Shorter, simpler DR-TB regimen expected later this year
Work is underway in South Africa to amend the country’s national guidelines for drug-resistant tuberculosis (DR-TB) to provide a shorter, six-month, all-oral regimen as a new standard of care treatment.
This regimen combines the new and repurposed medicines bedaquiline, pretomanid, linezolid, and moxifloxacin. It is known as BPaL when moxifloxacin is not included and BPaLM when it is. Whether or not moxifloxacin is included in the regimen depends on whether a person’s TB is resistant to a class of drugs called fluoroquinolones. Moxifloxacin falls into this class.
The World Health Organization (WHO) last month issued rapid guidance recommending the use of BPaL/BPaLM in countries’ national TB programmes.
Dr Norbert Ndjeka, director of South Africa’s TB programme, hopes that by implementing BPaL/BPaLM as a standard of care regimen, South Africa will once again be the world’s first in improving DR-TB treatment and care. He notes that South Africa was the first country to remove painful injectables with difficult side-effects (such as hearing loss) from DR-TB treatment regimens, as well as the first country to introduce bedaquiline as part of standard of care treatment. These moves, which resulted in improved treatment outcomes in the country, contributed to the WHO amending its global guidance on DR-TB – advising against the use of injectables and for the use of bedaquiline.
New 6-month regimens for MDR TB:
– bedaquiline, pretomanid and linezolid in combination with moxifloxacin (BPaL)
— UITB (@TB_UITB) May 9, 2022
Ndjeka says that while, this time around, in recommending BPaL/BPaLM, the WHO’s guidance has preceded changes to South Africa’s DR-TB treatment guidelines, the country is not far behind.
According to Ndjeka, the Department of Health is planning to implement BPaL/BPaLM as a standard of care regimen for DR-TB between September and December this year. By January 2023, all eligible DR-TB patients should be initiated onto a BPaL/BPaLM regimen, if new national guidelines under development are approved by the country’s National Health Council, he says.
How will implementing BPaL/BPaLM change DR-TB treatment regimens?
Dr Ronelle Moodliar, head of clinical trials at THINK: Tuberculosis and HIV Investigative Network, explains that South Africa’s current standard of care regimen involves the use of up to seven TB drugs for a duration of nine to 18 months, compared to six months for BPaL/BPaLM.
According to Ndjeka, “there are a number of DR-TB publications that have shown reducing duration of treatment improves adherence to treatment, your loss to follow up goes down, and you are able to increase favourable outcomes”.
He adds that in addition to reducing the length of treatment, the new regimen will significantly reduce the number of pills that patients must take over the course of their treatment. Current standard of care regimens require people receiving DR-TB treatment to take up to 23 pills per day. BPaL/BPaLM will reduce this pill burden to 23 pills per week, says Ndjeka. “When you decrease the pill burden you enhance ability for people to take tablets,” he says.
Wieda Human, of TB Proof (a TB advocacy group), says, “There is an urgent need to implement high-quality, less toxic, shorter, effective regimens for DR-TB. The BPaLM and BPaL regimens thus represent a major advance in enabling all-oral regimens for a six-month duration with high cure rates.”
Crucial research conducted in SA
Research conducted in South Africa has significantly contributed to global knowledge and evidence on the efficacy and safety data of the drugs used in the BPaL/BPaLM regimen, as well as the effectiveness of using these drugs in a six-month combination course to treat DR-TB.
Moodliar says, “South Africa has actively participated and significantly contributed to all three of the new drugs now available for the treatment of DR-TB in the last 20 years, namely bedaquiline, pretomanid, and delamanid, running the phase II/III randomised control clinical trials and access programmes for the registration of the drugs both internationally and locally.”
Ndjeka adds that pretomanid, which is in the same class of drugs as delamanid, was named after South Africa’s capital Pretoria in recognition of the country’s contribution to the drug’s development.
The BPaL regimen was first trialled for treatment of DR-TB in South Africa under the TB Alliance’s Nix trial. Positive results from the Nix trial led to the larger, multi-country ZeNix trial, which once again validated the efficacy of BPaL and demonstrated that regimen remained effective with reduced dosages or durations of linezolid. South Africa is also one of three countries in Doctors Without Borders’ TB-Practecal trial, whose initial results have shown high cure rates among patients receiving BPaLM and was critical to the WHO updating its DR-TB treatment guidelines.
“We are delighted to see that these pivotal trials, conducted by South African scientist leaders, are impacting policy and practice,” said TB Proof’s Human. She adds that these developments highlight “the importance of supporting and strengthening research capacity in high TB incidence countries”.Ndjeka notes that further operational research is underway in South Africa to evaluate BPaL’s efficacy against highly drug-resistant TB, which will inform future treatment options and guidance for this group (Read more about this research here.)
What must still happen before BPaL/BPaLM is available nationally?
Ndjeka says that the country’s expert committee on DR-TB met last week to discuss and plan for the implementation of BPaL/BPaLM as a standard of care regimen in South Africa. He says that new, national DR-TB treatment guidelines will be written in July. Once developed, the new guidelines, together with an analysis of the cost-effectiveness of BPaL/BPaLM, must be presented to and approved by the National Health Council before the new regimen can be implemented.
Ndjeka is positive that work underway to evaluate the cost-effectiveness of BPaL/BPaLM will demonstrate the regimen’s cost-effectiveness over existing treatments. “I like to believe that we are going to be able to afford it because we are going to cut drugs… we are also going to cut lab follow-up from nine or 18 months to six months, so those are massive savings to get better results,” says Ndjeka.
Human notes that research conducted outside of South Africa has found that the new regimen is cost-effective when compared to existing standards of care.
All of the medicines used in BPaL/BPaLM except pretomanid are already procured via tender for DR-TB treatment in South Africa. Ndjeka says that pretomanid will need to be added to the tender if the new guidelines are approved, adding that “the good news is it is registered in South Africa”. Pharmaceutical company Mylan’s 200 mg pretomanid tablets were registered in South Africa in March 2021.
How affordable are the drugs needed for BPaL/BPaLM?
Doctors Without Borders have highlighted the high prices of bedaquiline and pretomanid as potential impediments to the scale-up of BPaL/BPaLM in developing countries. The prices of linezolid and moxifloxacin are thought to pose less of a problem.
According to Doctors Without Borders, pretomanid and bedaquiline account for three-quarters of the cost of a four-drug BPaLM regimen.
In South Africa, only pharmaceutical company Janssen’s bedaquiline product is available, sold under the brand name Sirturo. At a cost of R28.72 per 100 mg tablet, a full course of bedaquiline as part of a BPaL/BPaLM regimen costs around R5 744 (US$358).
Researchers at the University of Liverpool have calculated that, with adequate volume and generic competition, the price of a six-month course of bedaquiline could come down to around R1 600 ($100).
Bedaquiline transformed treatment for drug-resistant TB. Global Fund Expert Review Panel just recommended first generic version, a 100mg tablet made by Macleods. But no one benefits immediately without government action. Patients can't wait until patents expire in 2023 or 2027! pic.twitter.com/ZYwWqD1wM2
— Treatment Action Group (TAG) (@TAGTeam_Tweets) June 9, 2022
The recent approval of pharmaceutical company Macleods’ generic bedaquiline product by the Global Fund’s Expert Review Panel raises the prospect of generic bedaquiline becoming available in South Africa, if SAHPRA approves the product and if market entry is not prevented by patents held by Janssen on bedaquiline, some of which will only expire in 2027.
No pretomanid product is currently procured by the Department of Health. According to Ndjeka, “what we have now is [a] donation for research projects”. As only Mylan’s pretomanid is registered in the country, it is likely that Mylan’s product will be procured if the new guidelines are approved.
While South Africa does not yet have a price for pretomanid, the medicine is procured through the Global Drug Facility (a mechanism that pools procurements of TB medicines for participating developing countries) at a price of around R5 841 ($364) for a six-month treatment course. University of Liverpool researchers have estimated that with adequate volume and competition, the cost of a six-month course of pretomanid could come down to between R1 043 ($65) and R3 290 ($205).
While currently only Mylan’s pretomanid is registered in South Africa, TB Alliance, the organisation that owns the intellectual property on the drug, has also licensed Macleods to manufacture and market this drug.