Investigating mortality risk in hospitalised patients in Africa with HIV-associated tuberculosis and positive urine diagnostics: a clinical, epidemiological and immunological study.

HIV-associated tuberculosis (HIV/TB) was responsible for an estimated 374,000 deaths globally in 2016. Much of this burden resides in hospitals in sub-Saharan Africa, where HIV/TB is usually disseminated and is the major cause of admission and death. Recently, urine-based detection of mycobacterial lipoarabinomannan (LAM) or nucleic acids (using the Xpert MTB/RIF assay) has improved diagnosis of HIV/TB in this population, with the potential to improve outcomes. However, disseminated ‘urine-positive’ TB may also be associated with a higher mortality risk and impaired immune responses compared to patients with HIV/TB disease who are urine TB test negative. This thesis addresses the hypothesis that positive urine-diagnostics in inpatients with HIV/TB disease are associated with mortality, can identify patients with impairment of immune responses, and can be used as useful prognostic markers for identifying patients with poor outcomes. First, a systematic review and meta-analysis was undertaken to synthesise existing evidence of the association between urine-LAM detection and mortality risk in HIV/TB (Gupta-Wright et al, BMC Med 2016). Ten eligible studies were identified, and random-effects meta-analysis demonstrated urine-LAM positive patients had a 2.3-fold greater mortality risk, and 2.5-fold greater adjusted odds of death than urine-LAM negative HIV-TB patients. Secondly, a prospective observational cohort study nested within a large randomised trial of urine-based TB screening was undertaken (STAMP trial in Malawi and South Africa, Gupta- Wright at al BMC Inf Dis 2016 and Lancet 2018). It included 322 patients with laboratoryconfirmed HIV/TB disease and demonstrated a remarkably high (31%) 2-month mortality risk despite rapid initiation of TB treatment. It also demonstrated that advanced immunosuppression was common in HIV/TB disease despite high antiretroviral therapy (ART) coverage. Cohort data were used to identify clinical phenotypes associated with poor outcomes: urine-test positivity (LAM, Xpert or both) was independently associated with a 50% increase in 2 month case-fatality. Thirdly, a study of immune responses was nested in the Malawi STAMP trial site. A functional whole blood assay of phagocytic activity was developed (Gupta-Wright et al, Frontiers Immunology 2017) and utilised in 65 HIV/TB patients and 16 matched HIV-positive TB-negative controls. Cellular and soluble markers of immune activation, ex-vivo monocyte and T-cell cytokine responses and multiplex plasma cytokine and chemokine levels were also measured. Poor outcomes and urine-positive HIV/TB disease were associated with broadly impaired immune responses, including phagocytic oxidative burst function, monocyte activation and dominant innate immune responses. Finally, urine-LAM was included in a simple, pragmatic clinical score to identify patients at high risk of a poor outcome in resource-poor settings, which was externally validated on an individual-patient record dataset combining data from 2 different studies over 5 African countries (Gupta-Wright et al, PLOS Medicine 2019). This PhD has demonstrated the high prevalence and case-fatality associated with disseminated HIV/TB disease in HIV-positive hospital admissions despite widespread access to ART, and the utility of urine-diagnostics in identifying patients at high risk of mortality, in addition to their diagnostic use. These linked studies could potentially inform on the choice and nature of interventions to reduce the high mortality of HIV/TB, including better identification and management of ART failure, therapies to address TB-related immune dysfunction, and improved supportive care and prevention and treatment of co-morbidities.