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What next for TB treatment after disappointing results for shortened regime?

With high hopes for a new, shortened regime to treat drug-susceptible tuberculosis (TB) in South Africa dashed recently after disappointing trial outcomes, have scientists reached the limit in such trials?

Many people find it hard to complete the current treatment regimen which involves a combination of four antibiotics, which is cheap and effectively cures TB, but takes six months. This is sometimes due to side-effects, and in other cases because people can feel well again long before the six months are over, writes Elri Voigt for Spotlight.

And while several clinical trials have evaluated the safety and efficacy of shorter regimens, mostly with disappointing results, this changed in 2021 when a study referred to as “Study 31” found a four-month regimen non-inferior to the current six-month regimen.

However, this is much more expensive than the current six-month regimen – mainly because it includes the drug rifapentine. This rifapentine-based four-month regimen is recommended by the US Centre for Disease Control and Prevention (CDC), and conditionally recommended by the World Health Organisation (WHO), for the treatment of TB in people aged 12 and older, but is not used in South Africa’s public sector. A four-month regimen specifically for children is due to be rolled out in the country.

The next big treatment-shortening studies on the horizon after Study 31 was SimpliciTB. The ambitious vision for this was not only to produce a shortened regimen for the treatment of drug-sensitive TB but a single regimen that could also be used for drug-resistant forms of TB (DR-TB).

But whereas the regimen may have promise for DR-TB, findings presented at the recent Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, dealt a serious blow to prospects of using this regimen for drug-susceptible TB.

Disappointing findings

SimpliciTB compared a four-month treatment course comprising the drugs bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) with the six-month standard of care for the treatment of drug-susceptible TB. While it was a randomised controlled trial, it was also open-label, meaning patients and healthcare workers knew who was on which study arm.

There was also a third study arm in which the BPaMZ regimen was given to people with DR-TB, but the study did not have a DR-TB control arm. A total of 303 people enrolled in the two DS-TB arms.

The researchers measured two key outcomes – culture conversion (two consecutive TB culture tests being negative) after eight weeks and unfavourable outcomes after 52 weeks.

BPaMZ did well on one measure but fell short on the other. By week eight, 84% of those in the BPaMZ arm had negative cultures, compared with only 47% of those in the six-month arm.

After 52 weeks, however, 17% of those in the BPaMZ arm had unfavourable outcomes compared with only 7% of those in the six-month arm. On the first measure, BPaMZ was found to be superior to the six-month regimen, while on the second measure, it failed to meet the threshold for non-inferiority.

Dr Muge Cevik, who presented the study results at CROI, said there were many early withdrawals in the trial – 14 in the BPaMZ arm but only one in the six-month arm. The picture is thus one of the BPaMZ regimen being highly effective but patients struggling to cope with the side-effects, mostly liver-related.

“I think how they presented it is they were saying if you’re looking at efficacy, this regimen is good at killing TB and curing TB,” said Lindsay McKenna of Treatment Action Group (a New York-based advocacy organisation). “However, if you look at the regimen on the whole that’s only true if someone can tolerate the regimen – so it’s effective but not safe, therefore, not a good regimen.”

Dr Vidya Mave, co-director of the Centre for Infectious Diseases in Pune, India, told Spotlight that BPaMZ did exactly what it was supposed to – kill TB. However, she also expressed concern over the high number of toxicity events, suggesting that using Pyrazinamide for four rather than the usual two months may have played a role, although more detailed study findings were needed to see if this was the case.

A novel approach

While Study 31, SimpliciTB, and several others largely focused on testing experimental shortened regimens, one called TRUNCATE-TB presents a novel treatment strategy rather than just a new antibiotic regimen. Its strategy is to treat people for a shorter period (eight weeks) and then stop treatment if people test negative, and extend treatment if they do not. Treatment can simply be restarted if someone’s TB returns after they’ve stopped taking treatment.

Initial fndings from TRUNCATE-TB were presented last year at the Union World Conference on Lung Health. Additional findings were presented last week at CROI and study findings were simultaneously published in the New England Journal of Medicine (NEJM).

According to the NEJM article, a regimen based on the antibiotics bedaquiline and linezolid given for eight weeks (with extension and retreatment as required) was non-inferior to the six-month standard of care. The mean treatment duration with the bedaquiline/linezolid regimen was 85 days, compared with 180 days with the six-month regimen.

TRUNCATE-TB lead investigator Dr Nicholas Paton said the rate of relapse on the bedaquiline/linezolid regimen was about 14%.

People whose TB relapsed were simply put back on treatment in line with the TRUNCATE-TB strategy. “What the trial has told us is that even with that 14% relapse rate, you can manage that within this strategy and people are fine at the end,” he said.

Some good news is that there does indeed appear to be a biomarker that predicts whether someone’s TB will relapse after the eight weeks of treatment. “We can pick people with a high disease burden on GeneXpert (a molecular TB test already widely used in South Africa) before they start treatment who don’t have a high chance of achieving cure with our eight-week treatment,” Paton said.

“We can now look at ways of improving the decision-making about when to stop treatment and also at improving the post-treatment monitoring so that we can simplify that, make it more accurate at detecting people who need re-treatment.”

What next?

Encouraging as the TRUNCATE-TB findings are, the only alternative to the six-month drug-susceptible standard of care currently recommended by the WHO and CDC is the rifapentine-based regimen from Study 31. But uptake has been slow, said McKenna, reasons including supply constraints, cost, and procurement challenges.

“There are environmental issues around how currently drug-sensitive TB drugs are procured and purchased … it’s a problem that must be solved before we can probably have equitable access to the four months regimen.”

McKenna suggested that research might have reached the limits of how short treatment for DS-TB can get with the existing crop of new and repurposed drugs. She said there’s a whole next wave of drugs, including advantaged alternatives to existing TB drugs, that might help shorten treatment duration.

Study details

Treatment Strategy for Rifampin-Susceptible Tuberculosis

Nicholas Paton, Christopher Cousins, Celina Suresh, Erlina Burhan, Ka Lip Chew, Victoria B. Dalay, Qingshu Lu, Tutik Kusmiati, Vincent Balanag, Shu Ling Lee, Rovina Ruslami, Yogesh Pokharkarv et al., for the TRUNCATE-TB Trial Team.

Published in the New England Journal of Medicine on 20 February 2023


Tuberculosis is usually treated with a 6-month rifampin-based regimen. Whether a strategy involving shorter initial treatment may lead to similar outcomes is unclear.

In this adaptive, open-label, noninferiority trial, we randomly assigned participants with rifampin-susceptible pulmonary tuberculosis to undergo either standard treatment (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks) or a strategy involving initial treatment with an 8-week regimen, extended treatment for persistent clinical disease, monitoring after treatment, and retreatment for relapse. There were four strategy groups with different initial regimens; noninferiority was assessed in the two strategy groups with complete enrollment, which had initial regimens of high-dose rifampin–linezolid and bedaquiline–linezolid (each with isoniazid, pyrazinamide, and ethambutol). The primary outcome was a composite of death, ongoing treatment, or active disease at week 96. The noninferiority margin was 12 percentage points.

Of the 674 participants in the intention-to-treat population, 4 (0.6%) withdrew consent or were lost to follow-up. A primary-outcome event occurred in 7 of the 181 participants (3.9%) in the standard-treatment group, as compared with 21 of the 184 participants (11.4%) in the strategy group with an initial rifampin–linezolid regimen (adjusted difference, 7.4 percentage points; 97.5% confidence interval [CI], 1.7 to 13.2; noninferiority not met) and 11 of the 189 participants (5.8%) in the strategy group with an initial bedaquiline–linezolid regimen (adjusted difference, 0.8 percentage points; 97.5% CI, −3.4 to 5.1; noninferiority met). The mean total duration of treatment was 180 days in the standard-treatment group, 106 days in the rifampin–linezolid strategy group, and 85 days in the bedaquiline–linezolid strategy group. The incidences of grade 3 or 4 adverse events and serious adverse events were similar in the three groups.

A strategy involving initial treatment with an 8-week bedaquiline–linezolid regimen was noninferior to standard treatment for tuberculosis with respect to clinical outcomes. The strategy was associated with a shorter total duration of treatment and with no evident safety concerns.


NEJM article – Treatment Strategy for Rifampin-Susceptible Tuberculosis (Open access)


NEJM article – Study 31: Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis (Open access)


Spotlight article – What next after shortened TB treatment fails in key trial? (Creative Commons Licence)


See more from MedicalBrief archives:


Long-term effectiveness of shortened DR-TB treatment regimen


MSF trial finds better, shorter, more effective treatment for MDR-TB


Shorter, simpler DR-TB regimen in the pipeline for South Africa


Promising results from stage 2 MDR-TB STREAM – world’s largest trial






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