Background: In high burden settings case fatality rates are reported to be between 11% and 32% in hospitalized patients with HIV-associated tuberculosis, yet the underlying causes of mortality remain poorly characterized. Understanding causes of mortality could inform development of novel management strategies to improve survival. We aimed to assess clinical and microbiologic determinants of mortality and to characterize the pathophysiological processes underlying death by evaluating host soluble inflammatory mediators and determined the relationship between these mediators and death as well as biomarkers of disseminated tuberculosis. Methods and Findings: Adult HIV-positive patients hospitalized with a new diagnosis of HIV-associated tuberculosis were enrolled in Cape Town between 2014-2016. Detailed tuberculosis diagnostic testing was performed. Biomarkers of tuberculosis dissemination and host soluble inflammatory mediators at baseline were assessed. Of 682 enrolled participants, 576 with tuberculosis (487/576, 84.5% microbiologically confirmed) were included in analyses. The median age was 37 years (IQR=31-43), 51.2% were female and the patients had advanced HIV with median CD4 count =58 cells/l (IQR= 21-120) and median HIV viral load=5.1 log10 copies/mL (IQR=3.3-5.7).Antituberculosis therapy was initiated in 566/576 (98.3%) and 487/576 (84.5%) started therapy within 48 hours of enrolment. Twelve-week mortality was 124/576 (21.5%) with 46/124 (37.1%) deaths occurring within 7 days of enrolment. Clinical and microbiologic determinants of mortality included disseminated tuberculosis (positive urine lipoarabinomannan, urine Xpert MTB/RIF or tuberculosis blood culture in 79.6% of deaths vs 60.7% of survivors, p=0.001), sepsis syndrome (high lactate in
50.8% of deaths vs 28.9% of survivors, p<0.001) and rifampicin resistant tuberculosis (16.9% of deaths vs 7.2% of survivors, p=0.002). Using non-supervised two-way hierarchical cluster and principal components analyses, we describe an immune profile dominated by mediators of the innate immune system and chemotactic signaling (IL-1Ra, IL-6, IL-8, MIP-1β/CCL4, IP-10/CXCL10, MIP-1α/CCL3) which segregated participants who died from those who survived. This immune profile was associated with mortality in a Cox proportional hazards model (adjusted hazard ratio = 2.2, 95%CI = 1.9-2.7, p<0.001) and with detection of biomarkers of disseminated tuberculosis. Clinicians attributed causes of death identified tuberculosis as a cause or one of the major causes of death in 89.5% of cases. We did not perform longitudinal sampling and did not have autopsy confirmed causes of death.Conclusions: In this study, we did not identify a major contribution from co-infections to these deaths. Disseminated tuberculosis, sepsis syndrome and rifampicin resistance were associated with mortality. An immune profile dominated by mediators of the innate immune system and chemotactic signaling was associated with both tuberculosis dissemination and mortality. These findings provide pathophysiologic insights into underlying causes of mortality and could be used to inform development of novel treatment strategies and develop methods to risk stratify patients to appropriately target novel interventions. Causal relationships cannot be established from this study.