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AMR Awareness Week (Day 6): MDR-TB, the existing anomolous AMR pandemic

The emergence and spread of multidrug-resistant strains of Mycobacterium tuberculosis (MDR-TB) represents one of the most daunting challenges to disease control worldwide let alone to controlling AMR.

What is such a tragedy, therefore, is how much it has been demonstrably neglected in the last thirty years – and, as we have written many times before, we can’t help but wonder whether this is simply because TB is so clearly a disease of poverty, and poor people (and poorer countries) can’t afford new drugs.

Since the 1990s, ‘ordinary’ TB (i.e. TB that has not developed resistance to the existing first line drugs) is treated with four antibiotics for six or eight months. None of them work fantastically well, unfortunately, because TB has a tough outer shell which drugs struggle to penetrate, so the goal has been to ensure that at least three different active drugs are able to work as successfully they can, so minimising the risk of any mutations developing that might survive and be resistant to any of these drugs.

In other words it’s an arms race , but it’s one that is always destined to be ultimately lost by the drugs, not just because the drugs are so tough to take for so long that many patients fail to complete their six months’ treatment and then relapse, but also because the probability is that (given that there are persistently 10 million new TB cases a year) a tiny stream of random mutations will emerge that will enable drug resistance in any course of time for any drug anyway.

The development of resistance to anti-TB drugs actually began shortly after the initial introduction of individual drugs to treat TB, which resulted in the four-drug protocol that was adopted in the 90s. But despite this multi-drug approach, it’s continued with incrementally more extensive drug-resistance even since this standard ‘DOTS’ four-drug protocol was implemented (with the original official anticipation that it would supress any increase in drug-resistant TB).

As TB and infectious disease expert Salmaan Keshavjee correctly identified – DOTS was a great first step, but it was a terrible long-term strategy because it would never stop MDR-TB.

MDR-TB is defined as TB caused by a multidrug-resistant strain, that is a strain that is resistant to rifampicin (known in America as rifampin) and isoniazid, the two strongest anti-TB antibiotic drugs.

Image of the four first-line drugs along with the dates they were developed. MDR-TB involves resistance to the two strongest of these four drugs.

This then leaves only the two remaining weaker first-line drugs to work (which they generally fail to do) so another set of second line drugs is added to them – drugs that are themselves weaker but are also associated with high risks of permanent side-effects and which need to be taken for up to two years daily (and cost a whole load more money).

Image of the second line drugs that need to be introduced in various combinations (in yellow) as much as six different ones a day.

In other words, with MDR-TB the treatment outcome is inevitably less favourable and mortality is higher. It has to be added, however, that new drugs HAVE been developed for MDR-TB (see bedaquiline and delaminid above) but both are still too expensive to be used as extensively as is required to control an airborne infectious pandemic, and both have to be very carefully managed, not just because of their side-effects but also because mismanagement will inevitably speed up the birth of new strains of resistance that will also disable these new drugs.

There is little that is ‘good’ about TB – but at least it can be said that it isn't as infectious as many other infectious agents (though still has an R number of more than 1) and that it develops very slowly which means that the same is the case with drug-resistance. It has been suggested that consistent community resistance to a TB drug normally develops around 15 years after the introduction of the new drug so, given that these two new drugs (bedaquiline and delaminid) were both approved in 2012, it was reasonably anticipated that a window of opportunity to suppress this pandemic was available at least until 2027.

Sadly, this may not already be the case because some instances of TB that were found to be resistant to BOTH of these new drugs in the lab have apparently been reported, although there is no evidence that we know of that these strains were particularly infectious.

This brings us to the ‘unknown’ aspect of this global health threat (one that is recognised by the WHO in its annual TB reports as an existing ‘crisis’ of its own but never split out as such as it could and should be). Exactly how infectious MDR-TB strains are compared to ‘ordinary’ TB is an ongoing uncertainty, and the fact is that no-one actually is sure about this. Some evidence suggests that it is significantly less infectious, while many experts contest that MDR-TB is generally as infectious and even, in some instances, more infectious than the local drug-susceptible strains. All evidence, meanwhile, suggests that, while the WHO is clear that this is a crisis (though not confident enough to declare it as the first AMR pandemic) it is intent on clinging to the former opinion.

The fact is that there are various regionally dominant strains of ‘ordinary’ TB, and the probability is that each is likely to develop its own infectivity profile once it has mutated to become resistant to those two strongest anti-TB drugs, which itself will be contingent on the relative susceptibility of the local population which itself varies as well. In other words, we can’t generalise.

But the fact is that the more successfully we control ‘ordinary TB’ the greater advantage we award MDR-TB even if it is less infectious – at least unless it is very non-infectious indeed.

So how much MDR-TB is currently out there?

We simply don’t know.

It has been estimated, however, that deaths from MDR-TB comprise one third of all AMR deaths which (if this estimate is correct) makes TB the most lethal current antimicrobial resistant pathogen, and further suggests it must kill about half a million a year which itself is about 30% of the total TB death toll.

The UK’s AMR Review (which we referenced in the second blog of this series) highlighted drug resistant tuberculosis as a 'cornerstone of the global AMR challenge', forecasting that one-quarter of the potential ten million annual AMR deaths by 2050 outlined in the report could by then be being caused by drug-resistant tuberculosis, which equates to a five-fold increase on today, or one MDR-TB death every 12 seconds.

Each year estimates of MDR disease incidence are trotted out in the WHO’s annual TB reports. For around a decade between 2006 and 2016 this number was increasing each year.

Since 2016, however, the number has been doing little in respect of change at all, stagnating at around half a million new cases each year (with a slight rise in the most recent report explained by the impact of COVID-19 on national MDR-TB programmes). Proportions of MDR-TB in relation to the numbers of ‘all’ TB cases (which in 2006 was estimated to be just under 5%) has also more recently stagnated at around 3-4% of new cases, and around 20% of elapsed cases. In other words, the proportion of TB that is drug-resistant is reckoned by the WHO to have reduced.

As you will already have realised, there are some odd anomalies here, not least that the official estimates suggest that these numbers of MDR-TB cases and their proportion are estimated to be effectively stagnating or even reducing.

So where’s the “crisis”?

Behind these anomalies lies an appalling paucity of surveillance data, unfortunately. Most MDR-TB is officially and consistently reported as occurring in India, China, Russia, South Africa and the former Soviet oblast states, with much less being reported where TB is reported in countries where there is as much or more 'ordinary' endemic TB.

There appears to be a clue here to our anomaly – because the first four countries listed above are also BRICS countries (only Brazil is missing) which definied as such because they are middle-income ones with growing economies. In other words, while they may still said to have ‘developing’ economies (and also still have significant endemic poverty) they are also classified as ‘middle-income’ countries and so have the capacity to find and treat at least a proportion of their MDR-TB cases. But even here the numbers aren’t dropping: they are stagnating.

Other lower income countries, meanwhile, report very little MDR-TB but, of course, have much less capacity to treat it, let alone find it first. What’s more, they show little official interest in doing so anyway for two reasons. One is because they lack the resource to respond to any demand they might expose; and another is that significant rates of MDR-TB inevitably expose a failing national TB programme (something which is historically recognised as having been a commonality in all of those four countries listed above back in the 1990s). No low-income country wants to risk its fragile international support by exposing existing weakness in its TB control when global support is so constrained.

Our bottom line is simple: we simply cannot compute the fact that MDR-TB was almost certainly increasing at pace in the first 15 years of this century with the reported stagnation of the last seven years. This is because there has been a poor treatment success rate (between 50 and 60% in this period) and a truly appalling case detection rate (which is only ever estimated, anyway, but which at best even now is reckoned to catch only one-in-three cases). This means that even today at least 5 out of every 6 MDR-TB cases remain infectious for the duration of their infection which is normally expected to last anywhere between two to three years dependant on other factors. And that proprtion has been as much as four times higher at some points in the last decade.

There are only two immediate possible explanations for this bizarre anomaly. One is that those earlier numerical estimations were wrong (which is possible); and the other is that more recent MDR-TB strains have become much less infectious than the earlier ones.

Both are certainly possible, but there’s a third possibility which is that the global health community is suffering from a drug-resistant case of myopia. We in Moxafrica comsider that we have good reason to believe that there is much more MDR-TB globally (and more extensively resistant strains as well) than is currently reported, and moreover that we face a slowly growing wave of MDR-TB that is going to be continuously concealed by rates of poverty increasing in the coming years, something which now appears an inevitability. Not only does poverty increase susceptibility to an infection like TB, an infection that is so contingent on compromised immunity in order to develop out of latency, but it will also mean that health ministries will generally struggle more and more and be unable to even contemplate considering the proportion of their endemic TB that is drug-resistant (whether it be to the older drugs or the new ones).

For some inexplicable reason, TB really does always seem to be ignored if it possibly can be. Only one-sixth of the Global Fund to Fight HIV, TB and Malaria has been being awarded to TB control for instance (when it should be awarded at least a third, but probably as much as half because now TB kills as many as the other two diseases combines).

This neglect was explained to us many years ago by a TB nursein Kampala. Politicians’ children can be bitten by a mosquito and made sick so they focus on malaria, she told us. Their own sexual activities mean that they are at risk of HIV so they focus on HIV as well, she added, but for these same poiuticians TB only exists in the slums where lives are expendable.

And it may even be worse than that. As the leading infectious AMR killer, MDR-TB has even been described as “the leading edge of the AMR challenge”, and yet it seems to be similarly ignored in the highest of circles: the WHO itself exposed what can be interpreted as its own institutional blind spot to MDR-TB in 2017 when it released its WHO Global Priority List of Antibiotic Resistant Bacteria, for which new antibiotics are urgently needed. Astonishingly this list of ‘priority pathogens’ didn’t include TB as an AMR infection when it was published, something that baffled and dismayed the entire world of TB, whether it be technical and implementation partners, researchers, donors, civil society, and, of course, most significantly of all, those people affected by TB and its drug-resistant strains. This omission was explained as being because MDR-TB was already being targeted by other ‘dedicated’ programmes though this explanation failed to satisfy most.

The question remains, in any case, as to exactly how dedicated is this programme for MDR-TB? We would certainly argue that it’s nowhere near dedicated enough which is a matter of grave concern, not just because of the ongoing uncertainties in respect of numbers and the missed targets (which again we've identified in earlier blogs), but maybe most importantly of all because of the following, on which note we will end this blog.

Drug-resistant TB is the only antimicrobial resistant infection that is airborne so is by any defnition the hardest AMR problem to contain.


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