INTENSE-TBM-2

The challenge

Although tuberculosis (TB) is primarily a disease of the lungs, it can also affect other body tissues, including the membranes lining the brain, the meninges. Tuberculous meningitis (TBM) is the most deadly form of TB. In sub-Saharan Africa, the TBM death rate is around 40%, but rises to 70% for patients who also have HIV infections. As well as deaths, TBM can also trigger damage to blood vessels, leading to localised brain damage and a wide range of neurological symptoms.

TBM is currently treated with the same multidrug regimens used for pulmonary TB. These are only partially effective, in part because the drugs do not reach high levels at the sites where TB bacteria are present in the brain. However, there is growing evidence that higher concentrations of key TB drugs such as rifampicin can be safely used and may be more effective in TBM.

The project

Funded through the EDCTP2 programme, the INTENSE-TBM project has been running a clinical trial evaluating a novel treatment regimen for TBM. The new approach has two key innovations:

• Use of high-dose rifampicin alongside linezolid, which is used to treat drug-resistant TB and shows good penetration into the brain.
• Inclusion of low-dose aspirin to reduce the risk of neurological damage due to leakage from blood vessels in the brain.

The trial, launched in Côte d’Ivoire, Madagascar, South Africa and Uganda, was badly affected by the COVID-19 pandemic, with recruitment significantly slower than anticipated. Global Health EDCTP3 funding will enable the INTENSE-TBM-2 project, the largest currently underway on TBM treatment, to complete recruitment up to its target of more than 750 patients, to follow up patients and to analyse trial data. 

The project is also exploring the nature and implications of the neurological damage linked to TBM, including impacts on daily life, to provide a picture of the full impact of TBM infections. 

In addition, in patients with HIV infections, the project is tracking possible interactions between anti-TB drugs and antiretrovirals, particularly dolutegravir, and monitoring for cases of TB-IRIS (immune reconstitution inflammatory syndrome), when antiretroviral treatment leads to a rebound in immune function that drives harmful reactions to TB.

Impact

The INTENSE-TBM-2 project is generating key evidence on the safety and efficacy of a potentially transformational treatment for Tuberculous meningitis (TBM). It will:

• Show whether the intensified treatment with high-dose rifampicin and linezolid reduces the alarmingly high TBM mortality rate.
• Demonstrate whether low-dose aspirin has similarly beneficial effects by reducing the likelihood of neurological impacts.
• Provide high-quality data to inform national and global policymaking.
• Generate evidence on the interactions between anti-TB and antiretroviral treatments for HIV, to guide care of this important group of patients.

The INTENSE-TBM-2 project is a crucial trial that will shape the future of TBM care, with each intervention anticipated to lower TBM mortality by 30% and reduce the risk of neurological harms that can severely affect day-to-day life.