If all goes according to plan, South Africa will, once again, be the world’s first in improving drug-resistant tuberculosis (DR-TB) treatment.
Spotlight reports that work is under way to amend national guidelines for DR-TB to provide a shorter, six-month, all-oral regimen as a new standard of care treatment.
This combines the new and re-purposed 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 Organisation (WHO) last month issued rapid guidance recommending the use of BPaL/BPaLM in countries’ TB programmes.
Dr Norbert Ndjeka, director of SA’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: SA was also 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 all improved treatment outcomes, contributing to the WHO amending its global guidance on DR-TB – advising against both the use of injectables and for the use of bedaquiline.
Ndjeka said 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.
The Department of Health wants 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 on this BPaL/BPaLM, if new guidelines are approved by the National Health Council.
Dr Ronelle Moodliar, head of clinical trials at THINK: Tuberculosis and HIV Investigative Network, said SA’s current standard of care regimen involves using up to seven TB drugs for nine to 18 months, compared with six months for BPaL/BPaLM.
Ndjeka said numerous DR-TB publications had shown that “reducing duration of treatment improves adherence to treatment, your loss to follow up goes down, and you increase favourable outcomes”.
Additionally, the new regimen reduces the number of pills patients must take. Currently, people on DR-TB treatment take up to 23 pills daily. BPaL/BPaLM cuts this to 23 pills per week, says Ndjeka.
Crucial research conducted in SA
Research 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 their effectiveness in a six-month combination course.
Moodliar said: “In the past two decades, South Africa has actively participated in and significantly contributed to all three of the new drugs now available for DR-TB, namely bedaquiline, pretomanid and delamanid, running the phase II/III randomised control clinical trials and access programmes for their registration both internationally and locally.”
Ndjeka added that pretomanid, in the same class of drugs as delamanid, was named after Pretoria in recognition of SA’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 led to the larger, multi-country ZeNix trial, which 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 were critical to the WHO updating its DR-TB treatment guidelines.
What must still happen before BPaL/BPaLM is available nationally?
Ndjeka said the country’s expert committee on DR-TB met last week to plan for the implementation of BPaL/BPaLM in South Africa. New, national DR-TB treatment guidelines will be written in July. Once developed, these and an analysis of the cost-effectiveness of BPaL/BPaLM, must be approved by the National Health Council.
“I like to believe we will be able to afford it because we will be cutting drugs… we will also reduce lab follow-up from nine or 18 months to six months, so those are massive savings.”
All of the medicines used in BPaL/BPaLM except pretomanid are already procured via tender for DR-TB treatment in South Africa. Ndjeka said pretomanid would 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 200mg pretomanid tablets were registered in South Africa in March 2021.
How affordable are the drugs needed for BPaL/BPaLM?
Doctors Without Borders highlighted the expensive bedaquiline and pretomanid as potential impediments to the scale-up of BPaL/BPaLM in developing countries. The prices of linezolid and moxifloxacin should pose less of a problem.
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 R28.72 per 100mg 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.
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 SA, 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.
“What we have now is (a) donation for research projects,” said Ndjeka. As only Mylan’s pretomanid is registered in the country, it is likely 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 around R5,841 ($364) for a six-month course. Liverpool University researchers said that with adequate volume and competition, a six-month course of pretomanid could drop 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.
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