When the United States Food and Drug Administration approved the use of bedaquiline to treat tuberculosis in 2012, it was the first new effective drug against the disease to be developed in over 40 years.
But a decade later, the bacteria that causes the disease is already learning to fight it – fast.
In 2015, Mumbai-based Foundation for Medical Research started studying samples of tuberculosis patients from across India. Most of the patients were from Mumbai, which accounts for over 10% of the country’s drug-resistant tuberculosis patients.
It made a startling discovery. Of the 7,000 samples sequenced till 2020, 1.4 % were found resistant to bedaquiline in initial analysis of 1,000 samples.
“These were patients who were not even exposed to bedaquiline,” said Dr Nerges Mistry, the institute’s director.
What Mistry meant was that these tuberculosis patients were never treated with bedaquiline. Their resistance to the new drug was baffling.
This was not a one-off observation. Cases of bedaquiline resistance have been reported from the Mumbai clinic of Médecins Sans Frontières and the PD Hinduja Hospital in Mumbai.
The bacteria’s ability to defy bedaquiline is worrying. Although a small trickle, doctors have begun to come across patients who fail to respond to the drug. This leaves them with limited treatment options. In most cases, there is one outcome: palliative care and eventual death.
How bedaquiline works
Mycobacterium tuberculosis, which causes the infectious disease, grows with the help of a protein called adenosine triphosphate, or ATP.
It is produced by ATP synthase located within the bacterial cells. Bedaquiline binds itself to the synthase and prevents it from producing ATP, gradually leading to the bacteria’s death.
Of the drugs available to treat tuberculosis, bedaquiline is the only one that attacks the ATP synthase. This makes it the only viable treatment option when most drugs fail.
But certain mutations in the bacteria are now preventing bedaquiline from binding itself to the ATP synthase, explained Dr Kayzad Nilgiriwala, assistant director at the Foundation for Medical Research. Mistry noted that mutation is a “natural evolution to allow the bacteria to adapt and survive”.
To understand these mutations better, India needs to up its game in whole genome sequencing, according to Dr Gyanshankar Mishra, associate professor at Indira Gandhi Government Medical College, Nagpur. “It is still an emerging technology,” Mishra said. In a paper he wrote for Lancet in 2021, Mishra said India is not developing diagnostic tools to detect bedaquiline resistance fast enough. This could lead to indiscriminate use of the drug and greater resistance, he warned.
This July, pharmaceutical giant Johnson and Johnson’s patent on bedaquiline ended in India, paving the way for cheaper generics. While that may benefit patients deterred by the high cost of the drug, the wider access to bedaquiline can lead to rampant use by Indian doctors, Mishra said.
The last resort
Months before he died on July 19 this year, Vivek Rajaram Chavan had known his end was imminent.
Chavan was diagnosed with TB in 2019. When the initial set of drugs, called the first-line drugs, did not control the disease, he was tested a year later and found resistant to some of them.
Under India’s national programme, a patient is tested for drug resistance if they fail to respond to first-line drugs, and then put on more potent drugs, called the second-line regimen.
Accordingly, Chavan’s treatment was changed. An injectable called kanamycin was introduced.
When he did not respond yet again, he was tested and found resistant to a few of the second-line drugs. In 2022, when those drugs failed, bedaquiline was introduced. For doctors, bedaquiline, in most cases, is the final resort.
The government programme provides it for six months, not more. So Chavan contacted Médecins Sans Frontières where the drug was provided in combination with another drug for 18 months for free.
When bedaquiline was new to India and had not been introduced as a part of the government programme, Médecins Sans Frontières would import the medicine under conditional access for compassionate use for extensively drug-resistant patients.
“In 70% cases, the treatment with bedaquiline would be successful,” said Dr Vijay Chavan, medical technical specialist at Médecins Sans Frontières’s independent clinic in Govandi, Mumbai. “It has relatively fewer side-effects and a faster cure rate.”
But an organism develops mechanisms to resist the effects of a drug. Over the years, Vijay Chavan has recorded a drop in the success rate of bedaquiline treatment. He has seen seven patients who did not respond to bedaquiline and were referred for palliative support. Vivek Rajaram Chavan was one of them.
When his condition deteriorated, Vivek Chavan’s sputum sample was grown in a culture, called a drug susceptibility test, and assessed for 45 days.
If the bacteria does not grow in the culture when exposed to bedaquiline, it indicates the drug is working. In Vivek Chavan’s sputum sample, the bacteria was multiplying. That meant he was resistant to bedaquiline.
“This left us with very few options,” Vijay Chavan said. In a final gamble, doctors then tried a cocktail of other drugs, some with toxic side-effects, for 10 months. That too did not work.
Early this year, scans showed Vivek Chavan’s lungs were damaged: they could barely diffuse oxygen into the blood. He required an oxygen concentrator.
Three months ago, Médecins Sans Frontières had to refer him to the government-run Group of TB Hospitals in Mumbai. This was not for further treatment, but to spend his final days in palliative support.
Too infectious to be looked after in his single-room home in a Chembur slum, his mother admitted him in the hospital. She told Médecins Sans Frontières counsellor Jogeshwari Sawant that since there are young children living in the neighbourhood, she could not risk the infection spreading. “She also feared social boycott,” Sawant told Scroll.
Chavan, only 34, died on July 19. Although rare, his is now amongst growing cases of bedaquiline resistance in India.
Dr Rajendra Joshi, deputy director general of Central TB division, did not respond to Scroll’s query on whether the government has begun to record similar cases.
Of the 183 people treated with bedaquiline and a combination of other drugs at the MSF clinic, analysis of 112 cases showed 23% of them failed treatment— an indication they were resistant to bedaquiline.
Resistance in children
The disease is particularly challenging when children are resistant to bedaquiline.
Manisha More, now 17 years old, says all she did since June 2015, when she was diagnosed with tuberculosis, was pop medicines. The daily routine of half-a-dozen pills, including bedaquiline, made her irritable and depressed.
For a year she was treated by private doctors, and then for a year at the government-run JJ Hospital. In 2020, when she was in Class 10 and preparing for her board exams, she decided to stop taking all medicines without informing her parents.
“Nobody counselled me to continue medicines, or explained the harm of stopping them,” she said. “The medicines had a lot of side-effects.”
The four-month gap worsened her condition. When a tuberculosis patient stops their drug regimen midway, often the bacteria gets time to adapt to become immune to that drug.
More became resistant to bedaquiline. In 2022, she finally went to the Médecins Sans Frontières clinic. “We ran short of effective drugs to treat her,” said Vijay Chavan, her case papers in his hand.
They tried amikacin, an injectable. But it causes hearing loss so it had to be stopped. She was also resistant to clofazimine, which is used to treat drug-resistant TB.
“Consuming these drugs has a variety of side-effects,” said Vijay Chavan. “We are desperately trying different combinations to see if they work”
More has stopped going to school. She has loose motions, stomach pain, boils on skin and a burning sensation on tongue. “I will start studying once I am cured,” she said.
But doctors are not sure if she will be cured. Once a patient is resistant to bedaquiline, there are not many drug combinations that work. “It is frustrating and challenging for us,” said Vijay Chavan.
The mutation in bacteria
Doctors at the Foundation for Medical Research say they have found at least three frequent mutations in the mycobacterium tuberculosis that are immune to bedaquiline.
The mutations in the three genes – RV0678, AtpE and PepQ – prevent bedaquiline from binding onto ATP synthase, said Nilgiriwala of the Foundation for Medical Research. This allows the bacteria to continue to multiply.
But there could be more mutations playing a role in bedaquiline resistance. Dr Camilla Rodrigues, consultant microbiologist in PD Hinduja hospital, said these mutations are a subject of ongoing surveillance.
She said there are over 19 different mutations that have been found in bedaquiline-resistant bacteria.
“We cannot yet confirm which mutations are definitely causing resistance to bedaquiline,” said Rodrigues. “We are awaiting the second version of the World Health Organization TB mutation catalogue to know which mutations are responsible.” The catalogue is a booklet released by the World Health Organization, with the second one expected soon, containing updated information on mutations causing drug resistance in TB.
In 2021, Rodrigues tested more than 600 samples of tuberculosis patients and found 4.6% were resistant to bedaquiline. That rose to 11% of 250 samples tested in 2022. The Hinduja lab, however, receives samples of severe cases, Rodrigues said, and the rate of bedaquiline resistance is expected to be higher in these samples compared to the country-wide TB population.
Unlike viruses that replicate and mutate faster, bacteria take time. Mycobacterium tuberculosis can live inactive for years in the air sacs of lungs waiting for the host’s immunity to dwindle. When it becomes active, it has a slow growth rate, sometimes taking 16 hours to multiply. This, fortunately for humans, makes mutation slow.
But in the case of bedaquiline, the bacteria seems to have adapted quickly. Bedaquiline was approved under conditional access in India in 2016 for use at a few centres. Before that, a handful of doctors had been importing it for select cases.
The number of sites administering the drug rapidly increased since 2018. But the Foundation for Medical Research began seeing cases of resistance as early as 2015, when only few patients had received the drug.
“One possible explanation is its structural closeness to clofazimine,” said Nilgiriwala. He pointed out that bedaquiline is analogous to clofazimine, another antibacterial drug that has existed since long and has been used to treat leprosy and tuberculosis.
Mistry said the bacteria could have been exposed to clofazimine during leprosy or tuberculosis treatment and developed some form of resistance.
“Since the structure of bedaquiline is similar to clofazimine, for the bacteria it is not entirely a new drug. That is one possible explanation,” Mistry said.
There is limited research in this sphere, she said, “In Africa too, bedaquiline resistance has been reported in populations never exposed to it before.”
But while some have managed to diagnose bedaquiline resistance, not many pulmonologists have that facility.
Difficulty in diagnosis
Bedaquiline resistance can be confirmed through whole genome sequencing, a newer technology in tuberculosis diagnostics, in which the DNA sequence of mycobacterium tuberculosis is analysed to check for possible mutations and which drugs the mutation will be resistant to.
Another method is phenotypic drug susceptibility test, or DST, which is widely used to assess drug resistance and considered a gold standard. The test requires growing the bacteria in a culture and exposing it to different drugs to see how it reacts. DST is used to check resistance to first- and second-line drugs.
For bedaquiline resistance, the test takes 45 days and requires a powder – also called bedaquiline powder – which is not widely available in India.
Very few laboratories conduct such a test – this includes PD Hinduja hospital in Mumbai, the National Institute of Tuberculosis and Respiratory Diseases in Delhi and a few government centres.
Rodrigues, from Hinduja Hospital, said currently they procure the pure drug powder for the test from the USA.
“Performing the drug susceptibility test is extremely important today as India ramps up the use of bedaquiline in multi-drug-resistant tuberculosis. We are requesting the Central TB division to help us with procurement of the pure powder,” Rodrigues said.
A poor patient is unlikely to be able to afford such tests.
“For this reason, we do not have many bedaquiline resistant cases reported,” said Dr DJ Christopher, pulmonologist at Christian Medical College, Vellore.
At Christian Medical College, he said, they have no cases of bedaquiline resistance because none were tested.
“Till we start testing, we will not know whether there is rampant resistance to bedaquiline. It is like with HIV,” said Christopher, referring to the human immunodeficiency virus that causes acquired immunodeficiency syndrome, or AIDS. “India claimed it had no HIV cases before it began testing and found there were many,” he said. HIV cases were first found in India in 1986.
In Gurgaon, Medanta Hospital began a clinic to treat drug-resistant TB patients a year ago. It is the only private hospital in Haryana to administer bedaquiline. The clinic has 25 patients from Bihar, Uttar Pradesh and Haryana and pulmonologist Dr Bornali Dutta has not found drug resistance in any of them.
“But again, we do not have the facility to test for it,” she said.
Dutta said whole genome sequencing, although expensive, could become the key to tailor-made regimens. “It will tell us which drugs the patient is resistant to well in advance,” she said. “We won’t have to try drugs and wait for patients to respond before we test them for resistance.” Dutta said.
On July 25, the World Health Organization approved targeted sequencing on certain platforms to aid in faster diagnosis and treatment. For now, India is in no hurry to implement whole genome sequencing on a large scale. “The technology is still very new for tuberculosis bacteria,” Christopher said.
This reporting was supported by a grant from the Thakur Family Foundation. Thakur Family Foundation has not exercised any editorial control over the contents of this article.