multi drug resistant TB

WHO Hopes New TB Regimen Will Be Shorter and Cut out Painful Injectable Drugs

The organisation recommended pretomanid, a new TB drug, but exercised caution.

New Delhi: The World Health Organisation (WHO) has announced changes for the treatment of drug-resistant TB. These are especially focused on knocking off toxic drugs which have long been part of TB treatments. The changes also hope to make the treatment course shorter.

The WHO is thus keen to increase priority for bedaquiline, a drug that has been gaining acceptance over the past few years. The organisation also recommended a new drug, pretomanid, but only for a limited and cautious roll out for now.

Drugs like bedaquiline and pretomanid can be taken orally, can shorten the regimens and can treat drug-resistant TB. They can replace painful injectable drugs that sometimes cause deafness.

India is also keen to hop on to the “all-oral regimen” and is updating its guidelines as of this year, as The Wire reported in September.

So firstly, WHO’s new communication hopes to move multidrug-resistant TB and rifampicin-resistant TB (MDR/RR-TB) patients on to shorter, all-oral regimens with the drug bedaquiline. Secondly, it has introduced the novel treatment regimen of drugs called BPaL, which has the new drug pretomanid.

Also Read: As Focus Moves to TB Prevention, Who Will Treat India’s 2.69 Mn Patients?

The problem of MDR/RR-TB is a unique challenge on its own, within the larger challenge of global TB. About 5 lakh new cases of MDR/RR-TB are said to emerge annually and only one in three are reportedly being treated as of 2018. The success rate for treatment in 2018 was 56% for MDR/RR-TB patients and 39% for XDR-TB patients.

The global health body hopes that the new regimens will show “significant improvements in treatment outcomes and quality of life for patients.” The communication is expected to influence and change various national TB programmes.

WHO hopes to eliminate injectable drugs. Credit: WikiImages/pixabay

New drug pretomanid is exciting but questions remain

Pretomanid is a new drug developed by the TB Alliance, a non-profit organisation. It is also an oral tablet, which makes it an attractive alternative to painful injectables. It has been approved by the US Food and Drug Administration just this August. The TB Alliance has not published the data on its study of this drug.

WHO’s new recommendation for BPaL is important and requires more analysis.

BPaL is a new regimen with bedaquiline, pretomanid and linezolid. Linezolid is an old drug, well known for TB treatment, bedaquiline has become known over the past few years, while pretomanid is new.

Data for BPal so far is from the single-arm, open-label Nix-TB study done by the TB Alliance, which also owns the drug. The study looks at whether BPaL is successful in a six to nine-month regimen for patients with XDR-TB when compared with other regimens. The study has also only looked at patients who have not had exposure to bedaquiline and linezolid so far.

WHO also noted the fact that there were only 108 participants in the study as a limitation. The study also did record some adverse events such as blood disorders, liver toxicity, peripheral and optic neuropathy. WHO says that reproductive toxicities have been seen in animal studies and there has not been enough evaluation of its impact on human fertility. It says that patients should be informed about this before being given the drug.

Also Read: India Looks to Expand TB Programme With New Drug Bedaquiline

Therefore, WHO has recommended that BPal is only given in “operational research conditions” which conform to the organisation’s standards for patient care, support and inclusion, good clinical practice, active drug safety monitoring and management, treatment monitoring, evaluation of outcomes and standardized data collection.

The global body says that BPaL is not for programmatic use worldwide “until additional evidence on efficacy and safety has been generated.”

WHO has weighed the benefits and risks of pretomanid and says that the experience with BPaL is limited but that “the BPaL regimen may offer benefits despite potential harms and may be considered under prevailing ethical standards.”

File photo of the headquarters of the World Health Organization (WHO) in Geneva, Switzerland, March 22, 2016. Credit: Reuters/Denis Balibouse/Files

File photo of the headquarters of the World Health Organization (WHO). Photo: Reuters/Denis Balibouse/Files

Concerns about pretomanid are pending answers

At The Union’s World Conference on Lung Health in Hyderabad recently, global health activists and TB patients demanded that the TB Alliance release more data and answer questions about the safety of the drug. They also demanded the Alliance drop the high price of the drug [pretomanid alone will cost about $364 (Rs 25,670) and when taken in combination will cost $1,040 (Rs 73,342)]

Twenty four TB experts have also recently written to the TB Alliance with questions. They want to know the results of patients on BPaL versus patients taking only bedaquiline and linezolid. They also ask if the Alliance has buried negative data from trials in 2015 about liver toxicity, when three deaths were reported. The data from this study has never been published and the new data for pretomanid has also not been published.

A piece in The Lancet recently said that analysts felt pretomanid “risks lowering the evidentiary standards required for new tuberculosis medicines.” The authors concluded: “We think more research is needed before pretomanid can be celebrated as a promising treatment for people with tuberculosis.”

The new changes were announced this week by WHO after their ‘Guideline Development Group’ deliberated in November 2019, to look at new evidence shared by countries and technical partners and through WHO’s public call for data on TB drugs.

The organisation will convene a global forum in 2020 to help countries, technical partners and civil society understand the important changes in the new regimens and also to restructure national guidelines and TB programme budgets.

Small Drop in TB Cases in India, but Number of Deaths Rise

India had 2.69 million patients in 2018, a drop of 50,000 from the previous year.

New Delhi: New data released by the World Health Organisation shows a decrease of TB cases in India by 50,000 since 2017. However, the country is still the world leader in TB cases, with an enormous 2.69 million patients, which amounts to 27% of the world’s patients.

The small decline in TB cases between 2017 and 2018 in India is in line with the global trend. The notification of TB cases in India has also increased, which is a positive development. However, while the decrease in TB cases and its rate in India is small and slow, deaths because of the disease have increased.

According to the WHO’s Global TB Report 2019, India had 2.69 million patients in 2018. In 2017, the number was 2.74 million cases. The drop of 50,000 patients is a 1.8% decline. The incidence of TB cases also dropped from 204 per 100,000 people in 2017 to 199 in 2018. The number of drug-resistant TB cases has also fallen, but by a mere 5,000 people. The current number of people with drug-resistant TB in India is still large at 1.3 lakh in 2018.

While the decline itself is good, the percentage of decline in comparison with the enormousness of India’s actual TB burden of 2.69 million people, indicates that India’s project of TB control is slow and the task at hand is large.

The notification of TB cases in India has increased. This is good news considering that figures for India’s TB burden were revised and increased a few years ago due to the phenomenon of India’s “missing millions,” where TB patients were being treated in the private sector or not receiving treatment at all. These cases were not being tracked by the Indian government.

But even then, at least 5.3 lakh TB patients could be missing from the government’s surveillance. While 2.69 million people are estimated to have TB as per the new report, only 2.1 million are notified.

Also Read: India Looks to Expand TB Programme With New Drug Bedaquiline

On the issue of notification, the WHO notes: “Most of the increase in global notifications of TB cases since 2013 is explained by trends in India and Indonesia, the two countries that rank first and third worldwide in terms of estimated incident cases per year. In India, notifications of new cases rose from 1.2 million to 2.0 million between 2013 and 2018 (+60%).”

India is among the eight countries which account for two-thirds of the global TB burden. But India is the only country where TB cases are in two-digit percentage points of the global count. While India is responsible for 27% of world’s TB cases, the other seven countries (China, Indonesia, Philippines, Pakistan, Nigeria, Bangladesh and South Africa) all contribute between 3% to 9%. In total, 30 countries, including these eight, account for 87% of the world’s TB cases.

Deaths from TB increase

While the number of TB cases fell by 50,000 between 2017 and 2018, the number of deaths from TB increased by 30,000. In 2018, 4.4 lakh people died from TB and the corresponding number was 4.1 lakh in 2017.

A reason for the rising number could be that a large number of TB patients in India don’t get treatment. The Global TB Report says only 74% of Indian TB patients are able to get treatment. Many TB patients are not notified and thus are not being tracked by the government’s TB programme. This also means they could be getting incorrect treatment or maybe no treatment at all. This also could be a reason for the deaths.

The global report says that among the 30 countries with a high burden of multi drug-resistant TB patients, the success rate of treatment was 50% or lower in India. In India, two reasons for the low success rates were high rates of death and loss to follow-up (19% and 19%), says the WHO.

TB Killed Shreya Tripathi, But Her Death Could Have Been Avoided

India’s health ministry wanted to distribute a life saving TB drug only to patients in big cities. A girl from Patna fought the government and won, but it was too late for her.

Shreya Tripathi loved to read. And it should come as no surprise that the 19-year-old, who died needlessly from a drug-resistant strain of tuberculosis (TB), felt a particular connection to the 2012 novel The Fault in Our Stars.

The story is, after all, focused on teenagers locked in a mortal battle with cancer as their biologic foe. Shreya’s sister had given her the novel after Shreya became too breathless to leave her bed, the result not only of an infectious TB pathogen but of a society’s unwillingness to help her survive.

Shreya was one of the 10 million people who become sick with TB each year and one of the almost 1.6 million who die annually from this curable infectious disease. Unfortunately for the young woman from Patna, she was also one of the 580,000 people who are stricken with a type of TB known as “drug-resistant TB.”

Scientifically, having this type of TB means that the most powerful anti-TB medications available no longer work against the strain and thus treatment must instead consist of five-seven “second choice” drugs that need to be given for a minimum of 9-24 months. Colloquially, this type of TB is often known as “killer TB” because fewer than 50% of those who receive treatment are cured of their disease.”

But the numbers – as shocking as they are – can be sterile and distance us from the profound individual suffering that seems to hide in the multitudes. And this is a story about the valiant struggle of a very specific young woman.

Her name was Shreya. She loved the color pink. Her favorite fruits were litchis whose cool juiciness made the hot summer days in India a thing to look forward to. That is, until her lungs became so scarred and clogged with the TB bacteria, that even the most minimal efforts left her gasping for air.

The bedaquiline drug

When bedaquiline, the first new drug developed for the treatment of TB in almost fifty years and the only medication for DR-TB that had ever been tested in a randomised, controlled clinical trial, hit the market, clever Shreya – who had been fighting drug-resistant TB for almost two years – heard about the medication and correctly thought “this is what my body needs.”

Although the phase III study result are not expected until 2020, results from thousands of patients assessed by the WHO show that early use of bedaquiline was associated with remarkably high rates of treatment success. In most settings, above 80% were successful, even when it was given to the most critically ill people living with the disease.

Why did the doctors, people who Shreya trusted and went to looking for help, not offer her bedaquiline? There may never be a satisfactory answer to this question – certainly not for Shreya’s family, who gave up everything to search for a cure for their beloved daughter.

Chemical structure of bedaquiline. Credit: Wikimedia Commons

The RNTCP’s hindrances

India’s Revised National TB Control Program (RNTCP) frequently tries to explain away the great injustice they perpetrated against this young woman. Sometimes, they hide behind a meaningless scientific facade, claiming there was not enough medical evidence to give Shreya the drug.

Most often, they cloak themselves in the respected mantle of public health responsibility and talk about preventing the development of resistance to this precious medication and how they need to “protect” bedaquiline in case people need it in the future. They almost never mention how they failed to protect Shreya, whose life depended on receiving bedaquiline as soon as possible.

No. Instead of protecting her, the RNTCP forced Shreya – who was fighting for her life – to have to spend some of her last days on earth fighting against the formidable bureaucracy. Because even though she should have been preparing for university, she instead asked her father to prepare for court, telling him that even if it was too late for her, she wanted her suffering to have meaning.

She was blessed by a family that listened to her. Her court case asserting her right to be treated with bedaquiline was taken up by human rights champions, Anand Grover and his colleagues at the Lawyers Collective. They filed a suit against the RNTCP in the Delhi high court, where over the course of several weeks, Shreya’s fate hung in the balance.

The court case

The RNTCP put up quite a fight to keep bedaquiline out of the hands of this dying girl. First, they claimed Shreya did not live in one of the cities where bedaquiline was approved for use.

When Shreya’s family moved to one of those cities, they then claimed that Shreya needed to prove she actually had highly drug-resistant TB, even though they themselves had the medical test results documenting such resistance from their own laboratories.

They then claimed she did not have a chance of being cured because there were not enough drugs with which to pair the bedaquiline to stop her TB. They did not want to “waste” the bedaquiline trying to save her life.

Advocating for Shreya was one of the best – and also the bravest – TB physicians in India, Dr Zarir Udwadia. He was backed by a team of international experts who could not help but be moved to action when they heard about Shreya’s fight.

Although Shreya eventually prevailed, with the judge ruling that the RNTCP must provide access to bedaquiline for her, the victory was hollow. Because of the months it took to overcome the endless barriers erected by the RNTCP, Shreya’s lungs were destroyed. Bedaquiline, along with other medications, was able to kill the TB germ. But nothing could be done to make the lung cells healthy again: only scars remained, leaving her breathless.

Delhi high court. Credit: PTI

Not much has changed

And perhaps what would be most troubling to Shreya: access to bedaquiline for people in India has not improved. Since 2015, only about 2,000 people in the country have received bedaquiline, a mere 3% of those in need of the drug using conservative estimates.

This is the case even though the drug is free. Even though it has been recommended for treating drug-resistant tuberculosis since 2013. Even though, almost 65,000 people in India develop drug-resistant TB each year and a mere 46% of them will be cured.

Shreya Tripathi did not need to die, and there is nothing more devastating than the senseless death of a child. In spite of having better lifesaving drugs like bedaquiline, every day, the list grows with the names and suffering of the young, who, like Shreya, officially die of multidrug-resistant TB but whose cause of death is far more insidious.

Taken alone, they are single points of heartbreak. But when viewed all together, they form something that should ravage our collective consciousness, not only because they did not need to die but because, in essence, we helped kill them.

Dr Jennifer Furin is an infectious diseases clinician and medical antrhopologist. She is currently a lecturer at Harvard Medical School. She was one of the experts who had filed an opinion in the Delhi high court in Shreya’s case, regarding giving her access to bedaquiline.

TB Patients on Bedaquiline Have Half the Mortality of Those Not on the Drug: WHO Chief

The WHO will be releasing new recommendations for the treatment of multidrug-resistant and rifampicin resistant tuberculosis (MDR/RR-TB) later this year, which will speak in more detail about the usage of the new drugs bedaquiline and delamanid.

The WHO’s deputy director general, Dr Soumya Swaminathan says that the new drug bedaquiline is highly recommended for certain patients suffering with drug resistant tuberculosis.

“There’s absolutely no doubt now that the benefits outweigh the risks. In fact, the cardiac toxicity noticed is extremely minor,” said Swaminathan. “It is extremely clear that TB patients on bedaquiline have half the mortality of those not on the drug.”

Swaminathan was referring to a recent WHO document that was the result of an expert committee’s deliberations. The committee recommended that debilitating injectables like kanamycin be replaced, in some TB regimens, with the new drug bedaquline. She was speaking on the sidelines of the Health Systems Global Summit in Liverpool last month.

Also Read: Tuberculosis and Bedaquiline: Now Is the Time to Discuss Clinical Trials

Swaminathan said that the WHO expert committee’s recommendations were issued after studying a large volume of data. “Now we have data from a much larger number of patients. In fact Janssen has shared all their data with us, including their most recent data. South Africa has also shared as they have the largest number of patients (being treated with bedaquiline). Russian data has been looked at. India has also sent data,” she said.

Soumya Swaminathan. Credit: Youtube

However Janssen, the sole company making bedaquiline, has not yet released its phase 3 trial data. So far, the only data from their phase 2b trial has been released. This trial was conducted on a small cohort of just 161 patients. Drug regulators like the US’s Food and Drug Administration have given Janssen permission to sell it with the condition that the company release phase 3 data by 2022. While the company has been submitting this data for the WHO’s periodic reviews of evidence for their guidelines, it has not released this data publicly.

Meanwhile, both India’s and the global TB crisis continues to be urgent: India has the highest number of TB cases in the world. In 2016, India had 27.9 lakh new TB patients and 1.47 lakh new MDR-TB patients, according to the WHO’s Global TB Report 2017. This notwithstanding, the current NDA government has announced that TB will be eliminated in India by 2025.

The WHO has been growing increasingly confident of bedaquiline as a drug for some TB patients suffering with multi-drug resistant TB. As an oral drug, it comes with fewer side effects in comparison with drugs currently being given to these patients such as kanamycin, which are painful injections administered for at least nine months and can cause irreversible hearing damage, abscesses and neoprotoxicity. The WHO’s recommendations come after experts studied the data on the safety-benefit profile of these drugs.

Also Read: Discrimination, Growing Resistance to Drugs Fuelling India’s Tuberculosis Crisis

“To the question of whether countries can start rolling out bedaquiline even without phase 3 clinical trial data, yes, we are fairly confident of the data now that the benefits far outweigh the potential risk,” said Swaminathan.

“The jury is in, as far as the safety of bedaquiline is concerned,” she said.

Medical and ethical questions on bedaquiline

Despite the medical confidence around bedaquiline, the ethical question of whether or not to wait for phase 3 data remains. India currently administers the drug through a highly controlled, government monitored programme. The Revised National Tuberculosis Programme (RNTCP) has been distributing the drug only in a few designated government centers and it is not widely available for purchase in the private sector.

WHO’s ‘Rapid Communication‘, released in August 2018, describes the changes it recommends in treatment regimens for MDR/RR-TB. One of the main takeaways of this document is that injectables like kanamycin and capreomycin are no longer recommended for lengthy treatment. Instead, an “all oral regimen” is preferred, which opens the door for bedaquiline. Drugs like bedaquiline, linezolid and clofazimine have risen in importance and ethionamide, prothionamide and the injectable agents (amikacin and streptomycin) have become less important.

On the issue of informed consent, its “treatment principles” says a WHO document. “Ahead of enrolment on MDR-TB treatment, all patients should receive appropriate counselling to enable informed and participatory decision-making,” she added.

Another WHO document says that, “Patients should be consulted regarding treatment decisions, and provided with updated information necessary to make an informed choice about whether they prefer the injectable-containing shorter MDR-TB regimen or an 18-20 month all oral regimen.” The WHO also says that there should be active drug safety monitoring and management for these patients.

Also Read: Interview: ‘You’re Going Into a Battle on Tuberculosis, and You Need to Have an Army’

However, the consent form that Indian TB patients are currently given has sparse information on the status of clinical trials and also says that patients will not be entitled to compensation in case of any adverse effects from bedaquiline.

The WHO says that “the decision about which regimen to use should be an informed decision”. This would include telling patients and clinicians complex things such as: “in eligible patients under trial conditions the shorter MDR-TB regimen showed similar efficacy to longer MDR-TB regimens without new drugs, but had the advantage of a much shorter duration and a lower likelihood of loss to follow-up.”

Chemical structure of bedaquiline. Credit: Wikimedia Commons

However patients also need to be conveyed that a regimen that includes bedaquiline and linezolid has a “lower risk of treatment failure, relapse and death,” says the same WHO document.

A second point of contention is the absence of phase 3 data and the collection of this data in a non-clinical trial framework through national programmes like India’s. The WHO addresses this and says that national programmes that do replace injectables with these new drugs like bedaquiline, linezolid and delamanid should also “collect and validate these data rigorously so that they may help inform future updates to the WHO guidelines.”

Bedaquiline is not being recommended by the WHO for short-course regimens (nine to twelve months). South Africa has been more ambitious, however, including bedaquiline even in the country’s short course regimens. The WHO says this is “not routinely recommended” and should be done only under “operational research conditions.” Long course regimens are between eighteen to twenty months and it is here that bedaquiline is being recommended by the WHO.

Anoo Bhuyan won a media-fellowship to attend the Health Systems Global conference in Liverpool. This report is the output of the author’s time attending the conference.

Under Ahmedabad’s Mounting Garbage, It’s the Migrant Worker Who Is Crumbling

Migrant workers who fuel Gujarat’s growth story face the disproportionate burden of high levels of air pollution due to Ahmedabad’s Pirana landfill.

As you approach Narol, you see the silhouette of something curving like a mountain, burning in the sunset. Soon enough, you realise it’s an open landfill – one that holds nearly all of Ahmedabad’s solid waste. The Pirana landfill in Ahmedabad is the seventh-largest open landfill in India in terms of land area and amount of solid waste disposed. Locally known as “kachre ka dhakla (hill of garbage)”, it’s a massive mound of garbage spread over 84 hectares (207.569 acres) of land and reaching a height of over 200 metres. It has been the city’s sole repository of garbage since the 1980s.

This landfill, which receives 2,300 metric tonnes of solid municipal waste per day, is located in Narol, an industrial hub in the outskirts of Ahmedabad.

Narol is one of the largest industrial clusters of Ahmedabad with over 5,000 garment, chemical processing, pharmaceutical and recycling factories. All these factories are run using cheap labour provided by a huge migrant workforce of more than 4.5 lakh from Uttar Pradesh, Bihar, Rajasthan, Madhya Pradesh and tribal districts of Gujarat. It is this invisible workforce thats fuels Gujarat’s growth story, but faces the disproportionate burden of the abysmally high levels of air pollution and serious health hazards due to the Pirana landfill.

A view of Pirana landfill in Ahmedabad. Credit: Goutam Kumar Mahanty

An adverse impact of growing urbanisation and rapid economic development of Ahmedabad is the increasing heaps of municipal solid waste in the Pirana landfill. Garbage dumped here is mixed waste that consists of paper, plastic containers, bottles, cans and, at times, electronic goods. Open burning of this mixed waste is practiced on a daily basis – an inefficient combustion process that releases significant amounts of air pollutants, ash, dense white or black smoke. According to the State of Global Air Report, air pollution is a substantial cause of morbidity and mortality worldwide, resulting in major public health impact as well as financial losses each year. According to the report, ambient air pollution resulted in around 4.2 million deaths in 2015.

The landfill in Narol has had a detrimental impact on the health and well-being of migrant workers employed in factories in its vicinity. Official data from the Urban Health Centre (UHC) in Behrampura ward, where the landfill is located, show that 649 people were found to be suffering from tuberculosis between April 2017 and March 2018 within a total population of 1,65,731. These figures are shocking for the incidence of the disease in this ward is approximately 2.5 time that of the national average – which is 134 patients for a population of one lakh.

Residents of this area are suffering from TB, other lung diseases and incidents of premature death due to poor health conditions. Credit: Sangeeth Sugathan

Sanketbhai Gohil, who heads the TB eradication programme in Behrampura UHC, says, “Patients identified with TB and other respiratory diseases are admitted or referred to the government hospitals where they are given proper medication, but once the patient goes back to the same polluted and unhygienic atmosphere, they fall prey to the same diseases and eventually succumb to them.”

Shahidbhai, who migrated from the Azamgarh district of Uttar Pradesh 18 years ago, came in search of a livelihood that could sustain his family back home. “When I started working, I had a dream of opening a small garment unit and making it big in Ahmedabad. But three years into my work, I began falling ill frequently due to asthma and I never had the option of quitting work as my entire family was dependent on me.” Even after nearly two decades in Ahmedabad, his life remains restricted to the industrial area of Narol. “I only had the option of renting out a small room close to where I work since rooms are cheaper in the industrial area. I find it really hard to breathe late in the evening as the air is filled with fumes and smoke generated by the burning of waste in the landfill.”

The landfill is in violation of the existing Solid Waste Management Rules, 2016. Credit: Goutam Kumar Mahanty

Rajubhai, an Adivasi from Jhabua district of Madhya Pradesh, migrated 13 years ago with his family to work at the boilers that produce steam to run machines in the factories of Narol. “While all parents leave behind something for their children, here I am leaving them with a deadly disease. In all its probability, the legacy would continue,” says misty-eyed Rajubhai. All four members of his family, including him, are victims of TB. His wife died six months ago due to multi drug resistant TB. His youngest daughter Vanita, who is only 14, has also been diagnosed with the same.

Ahmedabad, like any other Indian megacity, boasts of a metropolitan identity steeped in extravagance and consumerist lifestyle. But its elite and upper-middle-class citizens, living comfortably in their gated communities and producing endless amounts of garbage, have no clue who bears the cost of their actions. It is the migrant workforce who is left to subsist in the dark underbelly of the city drenched in nauseous garbage and stink. They lead sub-human lives intertwined with contaminated air, toxic chemicals and fatal diseases. Several complaints and a PIL have been filed on the environmental consequences of the Pirana landfill. However, nothing significant has been done to improve the situation on the ground.

Goutam Kumar Mahanty and Sangeeth Sugathan work with Aajeevika Bureau, a specialised non-profit initiative that provides services, support and security to rural, seasonal migrant workers.