The current treatment for drug-susceptible tuberculosis (TB) used in South Africa involves a combination of four antibiotics, last for six months, effectively cures TB, and is dirt cheap. Some people, however, find it hard to complete the full six months of treatment - in some cases due to side effects and in other cases because people can feel well again long before the six months are over.
Several clinical trials in the last decade or two have evaluated the safety and efficacy of shorter regimens, mostly with disappointing results. That changed in 2021 when a study widely referred to as "Study 31" found a four-month regimen to be non-inferior to the current six-month regimen. The snag, however, is that this regimen is much more expensive than the current six-month regimen - largely due to the inclusion of the drug rifapentine. This rifapentine-based four-month regimen is recommended by the United States Centers for Disease Control and Prevention, and conditionally recommended by the World Health Organization (WHO), for the treatment of TB in people aged 12 and older, but is not used in South Africa's public sector. As Spotlight reported last year, a four-month regimen specifically for children is set to be rolled out in the country.
One of the next big treatment-shortening studies to watch after Study 31 was called SimpliciTB. The ambitious vision with SimpliciTB 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 last week at the Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, dealt a serious blow to prospects of using this regimen to treat drug-susceptible TB.
Disappointing findings
SimpliciTB compared a four-month treatment course consisting of 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, which means 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 (treatment failure or relapse) after 52 weeks.
BPaMZ did exactly what it was supposed to - kill TB. - Dr Vidya Mave
As it turns out, 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 to only 47% of those in the six-month arm. After 52 weeks, however, 17% of those in the BPaMZ arm had unfavourable outcomes compared to 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.
Nice piece in @SpotlightNSP covering noteworthy clinical trial results presented at @UnionConference: Shorter TB regimens could be on the horizon, but key research gaps remain.
Featuring TAG TB Co-Director Lindsay McKenna: https://t.co/hniWRrd8Bo pic.twitter.com/wnEMdxSKID
-- Treatment Action Group (TAG) (@TAGTeam_Tweets) November 18, 2022
According to Dr Muge Cevik, who presented the study results at CROI, there were a lot of early withdrawals in the trial - 14 in the BPaMZ arm compared to 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, most of which were liver-related.
"I think the way that they presented it is they were saying if you're just 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, and so it's effective but it's not safe and so therefore it's not a good regimen."
@mugecevik kicks off the TB/hep session #CROI2023 with 4M BPaMZ superior to HRZE for primary endpoint (w8 culture neg) but not secondary (W52 favourable outcome) due to AE discont (mainly liver enzyme elevation) WITH AUTHOR PERMISSION @CROI_Official pic.twitter.com/4ktmuKTMww
-- Laura Waters (@drlaurajwaters) February 20, 2023
Dr Vidya Mave, the Co-director of the Center for Infectious Diseases in Pune, India, was slightly more upbeat. She told Spotlight that BPaMZ did exactly what it was supposed to - kill TB. She, however, also expressed concern over the high number of toxicity events. She suggested that using Pyrazinamide for four rather than the usual two months may have played a role, although more detailed study findings would be needed to see if this was indeed the case (the findings haven't yet been published in a medical journal). Her comments are in step with a wider sense that, even though the BPaMZ regimen is too toxic to be a viable option for the treatment of drug-susceptible TB, much can be learnt from the study and a somewhat similar regimen may still have a future.
A novel approach
While Study 31, SimpliciTB, and several earlier studies largely focused on testing experimental shortened regimens, a study called TRUNCATE-TB presents a novel treatment strategy rather than just a new antibiotic regimen. In short, the 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.
Spotlight first reported on findings from TRUNCATE-TB in November last year when initial findings were presented 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 to 180 days with the six-month regimen.
At CROI TRUNCATE-TB lead investigator, Dr Nicholas Paton presented additional data on the potential use of biomarkers to identify the patients most likely to relapse after the eight-week treatment. 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," Paton said.
I'm hoping within this decade we will know how low [in treatment days] can we go for DS-TB treatment. - Dr Mave
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.
"Essentially, that could then feed back into that strategy which we published as a sort of prototype if you like. We can now look at ways of improving the decision-making about when to stop treatment and also look at ways of improving the post-treatment monitoring so that we can simplify that and make it more accurate at picking up people who need re-treatment."
What comes next?
Encouraging as the TRUNCATE-TB findings may be, the only alternative to the six-month drug-susceptible standard of care that is currently recommended by the WHO and CDC is the rifapentine-based regimen from Study 31. But uptake of this regimen has been slow. According to McKenna, reasons for this include supply constraints, cost, and procurement challenges.
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There is a whole next wave of drugs, including advantaged alternatives to existing TB drugs, that might help shorten treatment duration. - Lindsay McKenna, TAG
"There are these environmental issues around how currently drug-sensitive TB drugs are procured and purchased that we haven't had to address because you haven't had anything new [in several years]," she says. "Now we do and it's a problem that has to be solved before we can probably have equitable access to the four months regimen."
As for future treatments, McKenna suggested it is possible that research has reached the limits of how short treatment for DS-TB can get with the existing crop of new and repurposed drugs. She said that there is a whole next wave of drugs, including advantaged alternatives to existing TB drugs, that might help shorten treatment duration.
Mave said there are a large number of chemical entities with the potential for treating DS-TB, somewhere between 26 and 30, and it is now the job of researchers to find out what combination of these drugs would have the least toxicity, be more efficacious, and easy to roll out in programme settings.
"I'm hoping within this decade we will know how low [in treatment days] can we go for DS-TB treatment," she said.
McKenna also pointed out that the WHO is in the process of trying to address how to balance the interplay between the cost and safety of future shortened DS-TB regimens. "WHO is doing a process right now to put together an update to their target regimen profile. It's out for public comment. It tries to weigh some of these questions. The indicators are price, safety,[and] duration. They try to come up with what are the ideal minimal, optimal scenarios to help guide developers," she explained. "What I feel is missing from some of these processes that help set the vision for what we want and that direct development and investment, is rigorous work to understand patient preferences. People with lived experience who have taken these drugs, who will take these drugs - what are their priorities and how would they rank different parts of that target regimen profile? That's what's missing."
