EX-DR TB

The challenge

Tuberculosis is difficult to treat, requiring several months’ treatment with a cocktail of antibiotics. When patients acquire infections resistant to components of standard drug regimens, even more intensive treatments are required, which have traditionally lasted at least 18 months.

The development of bedaquiline was a major advance in TB therapeutics. Of particular note, it has been incorporated into shortened and simplified regimens for multidrug-resistant TB (MDR-TB), including all-oral 6–9-month treatment programmes.

Unfortunately, there are growing signs that TB bacteria are developing resistance to bedaquiline. The situation is particularly severe in Mozambique, where 14% of multidrug-resistant TB isolates were resistant to bedaquiline in 2021, up from 3% in 2016. Resistance has also been detected in other countries in sub-Saharan Africa.

The project

Part of a major global initiative, the EX-DR TB project has twin aims: to promote improved stewardship of bedaquiline to reduce drivers of resistance, and to advance the development of new treatment options to supplement or replace bedaquiline. 

Although molecular diagnostics can detect resistance to some components of TB drug treatments (such as rifampicin), these are not routinely used, particularly for bedaquiline. As a result, a drug-resistant infection is often only detected when patients fail to respond to treatment, which may be several months after treatment has begun. 

It is becoming clear that patients primarily acquire bedaquiline-resistant infections from others; infections do not typically become resistant during treatment. Hence, if patients were tested for bedaquiline resistance as soon as the disease was detected, they could be initiated on a more effective regimen immediately.

Recently, a new strategy for detecting bedaquiline resistance has been developed. Mechanistically, resistance most often develops because of mutations that boost the activity of pumps that eject bedaquiline out of TB bacteria. Mutations can be detected by a combination of PCR, which specifically amplifies DNA copies of the gene coding for the efflux pump, followed by sequencing of this amplified DNA. Importantly, this approach can be applied directly to clinical samples, yielding rapid results. 

This technology is being widely introduced in sub-Saharan Africa thanks to a Gates Foundation project. Through the EX-DR TB project, this infrastructure to detect bedaquiline resistance will be explored. In addition, the technology will be used to detect a mutation associated with isoniazid resistance that is not picked up by existing molecular tests and is frequently found alongside bedaquiline resistance.

Alongside this work, consultations will be held to agree a standard treatment regimen for bedaquiline-resistant TB to ensure that use of the drug is optimised.

This will help to slow the development of drug resistance, but alternative treatments will still be needed. As part of a wider global programme, the EX-DR TB project will assess the efficacy and safety of two novel drug combinations. One will include a relative of bedaquiline showing significantly higher efficacy. The other will focus on drugs from different chemical classes, which should not be affected by bedaquiline resistance. The project is linked to multiple drug development networks, enabling them to select the most promising options. 

Impact

The EX-DR TB project is addressing one of sub-Saharan Africa’s most pressing health problems, multidrug-resistant tuberculosis. It will:

• Validate an approach for detecting bedaquiline-resistant TB bacteria.
• Ensure more consistent and targeted use of bedaquiline-containing regimens and improve treatment of bedaquiline-resistant infections.
• Advance the development of new TB drug treatments.

Collectively, project activities will help to preserve the potency of a critical drug central to the treatment of multidrug-resistant TB and also ensure the availability of additional drug treatments.