Now What? - (Part 1)

A couple of weeks ago we hooked up to to an online webinar (‘The Results Are in – Now What?’) organised by the Treatment Action Group (TAG). It reviewed the results of two recent scientific trials, one looking at a new drug for MDR- and XDR-TB and the other evaluating a new regimen for treating MDR-TB. We have our own take on each (which we’ll discuss in Part 2), but in this first part we want to report on the webinar itself because it was extremely interesting in its import.

As Erica Lessem (of TAG) stated in her introduction, this webinar related to the first-ever Phase III clinical trial for MDR-TB. Astonishingly this means ,that, despite MDR-TB having been out there and well identified as a major health threat for over 40 years no-one has ever conducted a Phase III trial that might demonstrate how it can best be treated with the existing drugs – let alone new or repurposed ones ones. “For decades”, Erica identified, “the standard of care for treating drug-resistant TB has not been based on randomized or clinical trial data.”

This is truly an astonishing observation that should be being highlighted by all concerned.

But at least now we have these two trials (“big news for the TB field” as Erica put it with some understatement) – one reviewing a significantly shorter drug regimen (the initial WHO-recommended regimen was a minimum of 18 months with six months of daily injections of which more later…) while this new one is nine months long; and the second study looking at the comparative efficacy of one of the new drugs.

The two sets of results were each analysed in the webinar by three experts – Francesca Conradie from Wits University in South Africa, Carole Mitnick of Partners in Health and Harvard, and Marcus Low of TAG.

The first study was called ‘STREAM Stage 1’ and was checking whether the shorter nine month regimen for MDR-TB was as good or better than the standard 18-24 months treatment. This is commonly referred to as ‘the Bangladesh regimen’ and surprisingly to many it was recommended by the WHO over a year before this official data appeared so there was high expectation of its publication.

The second was the ‘delamanid C213 trial’ looking to see whether this new drug produced better results than existing treatment. As Francesca described it, the existing treatment involves “at least 6 months of injections with other toxic drugs that if you didn't go into renal failure or go deaf, you ended up going crazy” with another 12-18 months of toxic oral drug treatment still in store (while the delaminid treatment didn’t use injectables at all). And, as we’ll see later, there appears to be astonishingly little (if any!) proper evidence of any real differential benefit from these ‘injectable agents’ (IA’s) when they’re used.

In the shorter regimen STREAM trial the final results indicated that there was little difference between it and the longer treatment (in fact unfortunately the shorter regimen performed a little less well). As such the study can easily be judged to have been a failure but, as Francesca added, it’s not quite that simple. For two good reasons the new regimen still has legs in her opinion in spite of the disappointments: one reason is simply because a good 20% of MDR-TB patients under the existing treatment get lost along the way during the existing treatment largely because it’s too much of an endurance test so never see cures anyway; and the second reason is because this shorter regimen comes in a lot cheaper than the longer one which could mean that many more MDR cases could be put on treatment. (MDR drugs cost a lot of money in comparison to standard TB drugs: to show how much they cost in comparison to first line TB drugs Francesca told how South African MDR drugs take 2/3 of the national TB drug budget but are only used on 12,000 out of the 290,000 treated TB cases each year (i.e. 66% of the drugs budget is used on a tiny 4% of all TB cases).

And, as Fransesca also pointed out at a more personal level, having to show up daily at a clinic for your painful shot for the first six months of treatment means that your ability to hold down your job is severely limited if not destroyed completely, effectively threatening destitution on top of disease. As she put it, “being able to use a shorter course [without injections] is very, very important.”

Carole Mitnick was less sanguine about this study because she sees evidence of efficacy as being the main priority with economics a lower second. She thinks that if efficacy were proved it could be used, however, to leverage prices downwards. Ultimately, however, she didn’t personally think that the results of either trial indicated any changes in clinical practice, and (more importantly still) she really couldn't see how the shortened regimen could be properly used anyway without drug-susceptibility testing for each one of the drugs in the regimen (something which is still sorely lacking in TB endemic countries).

For Marcus Low, the delaminid results in particular were a serious disappointment, although he could at least see that the safety profile was encouraging, and he’s sure that the drug is still worth having in the armoury as back up. He also had some concerns of his own around the shortened regimen, however, pointing out that there was increased mortality in people with HIV.

But on top of reckoning that there were no new regimens emerging yet, he raised a more pointed question about the use of injectable agents (IA’s) generally as are used in the existing longer regimen, referring to a recent study that reviewed the evidence for their use (or lack of it). “Is it acceptable,” he asked “to keep exposing people to hearing loss?” Or as he put it a little later in the webinar, we need to see an “end to the situation where we allow people to go deaf because they are poor” adding that “we let poor people take drugs we wouldn't take [ourselves].”

Strong words from a true TB activist.

Each of the three experts were then asked what sort of drug regimen they would choose for themselves if they had MDR-TB, and tellingly every one of them said they would not want an injectable in the mix.

So what exactly was this study in the injectables that Marcus was referring to? Well, it was one that was published in the International Journal of Tuberculosis Lung Disease challengingly entitled “The devil we know: is the use of injectable agents for the treatment of MDR-TB justified?”and it was co-authored by 14 TB experts (including Erica Lessem herself). This study baldly concluded that “there is limited evidence of the efficacy of IA’s, clear evidence of the risks of these drugs, and that persons living with MDR-TB should be informed about these risks and provided with access to alternative therapeutic options.”

It’s really no picnic being on these injectable drugs – because (as the study put it) they “cause a great deal of pain and distress for patients, and are associated with frequent, serious adverse effects. Perhaps the most serious problem associated with IAs is permanent hearing loss in as many as 50% of persons receiving them for MDR.”

Half of those treated with them go permanently deaf?

So would we want them ourselves if we were asked? Hell no – certainly not if the evidence for their use is so poor…! Are we crazy? But would we be asked anyway?

The study went on to describe how these drugs have held a “revered place” in treatment of DR-TB for almost 20 years despite such limited evidence of their beneficial effect, and that in contrast there is copious evidence of the dangers to patients from their use. In fact, quite astonishingly, it turns out that not one RCT has ever been published which evaluates their use.

The paper then quotes the WHO’s own post-2015 Plan to End TB, identifying that this Plan is founded on the idea of ‘patient-centred care’. It explained how, in 2017, the WHO had even released ethical guidelines for implementing its End TB Strategy, highlighting in the process that ‘trust and transparency’ are key to such patient-centred care. This in turn, the authors argue (quoting further from the WHO’s guidelines) requires “that decisions be made by providers and persons living with MDR-TB ‘in an open manner, through a fair process, and that the said decisions are responsive, factual and evidence-based’.” The paper further identifies that “patient-centred care in the context of MDR-TB must include providing information to patients on the potential benefits and harms of IA’s, as well as of alternative drug choices, and allow active participation in deciding on the most acceptable and appropriate treatment regimen.”

And then they went even further, concluding that IA’s should only be given after persons with MDR-TB are not just informed of the risks and benefits of the drug but also made fully aware of the other therapeutic options available to them. Failure to do this, they stated, simply contravenes the ethical and human rights standards set by the WHO itself for the delivery of high-quality TB care to all.

These are strong statements for these experts to have made, throwing shocking light into the darkness despair and neglect that makes up the world of drug-resistant TB.

Many activists are identifying that 2018 is going to be a make-or-break year for TB control with a massively important high level meeting slated at the UN in September. But if the shameful failure to properly address MDR- and XDR-TB is simply swept under the carpet at this meeting to save face (as it has been to date) it could well all end up meaning nothing.

So back to the title of the webinar – and this particular blog..’ the Results Are in – Now What?’. It’s difficult to say beyond recognising that the TB mycobacterium is no push over and hoping that there will be much better news in the next couple of years (the earliest we can expect any more according to our experts). It’s indisputable that MDR-TB is already at least a decade in front of the campaign to bring it to heel – possibly two – which is one of the other things we will discuss in ‘Now What? – Part 2‘.