Why India Must Discard Fear, Give Some TB Patients ‘Game-Changing’ Drug

Johannesburg, South Africa: Like South Africa, India should immediately make available the tuberculosis (TB) drug bedaquiline--till now used as a drug of last resort--to nearly 147,000 Indians with a multidrug-resistant version of the disease, a leading South African TB-HIV researcher told IndiaSpend.

In June 2018, after research that proved lowered mortality, South Africa became the world’s first country to make bedaquiline--the first new TB drug in 40 years--part of its public-health regime for adults and adolescents with multidrug-resistant TB (MDR-TB) and extensive drug-resistant TB (XDR-TB), replacing toxic injectable drugs with side-effects that include hearing loss, kidney failure and psychosis.

Bedaquiline is “the best drug we currently have for drug-resistant TB”, and India should allow more drug-resistant patients to access the drug now, than protect the drug fearing the development of resistance to it by the TB bacillus, said Francesca Conradie, PhD., clinical research specialist at Nelson Mandela University Tuberculosis Research Unit, Port Elizabeth.

“Drug resistance is a concern and we've got to keep a close eye on it,” said Conradie, 53. “We have to make sure [development of new drugs] agenda is pushed, so that when resistance has developed to bedaquiline--say 30-40 years from now--then we'll have another new drug.”

On August 17, 2018, the World Health Organization (WHO) released recommendations for improved treatment of drug-resistant tuberculosis (DR-TB), prioritising the use of several oral drugs, including bedaquiline, which was first developed by Janssen Pharmaceutica, a subsidiary of Johnson & Johnson, in 2004 and released for use in 2012 by US Food and Drug Administration.

The use of bedaquiline is crucial because TB is the ninth leading cause of death worldwide, killing an estimated 1.6 million people in 2016--of which 27% were Indians, who dominate the ranks of TB patients.

That same year, there were 600,000 new cases with resistance to rifampicin--the current first-line drug, now 47 years old--of which 490,000 had MDR-TB.

The estimated number of multidrug-resistant patients in India in 2016, according to government data, was 140,000, more than a quarter (28%) of the world’s burden.

For three years between 2013 and March 2016, Indian TB patients who went to private-sector doctors--11.4% of the total reported in India--could only access bedaquiline under a “compassionate-use” programme. In March 2016, the Indian government announced that bedaquiline could be given to patients in six centres under conditional-access programme--accessible under the government’s framework and protocol for drug-resistant TB patients. Till date, 824 patients have been given bedaquiline, according to a 2017 government affidavit submitted to High Court.

Since 2013, South Africa--with 4% of DR-TB burden--leads the world in allowing bedaquiline to its DR-TB patients. In June 2018, South Africa’s government announced that bedaquiline would be used in a short-course treatment regimen for drug-resistant TB, replacing the toxic antibiotic injectables kanamycin and clofazimine.

In July 2018, the South African department of health published a retrospective study of 19,000 DR-TB patients in The Lancet Respiratory Medicine, a global medical journal, showing how 13% of MDR-TB patients treated with bedaquiline died compared to 25% of those in standard treatment, while 15% XDR-TB patients treated with bedaquiline died--almost a third of the 40% mortality rate in standard regimens.

Conradie was the principal investigator for the first randomised, phase-2 clinical trial--which means one arm of participants receive the drug and another receive placebo and both are compared--for bedaquiline in 2010 and part of several others conducted for bedaquiline and delamanid [another new TB drug developed by Otsuka Pharmaceuticals] in South Africa. She has worked closely with South Africa’s department of health and is part of its TB Think Tank, which brings together experts from the government, academia and civil society to assist in guiding South Africa’s TB response. Our interview with Conradie:

What has been your role in the roll-out of bedaquiline for the treatment of MDR-TB?

I have been involved with the bedaquiline as a drug for the treatment of MDR-TB since the original registration [all clinical trials have to be registered in a public clinical-trial registry] of the bedaquiline trial. In one of the studies, patients were randomised to get the drug bedaquiline or a placebo. Right from there, I could see that this was a drug that was going to make a difference in patients’ lives who had MDR-TB. We recruited about 25 patients, and we never knew which patient was on treatment [bedaquiline], but we could tell by the chemical response which patients were on [bedaquiline] and when we were un-blinded a couple of years later, we were always almost right. The patients that put on weight quickly, who cleared the sputum quickly, were the ones who had bedaquiline; the ones who didn't, had standard care. So when trials were finished, I approached the national department of health’s head, Nobert Ndjeka, and I said it's [bedaquiline] not a registered drug here, but I really think we need to start making a plan. At that time Janssen had approached me and asked about doing a compassionate-access programme, and I said we need to roll this drug quickly. We started a thing called a clinical-access programme, where patients with pre-XDR-TB and XDR-TB were afforded access to the drug.

We had 200 patients onto the bedaquiline clinical-access programme, and they did fantastically well. Mortality rate was 12.5%, which is extraordinarily low for people with extensively drug-resistant TB; we can accept it is normal now, but then we expected about 50% of those with XDR-TB to die, so it was huge.

Based on that, Norbert Ndjeka--who is very forward thinking--put together a group of clinicians interested in drug-resistant TB. We are a motley crew of everything--clinical investigator, academic, pharmacologist, microbiologist--and we sat down together and decided who should be eligible for it [bedaquiline].

We had to be a little careful. We decided that everybody with rifampicin-resistant TB who had in addition resistance to quinolones [second-line TB drugs] and/or injectables--XDR and pre-XDR-TB patients--and anybody who had treatment-limiting side-effects on the current regimen would be given bedaquiline. This decision was made in 2014.

Now, it's quite difficult to make a good idea to work because you have to persuade people, cajole, threaten and do whatever you can, so that people change their practices, and then when their practices change, they can see that this was the correct decision.

The same thing happened when in our HIV programme we changed to anti-retroviral (ARV) treatment. Eventually the department of health had to go pick up the old drugs and say to doctors, “You can't use these anymore, here are the new drugs, use these."

The Tuberculosis Burden: India & South Africa
Country	TB patients	TB Incidence (Patients per 100,000 population)	TB Mortality Rate (Deaths per 100,000 population)	RR/MDR-TB patients	RR/MDR-TB Incidence (Patients per 100,000 population)
India	27,90,000	211	32	1,47,000	11
South Africa	4,38,000	781	41	19,000	34

Note: RR/MDR-TB: Rifampicin resistant/ multidrug resistant TB
Source: Global Tuberculosis Report 2017

What change did you notice as South Africa changed the standard treatment regimen to include bedaquiline?

In the first year or so when we were getting patients who had hearing loss before treatment started as a result of the injectable--that's the most common indication their medicines were changed--we stopped the kanamycin and we put them on bedaquiline. It started off that people were a little bit reluctant initially, until last year, when 70% of South Africans with rifampicin-resistant TB got bedaquiline.

The truth is that everybody could see it was a better drug, and if someone just said I refuse to have an injection, we had two choices: A suboptimal regimen that's not good for anybody or, alternatively, bedaquiline. So, we started looking for reasons to give bedaquiline to patients. If you have read the recent article published by Nobert Ndjeka, in Lancet's Respiratory Medicine, there were clear mortality benefits in South Africa, and, at the moment, you've got a better chance of survival if you've got XDR-TB and you get bedaquiline than if you have got MDR-TB.

We now have a cohort of up to 12,000 South Africans [who] have received this drug, and we've got a fairly robust birth register, so if patients taking bedaquiline were dying, we would know that, but we, in fact, know that people getting bedaquiline are surviving and those who aren't getting bedaquiline are dying.

So, what we do is pull out all stops trying to get as many new drugs as we can. We now also have a delamanid clinical-access programme.

The biggest concern in India is about resistance to new drugs with our deputy director general for central TB division claiming the access to “new drug has to be restricted due to resistance”. Since 2016, barely 1,000 Indian patients have got access to bedaquiline. Is drug-resistance to bedaquiline a valid concern?

Of course, it is a valid concern, but in fact putting bedaquiline for the patients with worst resistance [XDR and pre-XDR patients] is putting it [bedaquiline] as at most risk.

The fact is, every time we have an antimicrobial, we have resistance. We can go ahead in protecting it, but bedaquiline is a very useful drug. But if it is used as a single drug on failing regime [with existing drugs with low evidence like injectables or for XDR patients resistant to most other TB drugs], you will definitely get resistance. We're seeing a few cases with bedaquiline-resistance in South Africa, and they are limited to patients who have been treated with everything, including bedaquiline, and have linezolid resistance, which is a drug with a high barrier to resistance.

In a routine programme, we expect about 60% of patients on treatment will be cured, 20% will die and 5-8% will fail and 10% will be lost to follow up. But if we use bedaquiline, we can push the cure rate to 80%--that is the kind of success rate that we expect.

Yes, we are going to lose some people, and some will not survive, but we will have a far lower pool of people who are not treated and cured. So, those who are not adequately cured are the people who are going to be feeding the epidemic of resistance; [those numbers] are going to be small compared to what we are doing with our old way of doing it [restricting the drug for patients as a last resort after all existing drugs have failed].

Drug resistance is a concern, and we've got to keep a close eye on it. We should never ever fall asleep like we did before on TB. It shouldn't be 40 years before we get the next [TB] drugs. We have to make sure that [development of new drugs] agenda is pushed, so that when bedaquiline has resistance--say 30-40 years from now--then we'll have another new drug.

So bedaquiline-resistance is a concern, but that should not stop us from using it on patients who need it?

You know, we had the same discussion on giving ARVs on a broad scale to South Africans with HIV [South Africa rolled out universal ARVs in 2003. Today South Africa has the highest number of patients on ARVs.] In South Africa, about 7.5 million [13.8%] are HIV infected out of our population of 54 million.

It is the same principle--more we treat, the more resistance we are going to get. At the moment, if someone dies in South Africa, they are not dying because of HIV, but they are dying because the South African health system didn’t find them soon enough and put them on adequate treatment. We have about 3.8 million on first-line ARVs, and there are 200,000-300,000 on second-line ARVs.

So, the way to do it is to treat with the best drugs that you have, and, yes, resistance will develop, but it’s not the end of the world, we have plan B and plan C. Bedaquiline is the best drug we have for drug-resistant TB ever, and it is based on evidence. It is the drug that has enabled us to get patients back to health the quickest. Delamanid is nowhere close; it is a good drug but bedaquiline is the game changer.

The current regimen for extensively drug-resistant injectable TB drugs is “strong on advice but weak on evidence”, but there is huge debate about the safety of new TB drugs. What do you think?

It is complete craziness, isn’t it? We have got more evidence for both bedaquiline and delamanid than we do for any of the other [existing] drugs. So, drug-resistant TB was first acknowledged as a problem in the mid- to late-1980s. Rifampicin was the best drug then, and it was failing. So WHO quickly gathered a group of specialists and expert opinion groups--there were no trials. And they asked--a group of mostly all elderly men--“how should we treat them”? One of them said, “Second-line injectables are quite useful, let’s give them for two months, or let’s give them for six”. So, it was a consensus statement, and if you look at the original [document with recommendations] even for the longer course, it’s a strong recommendation with very poor evidence because they have never done randomised control trials.

How did South Africa become the leader in drug-resistant TB treatment?

Our health minister Aaron Motsoaledi is chair on the Stop TB Partnership [an international body working on TB] and aware of the issue. Also, the TB programme is funded by South African taxpayers; we don't rely on foreign donors. Even if all the foreign funding pulled out, we would still be alright.

I think to be a really good leader, you surround yourself with very good advisors. That's what Norbert Ndjeka [head of South Africa’s department of health] has done: He's put together this very factual ‘clinical-access committee’ that has really been able to have research implemented into policy really quickly. Bedaquiline was registered in India at about the same time as it was registered in South Africa, and we all looked at it and said, “no, hang on, we have to stop making people deaf [a reference to the side effects of existing injectable drugs]”. These were people who came to the healthcare system with a serious illness, and they left with a serious problem, deafness.

I think it's more common in South Africa, in Sub-Saharan Africa. It is linked to a particular genetic modification. About 60% of South Africans have a particular genetic mutation, that [if] you get an injectable, you've got a high chance of going deaf.

Do you have any advice for Indian policy makers related to access to bedaquiline?

Just do it. Janssen says they have sufficient stocks. Our health minister has yet again called for reduction in prices, and it is cheaper to use bedaquiline than it is to use an injectable. Because if you use injectable, there is a whole lot of monitoring that you have to do, and, sure, you have to do it for bedaquiline, but it’s probably cheaper. The cost of the drug is now cheaper, and there is enough evidence out there [about bedaquiline’s safety and efficacy]. You know that the average age for someone who gets MDR-TB is 35 years. When you are 35, you might have children and the loss of a 35-year-old is bad. You have got to save the life now. Forget bedaquiline-resistance, it is going to be someone else's problem [in the future].

(Yadavar is a principal correspondent with IndiaSpend.)

Reporting for this article was supported by Doctors Without Borders/Médecins Sans Frontières India

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