400 people in South Africa with highly drug-resistant TB to get new three-drug regimen

Key to this transformation in our public sector has been the rollout of the antibiotics bedaquiline and linezolid. These two drugs plus another two, or in some cases even another four or five, make up DR-TB treatment in South Africa today. Broadly speaking, the more resistant someone’s TB has become, the more complicated the treatment combination and the longer the treatment lasts. But that may be about to change with a new three-drug regimen taken for just six months.

Note: There are different levels of DR-TB: RR or rifampicin-resistant TB is resistant just to the drug rifampicin, MDR or multi-drug resistant TB is resistant to rifampicin and isoniazid, and XDR or extensively-resistant TB is resistant to an additional class of antibiotics on top of MDR-TB.

One patient, Nelisiwe Ngcobo, knows first-hand how exhausting the old DR-TB regimens can be. “It was a terrible time for me because I had to take TB tablets for long and added to this was my other chronic medication. In a day I took between 28 to 30 tablets. It was depressing, I hated taking my tablets. I was crying all the time because the medication I had to take was just too much. I lost weight and I was frustrated. It was a painful process and because of the injections I had all sorts of bumps on the lower back. I hated every moment of taking my injection,” she said.

Ngcobo was a participant in a briefing on the announcement of a new clinical access programme hosted in December by the TB Alliance (a non-profit drug developer responsible for the development of the drug pretomanid).

The BPaL access programme

In an effort to help patients like Ngcobo, the Wits Health Consortium and the National Department of Health is starting an initiative to provide a new, shorter treatment regimen for people affected with highly drug-resistant forms of TB. The programme was meant to start in KwaZulu-Natal, but will now start in Gauteng either this month or early in February.

The programme will enrol 400 people with highly drug-resistant TB in South Africa for treatment with a six-month, all-oral regimen of three drugs, bedaquiline, pretomanid and linezolid (known as the BPaL regimen). Pretomanid is not yet registered in South Africa and its doses are donated to the program by the pharmaceutical company Mylan, one of TB Alliance’s global commercialisation partners for pretomanid. The programme is funded by the United States Agency for International Development.

Since pretomanid has not yet been registered by the South African Health Products Regulatory Authority (SAHPRA) permission from the regulator was required to provide the drug as part of a clinical access programme (CAP). A CAP offers a means to make an unregistered medicine available to people under controlled conditions – thus both allowing for access to the drug, for strict monitoring of potential side effects, and for data on safety and efficacy to be gathered.

The United States Food and Drug Administration registered pretomanid in August 2019, but only for use as part of the BPaL regimen. At the time, Spotlight published an opinion piece on the difficulty in untangling how much pretomanid was contributing to the success of the three-drug regimen. Pretomanid was added to the WHO’s list of prequalified medicines in November 2020.

Who is eligible?

Coordinated by the Wits Health Consortium, the BPaL CAP will enrol male or female participants aged 14 and older with confirmed sputum pulmonary XDR-TB, fluoroquinolone-resistant DR-TB (fluoroquinolones are a class of antibiotics) and selected rifampicin-resistant TB cases that have been pre-approved for treatment by the National Department of Health (rifampicin is one of the four drugs used to treat drug-sensitive TB).

The programme will start by enrolling patients from high-burden provinces including the Western Cape, Gauteng, KwaZulu-Natal and North West.

‘A huge improvement’

Speaking during a webinar announcing the programme in December, Dr Francesca Conradie of Wits said: “TB is the world’s deadliest infectious disease. A disease associated with poverty. When I was an intern many, many years ago in KZN 52 out of 53 people who acquired the disease (DR-TB) died. With this access programme, 400 patients will have access to treatment for the first time outside the clinical trial. It is a shorter treatment and only 23 tablets per week, so it is much simpler. [This] is a huge improvement,” she said.

The BPaL regimen resulted in a favourable outcome in 90% of patients with XDR or pre-XDR-TB in a landmark study conducted in South Africa called Nix-TB. In an interview with Spotlight, Conradie explains that the Nix-TB trial had 109 participants. “This was not a randomised trial so there was no control or comparison group. Many of the patients who were started in the beginning were very ill and had been for years. Even in the first 10 patients, we were able to see what I thought was remarkable recoveries. Patients put on weight (this is a good sign in TB as many patients are very underweight) and stopped coughing and sweating at night very quickly. Soon,” Conradie says, “we were not able to detect TB in their sputum anymore and 90% of the patients were cured.”

Ngcobo who was one of the patients in the initial clinical trial said when she was told about the trial she jumped at the opportunity to participate. “I wanted to be part of the change. I wanted my name to be counted [among] the names of people who made this work. Lo-and-behold, it was only a couple of tablets. It was practical, and it was doable,” she says.

Ncgobo said she was concerned at first that there were only a small number of patients participating in the trial while many people suffered like her. “I continued with the programme and I’m happy to report that I’m clear and have remained clear since February (2020).”

Conradie explains that in the CAP they will monitor people taking the BPaL regimen for safety and efficacy. “So we look to see if the medications cause any harm by doing regular blood tests and clinical assessments including eye tests and nerve examinations. While patients are on treatment, we see them every two weeks in the beginning and then after the second month, once a month. To assess if someone is cured from TB (efficacy) we send a specimen of their sputum to the laboratory every month,” she says. “This is cultured to see if there are any live TB bacilli remaining. We declare someone cured if they do not have TB in their sputum for at least three months and then we follow them up for a year to make sure it does not come back,” she tells Spotlight, adding that they are planning to expand these indications to patients with DR TB, which are about 14 000 per year.

As part of the project, USAID has donated 34 Electrocardiograph (ECG) machines. These are important to have in the healthcare system since some drugs used to treat DR-TB, including some in the BPaL regimen, can cause cardiac abnormalities – something that can be picked up early with regular ECGs.

But questions remain about the BPaL regimen

TB Project co-director at the US-based NGO Treatment Action Group (TAG), Lindsay Mckenna tells Spotlight that South Africa has always been at the forefront, an early adopter and a leader when it comes to TB. “Take for example what was done with bedaquiline. South Africa was ahead of the World Health Organization in terms of offering bedaquiline in place of the injectable agents. Data and experience from South Africa shaped [global] policy for all-oral, bedaquiline-based regimens as the new standard of care. South Africa is good at collecting data on new interventions and using those data to inform policy and how interventions are rolled out on a broader scale,” she says.

Mckenna says BPaL is attractive, three drugs and only six months of treatment, however “it was studied in a small group of 109 patients in the Nix-TB trial, which is less than what’s usually expected by regulatory authorities tasked with evaluating the efficacy and safety of new medicines. Phase III trials are typically much larger and include an internal concurrent control arm. Because the Nix-TB trial was a single arm study, it is difficult to say how it compares to other regimens,” says Mckenna.

“Randomised control trials (RCTs) are the gold standard, and should remain the expectation in TB. RCTs are important for informing us about the efficacy of a new treatment, for example, its ability to cure TB and prevent relapse, and about whether it is safe and tolerable compared to the existing standard of care. Large, randomised trials allow us to compare new regimens to what is already out there while minimising bias,” she says.

As yet there is no RCT data on how the BPaL regimen compares to other cutting edge regimens used to treat highly resistant forms of TB.

Professor Keertan Dheda, a general physician, pulmonologist and critical care specialist who heads up the Division of Pulmonology at Groote Schuur Hospital and the University of Cape Town says the BPaL regimen is definitely a milestone worth celebrating as it means that the duration of treatment (about 18 to 24 months not so long ago) has been dramatically reduced and with fewer drugs, many of which are much more effective than the previous ones being used.

“We all hope that patients who receive BPaL will be better off and have improved outcomes,” Dheda says. “However, BPaL has thus far only been used in the context of an observational research study with limited patient numbers, and has not been directly compared to other types of treatment regimens. This is why the BPaL access programme is so important. We need to know how this regimen works in the real world in larger numbers of patients. Some drugs used in the BPaL regimen are toxic and can lead to irreversible and sometimes fatal side effects.”

Asked about why the BPaL regimen could not be used as a single regimen for all TB patients Dheda explains that the standard six month TB regimens are low-cost and still offer good outcomes for people who do not have DR-TB. “Whilst using one regimen like the BPaL regimen for everyone (both drug sensitive and resistant TB) with TB in large numbers will have obvious short-term benefits. In the long run there would be more rapid development of resistance (including spread of resistant strains in the country), and more drug-related toxicity.”

The bigger picture

Dheda says the overall incidence of TB in South Africa has been gradually declining over the last 10 years but still remains substantial, with almost 400 000 people becoming newly ill from TB in South Africa every year.

“South Africa remains one of those countries with the highest incidence of TB globally,” says Dheda. “However, the situation has improved considerably with the Department of Health having done a good job at introducing a number of interventions that have made a difference. Some of the key interventions include improving the diagnosis and treatment of HIV (a major risk factor for TB), the introduction of state-of-the-art molecular diagnostic tests throughout the country (South Africa is one of the few countries to have comprehensively rolled this out via a national health system), the introduction of newer drugs to treat drug-resistant TB such bedaquiline and delamanid, and the use of TB preventative therapy in high-risk groups. There are others, but these are some of the key ones,” he says.

While finding better treatments is clearly very important, Dheda says that there are many interventions that could cause a substantial reduction in TB cases and deaths. “In the longer term, good governance and economic prosperity will have the biggest impact on TB. TB is a disease associated with poverty and overcrowding, and the TB burden automatically decreases with better living standards independent of the use of better diagnostics and drugs,” says Dheda.

“Another potent driver of TB in South Africa is HIV. Thus, efforts to improve the diagnosis of HIV and initiating antiretroviral treatment, has and will continue to have a major impact on reducing TB numbers,” he says. “Poor lung health associated with smoking and biomass fuel exposure (the burning of fossil fuels in homes for cooking and eating without proper ventilation) is also a major driver of TB and efforts to curb this will have an impact on TB in the future.”

Dheda says another critical intervention will be to change the case finding strategy for TB. “Currently almost all the TB cases are passively detected,” he says meaning that the system relies on people with symptoms reporting to healthcare facilities, by which time people have often been infectious for some time. “However, we need to move to an active case finding strategy whereby diagnosis and case finding is moved out of clinics and hospitals and into the community. It is only in this way that we can have a major impact on interrupting the TB transmission cycle (for drug-sensitive and drug-resistant TB),” says Dheda.

“We are engaged in innovative studies to implement a scalable community-based active finding strategy using portable molecular tools such as GeneXpert (the XACT study). However, other innovative active finding models such as using screening Apps will likely also be effective (as has been demonstrated in the COVID-19 epidemic). Some of the lessons learnt should be applied to TB,” he says.

Source: Spotlight