The standard-of-care treatments for drug-resistant TB (DR-TB) are nine to 20 months and have side effects that often cause patients to stop taking their medication. But the results of a multi-country Doctors Without Borders (MSF) clinical trial show that a new six-month treatment regimen is safer, more convenient, and much more effective than any other regimens.
The all-oral, six-month treatment regimen is safer and more effective at treating multi-drug-resistant tuberculosis (MDR-TB) than the current options for people with DR-TB, according to the study, published recently in the New England Journal of Medicine (NEJM),
The findings result from MSF’s TB-PRACTECAL, the first-ever multi-country, randomised, controlled clinical trial to report on the efficacy and safety of a six-month, all-oral treatment regimen, which was recommended in the updated World Health Organisation’s (WHO) global TB recently released treatment guidelines.
“We’re delighted that the trial results have been published in the NEJM after a stringent peer review process,” said Bern-Thomas Nyang’wa, MSF medical director and chief investigator of the trial. “This publication will provide deeper evidence to policymakers and treatment providers deciding to use the TB-PRACTECAL regimen, in addition to the WHO recommendations.
“Until relatively recently, there were no new treatments for TB introduced for more than 50 years. Why? Because the disease doesn’t affect the people who have the resources to deal with it. This trial was an attempt by MSF to try to fill that gap. Now it is essential that the new treatment is made available to everyone who needs it.”
The trial ended enrolment in March 2021, with 552 patients overall, and took place in seven sites across Belarus, South Africa and Uzbekistan. Five MSF-supported countries have already begun implementing the shorter regimens, with almost 400 patients starting the treatment and eight more countries set to implement it this year.
Launched in 2017, TB-PRACTECAL tested three combinations of new treatments against the locally accepted standard of care. All were shown to be favourable against the standard of care. A six-month regimen of bedaquiline, pretomanid, linezolid and moxifloxacin (BPaLM) proved most effective and safe. The trial also studied a bedaquiline, pretomanid and linezolid (BPaL) regimen; and a bedaquiline, pretomanid, linezolid and clofazimine (BPaLC) regimen.
“We began the TB-PRACTECAL clinical trial nine years ago because something had to be done,” Nyang’wa said. “Patients were telling us that the previous regimens were lengthy, ineffective, and gruelling and that the side effects were worse than the disease itself. They also weren’t very effective; just one in two people were cured. The new regimen, BPaLM, has an 89% cure rate, is safer, shorter and more tolerable, with many fewer pills.”
MSF’s phase II/III clinical trial found that the new shorter BPaLM treatment regimen was very effective against rifampicin-resistant TB (RR-TB), and safer than the current standard of care: 89% of patients in the BPaLM group were cured, compared with 52% in the standard-of-care group, and there were fewer recorded side effects in the BPaLM group than the standard of care group. BPaLC and BPaL also performed significantly better than the standard of care.
While this new regimen provides hope for the 500 000 people who fall sick each year with DR-TB, the current lowest global price provided to the Global Drug Facility (GDF) for a six-month treatment course of BPaLM is around $600, still above the $500 ceiling price called for by MSF.
One of the other newer TB drugs, bedaquiline, developed by Johnson & Johnson with substantial government and philanthropic support, is priced at $270 for six months as the lowest global price.
This is despite the fact that researchers have estimated that bedaquiline could be produced and sold at a profit for less than $102 for six months. In fact, all three regimens studied in TB-PRACTECAL are likely to reduce treatment costs compared with the current standard of care.
“Rolling out the shorter, safer, and more effective BPaLM treatment regimen trialled in TB-PRACTECAL could transform the lives of people with TB, but only if the drugs in this regimen are affordable,” said Christophe Perrin, TB advocacy pharmacist with MSF’s Access Campaign. “As significant public funds helped to pay for the development of bedaquiline, we’re calling on Johnson & Johnson to bring down the price of this drug so that a complete DR-TB treatment course is no more than $500 per person. Too many lives have been lost due to this killer disease. People with TB deserve urgent access to shorter, safer, and affordable treatments.”
Sheilly Gupta, communications adviser for MSF, told GroundUp that because TB is most prevalent in developing countries, it has not become a profit-making business for pharmaceutical companies. “This means there has been very little research and development on TB drugs, and new drugs such as bedaquiline are few and far between. Meanwhile, resistance to existing drugs is growing, leading to an increase in DR-TB.”
Gupta says that because the new drugs are still under patents, there is no generic competition and prices remain high.
South Africa is currently using a nine-month regimen containing seven drugs for DR-TB. BPaLM will shorten this to six months, with fewer drugs, and is more cost effective.
Study details
A 24-Week, All-Oral Regimen for Rifampin-Resistant Tuberculosis
Bern-Thomas Nyang’wa, Catherine Berry, Emil Kazounis, Ilaria Motta, Nargiza Parpieva, Zinaida Tigay, Varvara Solodovnikova, Irina Liverko, Ronelle Moodliar, Matthew Dodd, Nosipho Ngubane, Mohammed Rassool, et al., for the TB-PRACTECAL Study Collaborators.
Published in The New England Journal of Medicine on 22 December 2022
Abstract
Background
In patients with rifampin-resistant tuberculosis, all-oral treatment regimens that are more effective, shorter, and have a more acceptable side-effect profile than current regimens are needed.
Methods
We conducted an open-label, phase 2–3, multicentre, randomised, controlled, noninferiority trial to evaluate the efficacy and safety of three 24-week, all-oral regimens for the treatment of rifampin-resistant tuberculosis. Patients in Belarus, South Africa, and Uzbekistan who were 15 or older and had rifampin-resistant pulmonary tuberculosis were enrolled. In stage 2 of the trial, a 24-week regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) was compared with a 9-to-20-month standard-care regimen. The primary outcome was an unfavourable status (a composite of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of tuberculosis) at 72 weeks after randomisation. The noninferiority margin was 12 percentage points.
Results
Recruitment was terminated early. Of 301 patients in stage 2 of the trial, 145, 128, and 90 patients were evaluable in the intention-to-treat, modified intention-to-treat, and per-protocol populations, respectively. In the modified intention-to-treat analysis, 11% of the patients in the BPaLM group and 48% of those in the standard-care group had a primary-outcome event (risk difference, −37 percentage points; 96.6% confidence interval [CI], −53 to −22). In the per-protocol analysis, 4% of the patients in the BPaLM group and 12% of those in the standard-care group had a primary-outcome event (risk difference, −9 percentage points; 96.6% CI, −22 to 4). In the as-treated population, the incidence of adverse events of grade 3 or higher or serious adverse events was lower in the BPaLM group than in the standard-care group (19% vs. 59%).
Conclusions
In patients with rifampin-resistant pulmonary tuberculosis, a 24-week, all-oral regimen was noninferior to the accepted standard-care treatment, and it had a better safety profile. (Funded by Médecins sans Frontières).
NEJM article – A 24-Week, All-Oral Regimen for Rifampin-Resistant Tuberculosis (Open access)
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