cascade gap for TB disease 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 workup (Gap 2), start treatment (Gap 3), achieve treatment success (Gap 4), or achieve TB recurrence-free survival (Gap 5). Three systematic searches of PubMed, Embase, and Web of Science from January 1, 2000 to August 14, 2023 were conducted. We identified articles evaluating factors associated with unfavorable outcomes for each gap (reported as adjusted odds, relative risk, or hazard ratios) and, among people experiencing unfavorable outcomes, reasons for these outcomes (reported as proportions), with specific quality or risk of bias criteria for each gap. Findings were organized into person-, family-, and society-, or health system-related factors, using a social-ecological framework. Factors associated with unfavorable outcomes across multiple cascade stages included: male sex, older age, poverty-related factors, lower symptom severity or duration, undernutrition, alcohol use, smoking, and distrust of (or dissatisfaction with) health services. People previously treated for TB were more likely to seek care and engage in the diagnostic workup (Gaps 1 and 2) but more likely to suffer pretreatment loss to follow-up (Gap 3) and unfavorable treatment outcomes (Gap 4), especially those who were lost to follow-up during their prior treatment. For individual care cascade gaps, multiple studies highlighted lack of TB knowledge and structural barriers (e.g., transportation challenges) as contributing to lack of care-seeking for TB symptoms (Gap 1, 14 studies); lack of access to diagnostics (e.g., X-ray), non-identification of eligible people for testing, and failure of providers to communicate concern for TB as contributing to non-completion of the diagnostic workup (Gap 2, 17 studies); stigma, poor recording of patient contact information by providers, and early death from diagnostic delays as contributing to pretreatment loss to follow-up (Gap 3, 15 studies); and lack of TB knowledge, stigma, depression, and medication adverse effects as contributing to unfavorable treatment outcomes (Gap 4, 86 studies). Medication nonadherence contributed to unfavorable treatment outcomes (Gap 4) and TB recurrence (Gap 5, 14 studies). Limitations include lack of meta-analyses due to the heterogeneity of findings and limited generalizability to some Indian regions, given the country's diverse population. Conclusions: This systematic review illuminates common patterns of risk that shape outcomes for Indians with TB, while highlighting knowledge gaps—particularly regarding TB care for children or in the private sector—to guide future research. Findings may inform targeting of support services to people with TB who have higher risk of poor outcomes and inform multicomponent interventions to close gaps in the care cascade. Tulip A. Jhaveri and team report findings of a systematic review to identify factors contributing to unfavorable outcomes across each care cascade gap for tuberculosis disease in India. Author summary: Why was this study done?: India has the highest tuberculosis (TB) incidence, accounting for about one-quarter of people with TB disease and nearly one-third of TB deaths globally. Many Indians with TB do not traverse all care stages needed to receive treatment and achieve an optimal long-term outcome, with serial losses of people across these stages referred to as the "care cascade." Understanding why losses of people with TB disease occur across the care cascade is crucial to inform interventions to prevent unfavorable outcomes. What did the researchers do and find?: We conducted 3 systematic searches to identify papers published from 2000 to 2023. We extracted information from these studies on risk factors for unfavorable outcomes for each care cascade gap, as well as reasons reported by people with TB who experienced unfavorable outcomes and were surveyed by researchers. Some factors contributed to losses at multiple care cascade stages, including male sex, older age, poverty-related factors, history of prior TB treatment, lower symptom severity or duration, undernutrition, alcohol use, smoking, and dissatisfaction with health services. Other barriers included: lack of TB knowledge and transportation barriers to clinic contributing to lack of care-seeking (Gap 1), poor accessibility of testing and failure to identify people eligible for testing contributing to non-completion of the diagnostic workup (Gap 2), early deaths from diagnostic delays and poor recording of contact information contributing to losses of people before treatment (Gap 3), lack of TB knowledge and depression contributing to unfavorable treatment outcomes (Gap 4), and medication nonadherence contributing to unfavorable treatment outcomes and TB recurrence (Gaps 4 and 5). What do these findings mean?: Reasons for losses of people with TB disease across the care cascade are complex, vary by care cascade gap, and involve patient- and health system-related barriers. India's TB program should target additional services to people with higher risk of poor outcomes and develop multicomponent interventions to address the diverse challenges faced by people with TB. Study limitations include lack of meta-analyses (i.e., estimation of the average effect of each risk factor by combining findings across studies), and caution is required when applying findings across India's diverse population. [ABSTRACT FROM AUTHOR]