Understanding and intervening in tuberculosis and HIV associated tuberculosis

Lead Research Organisation: The Francis Crick Institute

Abstract

In sub-Saharan Africa, people with human immunodeficiency virus HIV infection frequently also develop tuberculosis (TB). People arriving at clinics with TB symptoms are often found to have both HIV infection and active TB disease. In these patients with immune systems weakened by HIV, TB treatment is first started followed by antiretroviral therapy (ART) for the HIV a few weeks later. This is known to save lives.
However in some patients, in some studies up to 40-50%, the TB suddenly gets much worse. The reason is that, in addition to restoring good immune responses, the ART restores bad immune responses.
We recently carried out a trial that randomized patients to steroids as an anti-inflammatory drug, as well as the TB and HIV treatments. This is perhaps a surprising approach in HIV patients - we're looking to dampen the immune system even more.
The proportion of patients diagnosed with TB-IRIS was significantly lower in the group receiving the steroid. 33% of patients in the prednisone group developed TB-IRIS compared with 47% of people receiving placebo.
The blood samples and materials arising from this trial therefore give a good chance not only to work out how HIV-TB might be better treated, but to answer a much wider question. By what mechanism does steroid anti-inflammatory therapy prevent tissue damage.

Technical Summary

This work was supported by the Francis Crick Institute which receives its core funding from the UK Medical Research Council (FC001000), the Wellcome Trust (FC001000),and Cancer Research UK (FC001000)

I am a Physician-Scientist whose work is in understanding and intervening in tuberculosis and HIV-associated tuberculosis. For 12 years I have been 75% based at the Institute of Infectious Disease and Molecular Medicine at the University of Cape Town. South Africa has borne the brunt of HIV-tuberculosis epidemic and 1% Capetonians develop tuberculosis annually, 60% HIV-1 co-infected. Via competitive applications (Wellcome, NIH, European Commission and Gates) we have developed extensive clinical research infrastructure and allied laboratory capacity recently recognized by the award of Wellcome Trust Centre status. Clinical trials work has been incorporated into national and international policy.

The 9-year link with Crick has a consistent vision which is to harness and link excellence in basic Biomedical Science to the ‘real world’ situation of HIV-TB adopting forward and backward translational approaches. Capitalizing on access to large patient populations enrolled into very high quality clinical studies Anne O’Garra and I have had particular success in applying Systems Immunology approaches (especially transcriptomics) in which we have led the world. The forward translational potential of transcriptomic signatures to help understand, diagnose, refine prognosis, monitor treatment and provide correlative endpoints in Experimental Medicine studies will continue to be exploited. Materials arising from two very high quality cohort studies will be used. The first is complete, having recruited 660 severely immunosuppressed HIV-infected TB patients of whom 23% died. We have found evidence that mortality is contributed to by a mycobacteria-driven sepsis syndrome and anticipate the transcriptomic correlates of mortality will provide both insight and clues how to better treat such direly sick young people. The second study is a prospective NIH funded cohort of 440 persons about to open to recruitment that will include site of disease samples. This will serve the dual purpose of validation and also provide materials for collaborative and novel analyses of the intracellular biology of tuberculosis led by Max Gutierrez.

A second related area of world-leading research relates to the role of immunopathological inflammation in tuberculosis, in particular in understanding and managing the HIV-tuberculosis associated immune reconstitution inflammatory syndrome (TB-IRIS), and on the modulatory effects of corticosteroid and vitamin D adjunctive therapies. We led the derivation for a very widely accepted clinical case definition of this complication of combined antitubercular and antiretroviral therapies. We have recently completed a placebo-controlled randomized controlled trial in 268 patients at risk of TB-IRIS and found adjunctive steroids reduce the frequency of TB-IRIS by 30%. In a reverse translational approach we will use the stored materials arising to dissect the mechanism by which corticosteroids prevented inflammation and expect this to illuminate pathways that could be targeted by more specific and powerful adjunctive immunotherapies.

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