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DNA technology may impede MDR-TB progress – SA Health Department

The National Department of Health plans to use DNA technology to test whether the genetic make-up of TB germs has changed in such a way that they could be resistant to antibiotics, said the department’s chief TB director at the 8th SA TB Conference in Durban last week.

These tests may help to slow down resistance to bedaquiline, the antibiotic that can slash treatment time by two thirds for a form of TB that doesn’t respond to the usual regimen.

This will be especially useful seeing that results from three provinces show that in about 6.5% of people with this type of TB, bedaquiline has already become ineffective, writes Zano Kunene for Bhekisisa.

Norbert Ndjeka, the department’s chief TB director, said in about one in 16 patients with MDR-TB in KwaZulu-Natal, the Western Cape and the Eastern Cape, bedaquiline is ineffective at killing the germs causing the illness.

This means that if the patients are started on this drug, and it doesn’t work for them, they’ll remain sick; more and more of the bugs can become resistant, and these hardy strains can then spread.

Currently it can take up to eight weeks to decipher which drugs will actually work for a patient with MDR-TB, because bacterial cultures have to be grown from a patient’s sputum and then tested with the different drugs that are options for the treatment regimen, to see how the bug reacts.

But tests that use DNA technology can yield results in a few days (in some cases, within two days), meaning patients can get on the right treatment sooner, and not unnecessarily be given bedaquiline if it won’t work in the first place.

Why shorter treatment is better

Before bedaquiline, the type of antibiotics to treat MDR-TB, like kanamycin, amikacin or streptomycin, could cause serious hearing loss – in up to half of the people who took the drug. In addition, the medicines are given as injections deep into a muscle, which can be painful and deter people from taking the treatment.

Patients who have become resistant to bedaquiline, or who are infected with an already resistant strain of the TB germ, have to be treated with a personalised course of medication that may take as long as 18 months and which would include drugs from a list of 11 options, and cost more than the shorter bedaquiline treatment.

By the end of 2022, around 280 000 people in South Africa had TB: about 11 000 cases were of the MDR type.

In September last year, the health department introduced a new treatment plan called BPaL-L, and which includes bedaquiline, against MDR-TB. By the end of April, 2 456 patients had started this course.

It involves a combination of four types of antibiotic tablets — bedaquiline, pretomanid, linezolid and levofloxacin — for six months. (For the first two weeks of treatment, bedaquiline is taken daily, and then only three times a week; the others are all taken daily.)

The health department pays R3 148 for six months of bedaquiline treatment for one patient, down from the close to R5 600 they used to pay, after an investigation by the Competition Commission.

Having a shorter treatment for MDR-TB patients is important, said Ndjeka, because “we have better retention [of] patients than in the longer regimens”.

While the complete set of data on South Africa’s bedaquiline roll-out (as part of the BPaL-L regimen) will only be available later this year, results from three provinces already show that resistance to the drug has been found in 149 patients out of 2 308 with MDR-TB (close to 6.5%), including in patients on the new treatment plan, Ndjeka told Bhekisisa.

What causes resistance: the drugs or the bug?

TB drugs are one of the big culprits of antimicrobial resistance (AMR). Antimicrobial resistance means the germs that cause a disease are no longer killed by the drugs that used to work well before, and so it becomes more difficult to cure the illness.

In bacterial infections, like TB, some germs will naturally change over time to try to protect themselves against antibiotics. The longer it takes for the infection to be cleared, the more time the bugs have to change and the bigger the chance that some of these changes will work to stop the antibiotic from killing them.

As time passes, more and more of these resistant bacteria can develop.

With TB, a six-month course of the antibiotics rifampicin, isoniazid, pyrazinamide and ethambutol is commonly used to clear up the infection caused by the germ Mycobacterium tuberculosis. But once the bug has become resistant to this first line of treatment, a patient has to be put on a more complex and expensive course of antibiotics.

Why bedaquiline resistance is a worry

A bacterial infection that takes long to clear up will require a combination of antibiotics to kill the bug.

The idea is to hit hard and fast, to wipe out the infection as quickly as possible and limit the chance for some germs to escape the drug – and make sure there’s not enough time for them to become resistant.

Bedaquiline is a good option to add to the combination for treating MDR-TB, because it doesn’t have to be taken for long, and has fewer side effects than older drugs.

Results from a large study in South Africa in 2022 showed that a treatment regimen that includes bedaquiline kills the resistant bug in 70% of patients ,compared with using only injectable antibiotics (like kanamycin), which cleared up the infection in only 57% of patients.

The WHO has recommended the BPaL-L regimen as the preferred treatment for MDR patients since 2022.

However, bedaquiline stays in the body for longer than the other antibiotics, so once a patient stops taking it, there’s more chance that resistance can begin to develop against the drug, Ndjeka said.

“When people just stop taking the treatment, it’s a problem … the risk with this resistance [bedaquiline] is that if we don’t take measures it will just continue growing.”

Moving forward

Finding quicker ways to test patients for resistance to TB drugs and teaching them about why it’s important to stick with their treatment are two ways the health department aims to tackle this emerging reality, Ndjeka added.

Resistance to bedaquiline isn’t new, though; in fact, it’s been seen around the world, including in South Africa, when the drug first replaced kanamycin and amikacin injections to treat MDR-TB in 2018.

Initially, it was part of a regimen of pills that included seven drugs which had to be taken over nine months. But recommendations from the WHO showed that swopping four of the drugs for pretomanid instead worked just as well and shortened the treatment to six months.

In a South African study, researchers tracked possible bedaquiline resistance in 2 023 patients treated for MDR-TB at public hospitals and clinics between 2015 and 2019. At the start, 76 patients were already resistant to the drug even though they had never taken it before.

This was worrying, because resistance was expected to be more likely in patients who had previous exposure to the drug.

Data from three provinces from March 2023 to February 2024 show this figure has jumped to about 6.5%, said Ndjeka.

South Africa’s TB Recovery Plan, a strategy introduced in 2022 and which gets updated every year to undo the backslide in fighting TB during the pandemic and its restrictions, outlines ways to deal with bedaquiline resistance.

This includes speeding up the way SA tests how anti-TB drugs work in patients, and with the new DNA-based method, a single test can be used to check for resistance against many drugs — fast.

But two things will remain important to fight TB in South Africa, said Ndjeka. One is to find patients with resistant disease; the other is to start treatment and make sure they stay on their medicines.

“You can’t deny two thousand people [treatment] because you might get a hundred of them who are resistant and for whom treatment won’t work. We are making the effort to find these people early and give them the treatment.”

 

The Lancet article – Treatment outcomes 24 months after initiating short, all-oral bedaquiline-containing or injectable-containing rifampicin-resistant tuberculosis treatment regimens in South Africa: a retrospective cohort study (Open access)

 

The Lancet article – Bedaquiline resistance in patients with drug-resistant tuberculosis in Cape Town, South Africa: a retrospective longitudinal cohort study (Open access)

 

Bhekisisa article – Faster tests, shorter treatments: How new tech could help slow down drug-resistant TB (Creative Commons Licence)

 

See more from MedicalBrief archives:

 

SA in five-country trials for drug-resistant TB treatment

 

Clinical trial reveals ‘breakthrough’ treatment options for MDR-TB

 

Promising new treatment regimens for MDR-TB

 

 

 

 

 

 

 

J&J drops price of lifesaver TB drug

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