Completed Infection & Immunity Pregnancy, Children & Inherited Conditions

Defining interventions to reduce mortality in severe HIV-associated tuberculosis.

Funder Wellcome Charity-funded
Recipient organisation University of Cape Town
Funding £1.3M
Period Jan 2013 — Jun 2018

In plain English

AI plain-English summary

In a hospital ward in sub-Saharan Africa, 660 patients with both HIV and severe tuberculosis will have their blood, urine, and spinal fluid tested repeatedly over 12 weeks to find out why so many die despite treatment. Tuberculosis is the leading killer of people with HIV, yet doctors do not know why standard TB drugs fail to prevent death in these patients. The problem is not simply drug resistance—many patients die within the first weeks of treatment, suggesting hidden infections, immune system chaos, or inadequate drug levels are to blame. This study will measure seven specific factors: mortality rate, bacterial load in the blood, gut bacteria leaking into the bloodstream, cytomegalovirus reactivation, immune cell death signals, paradoxical immune reconstitution inflammatory syndrome, and whether TB drug concentrations in the blood are too low to work. If the study identifies which of these factors drives mortality, it will allow researchers to design targeted interventions—such as adding antivirals, adjusting TB drug doses, or blocking specific immune pathways—and test them in future randomised controlled trials. The work is directly applied: its goal is to produce evidence for new treatment protocols that could save lives within a few years.

View original technical description
We propose a prospective observational cohort study of 660 hospitalised patients diagnosed with HIV-associated TB with a CD4 count < 350/microlitre and not currently on ART. Participants will be managed according to local guidelines and followed for 12 weeks. We will determine: 1) Cumulative mortality at 12 weeks. 2) Whether quantitative markers of Mycobacterium tuberculosis load correlate with clinical and laboratory markers of sepsis syndrome and whether these are associated with mortality. 3) If severe HIV-TB is associated with high levels of intestinal translocation of bacterial products and viable bacteria and the association with mortality. 4) The proportion of participants with cytomegalovirus viraemia and its association with mortality. 5) Whether immune activation-induced apoptosis and anti-inflammatory signalling (PD-1 pathway and anti-inflammatory cytokines) are higher in participants with fatal outcome. 6) The contribution of paradoxical TB-IRIS to mortality. 7) Wh at proportion of hospitalized HIV-TB patients have subtherapeutic concentrations of antitubercular drugs (INH, rifampicin, PZA) during the critical early period of TB treatment (pharmacokinetic study at 3 days on treatment). Significant findings from this study will allow us to propose novel interventions aimed at reducing mortality in severe HIV-TB and seek funding for RCTs.

View the original record at the funder ↗

Researchers

Graeme Meintjes (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Investigating the pathophysiology and contribution of co-infections in fatal HIV-associated tuberculosis. Prof. Graeme Meintjes. Uni of Cape Town
Integrated management of cryptococcal and opportunistic infections to improve outcomes in advanced HIV disease.
Predicting tuberculosis treatment outcome using pharmacokinetics, pharmacodynamics and host transcriptomics within a London cohort
Investigating local determinants of outcome in human tuberculosis
TB fast track: effect of a point-of-care TB test-and-treat algorithm on early mortality in people with HIV accessing ART

Original classification

International Intermediate Fellowship - Full

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.