RECENT-TB

The challenge

Every year, around 1.5–2 million people in sub-Saharan Africa are treated for tuberculosis. Of those successfully treated, around one in ten suffer a relapse or reinfection (collectively termed TB recurrence) within two years. Although they represent around 5–30% of the global TB burden, such patients receive relatively little attention.

TB recurrence is associated with a range of risk factors, linked to patient characteristics, exposure risks, and microbiological factors such as residual bacterial load. Although a simplified preventive antibiotic regimen is used in certain high-risk groups to reduce the risk of TB recurrence (secondary preventive treatment), the lack of evidence of its effectiveness for other patient populations means that it is only recommended for people living with HIV.

Potentially, secondary preventive treatment could be used more widely. Modelling suggests that it could reduce the incidence of TB by 40% over 10 years and save costs. In addition, as an alternative to blanket use, risk stratification might enable secondary prevention to be directed at those who would benefit most.

The project

To close this knowledge gap, the RECENT-TB project is conducting a large-scale trial of secondary preventive treatment for tuberculosis in two high-burden settings, South Africa and Uganda, while also evaluating the implementation context and the potential of various simple tests to identify patients at the highest risk of recurrence.

The project’s main trial is recruiting 1,800 patients following treatment for pulmonary TB, with half receiving secondary preventive treatment (12 weekly doses of isoniazid plus rifapentine, known as 3HP). Participants will be followed for two years to determine their impact on recurrence. The trial’s hybrid implementation design will allow gathering information on the feasibility and acceptability of secondary preventive treatment to inform future policy and practice.

Embedded within this trial will be a cohort study evaluating four potential risk markers for recurrence:

• C-reactive protein (CRP): A simple point-of-care test for inflammation based on a finger-prick blood sample.
• Haemoglobin: Another simple point-of-care blood finger-prick test, which detects anaemia, a risk factor for TB.
• CXR+CAD4TB: Computer-aided interpretation of chest X-ray images which detects lung abnormalities related to TB. This will detect patients with structural abnormalities at the end of TB treatment, which may increase the risk for TB recurrence.  
• TB-Microbial Load Assay (TB-MBLA): A molecular assay that detects RNA from TB bacteria, so it provides a highly sensitive test for live bacteria. 

The project will collect data on these markers to determine if they are predictive of recurrence. A personalised risk score will be developed based on the best combination of markers, which will then be integrated alongside other patient data into a risk-stratification algorithm – providing a simple ‘high/medium/low’ TB recurrence risk assessment that could be used to select patients for secondary preventive treatment.   

In addition, the project will include a study to evaluate the potential use of TB-MBLA for diagnosing recurrence. A case–control approach will be used, with TB-MBLA data on participants with recurrence compared with data from participants in the same cohort who remained healthy. The diagnostic performance of TB-MBLA will be compared with gold-standard culture methods and a widely used molecular diagnostic (Xpert Ultra).

Impact

The RECENT-TB project could provide a new option for a relatively neglected group, those recovering from tuberculosis disease. It will:

• Demonstrate whether the 3HP regimen reduces the risk of recurrence after TB treatment.
• Provide data on implementation considerations for scale-up of secondary preventive treatment in policy and practice.
• Reveal whether simple tests can distinguish patients at the highest risk of recurrence, so 3HP use could be targeted at those most in need.
• Provide an estimate of the likely cost-effectiveness of different approaches to secondary prevention with 3HP. 

If shown to be effective, wider use of 3HP for secondary prevention of tuberculosis could improve the survival and quality of life of TB patients after treatment, reduce community transmission of TB, and lower the overall cost of treating TB (thanks to a reduced number of patients with recurrences requiring treatment).