'25 at 25': Shortening treatment for tuberculosis

22 Mar 2024

A long road to recovery lies ahead for people diagnosed with tuberculosis (TB). Treatments lasting several months can be tough for patients due to challenging side effects, the burden of daily medication and frequent visits to the clinic, as well as social isolation due to the stigma of this infectious disease.

This piece explores how our clinical trials have helped deliver shorter treatment regimens for TB, improving quality of life for the millions of people around the world who fall ill with TB every year. It is part of a series detailing 25 major achievements from the 25 years since the MRC CTU at UCL was formed.

Study A:

Nowadays, the gold standard for treating drug-sensitive TB is a six-month regimen based on rifampicin and isoniazid given throughout treatment, supplemented by pyrazinamide and ethambutol given in an initial intensive phase. This recommendation is largely thanks to a clinical trial named Study A, which was run by the MRC Clinical Trials Unit at UCL in partnership with the International Union against TB and Lung Disease.

In the 1970s and 80s, trials conducted by the MRC Tuberculosis and Chest Diseases Unit led to the adoption of short course chemotherapy for drug-sensitive tuberculosis, with regimens based on rifampicin and isoniazid. There was strong evidence to support a regimen in which these two drugs were given throughout treatment, but because of the cost of the rifampicin, many countries adopted an eight-month regimen in which ethambutol was given in place of rifampicin after the first two months. There was limited evidence for the effectiveness of regimens which shortened the duration of rifampicin to two months, while extending the total treatment duration from six to eight months.

The eight-month regimen was recommended by the World Health Organization (WHO) because they considered it less likely to result in rifampicin resistance when treatment was not fully supervised. However, the regimen had never been tested against the rifampicin-based six-month regimen.

Study A was designed as a non-inferiority trial to make that critical assessment. The results were published in The Lancet in 2004, filling an important gap in the TB literature. The study found that patients treated with the six-month regimen had significantly fewer relapses and treatment failures than those treated with the standard-of-care regimen at the time. This demonstrated the eight-month regimen was clearly inferior to the six-month regimen. As a consequence, in 2010 WHO withdrew its earlier recommendation and recommended that all patients should receive a regimen containing six months of rifampicin.

By 2011, 196 of 206 countries reported using the new gold standard six-month regimen, treating millions of patients every year. Many of these will have avoided unnecessary suffering due to treatment failure and relapse thanks to Study A.

REMox and RIFAQUIN:

In the early 2000s, interest had grown in a class of antibiotics called fluoroquinolones. Studies in mice and humans indicated that they had promising activity against mycobacteria and researchers proposed that fluoroquinolones might play a role in reducing the duration of TB treatment.

In 2008, the REMoxTB trial put this theory to the test, comparing two new, four-month regimens including the fluoroquinolone moxifloxacin against the six-month regimen which was recommend. But while the shorter, moxifloxacin-containing regimens achieved a faster initial decline in bacterial load, neither was as effective in the long term as the control regimen.

But the trial did yield some valuable findings. REMoxTB was the first regulatory study to confirm that moxifloxacin was safe to take daily over a four-month period. This, combined with its activity against the bacteria laid the groundwork for future clinical testing of moxifloxacin as part of other new regimens.

RIFAQUIN was another clinical trial built on high hopes for moxifloxacin – this time combined with another drug called rifapentine. As with REMoxTB, RIFAQUIN found that although a four-month moxifloxacin and rifapentine regimen led to more relapses than the standard six-month regimen, six-month regimens of moxifloxacin and rifapentine were just as effective as the standard-of-care regimen.

This was promising, as the new RIFAQUIN regimen involved once-weekly treatment for the final four months, which would be much more manageable for patients and allow healthcare providers to closely supervise treatment. In addition, because the RIFAQUIN regimen did not include isoniazid, the results were of particular interest in areas with high levels of isoniazid resistance.

STREAM:

So far, we have looked at trials which addressed treatment for drug-sensitive TB. Approximately 5% of TB cases worldwide have rifampicin-resistant disease. This has historically had very poor outcomes despite two gruelling years of treatment, typically involving a total of 7,200 pills and 240 injections.

This was the case until STREAM, the world’s first phase III clinical trial in rifampicin-resistant TB. STREAM involved over 1,000 participants in eight countries in Asia, Africa and eastern Europe. The trial was designed to assess whether the encouraging results from a series of observational studies conducted in Bangladesh could be validated. The studies suggested that a new nine-month regimen could be more effective than the . Stage 1 of STREAM found that the new nine-month regimen was at least as effective as the much longer regimen, saving patients from many months of daily pills, isolation and stigma.

But problems remained. The nine-month regimen tested in STREAM involved kanamycin injections, which can cause deafness. STREAM Stage 2 assessed two alternative short course regimens. The first was another nine-month regimen, which replaced kanamycin injections with a new drug called bedaquiline and replaced moxifloxacin with levofloxacin, as there was concern that the combination of bedaquiline and moxifloxacin might cause cardiac problems. The other new regimen was just six months long with a shorter intensive phase, which also included bedaquiline but retained the injectable kanamycin for two months. In 2022, the STREAM results revealed that both new regimens were as effective as the nine-month regimen tested in Stage 1, leading to fewer treatment failures and relapses.

This randomised controlled trial strengthened the evidence base for treatment guidelines which have historically been based on observational data. Looking to the future, this high-quality evidence could help guide policymakers deciding on the best treatment regimens for multidrug-resistant TB.

TRUNCATE-TB:

Perhaps most dramatic cut to TB treatment duration came last year, with the results of the TRUNCATE-TB trial in south-east Asia and Uganda. TB researchers have known for some time that not all patients require a full six months of treatment to cure their TB. This groundbreaking trial demonstrated that a strategy of treating patients for just two months, followed by close monitoring and re-treatment if required, was as effective in the long term as the standard-of-care six-month regimen.

TRUNCATE-TB involved 674 patients with drug-sensitive TB. Participants were randomly allocated to either standard treatment for six months or the new TRUNCATE strategy. This involved one of five intensive drug regimens given for two-months. Treatment could be extended for a further two to four weeks if needed, followed by monitoring after treatment. Anyone whose TB was not cured or subsequently relapsed was retreated with a second course.

Two years after starting their initial treatment, researchers assessed the status of participants’ TB. They compared their outcomes with those receiving the standard six-month regimen. The TRUNCATE strategy drastically shortened the total length of treatment for trial participants receiving the regimen which contained bedaquiline and linezolid. They had an average treatment duration of 85 days, compared with 180 days for standard treatment. This is great news for TB patients, who will find it easier to stick to their prescribed treatment plan and avoid treatment failure.

Future cost-effectiveness analyses will explore whether the added costs of monitoring and retreatment are offset by the costs saved with a shorter treatment duration. This will be important for policymakers when deciding to recommend the TRUNCATE strategy in treatment guidelines.

Throughout the past 25 years, the MRC CTU at UCL’s work towards shortening and simplifying TB treatment has encompassed several other trials. This included the Nix-TB and ZeNix trials which both tested new drug combinations for patients with TB that has developed resistance to most existing anti-TB medicines. Our SHINE trial tackled the issue of TB in children, and found that treatment for those with minimal disease could safely be cut by two months. Currently, our PARADIGM4TB trial, which forms part of the UNITE4TB collaboration, is using a new trial design to address multiple simultaneous questions about the best drug combinations and treatment length for TB.

For people affected by TB, rapid access to shorter and more manageable treatment regimens is a huge priority. We are building on our Unit’s history of world-leading TB research to continue delivering these improvements for patients.

Further information: