Improving survival with tuberculosis & HIV treatment integration: A mini-review.

Tuberculosis (TB) is a leading cause of morbidity and mortality among HIV-infected patients while HIV remains a key risk factor for the development of active TB infection. Treatment integration is a key in reducing mortality in patients with HIV-TB co-infection. However, this opportunity to improve outcomes of both infections is often missed or poorly implemented. Challenges in TB-HIV treatment integration range from complexities involving clinical management of co-infected patients to obstacles in health service-organization and prioritization. This is evident in high prevalence settings such as in sub-Saharan Africa where TB-HIV co-infection rates reach up to 80 per cent. This review discusses published literature on clinical trials and cohort studies of strategies for TB-HIV treatment integration aimed at reducing co-infection mortality. Studies published since 2009, when several treatment guidelines recommended treatment integration, were included. A total of 43 articles were identified, of which a total of 23 observational studies and nine clinical trials were informative on TB-HIV treatment integration. The data show that the survival benefit of AIDS therapy in patients infected with TB can be maximized among patients with advanced immunosuppression by starting antiretroviral therapy (ART) soon after TB treatment initiation, i.e. in patients with CD4+ cell counts <50 cells/µl. However, patients with greater CD4+ cell counts should defer initiation of ART to no less than eight weeks after initiation of TB treatment to reduce the occurrence and extent of immune reconstitution disease and subsequent hospitalization. Addressing operational challenges in integrating TB-HIV care can significantly improve patient outcomes, generate substantial public health impact by decreasing morbidity and death in settings with a high burden of HIV and TB.

Intracellular growth of Mycobacterium tuberculosis after macrophage cell death leads to serial killing of host cells.

A hallmark of pulmonary tuberculosis is the formation of macrophage-rich granulomas. These may restrict Mycobacterium tuberculosis (Mtb) growth, or progress to central necrosis and cavitation, facilitating pathogen growth. To determine factors leading to Mtb proliferation and host cell death, we used live cell imaging to track Mtb infection outcomes in individual primary human macrophages. Internalization of Mtb aggregates caused macrophage death, and phagocytosis of large aggregates was more cytotoxic than multiple small aggregates containing similar numbers of bacilli. Macrophage death did not result in clearance of Mtb. Rather, it led to accelerated intracellular Mtb growth regardless of prior activation or macrophage type. In contrast, bacillary replication was controlled in live phagocytes. Mtb grew as a clump in dead cells, and macrophages which internalized dead infected cells were very likely to die themselves, leading to a cell death cascade. This demonstrates how pathogen virulence can be achieved through numbers and aggregation states.