World TB Day 2017 (3) - lighting up the world in red ('dream, mirage or nemesis' and the 'McKeown Thesis')

As usual, March 24th was World TB Day and this year the Stop TB Partnership literally wanted to see the world ‘lit up’ for TB – meaning that they wanted to see as many iconic buildings around the world illuminated in red during the evening hours.

Well, how could we (as one of STBP’s many partners) not respond to such a call? So we shortlisted a few iconic buildings in our neighbourhood here in the UK’s West Midlands, and we approached them all accordingly. We’ll spare you the list of those who either refused, wanted ridiculous sums of money, or didn’t bother responding at all, but we can record with real gratitude that one did respond to our approaches positively – and it was our local University. (This was especially meaningful to us because two of our seven trustees happen to be alumnis but there are other reasons as well which we’ll explain below).

The university’s clock-tower (affectionately known as ‘Old Joe’) is the highest free-standing clock-tower in the world. It’s also over a hundred years old, meaning that when it was originally built there was a lot of mycobacterium tuberculosis being coughed up in the streets and buildings of this city (the so-called ‘workshop of the world’ that was at the heart of the industrial revolution).

                          'Old Joe'

                          'Old Joe'

March 24th is commemorated because it was the day in 1882 when the TB bacterium was first identified by Robert Koch in Berlin. Germany’s industrial revolution had followed close behind the UK’s and levels of TB had followed suit. In the course of his famous presentation Koch reckoned that one in seven deaths in industrialising Europe at the time were down to TB.

Birmingham University, by the way, is currently actively investigating new treatments for anti-microbial resistant disease (about a third of which currently is tuberculosis) – so we knew that we had a neat convergence of interests at hand. But we were also aware of another connection that made the idea of Old Joe being lit up in red on World TB Day something to be truly relished – this related to Professor Thomas McKeown who was professor of social medicine at the university from 1945 until his retirement in 1977. Amongst many other contributions he made tothe field he is particularly remembered for a controversial lecture he (rather provocatively) titled The Role of Modern Medicine: Dream, Mirage or Nemesis. The reason we identified him in connection with ‘Old Joe’ was this: the thesis that the professor developed through his professional years (and which he specifically discussed in this famous lecture) tells us an awful lot about TB - not just about TB back in 1882 when Koch identified the bacillus, nor when ‘Old Joe’ was constructed brick-by-brick by labourers who would have been more than familiar with the disease, nor even about post-war TB in the UK - but about the global situation of TB today.

In fact we think that Professor McKeown would have been pleased to see the clock-tower lit up in red on World TB Day, and might even be identifying the same important connections that we do in the event.

The ‘McKeown Thesis’ (as it became known) proposed some fresh theories as to why there had been such a significant population increase in Europe beginning in the 19th century. Some of his ideas have been challenged and some endorsed since, but one of his theories still remains largely undisputed (although it’s popularly ignored). This was that ‘curative measures’ actually played little part on their own in mortality decline in England and Wales, not only prior to the mid-20th century but also well into its second half. And by ‘curative measures’ he meant drugs and vaccinations.

It should be noted that McKeown was far from blind to the social misery that had accompanied industrialisation, not least in his adopted Birmingham. Such misery included grinding poverty, overcrowded slum housing, appalling working conditions and foul drinking water – and yet despite such Dickensian conditions according to all available records the national population had significantly increased. This seemed illogical given the appalling conditions people were living and working in but, after ruling out any other plausible explanation, he figured out why it must have happened. He concluded that it was fundamentally because of one of the few virtues of early industrialisation – because of farm machinery which (at the same time as it was effectively renedering most of the rural labour-force redundant and driving them from the countryside to the burgeoning cities in search of work) was producing more and better food than had ever been previously seen or (more importantly) widely consumed.

This is what had provided the primary impact on mortality rates in the mid 19th century – it was improved immune systems arising from better nutrition which in turn were protecting the population from the effects of simple infections that normally could easily become complcated and lead to death - and when these benefits in immune systems were followed by better housing, clean water supplies, proper sewage and sanitation systems (along with legislation that improved working conditions), the curve of mortality was driven downwards dramatically.

What McKeown in particular proved from the available data was that mortality from infectious diseases was already significantly lower BEFORE any effective treatments or vaccinations were introduced into medical practice (and by ‘significantly lower’ we're relatively speaking meaning very low indeed). What this suggested to the professor (very much contrary to conventional wisdom) was that much of the medical advancement of the 20th century actually had an insignificant impact either on mortality or population growth – most particularly in relation to infectious disease.

He particularly used tuberculosis as an example of this phenomenon, quoting the falling TB mortality in England and Wales beginning in the mid-19th century. Back in 1850 it was at frightening levels, but this was still a century before the first effective drugs were developed and introduced, and 120 years before the vaccine was rolled out. The following graph illustrates what happened:

In fact by the time that the first drugs arrived (something which had been dreamed about by physicians for centuries) nearly 80% of the mortality rate was already historic. It’s been calculated in fact that TB drugs and the BCG vaccination together may have contributed as little as 3.2% to the massive mortality reduction from TB in England and Wales since the 19th century.

So what does this imply for tuberculosis today – or rather (in the glowing red light of ‘Old Joe’ on March 24th) what might the late Professor be telling the new Director General of the WHO today (he had been, after all, a consultant to the Organisation in the decades prior to it declaring TB to be a Global Emergency in 1993). Well, as the late Professor Stephen Lawn also pointed out, it means that if we’re serious about ending this monumental pandemic we actually need to eradicate global poverty, clear the slums, and house and feed the poorer people of our world much better – and then the drugs can clear up what’s left of the disease and the job will be done. At least that’s what the history of TB in the industrialised world tells us very loud and clear according to the McKeown Thesis.

We should add that we’re also sure that he wouldn’t for a second suggest that we should let up on the search for new and better treatments or for a better vaccine. We suspect, however, that he would be advising the DG that we shouldn’t fool ourselves into expecting that the results of such heroic efforts will make the impression we’d logically hope for. What was the title of his lecture, after all? 'Dream, Mirage or Nemesis...'

Well let’s never stop dreaming, but let’s also never stop working for a fairer world if we seriously intend to end the scourge of tuberculosis.

(‘Old Joe’ was in good company on March 24th, by the way. Sadly there was only one other building in the UK that got lit up [The Gateshead Millennium Bridge in Newcastle] but elsewhere there were some spectacular buildings or locations: the Statue of Christ the Redeemer in Rio de Janeiro, the Inca Temple of the Sun in Cuzco Peru, the Jet d’Eau in Geneva, the Niagara Falls in Canada, the Palacio de Cibeles in Madrid, the Terminal Tower in Cleveland Ohio and the Mazar-e-Quaid national mausoleum in Karachi amongst others. So thank you so much, Birmingham University, for being part of this global light show!)

World TB Day 2017 (2): Something serious doesn't add up in the WHO numbers...

As a tiny stakeholder in the battle against tuberculosis we’ve been monitoring the pandemic through the lens of the annual WHO Global TB Reports year on year. We have to confess that we often found them difficult to penetrate beyond their executive summaries. This year, however, we’ve identified what we think are some major and very serious anomalies. We’ve written twice to Dr Katherine Floyd (the Report’s lead author) to ask if either she or her colleagues could clarify them for us without reply. Given the disappointing lack of response, we’re concluding that the WHO is reluctant either to explain or explore them so (in both exasperation and despair) we now publish the principle issues we raised below only because we think that they imply something that is very serious indeed.

The issues both revolve around the numbers as reported in the recent Report (a report which effectively wound up the era running up to the end of 2015). Whilst they may not immediately seem that important because they're historical, they are actually still of live concern because of how they inevitably impact on how these same numbers are going to be reported in the coming five, ten, fifteen and twenty years (which will, of course, be vital in terms of how we fare globally with this disease).

A summary of our observations

1. By the Report’s own definitions, the way that the 2015 Target of reducing the global death rate was reported (by comparing a 2015 estimated death rate to that of 1990) was not valid (to the extent that reasonable conclusions relating to the Targets that were set for 2015 could not  drawn).

2. Notwithstanding this, in the latest Report two of the main graphs are incoherent with each other and data within them have been misrepresented. Furthermore the published non-HIV death rate of 15/100,000 is demonstrably wrong (it is actually 19/100,000) and this in turn means that the reduction in non-HIV death rate can be nowhere near 50% as is claimed.

3. There are no baselines yet set for 2015 and, given the ongoing improvement in surveillance, it looks like any new baselines will have to be subject to continuing retrospective re-adjustment throughout the post-2015 period. This hasn’t been done up to now in respect of the 2015 Targets (which is why they are invalid) but having to do so now is going to make things extremely confusing throughout the post-2015 period specifically in terms of how the data can be monitored by those who have most at stake in them.

4. There are also inevitable implications from this for both the World Health Assembly (WHA) and the UN, and also, of course, for the new Director General of the WHO when he/she is in post. We remain unconvinced that these major game-players are truly alert to these complexities as they need to be. 

An explanation of these serious issues follows.


The Graphs

We took a quick overview of the summaries in this new 2016 Report, and particularly we took a look at the main graphs. Initially we noted that they largely followed the same vein as the years before and also accorded with the summary of the new Report which said that “the number of TB deaths and the TB incidence rate continue to fall globally”. This was further qualified by the Report’s statement that the “estimated trends in TB incidence and mortality remain similar to those published in previous years, with incidence falling by 2% per year over 2000–2015 and mortality falling by 3.3% per year over the same period.”

Of course, because it wasn’t concealed, we’d also spotted the fact that the reported estimated death toll had shot up this year by a third of a million and that the estimated number of new cases of disease had shot up by 800,000 as well. Clearly things weren’t as simple as they sounded and we realised though that these diverse statements deserved further examination.

In fact the Report appeared to be both explicit and coy at the same time on these extra numbers: “the [2016] report shows that the TB burden is actually higher than previously estimated, reflecting new surveillance and survey data from India” it explained. But in all respects the vitally important overall trends were still being reported to be in decline – we could even confirm this from the graph of trends of rates of disease 1990-2015, one of which showed that the non-HIV death rate had dropped by about 48% (as had been predicted in previous Reports), importantly adding up to the 2015 Target nearly being met. What’s more we noted that there was no visible up-kick in the graph reflecting the newly estimated 300,000 extra deaths – which we recognised meant that the line in the graph must have been generally shifted upwards in its entirety since the previous Report.   

So far, so good. We also noted, however, that several respected commentators read the Report in a less positive way – specifically identifying that the number of people dying of TB was “growing”. But what, we wondered, about the Report’s executive summary that states so so explicitly that mortality was still falling during 2015 at 3.3% a year? So we took a look at the second main graph that focused on the one depicting mortality numbers (not this time the rates per 100,000 population). Again we could see no visible up-kick in the graph for the most recent year on record (for 2015): in other words, according to the Report both the death rate AND the numbers were still falling so the declining lines in both graphs must have been adjusted upwards to allow for this along with the extra numbers.

Of course we were also well aware of the usual small print at the bottom of this graphic that this “excludes TB deaths among HIV-positive people" (so the graph doesn’t in any case include every estimated TB mortality) but, notwithstanding this, it did seem reasonable to try to figure out exactly where those extra 300,000 deaths were in the graph. What follows is the result of our investigation.

Absolute numbers and the 1990 baseline

Before explaining further, we should add that we also noted something else: whilst the first graph goes back to 1990 (the baseline for the 2015 Targets) this second graph of absolute numbers only covers the period 2000-2015. As such we realised that the Report effectively leaves us in the dark about the actual numerical death toll that must have originally been estimated for 1990. What we COULD be sure about, however, (in spite of the downward trend in mortality rates in the first graph) was that annual numerical deaths had been rising from 1990 right through to around 2005 when (at least according to the most recent estimate in the graph above) they are now believed to have peaked when running at somewhere around 2.2 million a year.

We turned to the WHO Reports from 1997-2002 for further help (the ones which reported on data from the year 2000 and before) but unfortunately we couldn't find anything in them to enlighten us about that original 1990 death toll either. This was simply because the estimated annual death tolls from TB weren’t published in the annual Reports until 2005 because (we assume) of the paucity of available data. But at least in the following year’s Report (i.e. the one for 2006) we finally found the original baseline death rate for 1990 identified, which was 29/100,000.

The estimated death tolls for 2015 and what appears to be a serious mistake in the graphs

But we were still left wondering about HOW MANY people were estimated to have been dying from TB back in 1990. We could see that this wasn't identified because prior to 2005 they weren’t being estimated, but we realised that it would still be possible to figure this out by using the death rate that was pegged for 1990 that year (i.e. 29/100,000) and then computing it against the global population for the same year. So we ended up drawing up a rough table to help illustrate this for ourselves and (as can be seen below) we realised that this not only made for more confusion, it created some very significant disquiet about the current estimates and how they are being represented, not least because there now appeared to be a major error in the first graph above.

First we established that the global population in 1990 was estimated to be 5.28 billion which made the numerical non-HIV TB death toll 1.53 million at the quoted death rate of 29/100,000. Today the non-HIV TB numerical death toll is estimated to be 1.4 million, so the absolute number of non-HIV deaths can be deduced to have reduced by only 9% (1.53 million down to 1.4 million) between 1990 and today. But that was far from the end of it as we'll explain immediately.

This was because in the course of figuring this out something significant jumped out that hadn’t been visible at all, at least as far as we could see, within the 2016 Report itself.

The death rate for 2015 is reported/estimated to have been 15/100,000 (making for that supposed 48% reduction). On a whim we decided to compute this against the population estimate of 7.3 billion for 2015 in exactly the same way that we’d just done for 1990, and we found that this makes for a calculated death toll of 1.1 million. But the Report had categorically pegged the non-HIV death toll from TB at 1.4 million! We double checked, and realised that these two estimates, both drawn directly from the Report’s own data, are simply incoherent with each other.  In fact they are out by 300,000 and we realised that we’d stumbled across those extra deaths, and that they weren’t actually being shown in one of the graphs.

We think that this comprises a major and misleading error..

Try as we could, we could see no other explanation of the discrepancy, but in trying to explain it to ourselves, we also realised that there were several other observations which can be reasonably made from our little table – all of which are, we think, are of sufficient public concern for them to need to be published.

1.       The published reduction in non-HIV TB death rates (29/100,000 -> 15/100,000) may add up to a decrease of 48% but during this same period there appears to be a 12.5% increase in the OVERALL annual death toll (from 1.6 million [see note 3 below] to 1.8 million). We realise, however, that while this might at first appear to be gobbledygook, it should be borne in mind that there have been substantial population growths in many high burden countries which at least explains some of this (and of course also a lot of HIV/AIDS).

2.       Then we figured out with some simple maths that a non-HIV death toll of 1.4 million in a population of 7.3 million actually makes for a death rate of 19/100,000, which is not really that close to 15/100,000 at all. So why, we now ask, was this re-estimation not shown in the graph that relates directly to one of the Targets set for 2015? According to our table this means that it looks like the death rate can only be claimed to have reduced by 38% and not by 48% (the latter percentage looking much closer to that 50% MDG Target that is still been reported in this latest Report to have been nearly achieved). At the very least these are significant anomalies that need further explanation.

3.       We also know that 1990 saw the HIV pandemic still very much in its infancy. According to UNAIDS data there were estimated to be 300,000 HIV-associated deaths worldwide in that year. We quickly figured out that if 25% of them actually died of TB (which might be a reasonable percentage based on later data) then 75,000 deaths needed to be added to our 1990 non-HIV death toll of 1.53 million which we’d just calculated – which made 1.6 million as our own total ‘all TB’ death toll for 1990. Since the current death toll is pegged at 1.8 million, this in turn suggests that the TOTAL absolute number of annual TB deaths may have increased by 12.5% during the period 1990-2015 that was governed by the Millennium targets. This surely shows how poorly the HIV-TB syndemic was managed in the early years - but since the post-2015 targets for mortality now demand reductions of ABSOLUTE NUMBERS of all TB deaths it surely also tells us (if any of us were still under any illusion) how immensely challenging meeting these targets is going to be.

4.       And once we'd included these HIV/TB deaths in the totals (i.e. 1.8 million deaths as per the most recent Report) the current overall TB death rate looks to be nearly 25/100,000 making for a rather paltry reduction of just 14% in the overall death rate for TB for the total period of 1990-2015. It occurs to us that this sort of insignificant reduction really deserved to be reported alongside that of non-HIV deaths because of the impact it must inevitably have on the post-2015 period and its targets.

5.       We also noted (again using UNAIDS data) that there were 1.5 million HIV deaths in 2000. Using our previous estimated percentage of 25% of these actually dying from tuberculosis, this made for a possible 2.1 million total all-TB’ deaths during 2000 so this is what we added into the table above in order to complete it. It may not be accurate but it certainly didn’t make it look incoherent.

6.        Finally we made a quick check of the estimated reductions in each of the ‘Big Three’ infectious killers in this period 2000-2015 (HIV, malaria and TB). The numbers of new HIV infections dropped by 32 percent, and the number of HIV deaths declined by 31 percent. Malaria infections dropped by 18 percent, and deaths by 48 percent. New cases of TB, meanwhile, appear to have only globally dropped by about 1 percent, and deaths — when not including the numbers of tuberculosis-related deaths among people with HIV — only fell by 22 percent, while ‘all-TB’ deaths only fell 14%. In other words TB has very much emerged as the biggest of the big three at the end of the 2015 era, and we feel that this surely should have been reported as it is a matter of such grave concern to us all.


Reductions between 2000 and 2015             Deaths           New cases

Malaria                                                               48%                 18%

HIV                                                                     31%                  32%

TB                                                                       14%                   1%

If these rough calculations are remotely correct, it occurs to us that all of these findings shouldn’t just be in the public domain, they should also be particularly in both the hands and minds of those in the World Assembly and the UN (and also the new Director General) who all have the influence to make the very necessary changes to the battle against this pandemic in the next couple of years.


The difference between 2000-2015 time period and the one before it and the (in)validity of direct comparisons

We also noticed something else, however. We saw that this same baseline 1990 death-rate of 29/100,000 is also indicated in the current Report's graph (above) for 2015 – something which contrats with all of the subsequent retro-calculations that have been historically re-estimating the numbers..

Since this original 1990 death rate of 29/100,000 is exactly the same as the rate that appears in the current graph (the current one computed for 2015), and given that this rate has been in all the Reports since 2005, we realised that not everything can have been subjected to retro-calculation in these Reports as one might have expected. In fact the evidence suggested that the 1990 baseline (and quite possibly the entire data for the whole period 1990-1999) has actually NEVER been retro-calculated while almost everything since the year 2000 has been. We then homed in on a small-print disclaimer in the Report that (as we read it) implies that it should be assumed that no retro-calculation has ever been attempted or applied for any data prior to 2000:

“The updates can affect the entire time-series back to 2000. Therefore, estimates presented in this chapter for 2000−2014 supersede those of previous reports, and direct comparisons (e.g.between the 2014 estimates in this report and the 2014 estimates in the previous report) are not appropriate.”

This may all sound like a load of unimportant semantics to most readers of these reports but this disclaimer, while it may explain one anomaly, surely creates another which we believe is a very big deal indeed. This is because if “direct comparisons” aren’t appropriate between Reports (which is what the above disclaimer avers), then the same thing applies to any claims being made relating to the Goals to 2015 because they DIRECTLY compare current data (ones which have been adjusted based on better surveillance and now supersede all previous) with data from the 1990s which have never been retro-calculated nor superseded.

As such, in the Report’s own words (and by its own definitions) any comparisons made between data from 1990 and 2015 and any claims made about them cannot be deemed to be “appropriate”. In turn this suggests that all the reporting that’s been made in relation to meeting these targets has been questionable if not meaningless. This was a shocking conclusion for us to have drawn.

But there were now some other things that weren’t adding up as well. We still couldn't completely resolve, for instance, how (according to this Report) things seemed to be both deteriorating and improving at the same time.

More on the 1990 baseline

First of all, 1990 was both previous to and outside of the current time line series of 2015 back to 2000 (the time line which the Report states is subject to re-adjustments). As such it might seem to be reasonable to argue that it’s exempt from adjustment, but the truth is that the 2015 Targets (and thus the death rate for 1990) were actually set in 2005. As such it must have been set with the available data and intelligence from that year (i.e. from data available within the 2000-2015 period). This means (at least it does to us!) that despite the fact that 1990 is outside the 2000-2015 period, the estimated 1990 death rate is implicitly still a component part of the current time line series and so could (and should) have been re-adjusted and superseded in the same way as all the other post-2000 data have been. 

The bottom line is that a set of goal posts at one end appear to have been moved regularly, while the one at the other hasn’t been moved at all.

Of course we also appreciate the enormous challenges that are faced by those compiling the Reports. We can’t help but conclude, however, that the disclaimer that states that each Report supersedes all previous ones has effectively made any assessment of any real progress in defeating this disease by the rest of the world difficult if not impossible. By not moving any goal posts from the period 1990-1999 it makes any assessment of the Millennium targets (including when done by the WHO itself in its Reports) a very tentative endeavour indeed - if not worthless. We can't help but wonder, moreover, whether anyone of those 192 signatories in the World Health Assembly was aware of this two years ago when they all signed up to the Post-2015 targets. In other words, do the play makers who’ve signed up to this deadly 'game' really have any ral idea about its true realities in terms of what does or doesn’t get adjusted as we go along?


World TB Day 2017 (1) -

In 1917, exactly one hundred years ago, a London-based physician called out his native country on tuberculosis[1]:

“As long as apathy, arrogance, ignorance and indifference endure, so surely will tuberculosis claim its hourly victims,” he railed.

Tragically these same words can still be applied to TB today. Apathy is out there in spades along with undeniable and unacceptable arrogance in some quarters. And there’s no question that both ignorance and indifference prevail as well. So has NOTHING changed in the world of TB in the last hundred years?

Well, one thing has done – it’s certainly changed here in the UK. Back in 1917 when Dr Halliday Sutherland made his impassioned speech it was reckoned that one in every eight people were dying of TB in the UK. Today this rate is roughly one in every 2,200.

So what would Dr Sutherland be making of today’s pandemic, given that its victims are not being counted “hourly” as he did in his speech, but rather by minutes and even seconds (one TB death occurs roughly every 15 seconds)?

We suspect he’d be outraged. History here in the UK proves beyond doubt that TB CAN be driven into the gutter by medicine when it’s accompanied by effort commitment to social change. A century ago he identified that “modern medicine [had] … found the cause, sources and cure of this disease” so he’d surely now be asking why the hell a century later we’ve so abjectly failed to defeat it yet. In fact he as good as nailed it in 1917 identifying that:

“… man and man alone has created the conditions under which it may arise, spread and destroy.”

In other words it’s humanity itself (or perhaps more accurately our lack of humanity) that has allowed this disease to thrive in our globalised world right under our noses in spite of a vaccine and a set of drugs that plainly worked in the UK.

He also stated in his speech that prior to the 1914-18 war TB had been creating “one-eleventh of the total pauperism in England and Wales”.  Today Archbishop Tutu is saying much the same thing, pointing out that TB is not just the awful child of poverty, it is also both its parent and provider.

Dare we suggest it, but that appalling  one-eleventh factor for impoverishment might well be even higher today in some middle- and low-income countries – that is if anyone cared or dared to measure it.

But they won’t, will they, exactly because of those same four apocalyptic etiological horses - “apathy, arrogance, ignorance and indifference”.




WHO's response to our letter

In our last blog we published the letter we wrote to Dr Matteo Zignol of the WHO in response to a letter which he wrote to the Guardian dismissing a study of MDR-TB prevalence in West Africa (conducted in eight countries) as being "unhelpful" and "misleading" without any real substantiation.

Given the fact that there is very clearly an MDR-TB problem in the region (indeed the estimated rate of MDR-TB in Nigeria rose 20% in a single year in the most recent WHO Global TB Repor) his letter disturbed us enough that we decided it would be right to publish our letter to him (which, of course we advised him of). He recently responded, our letter having somehow  got lost at its first sending.

We publish his response in full below. It's not a response, unfortunately, which has satisfied our concerns although we very much appreciate his efforts to explain his original letter. Regrettably we still don't understand why he found the study to be so unhelpful and misleading - enough to have written to the Guardian newspaper. We have therefore responded explaining our continuing concerns. Meanwhile we publish his letter in full for your own assessment.

Dear Mr Young,

For some reasons I don’t seem to have a record of your previous message. Thanks for the reminder and sorry for the inconvenience.

 I fully share your concerns re. the lack of data on the magnitude of the problem of drug-resistant tuberculosis in Western Africa.

The point I wanted to make with my letter is very simple: the conclusions put forward by the authors of the study and reported by the journal (” West African drug-resistance prevalence poses a previously underestimated, yet serious public health threat, and our estimates obtained differ significantly from previous World Health Organisation (WHO) estimates. Therefore, our data are reshaping current concepts and are essential in informing WHO and public health strategists to implement urgently needed surveillance and control interventions in West Africa.”) are not supported by the study design and therefore are misleading.

I think everyone understands that results of a study conducted in selected national TB referral centers cannot be extrapolated to entire countries. It is well known from evidence from all over the world that in hospital settings and health referral centres, levels of resistance to anti-tuberculosis drugs are significantly higher than those found in a nationally representative surveys of TB patients. A proper understanding of the epidemiology of drug resistance in tuberculosis in a country can only be achieved through well designed population-based surveys or routine surveillance among all TB patients.

 As you know WHO updates country-level estimates of the burden of TB and drug-resistant TB every year as soon as new evidence becomes available. Unfortunately the results of this study are not helpful in this regard. In this region population-based national surveys are currently ongoing in Burkina Faso, Ghana, Ivory coast and a survey will soon start in Togo.  These efforts are clearly not enough but will surly contribute to a better understanding of the magnitude of the problem of drug-resistant TB in these countries.

 Best regards,

 Matteo Zignol

A letter to the World Health Organisation

Dear Dr Zignol ~

I write with reference to your letter to the Guardian of November 7th. You will recall, I’m sure, that you wrote in relation to a study that was recently carried out in West Africa by the West African Network of Excellence for TB, Aids and Malaria and which was reported by the Guardian on 3rd November. Your letter made it clear that you considered the “claims” which you reckoned the study had made to be “misleading and unhelpful”. Given the perilous state of the drug-resistant TB epidemic in the African region we took careful note of your comments and have equally carefully reviewed them in the light of the study itself. Unfortunately we have  concluded that it was actually your letter which may have been misleading, and not the study.

We have decided to explain our misgivings to you and invite your further engagement on the matter. We are copying this letter to Sarah Boseley, the journalist who wrote the original piece, and we are also publishing it on the blog page of our website because we consider this wider topic to be a matter of immense public concernwhich is still not being given the attention it deserves. As such we will welcome your response at your convenience, and in anticipation of this we also advise you that we will publish it on the same blog page for wider public consumption.

At first we wondered whether your letter might have simply been written in direct response to the journalist, i.e. you may have been challenging her journalism for not properly reflecting the study itself. After careful consideration, however, we don’t believe this to have been the case because you didn’t specifically call into question what the journalist wrote. What you did appear to call into question were the “claims” (a word which you used twice) that were apparently being made that rates of MDR-TB in West Africa are currently higher than WHO estimates; in other words you were challenging the actual content of the study.

Given that the estimates of the rates of MDR-TB for the African region generally are still being calculated to be below the global average (when we consider that the opposite is far more likely) we find such a conclusion to be a significant public health concern. We know, for instance, that TB epidemics thrive on weaker health infrastructures, and that weak health infrastructures in turn almost inevitably spawn MDR outbreaks in the course of time because of what will have been an anticipatable poor management of first line drugs. Our own view is that the African TB epidemic must be considered as such - to have a strong probability of having a significant proportion of MDR within it, with or without the benefit of any national surveys that may in any case be beyond local resource to conduct without immense outside help. Furthermore, the fact that HIV is considered by the WHO to be a risk factor for MDR development (as witnessed by its 2010 ‘strong recommendation’ for GeneXpert to be used to test for Rifampicin resistance in all co-infected patients) must surely only amplify this probability. As such we have been consistently baffled by the continuing low estimates of MDR-TB for the African region and are worried by the consequent lack of resource for the region to contain MDR-TB because we believe that they fly in the face of what should be the implementation of judiciously implemented precautionary principles to protect those most at risk of this disease.

But to return to your letter to the Guardian: you specifically stated that the study was claiming that “multidrug-resistant TB (MDR-TB) rates in west Africa ARE actually higher than estimates published by the World Health Organisation”. You then concluded that these claims “ARE both misleading and unhelpful” because there is a lack of epidemiological evidence for them. We have capitalised the word ‘are’ in both instances in order to emphasise its use since we are deeply concerned by what its employment seems to reveal. We would go so far as to suggest that the use of the word ‘are’ in this context may actually render your own letter, and not what you describe as the study’s claims, to be misleading or unhelpful (or possibly both).

In fact after evaluating the text of the study itself we could find no such categorical claims being made as your letter described. Rather we found suggestions, and we underline them accordingly for you in the following extracts. The authors of the study were “highlighting the possibility that drug resistance in West Africa is currently underestimated”. They further added that “the situation appears especially alarming in Nigeria”. They reasoned that “the presented MDR data … indicate that the drug-resistant problem in West Africa may be greater than currently assumed,” and concluded that “drug resistant TB could become a serious public health problem in West Africa if required control measures are not taken”. Could you help us understand what exactly caused you to react so negatively to what seemed a quite reasonable study which seemed to draw quite reasonable suppositions from the data it revealed?

 Of course there were indeed some limitations to the study as your letter intimated, but actually these were adequately identified by the authors in the study itself. Certainly they didn’t seem to warrant such outright dismissal of the study as you made in your letter.

In fact even the Guardian (while its choice of wording may have been less judiciously chosen - it’s a newspaper after all and not a scientific journal), was hardly guilty of sensationalising the study. It in turn only reported that the study was “suggesting” that the seriousness of the epidemic had been “considerably underestimated”.

(We can identify only one significant inaccuracy, in fact, in the Guardian report  - that XDR-TB has been found in new cases in both Togo and Ghana, when in fact these strains were actually pre-XDR.)

We did take some comfort from your observation that “west Africa remains a part of the world where MDR-TB surveillance data are most lacking”, particularly when we considered this alongside the study’s own conclusion that there is “an urgent need for country wide drug resistant surveys according to WHO guidelines”. But your letter doesn’t seem to draw this same secondary conclusion – in fact it seemed to us to do the opposite by implying that without any visible substantiation the rates of MDR-TB in the region may not even be on the rise at all so no survey would appear to be necessary. Why, otherwise, would this study have seemed to you to be so “unhelpful”?

The real problem is that so little has been done to facilitate better surveillance of MDR-TB for the region. You very rightly stressed in your letter that the collection of data is vitally important for all diseases, but I’m afraid that we found ourselves deeply troubled when you followed this by stating that “WHO estimates on MDR-TB are based exclusively on population-based surveys, such as those recently conducted in Nigeria and Senegal”.

First of all, we believe that this statement is misleading if not factually incorrect – at best WHO MDR estimates for the African region are based on surveys that are sometimes years out of date, or on single surveys from which trends cannot be evaluated, if any exist at all. In fact of the eight West African countries included in the study in question only two (Nigeria in 2010 and Senegal in 2014) have ever conducted an MDR study which surveyed both new and retreatment cases.

We can’t help adding a further observation in relation to South Africa, however, which may well reflect on the general assessment of MDR-TB in the whole of the region as well as on your statement that estimates are based so exclusively on population-based surveys. Until this year the published estimates for South Africa as published in WHO Reports  have been based on a survey that was completed back in 2002 meaning that it has been hopelessly out of date for years: the trouble was that this population based survey was used in the WHO’s own Reports without any attempts at adjustment  meaning that published estimated incident numbers of MDR cases for South Africa were year on year significantly less than the actual cases that were being notified each year to the national TB program (which I think all of us agree is an impossibility). This anomaly even now appears to have bizarrely lingered on into the current Report, despite a new DR Survey having been completed in 2014. The estimated number of MDR/RR-TB cases being quoted in the current WHO Global Report amongst pulmonary cases notified in 2015 was 10,000, whilst elsewhere the estimated numerical incidence of MDR/RRTB was suggested to be 20,000. Meanwhile the number of laboratory confirmed cases was over 20,000 (at 68% CDR this would suggest a more probable estimated incidence of MDR of around 30,000) and the number of cases started in second line treatment was over 13,000. These sorts of obfuscations (which of course in turn are being used to build a wider picture of the African MDR-TB epidemic) isn’t new and can hardly help to build any sort of true picture of the African epidemic as the crisis deserves.

Secondly, the reference you made to the 2010 Nigerian MDR prevalence survey should surely only amplify our collective concern and not reduce it. You will recall, I am sure, that the 2012 Nigerian TB prevalence Survey revealed five times the amount of prevalent sputum positive TB than was notified that same year to the Nigerian NTP (nearly half of which wasn’t sputum positive anyway). This meant that the following WHO Global Report in 2013 hiked the Nigerian prevalence rates by over 100%, incidence rates by over 200% and mortality rates by over 400%, with the regional rates for Africa hiked by 4%, 12%, and 44% respectively as well. The Case Detection Rate for Nigeria meanwhile was reduced from 51% to a terrifying 16% at a stroke. Whether not these hikes were accurate is beside the point; the point is that even in an HBC country like Nigeria, where expert opinion should be expected to be at least somewhere near the button (if not actually on it), a national prevalence survey can render previous estimates deduced with the help of expert opinion to be in an instant appallingly inaccurate. This 2012 survey doesn’t only show that TB estimates, even of drug-susceptible TB, can be terribly underestimated twenty odd years into a Global emergency, it also suggests the possibility that this could occur as easily in West Africa as anywhere. That 2012 Survey effectively suggested that the prevalent amount of sputum-positive TB might have been as much as ten times more than was being notified into the system in the course of that same year. The Guardian report was only suggesting that the rates of MDR-TB for West Africa might be three times higher (though that’s worrying enough if it’s near the truth)!

In the light of these considerations, surely it’s entirely reasonable for the authors of this study to have hypothesised, based on its findings, that the true levels of MDR-TB might just be higher than the WHO estimates? Might not a full prevalence survey of MDR-TB for the region reveal such an epidemiological underestimation? The truth is, of course, that we simply don’t know how much MDR-TB there is in West Africa and we will only ever know, of course, if a wider survey or surveys are conducted as they should be. Surely this study wasn’t in any way “unhelpful” in respect of encouraging this to happen, is it? In our view it is quite the opposite.

In conclusion your letter leaves us both confused and concerned because these uncertainties leave so many lives are at risk. 

 We are left very seriously wondering whether the WHO is yet taking the threat of MDR-TB to the African region as seriously as it could and should do. Furthermore we find ourselves fully agreeing with the study’s authors’ conclusions that “efforts [should] be put in place for containment of a potential west African TB epidemic at the earliest possible stage … as west Africa, with its 245 million inhabitants, is one of the poorest regions globally, whose fragile health systems can easily be overwhelmed by infectious disease epidemics, as seen in the recent Ebola outbreak.” It’s no secret that the WHO itself recently came under considerable criticism for its tardiness in responding to the Ebola outbreak in the same region. It would surely be a far larger tragedy if we are witnessing the same thing happening with MDR-TB at a much larger scale in slow-mo.

 This isn’t just the responsibility of the WHO, of course, it’s also the responsibility of regional governments and donor nations, exactly as was identified in the Guardian piece when Ms Boseley quoted Professor Antonio, the principal investigator at the Medical Research Council unit in the Gambia who said that this study was “a wake-up call for the ministries of health and the governments to take MDR-TB seriously.”

 It must surely be the responsibility of the WHO, however, to take a positive and proactive leadership role in this process.

 We look forward to receiving your comments on the above, and will welcome corrections if or where we have made any misleading or inaccurate representations ourselves.

 Merlin Young

Chair and Co-founder - Moxafrica.

‘The time has come to move TB to centre stage’ – but what’s happening in India?

The UN has only ever previously called summits on health issues for three reasons: HIV, Ebola, and widespread chronic diseases (which essentially means diabetes). This week has been the fourth, with the UN hosting a panel discussion and making a resolution regarding the growing global threat from AMR or anti-microbial resistance – or the disquieting ability of microbes to morph and mutate to make themselves immune to assaults by the drugs meticulously developed to kill them.

Within the resolution itself there is an important reference to tuberculosis: “Within the broader context of AMR, resistance to antibiotics which are not like other medicines, including medicines for the treatment of tuberculosis, is the greatest and most urgent global risk that requires increased attention and coherence at the international, regional, and national levels.”

So far so good, because anti-miocrobial resistance (with MDR- and XDR-TB very much acting as its vanguard) unquestionably poses a major health risk worldwide. We have already recorded our concerns, however, that this threat is still being dangerously numerically underestimated, but whilst Dr David Nabarro, the UN Special Advisor on the 2030 Agenda for Sustainable Development,might well not agree with some of our calculations, we certainly would agree with his own observation that “Multi-drug resistant TB needs to be high on the global antimicrobial resistance agenda as we discuss these issues at the upcoming United Nations high-level meeting.”

We’d go further, though, and line up behind South African Health Minister and Chair of the Stop TB Partnership Aaron Motsoaledi who has proclaimed that, “The time has come to move TB to the centre of the stage”. He reckons that this week’s summit should be seen as only a first step towards doing this: “A United Nations High-Level Meeting devoted [entirely] to TB in 2017 is an important way to do this and to reframe TB from simply a technical health problem, to a global development challenge requiring a whole of society response.”

The true enormity of this challenge (as well as its urgency), however, has been highlighted by two separate papers which have been recently published in the Lancet. Both concern the management of TB in India, a country estimated to have as much as one quarter of the global burden of the disease, as well as what is reckoned by many experts to be MDR- and XDR-TB problems that are already well out of control.

(photo by James Nachtwey)

(photo by James Nachtwey)

The first study[1], led by Nim Pathy of Imperial College London and funded by the Gates Foundation, fundamentally challenges the estimate of tuberculosis in the country, calculating that the total number of patients receiving TB treatment in India in 2014 wasn’t 2.2 million (as per the most recent WHO Report), but was much more probably at least 3.6 million. Put another way, the WHO estimated that 800,000 cases of TB were missed by the Indian National TB programme (RNTCP) in 2014 (which is surely bad enough), but this study puts this missing number at 2.2 million (i.e. a case detection rate of just 44% instead of an officially suggested 74%). And this number doesn't include those who just weren't treated at all. If this study is right then this in turn adds up to more than two million infectious cases who weren’t properly treated in 2014, many of whom will have remained infectious, and a proportion of whom will inevitably have become drug-resistant because of partially completed treatment. (This is no fantasy – the study calculated that the average length of time of the treatments which were conducted in the private sector was only four months’ duration – two months short of the WHO requirement.) It surely suggests a TB programme that is dramatically failing the nation.

Compute the study’s conclusions into the global numbers and it doesn’t make for very cheery reading at all for those tasked with bringing the numbers down either. Current global ‘new case’ estimates of TB incidence run at 9.6 million a year; if this current study is correct in its conclusions, then the global incident rate is actually running at 11 million (globally a 15% hike at a stroke). Meanwhile according to the WHO the current global estimate of missed cases runs at 3.6 million – but this study’s estimate hikes this number up to over 4.4 million (or at least four out of every ten TB cases worldwide). Meanwhile God alone knows what this might be doing to the annual death toll…

The team reached their conclusions by analysing the nationwide sale of anti-tuberculosis drugs which occurred nationally across the private sector in India in the course of 2014 (sales which legally have to be recorded and reported, which amounted to almost 18 million patient months of treatment). They then allowed a generous deduction for TB drugs which would have been probably mis-prescribed to patients who wouldn’t have had TB at all (they cut these reported numbers by half), and then coupled this number up with the number of known notified treatments made by the national TB programme (RNTCP) to come up with a grand total of estimated incident cases of TB – amounting to 3.6 million instead of 2.2 million.

It’s tempting to point the finger at India’s huge informal health sector as being responsible for what is such a truly immense consumption of tuberculosis drugs (half of which, or 9 million patient months’ worth, is believed by the study team to be straightforward misuse which of course itself will increase rates of anti-microbial resistance). The second study, however, (which we’ll come to in a minute) shows quite clearly that anti-tuberculosis drugs are actually very rarely dispensed by the sector’s other operatives – by its pharmacists, informal health providers, and practitioners of alternative medical systems. In fact it’s fully qualified, allopathic doctors who are the primary source of these anti-tuberculosis drug sales, and should surely thus be the immediate and well overdue target of far more proactive engagement to ensure better antimicrobial stewardship if this week’s UN resolution stands a prayer of adding up to anything.

Unfortunately, this first study’s numerical conclusions are almost certainly an underestimate anyway, because there are also several types of TB patient that this data didn’t capture at all. There are those who must indeed be receiving treatment for tuberculosis in the more informal health-care sector (of whom there are bound to be many); there are those who for many reasons don’t ever contact the health-care system at all (the number of whom is certain to be substantial); and there are also those who receive very risky treatment for multidrug-resistant tuberculosis in the private sector (a number which is known to be growing and which is surely the most frightening of all since it’s already been well recognised that these are the worst served and can easily stoke community rates of untreatable XDR-TB). Taken together, these factors would suggest that the true burden of tuberculosis in India is probably even greater than what is suggested in this paper.

What’s of additional concern is surely this, though– why on earth are TB patients resorting in such droves to the private sector of India’s health system and paying for this dubious privilege when TB drugs are free at point of care in this country? Can the public sector really be so appallingly bad? India’s RNTCP, after all, is fully committed to providing free high-quality tuberculosis care to patients in the private sector as well as the public one. (See: Sachdeva et al. New vision for Revised National Tuberculosis Control Programme(RNTCP): universal access—“Reaching the Un-reached”. Indian Journal of Medical Research 2012; 135: 690–94).

If a 6-month course of first-line TB drugs costs US$20, this first Lancet paper implies (quite incredibly) that nearly US$60 million was spent in out-of-pocket expenditure on first-line tuberculosis drugs by Indian TB patients (forget consultation charges) – by a patient group that is already well-recognised to be the most vulnerable to this disease because of their poor economic status.

Something has clearly been going drastically wrong with India’s TB programme and it’s been going on for years right under the global authorities’ noses.

Well, so far we’re pointing our finger towards India’s doctors, many of whom seem happy to ignore WHO recommendations and take money that they shouldn’t do from their patients. So what about this great nation’s pharmacists – how do they hold up to scrutiny in this respect?

This question is a valid one because many tuberculosis patients in India seek both medical advice and drugs from their nearest pharmacies, understandably so because of ease of access and the chance of avoiding the doctors’ consultation charges by doing so.  Unfortunately, it looks like this sector of health care is also sorrily suspect as regards of promoting AMR, though for other reasons. Certainly this is the case as far as the second paper is concerned.

This second study[2], conducted by a team led by Srinath Satyanarayana (of McGill University, Canada), mobilised a group of standardized patients (otherwise called ‘simulated’ or ‘mystery patients’) to reveal how pharmacies in three Indian cities respond to members of the public who might present to them either with TB symptoms or with clinical TB diagnoses, and thus determine whether or not these pharmacies are contributing to the inappropriate use of antibiotics.

These 1200 ‘mystery patients’ presented themselves in 622 pharmacies in Mumbai, Chennai and Pathna in 2014-15. They split into two categories, either reporting symptoms which should immediately have alerted the dispensing pharmacist that the person in front of them had a high probability of having active TB, or alternatively presenting them with evidence of bacteriological confirmation of TB diagnosis (in other words leaving no doubt at all about it). In either case, if the pharmacist responded properly, the mystery patient should have been directed immediately to an appropriate TB DOTS centre without dispensing either antibiotics or steroids.

Unfortunately the team recorded ‘ideal management’ of these patients (defined by the team as a referral at least to a ‘health care provider’ and without a prescription of either antibiotics or steroids in the process) in only 80 (or 13%) of the 599 cases who presented with ‘TB-probable’ symptoms.  That’s a terrifyingly low number. The pharmacists did better with the patients who came in with confirmation of diagnosis, but even this only occurred in 372 (or just 62%) of the 601 cases who presented with indisputable bacteriological evidence of disease.

Most astonishingly of all, in only three instances of all 1200 pharmacy presentations was the standardised patient referred specifically to an official ‘directly observed treatment, short-course’ (DOTS) centre as opposed to a health care provider – as should have been optimally (and reasonably) expected to be the case if procedures were being properly followed.

We’ve noted already that many patients resort to pharmacists in order to avoid doctors’ consultation costs. It seems, however, that India’s pharmacists show little sensitivity to this economic vulnerability, being as they are quite happy to inappropriately sell these patients drugs (albeit not TB drugs, but still other antibiotics or steroids) that not only will probably do these patients no good, but might also stoke the national AMR problem at the same time. It’s no wonder, perhaps, that India has the highest total national consumption of antibiotics: it may well be because it makes such financial sense to the nation’s pharmacists. What we now ask is whether the nation’s pharmacists will still try to keep it that way in the light of the UN resolution.

We also sadly note that, of the total referrals that were made, 60% were to doctors in the private sector where the patient would most certainly have to pay at least for their consultation. This begs the logical question as to whether informal financial arrangements might exist between pharmacists and private physicians which might induce such unnecessary referrals.

So three further questions need asking.

The first is this rather blunt one: does the Indian pharmacy industry in these cities give a flying fig about the people it serves? The second is more fundamental: does it have any real clue about how TB cases, either probable or definite, should be being handled?

The third is the biggest one of all: is the Indian Health Ministry going to do something about all of this?

Meanwhile, if you are a person who prays, it looks like every TB patient in India is in need of your active and immediate help.

[1] The number of privately treated tuberculosis cases in India: an estimation from drug sales data

[2] Use of standardised patients to assess antibiotic dispensing for tuberculosis by pharmacies in urban India: a cross-sectional study


Seeing politicians getting behind TB...

 Last week at the ‘TB2016’ Conference in Durban, the official launch of an African TB Caucus was hailed as “a renewed political commitment” to ending TB in Africa. Let's hope that it is one.

 Political representatives from twenty African countries had gathered to launch a formal network of parliamentarians from the entire African continent  -  politicians who are now saying that they are dedicated to leading the fight against tuberculosis. It should be cautiously noted that twenty countries in Africa add up to less than half of the countries in the region, which surely must leave some concern, but the same thing’s been happening recently global regions as well, each caucus representing a regional effort to launch parliamentary networks specifically dedicated to ‘upping the anti’ on TB, particularly to raise the disease higher up the list of priorities for Ministers of Health across every regions, and to generally build pressure for action on TB through parliamentary routes.


Parliamentarian Abera Buno Adula from Kenya signing the statement of commitment.

Parliamentarian Abera Buno Adula from Kenya signing the statement of commitment.

It all sounds really good, but we only too well know what politicians can be like, don’t we? (They’ll pretty much sign up to anything if it gives them a soundbite in the media and a few votes..)

 Well, the day before the African Caucus was launched, the Stop TB Partnership and MSF (who were also in Durban) co-launched their Step Up for TB Campaign, demanding that countries  do something more than focus their attentions on this neglected pandemic at TB conferences –  that they must specifically ensure that their TB Policies are updated to align with current WHO global guidelines and that they must do so “within the next 500 days”. They have several good reasons to be more than insistent as we’ll see below.

One reason (which they didn’t mention in the report) is that three years ago another group of African politicians (this time the Health Ministers from the eight Southern African Development Zone countries - a region with the highest regional rates of TB anywhere in the world by a country mile) signed what they called the “Swaziland Statement” – on this occasion pledging to catch up on TB targets in the “following thousand days” – targets which had been most appallingly missed in the previous two thousand having been set as part of the Global Targets for TB set in 2006.

2013 through till 2016 …  hmmm. This interval of time pretty much amounts to that thousand days which makes that pledge sounda litttle hollow today because there's far too little still to show for it. And now we’re seeing another pledge for the next 500 days? And what then? Should we simply expect another pledge, or another statement of intent?

Perhaps this sounds unfair, but we’re far from sure that it is. Last November the Stop TB Partnership and MSF (those same co-authors of the ‘Step Up for TB’ campaign) published the results of the first ever survey reviewing the true status of countries’ adoptions of the WHO's TB policies and guidelines. They published them in their ‘Out of Step’ Report, a document which surveyed the situation in 24 strategically important countries, all with big TB problems. Fifteen of the 24, for instance are on the WHO’s list of 22 so-called TB High Burden Countries (HBCs), and 13 of them are on the WHO’s other list of 27 so-called High Burden MDR-TB Countries (HBMDRTBCs).  (All of them except one are on one or other of these lists, and six were on both lists). In other words all of these are key countries in the battle against TB.

 In the report they took a look at how well these countries’ had adopted WHO policies and guidelines – basically assessing how they’re all doing in terms of responding to the WHO’s 1993 rallying cry that TB is a life and death global emergency, and also looking at how they were addressing the growth and threat of MDR-TB. These countries, we must stress, form the bulk of those which have had the most international focus directed on their epidemics (both by the global authorities and by international donors). As such it would be reasonable to expect that they’d be pretty up to date in their compliances with WHO recommendations and policies – as up to date, in fact, as any countries in the world.

Unfortunately the report shows that it’s not like that at all. Here’s one quote from the report as an for example:

 “No country has [yet] registered the full set of DR-TB medicines recommended by the WHO guidelines.”


The truth is that a national TB program needs a bunch of different drugs to properly respond to a TB epidemic. One group of drugs (Group 1) are effective for treating drug-susceptible disease (which is thankfully still the bulk of the pandemic), and then four more groups can eaxh come into play when the disease becomes resistant (usually a drug is selected from at least three groups to maximise chance of cure). Here’s the list of the groups of drugs:

Group 1: pyrazinamide, ethambutol, rifabutin, isoniazid, rifampicin, rifapentin
Group 2: kanamycin, amikacin, capreomycin, streptomycin
Group 3: levofloxacin, moxifloxacin, ofloxacin
Group 4: para–aminosalicylic acid, cycloserine, terizidone, ethionamide, prothionamide
Group 5: bedaquiline, delamanid, clofazimine, linezolid, amoxicillin/clavulanate,
thioacetazone, imipenem/cilastatin, high-dose isoniazid, clarithromycin.

Notwithstanding this registering of the drugs (or lack of it), it also transpires that only three of the 24 countries actually had all the medicines in these five groups even in their National Essential Medicine List (EML) and so would comply with the Global WHO Model List of Essential Medicines. In fact five of the countries didn’t even have one single complete group of any of these anti-MDR-TB drugs (i.e. in groups 2-5) in their EML.

So let’s tell this the way it is (and the way we think it should have been told at the UN when another bunch of politicians signed up to the wonderful sustainable development goals) or at the World Heath Assembly (when another bunch still merrily and unanimously endorsed the Plan to End TB by 2035 when they must of known it was a dream): no country, let alone any region of our world, is going to defeat this disease pharmaceutically by 2030 if they don’t have the necessary drugs to do so in their drug cabinets.

The reality, at least according to this report, is that none of these special countries has all the drugs they need registered for use, and only three have all of them on their EML. Of the remaining countries, a shameful five of the 24 had only one complete group of anti-TB drugs on their national EML – the other four groups were incomplete. A further four countries had just two complete groups, and five countries had only three complete groups. And truly shockingly, five countries (India, Nigeria, Kyrgyzstan, Kenya and Zimbabwe) didn’t have a single complete group of any of the MDR-TB drugs on their EML – with the first three of these hanging out there in the WHO’s HBMDR-TBC list (with India being one of them with the dubious honour of being home to the most MDR-TB cases in the world).

And then this gets worse.

Only “half of the countries surveyed” says the report, “have guidelines in place to allow the initiation of DR-TB treatment at district level” – in other words in these countries MDR-TB treatment will only be administered to MDR patients at their major city centres.

And we still hope to see TB ended by 2030?

At least there's been some good news appearing in the media in the last couple of years on TB - on the ‘much needed and long overdue new TB drug’ front. Bedaquiline received accelerated approval from the US Food and Drug Administration in 2012, and then delamanid received approval from the European Medicines Agency and Japan’s Pharmaceuticals Medical Devices Agency in 2014 - the first new TB drugs appearing in the last fifty years. So how are these two new drugs being received out there in these critical countries where TB and MDR-TB is entrenched? Are patients seeing them as they should be (and as they certainly would be in high-income countries)? Well, according to the report only eleven of them even have national guidelines in place on the use of the first one (bedaquiline approved in 2012) – and only four had national guidance on delamanid. That’s some enthusiastic response in the countries where patients most need them…

The report looked at this same thing another way as well. They surveyed each country in accordance with four different criteria for their capacity to address MDR-TB: whether they had a national policy on bedaquiline, and whether they had a policy on delaminid (as discussed immediately above); but also whether they had an essential medicines list which included drug groups 2-5; and finally whether they had either new or repurposed drugs available for compassionate use. Four of the 24 countries failed on all four counts (two of these being HBMDR-TBCs); seven of the 24 failed on three of the four criteria (four of whom were HBMDR-TBCs). And only one country out of all 24 met all of them – so let’s name it because they deserve an accolade: it was Belarus.

Okay, we hear you say - so here they are banging on about MDR-TB. But it’s only a small proportion of the pandemic, after all, and the WHO say it isn't really rising: surely the rest of the disease must be being handled better…?

Well (leaving aside what the true state of the MDR pandemic may really be) the report took a look at DOTS – the very cornerstone of the WHO global TB strategy (‘Daily Observed Treatment Short Course’). As part of this policy the WHO, the report explains, recommends daily dosing “wherever feasible”.

Bizarrely, though, India and China still recommend intermittent therapy for DS-TB instead of daily therapy (with these two countries alone accounting for almost 40% of the estimated global burden of TB). In fact, six of the 24 countries surveyed reported still using intermittent treatment. In other words a quarter of these countries with global focus directed on their well-recognised epidemics for nearly two decades don’t see fit even to properly implement DOTS.

And what about the standard Group 1 drugs themselves? Well, since 2010 the WHO guidelines have recommended so-called “fixed-dose combinations” (FDCs) of these for the optimal treatment of drug-susceptible TB. In the 'Out of Step' report, however, three countries (India [again!], the Russian Federation and Ukraine) were reported as not using FDCs as their preferred formulations in their national guidelines. Why on earth are any HBCs still using FDCs let alone any others?

Since 2010 the WHO have also not recommended the empirical use of the ‘Category II’ regimen for re-treatment TB cases. (Category II adds streptomycin as a single additional agent to a standard four-drug Group 1 combo when it’s seen to be failing). We should add that in our humble opinion this practice shouldn’t just not be recommended – it should be immediately globally banned because it’s long been accepted that adding a single drug to a failing multi-drug regimen for TB likely amplifies drug-resistance. Whatever the case, the report records that only “ten [of the 24] countries are in line with WHO guidance” on this aspect. Dear God – fourteen of 24 critical countries still use a regimen that is known to potentially stoke drug-resistance?

It’s looking pretty bad, isn’t it? Actually the report itself could even be accused of understating how bad it is, cautiously qualifying that Category II has been shown to have “poor outcomes” in countries with high background rates of MDR-TB. For “poor outcomes”, we’d say it would be more accurate to have said ‘more dead patients along with more avoidable untreatable infectious airborne disease’.

In fact this looks even worse when we read in the report that Category II is still recommended by both India and China (these countries together having 40% of the total estimated burden of TB - or about four million new cases each year) and both also with recognised existing high burdens of MDR-TB (Well - surprise, surprise…).

Any reader of these blogs will be aware that we are more prone to direct the focus of our concerns at the WHO in Geneva. This blog’s a little different in this respect: whilst we think it’s still quite reasonable, in the light of the report, to suggest that WHO’s officers on the ground might have been making a lot more effort to influence policies and implementation of TB treatment in these key countries, we find ourselves focusing our admonishments at health ministers of these countries and at the managers of their national TB programs. Twenty-two years into a Global Emergency there can be NO excuses at all for what’s still going on out there. This is still a shameful response to an ongoing public health disaster.

So if parliamentarians are now seeing it as a good thing to be seen to be getting stuck into this issue, then we say “Well and good, and not a moment too soon!”.. but we'll take this back if it all ends up changing too little too late. Not if we see another deadline being set behind another deadline, and another pledge made as if an earlier one had never been made. There's a mountain to climb here. It can be climbed for sure but it needs real political will and resource. Dr Joanne Carter nailed it last week when she explained how TB “has climbed the list of major killers”. She said that it’s simply “because it is at the bottom of the list of political priorities". She’s Executive Director of RESULTS and Vice-Chair of the Stop TB Partnership Board, and she should know.

So please, politicians to step on up in your caucuses -  but make sure that we see you staying standing for the duration - staying there for TB till we see this disease properly defeated. The whole world’s need to start watching.












World TB Day 2016 - and 'bending those curves'..

It's World TB Day 2016, a full 23 years since TB was declared a Global Emergency, and FINALLY we are seeing some heat being turned up on this treatable disease (with the unmistakable handwriting of the inspirational Dr Lucia Ditiu of the Stop TB Partnership evident in almost every initiative). There's good reason to rejoice, but there’s still little reason to believe that the tide in this war has even really turned, let alone ebb away more quickly. 

A major new initiative is the Stop TB partnership’s new five year Plan for 2020, complete with its catchy slogan (the ‘90-(90)-90’ target). What's being demanded now is what's being called a ‘paradigm shift’ in thinking about TB. We hate to say this, though, but there's still way too little evidence of new paradigmatic thinking about TB.

The intention now is to “bend the curve” of what is a painfully slow decline in disease, bending it more steeply downwards so that the disease can be finally brought to its knees within a generation rather than festering on for another hundred or more years. It’s been hailed as an ‘ambitious’ strategy and it surely is. It can also succeed if it’s really well managed, but unfortunately we see a fundamental deficiency at its very heart and we fear that this flaw is more reflective of old-style TB thinking rather than of anything resembling the necessary paradigm shift. Highlighting this deficiency today might not be so welcome to the authors of the Plan who want to see everything done to add to the new momentum, but we believe that failing to do so is more likely to help see the Plan derailed than to see it stay on track to its anticipated end.

So here's the fundamental weak spot:

All of the post-2015 targets published so far are talking about TB as if it’s a single disease when it’s not.

What TB is today is an infectious disease which comprises three sub-diseases that are so clinically distinct from each other that we should be seeing them individually – each one requiring different targets, different drugs, different diagnostics, different resources and different strategies. It’s responding to this reality, we think, that's the real paradigm shift thinking that’s now needed.

Here’s what we mean...

If we see the disease as a single whole we can usefully represent it as an ‘all- TB’ pandemic with its associated total prevalence, incidence and mortality rates. Actually this is exactly how the state of disease is most regularly reported (with its most recent numbers being 13 million, 9.5 million and 1.5 million respectively). But what's so easily forgotten is that this ‘all-TB’ pandemic comprises not just the strains which are susceptible to the standard drugs, but also the ones which aren’t.

Meanwhile, at the core of this new End TB Strategy is a single curve, the trajectory of which is currently being reported to be sloping downwards at around 1.6% each year. (Even this far into the Emergency it’s believed that we’re still missing more than a third of all-TB cases each year and largely because of this the pandemic is not dropping as fast as it could be.)

What's now suggested is that this single curving trajectory (of the whole pandemic) can now be bent further downwards by finding those missing millions and then treating them more effectively. We have no issue at all with this idea, but we’re worried that this won’t end the pandemic as is anticipated and we’ll try to explain why.

Here’s the recently published WHO’s graph of how this curve is intended to be bent downwards.

                             Graph #1: the End TB Plan's graph showing how TB will 'end' by 2035.

                             Graph #1: the End TB Plan's graph showing how TB will 'end' by 2035.

Look first at the higher dotted line. This shows the current global trend of the whole all-TB pandemic with a downward trajectory of a little less than 2% a year (which is what’s been being consistently reported for the last ten years). A solid line is planned to split off from it in a year or so and this shows what’s hoped will happen as the new End TB Strategy begins to take effect. The decline should begin to accelerate to around 10% a year, and then accelerate further in 2025 to average an annual decline of 17%.

Viewing the disease in this way very reasonably leads us to believe that the disease can be seen off as a whole by 2035 - largely with some more efficient use of existing interventions in the first ten years, and then with a new vaccine in the second.

But this model completely ignores something important: it ignores the individual dynamics of those three subordinate parts of the ‘all-TB’ pandemic which comprise the whole. If we choose to see the disease without ignoring this then we don’t actually have a single curve to bend downwards at all: we end up with four of them which makes things a lot more challenging.

So here’s a similar simple graph to illustrate this. It’s directly reflective of the first one, but incorporates four separate lines, each one reflective of a component estimable part of the pandemic.

               Graph #2: disaggregating the pandemic into its drug-susceptible and drug-resistant parts

               Graph #2: disaggregating the pandemic into its drug-susceptible and drug-resistant parts


Exactly as in the first graph the top line is reflective of 'all-TB' (the dotted line of the first graph). It’s the existing decline of the ‘all-TB’ pandemic dropping at just under 2% a year.

The second line reflects the largest proportion of this wider pandemic. This is the disease which is sensitive or susceptible to the standard DOTS drugs regimen (in other words that’s curable by the standard one-size-fits all approach) – we can call this ‘drug-susceptible’, or DS-TB for short. This is currently estimated to comprise 95% of the existing pandemic (though we’re sure it must be really be a bit less than this), and it’s curable in at least nine out of ten cases.

We can be confident that this second DS-TB curve is already be dropping downwards a little faster than the top ‘all-TB’ line – that one which represents the whole pandemic. This is because we know that the first curve of ‘all-TB’ in the graph above must inevitably contain the estimated 5% of the pandemic that's now MDR (a very significant majority of which is neither detected nor treated).

We need to acknowledge something at this point. We are NOT epidemiologists, nor are we expert mathematical modellers. Such expertise relies on complex algebraic calculations which were not attempting to emulate here. Because we're far from sure that these experts are presenting the whole diverse picture of this huge global health threat, we're simply applying what we consider to be simple logic and a little basic maths. And please be assured - we will be only too relieved if the results of our projections can be successfully challenged because of what they suggest.

Because you will see that we also have a third (red) line on our graph. This one represents the ‘other’ 5% - the proportion of the disease that’s resistant to at least the two strongest DOTS drugs (and which therefore isn’t curable by standard treatment nor is 'normally' diagnosable). At least 75% of these MDR cases are never diagnosed (and in we believe that it’s probably substantially more), and of those that are diagnosed and put on treatment less than half of them currently enjoy successful outcomes. It’s a very different story indeed o that of the line immediately above it.

Given the low detection rates and the poor treatment outcomes (using the WHO’s own published data) we’re sure that this line must be rising. The WHO, for reasons that we can't figure out, reckon that it's not. We're simply no longer prepared to accept this as a logical possibility, and actually we suggest that this proportion of the pandemic could logically be rising at around 10% a year (something which we discuss further shortly). So this is how we’ve pitched its trajectory in the graph above.

And finally we have a fourth line - the proportion of the disease that's resistant to even more of the anti-TB drugs, including at least two that we might first want to use in any alternative drug regimen to DOTS. This is XDR-TB - what Mario Raviglione, the WHO’s TB czar has called “the worst thing we could have imagined”. It’s currently being officially estimated that this part of the pandemic comprises just under 10% of the MDR component of the pandemic – which effectively means that it’s currently believed comprise about 0.5% of ‘all TB’. This may not sound like much at all, but it’s important to bear in mind that this type of TB is not just vastly more challenging to treat, it’s also vastly more dangerous, with treatment reported to only succeed in one-in-every five patients. Not only that, but the diagnostic capacity to actually diagnose and notify XDR-TB in most TB-endemic countries (let alone treat it) is in terrifyingly short supply, so logically it’s a certainty that this part of the pandemic is also rising, and it’s probable that it’s rising faster than MDR-TB. In our graph above we’ve pitched it as incrementally rising at a modest 0.5% more than the 10% rise we’re reckoning for MDR-TB. Because it starts from a much smaller number this makes it look a lot less threatening but, given everything we know about XDR-TB, we know that we should remain as alert to the trajectory of this curve as to any of the others.

 We should add that everything about XDR-TB numbers are currently terribly uncertain and we’ve included this line really only because it’s so important to show that it exists.

What we wanted to particularly focus on on this World TB Day is the way that the blue and the red lines converge around 2034, each one with an incident rate at this point of time of about 30/100,000. According to our graph we can suggest that if there are no other successful interventions there’s a likelihood that after this there will be more drug-resistant disease within the pandemic than there is disease that is drug-sensitive.

You may well think that our tentative extrapolations are extreme. They’re  certainly unapologetically tentative, but we’re not sure that they’re that extreme. David Dowdy, who is an associate professor at John Hopkins Bloomberg School of Public Health and an expert in MDR-TB epidemiology, is on record as saying that “scenarios in which MDR-TB rates double in 15-20 years are a reasonable expectation”. In the light of his expert opinion our extrapolation does look a little over-egged because, by using a 10% cumulative rise, our rates pretty much quadruple (not double) in a twenty year span. In the previous blog in this series, however, we put on record that six years ago the WHO itself was reckoning that MDR-TB was rising at around 9% a year. Not just that, but between 2000 and 2008 this sort of rise was being estimated to be pretty much the norm. Furthermore published data from South Africa has showed MDR-TB increasing more than four-fold in a period of just six years, with XDR-TB increasing a very scarey eighteen-fold in the same period. There is appalling uncertainty here. In fact, even if we stuck with David Dowdy’s scenario, these two lines would still converge before 2040, so unless anyone is able to confidently give us real numbers (which no-one can) we’re sticking with our extrapolations simply because they comprise an exercise in precautionary principles which we are convinced the precarious situation warrants.

Taking this further, we believe that the best way to prevent this convergence happening (in fact probably the only way to prevent it if the current successful trends in treating DS-TB are maintained and accelerated ) is to begin aggressively attacking this MDR portion of the pandemic immediately wherever we can to keep this third red line from rising. As such, prioritising and funding distinct MDR-TB programs should be an absolute fundamental part in any post-2015 strategy. What worries us is that we don’t see this in the current plan, not least because there are no distinct targets for TB yet set and the existing budgets won’t really allow for them anyway.

There are plenty of things that could change this of course. The most probable is that parts of the the End TB Strategy are successfully implemented, including “optimising current tools”, and “pursuinguniversal health coverage and social protection” as we saw above – but if this isn’t done without successfully and aggressively attacking MDR-TB in a way which hasn’t yet happened nor is yet planned, then actually we could even see the convergence happening even more quickly.

The next very simple graph attempts to illustrate this and unfortunately it shows both good news and bad..

Graph #3: Extrapolation of MDR-TB pandemic if the curve of 'all-TB is successfully bent downwards.

Graph #3: Extrapolation of MDR-TB pandemic if the curve of 'all-TB is successfully bent downwards.

In this graph we’ve left out the XDR-TB line for simple reasons of clarity, and we’ve bent the top blue line of ‘all-TB’ downwards to reflect the anticipated curve of the WHO’s graph (the solid line in the very first graph in this blog). This puts it in line with the Plan, with the number of new cases dropping from 9 million each year to around 2 million by 2030. Similarly to what we saw in our own second graph, the line of DS-TB now curves downwards even faster too, in fact it even looks like DS-TB could peter out into epidemiological insignificance sometime around 2030 (which by happy coincidence happens to be the SDG target date for ‘ending’ TB).

But we've not changed our MDR-TB line. It's the same as in the graph above, rising at 10% each year and so the convergence point at which drug-sensitive and drug-resistant TB become essentially equal in incidence will have already occurred around three years before DS-TB might peter out - in 2027. After this (because the DS-TB component will now be becoming so insignificant) the line of ‘all-TB’ can be expected to essentially follow that of MDR-TB and so will begin to rise again for the first time since around 2005.

In other words by around 2030 ‘all TB’ will have essentially become a single MDR pandemic – at an incidence rate of around 25/100,000 (or roughly four times what MDR-TB is today, but about a quarter of what ‘all-TB’ is).

Now this needn’t happen, and it won’t do if we anticipate its possibility and aggressively attack MDR disease at the same time as we attack the drug-susceptible pandemic. But we’re quite sure that something like this will happen if we don’t attack MDR-TB really vigorously starting today.

And this definitely can't happen unless we begin to confront the probable numerical realities of MDR-TB.

To the UN, the WHO and the Stop TB Partnership: where are the targets for MDR- and XDR-TB?

Today is the UN's World Day of Social Justice. It's been marked on February 20th each year since 2007 (in recognition that exclusion and inequality are both globally on the rise).

Well the right of access to effective treatment for MDR- and XDR-TB is undeniably an issue of social justice. It's one, as Joni Mitchell once put it, of "who gets the gravy, who gets the gristle, and who gets the marrow bone - and who gets nothing though there's plenty to share..."

Actually there's not much in the way of gravy at all really in treatment for DR-TB - unfortunately it's all pretty much gristle or worse - but there's far too many who get nothing at all in the way of treatment and then infect others before dying. 

So today we have to ask a question of the UN itself in New York - since incidentally it has set as one of its Sustainable Development Goals (SDG) a target of ending TB by 2030.

In the hope of achieving this some specific targets have been set for the next 20 years. These targets were set by the WHO (unanimously endorsed by the World Health Assembly itself) and since then they've been developed by the Stop TB Partnership. So we ask the same question of these august organisations in Geneva as well. (They've set some ambitious targets for sure, but they reflect 'all TB' with not a mention of MDR or XDR disease.) 

We ask this:

Where are the targets for these most dangerous and poorly addressed parts of the 'all-TB' pandemic - for MDR- and XDR-TB? Because we can't see them anywhere. 

Some certainly existed previously in the targets that were set by the Stop TB partnership for 2015. Unfortunately each one of them was abjectly missed. So is that why they don't exist within the current strategies to defeat this ancient disease? Surely that can't be the reason, can it?

We don't know - nor do we understand why no-one out there is screaming about this -especially because MDR- and XDR-TB pose the greatest threat of all to exactly those one (or two) billion  who are most affected by exactly that exclusion and inequality that the UN (particularly today) acknowledges exist.

So here's our own scream on the UN's World Day of Social Justice:


How to manage a drug-resistant pandemic? (2) Estimating the burden of disease at a national level…

In the previous blog we discussed the ways that the WHO generally use to estimate the proportion of the global TB pandemic that's drug-resistant, concluding that the method seems to be fundamentally flawed and that it's almost certainly dangerously under-estimating the threat.

 In contrast, in this blog we take a look at one particular country – at South Africa – and we examine  how the estimates for MDR-TB and the notified numbers are being incoherently represented and reported for it. We then explore some of the reasons behind these variations. Some of them relate directly to the previous Blog (How to manage a drug-resistant pandemic? [1]);  but mostly they seem to expose fresh issues of concern.

In the most recent WHO Global TB report (published late in 2015) the WHO’s estimate of the burden of MDR-TB for this rainbow nation was 6,200 incident cases (comprising 4,700 new and 1,500 re-treatment cases). This can be seen in the upper ringed text in the graphic below which is reproduced from page 141 of the WHO’s most recent Report. It’s very important to bear in mind that this number is the one that’s used to help build the estimate of MDR-TB for the African region, and also, therefore, for the whole world.

So far so good, but with only a minute’s further review of this same graphic we can spot an embarrassingly large South African elephant in a roomin Geneva because we can see (in the lower ringed text) that the number of actually reported laboratory confirmed cases of MDR-TB for the same year was 18,734 – or pretty much three times the published estimated number. Unless expert opinion considers the country’s laboratory-confirmed bacteriological data to be gobbledygook (which it doesn’t), this makes the WHO’s estimate of MDR burden for South Africa a de facto statistical impossibility.

Of course any proper estimate of incidence for a disease like TB has to always include the number of cases that are believed to be being missed by the national TB program (which globally was a worrying 37% in the last Report, but for South Africa it was a bit less at 32%). In any imaginable scenario, of course, this total must always be higher than the number of reported cases, but in this instance it’s not – it’s a lot less.

Might we have got this wrong? Well we know that we haven’t because we tried to resolve this anomaly with two WHO experts in Geneva and also two experts in South Africa. All of them were helpful, but nothing got resolved and our concerns were actually left considerably more acute at the end of their efforts.  

The two South African experts explained that enormous efforts have been made to improve general epidemiological intelligence regarding to their national epidemic. And they reckoned that about about 18,000 (or between 15,000 and 20,000) incident reported MDR cases is "close to the truth" for the country. Furthermore they didn't think that many MDR-TB cases who were attending for treatment were being missed (largely because of the roll-out of GeneXpert diagnostic device). And as a result we agree that the case detection rate for MDR in this country can be quite reasonably assumed to be similar to that for all-TB (i.e. 68% which is far higher than the 26% which is the optimistic global average).

So we tried running this same estimate using the principles described in Method I as described in the previous blog, using the notified number of cases and then inflating it by using a case detection rate that (in this case) we’re pretty confident with. Our calculation runs as follows: 18,734 divided by 68 multiplied by 100. This gave us 27,750 which is certainly a lot more than the WHO's estimate of just 6,200 - in fact it's four-and-a-half times more.

 What initially alerted us to all of this were these curious percentages of new and re-treatment MDR cases that have year-on-year been being entered for South Africa in the WHO Reports. Thestwo percentages have for the past years always been 1.8% of all cases for new TB cases and 6.7% of retreatment ones (which you can also see in that graphic above in the upper ringed text). We noted that these percentages are a lot less than the most recent global percentages which were 3.3% and 20% respectively and that this would suggest, therefore, that the rate of new MDR cases occurring in South Africa is around half the global average, and the rate of retreatment cases a third of it. Yet South Africa is not only recognised as a high burden MDR-TB country by the WHO itself, it’s also widely recognised to have an MDR-TB problem that is out of control. As such these consistently reported percentages just don’t add upfor us at all.

With the help of the WHO experts we managed to establish that these percentage estimates actually relate to a survey that was carried out in 2002 so are obviously way out of date. This may well be the explanation, but we still don’t understand why they haven’t been adjusted by a single point in the thirteen years since. Not just this, but we are appalled that they could still be used to calculate the numbers which are then fed into both regional and global estimates of MDR-TB, despite their being fundamentally meaningless to the current state of the pandemic and so misleading. To put it bluntly they render any resulting estimate of the regional and global MDR pandemic illegitimate.

A couple of simple sums can prove that these percentages have indeed been used, incidentally. The total estimated number of new all-TB cases in South Africa for 2014 (the year reported on in the 2015 Report) was 261,955, and 1.8% of cases gives us one the numbers that appear in the graphic above (4,700). Meanwhile the total estimated number of relapsed or previously treated was 22,716, and 6.7% of this number also gives us the second number entered above (1,500). So we can confirm that the estimated percentages for 2002 have been used to misleadingly calculate the MDR estimates for this country in 2015 and in every other year since 2002.

As mentioned above, we’ve not been given any acceptable explanation as to why these percentages from the 2002 survey haven’t ever been adjusted by expert opinion. We have learnt, however, that there was supposed to have been another drug-resistant survey conducted in the meantime (though we don’t know why it never happened). But we’ve also learnt that the results of a new and long-overdue survey are nowimminent. From the existing correspondence, however, we understand that the experts in Geneva aren’t expecting the existing percentages to change much in the new survey. It’s not at all clear how this can possibly be the case, but it’s what we’ve been told nevertheless.

But let’s go back to the actual numbers for a minute. If we accept that the South African 18,734 MDR laboratory notifications are correct (and if we assume most of them to be pulmonary which we think is probable), we can compute this number as a percentage of the current Report's 261,955 notified new pulmonary cases, and then we can calculate that the overall percentage of TB in the country is MDR may be 7%. This is higher than the overall global average which is 5.5%, and it’s a lot nearer what we’d expect it to be.  

We appreciate that there’s a lot of detail here and a also lot of tentative playing around with the numbers. Some of it may be difficult to appreciate in a single read, but we want any reader to understand that all we're doing is trying to apply some logic to a quite illogical report. We're sure that submitting illogical and misleading numbers into regional and global estimates isn't be any way of monitoring and responding to a drug-resistant pandemic which also includes XDR-TB – what Mario Raviglione of the WHO himself calls the “worst thing we could have imagined”. The idea that these percentages can be so casually misrepresented actually appals us, not least because of what it implies for other neighbouring countries given known migratory patterns and their comparative lack of resources in comparison to South Africa.

Such concerns are even more worrying when it’s appreciated how acutely aware of this risk the WHO was in earlier years. Back in 2009 several top TB experts in the WHO presented a paper at the Union Conference in Mexico. They reckoned that 75,000 new MDR cases were probably occurring that year in the African region (i.e. more than twice what they reckoned for the region last year!) – and bear in mind this was six years ago. This wasn’t even a one-off: the year before that (in a specialist WHO Report on MDR-TB) the number of new African cases was reckoned at 69,000, so it would appear that six years ago the WHO was comfortable in suggesting that the incidence of African MDR might have increased by 9% in a single year. Since then, though, the picture that’s been presented hasn’t just been flatlining (which is what’s happened for the global picture) - for Africa it appears to have actually collapsed! The current Report estimated that only 32,000 new African MDR cases emerged in the last reported year (albeit pulmonary-only) – in other words it seems to be being belived that there’s been a reduction in African MDR-TB of over 50% in five years. Can this possibly be the case given everything we know about MDR-TB? Of course it can’t.

But here’s one further calculation.

The recent Report also recorded 25,531 MDR cases being notified in the Africa region (18,734 of whom we already know were South African), which leaves less than 7,000 for the whole of the rest of the region. Of course this is nonsense as well, but it’s all in there in the reported numbers and it’s there partly because of those thirteen year-old South African percentages, of course! 

But then we know we’re all only pretending at this anyway because the surveillance is so poor. So let's finally pretend for a minute in this way: if the WHO’s 75,000 estimate of 2009 was right and the regional epidemic has been rising at 9% a year the total number of new cases of TB that are MDR in Africa can’t possibly be 32,000; it could easily be over 100,000...

 This might not be such nonsense as it first sounds because that WHO 2008 specialist MDR Report made a very serious statement indeed. It suggested that the incident rates of MDR-TB in “some southern African countries” might have then been “5-6 times higher than that of China or India”. This seems to us to be a sentence which was deliberately worded to alert the world to a drug-resistant disaster that the organisation realised threatened the region. Currently, however, no country in the African region is being reported to have percentages of MDR-TB that are even equal to the global average let alone above it. Something seems to have changed in the last six years.

But is it in Africa that something might have changed wthout being properly reported, or is it in Geneva?

How to manage a drug-resistant pandemic (1) - estimating the global burden

For some time we’ve been struggling to figure out how the WHO has been reporting that the proportion of MDR-TB hasn’t been rising (or at least that it has “changed little in recent years”). This isn’t just for the last couple of years, by the way, it’s been reported it this way for about a decade - in fact for almost half of the period during which TB has been an official Global Emergency. In 1993, when the emergency was first declared, MDR-TB was hardly being taken seriously at all – but it’s not always been that way because thirteen years later it was – as the WHO/StopTB’s own graphic from 2006 (shown below) clearly demonstrates:

WHO graphic from 2006 identifying the global burden of MDR-TB

WHO graphic from 2006 identifying the global burden of MDR-TB

The WHO’s most recent estimated number of new cases (for 2014) was 480,000 (i.e. 9,000 less), with the death toll estimated at 180,000 (i.e. 60,000 more, probably because the success rate of treating MDR-TB has been significantly downgraded in the past decade). Meanwhile the number of XDR-TB cases was estimated last year at about 46,560, and the death toll from XDR-TB wasn’t even guessed at (which is hardly surprising since the infrastructure required to diagnose (let alone treat) XDR-TB is almost invisible in TB endemic countries).

Let’s put our cards on the table. We’re sure that the real drug-resistant numbers are much higher today than the WHO estimates that are being published and here are just a few reasons why:

-          Between 2006 and 2015 the number of countries reporting at least a single case of XDR-TB has more than doubled from 49 to 105.

           In 2008 MDR-TB rates approached “25% in several Eastern European countries; now some are over 50%.

-          The recorded success rates of treating MDR-TB has dropped 2006-15(from 67% to 50%).

-          MDR-TB is believed to be just as infectious as ‘normal’ TB (but with 'normal' TB being successfully treated in 87% of cases, but MDR only successfully treated 50% of the time).

-          The relative case detection rates of drug-resistant disease is still (at the very best) just 26% as opposed to 63% for all-TB.

-          Meanwhile the latest outcome data for MDR-TB patients (for the 2011 global cohort) comprised just 25,319 patients (or less than 6% of the WHO's estimated new MDR cases for that year) suggesting that the data that’s available is extremely poor.

-          And, as we’ll see below, the way that these estimates of new MDR cases are prepared for most countries where TB is endemic is flawed.

Everything tells us that the proportion of MDR-TB must have been increasing in the last decade, although bafflingly no-one seems keen to challenge the WHO’s suggestion that it isn’t. Well we’ve taken our own look and we think we’ve unearthed a couple of reasons why the WHO’s numbers keep spitting out the way they do. It’s a little complicated unfortunately so we ask you to bear with us while we do our best to explain and expose why this is so.

The background

The first global and country-specific estimates of the drug-resistant disease burden associated with TB were published by WHO in 2001. It was estimated then that there'd been 272,906 new cases of MDR-TB globally the previous year (in 2000). The number estimated for 2004 rose to 424,203, a rise of 55% in four years - although this was partly explained as being because this estimate included incident cases of MDR-TB “among previously treated TB cases as well as those diagnosed for the first time”. (It’s not clear exactly, however, why these cases weren’t included in the earlier numbers because clearly they should have been). As we can see in the graphic above, however, the number estimated for 2006 was 489,000 – so there was estimated to have been a further 15% rise in the next two years. So we think that there’s more than reasonable evidence within the WHO’s own earlier numbers that MDR numbers were rising pretty fast, at least by 7% each year. Since then, however, something appears to have changed for no logical reason because, during this last decade, these estimated numbers first dropped (the estimate issued for 2008 was 440,000) and since then they've barely risen in spite of all of those simultaneously-published poor detection rates, the consistently poor treatment roll-outs and the dropping success rates, all of which normally would contribute to a growing pandemic. And the WHO reckons that the state of the MDR pandemic is “essentially unchanged from previous years”.

So how the numbers are actually being estimated?

Ideally, each country’s burden of MDR-TB should be being estimated from national drug-resistant surveys (DRS). Unfortunately resources dictate otherwise (and in the next blog in this sequence we’ll be looking at what can happen when one of them does have data from a DRS).

The reality is that most TB endemic countries have no valid data on MDR-TB, and for them the WHO have two ways of estimating MDR. They then put the two methods together using each to validate the other. (This can all be found in detail on , a document which was published by the WHO in 2014). By combining these two estimates the WHO establishes its annual global estimate.

In the example that’s given in this document itself these two methods do roughly correlate with each other so at first glance it looks like a useful technique: one method came in with a global total of 450,000, the other 420,000. But should we accept that the estimates which this methodology produce are correct given the anomalous implication of what this implies (that this pandemic is stagnating when logic suggests it must be on the rise)? Sure, if this way of developing the estimate is indeed correct then the disease must indeed be stagnating and we have less to fear from it. But if it’s wrong then the problem may be far more serious than is reported.

 So what exactly do these methods consist of?

Well, the first method approximates the total estimated number MDR-TB incident cases (new cases) by first adding together the number of notified MDR-TB cases from among the three distinct types of TB case notifications (‘new all forms’, ‘relapse all forms’, and ‘all retreatments that are not relapse forms’). Such case notifications are those which are diagnosed and notified by national TB programs, however, so they can't comprise any estimation of all new MDR cases. In order to approximate a more realistic grand total, therefore, this initial sum is then “inflated upwards by the estimated amount of incident cases not identified by the surveillance system, for all forms of TB”. We enter this as a direct quote from the document referred to above not just so that we leave no doubt about it, but also because the last five words (in bold) exposes the invalidity of the method itself. As anyone who knows anything about TB knows, the number of infectious TB cases “not identified by the surveillance system” vary dramatically between the different forms of TB. For ‘all-TB’, for instance, it’s most recently been pegged at 63%. For MDR-TB, however it’s reported as being about 26% (and actually we’d suggest it’s almost certainly a lot less than this). But the document is unembarrassed about this anomaly explicitly stating that: “The number of incident MDR-TB cases missed by the surveillance system is assumed to be the same as that for drug susceptible TB, and does not vary according to retreatment categories” with this assumption made in full knowledge of the vast discrepancy between the two estimated case detection rates.  

To give an idea of what this means, let’s run some numbers. Let’s say we found  a total of 100 new cases of MDR-TB and notified them to the WHO, using the method above we would then divide it by 63 (for the 63% global detection rate) and then multiply it by 100 to ‘inflate it upwards’ to the final figure. This makes for 159 estimated new cases. If we used the 26% case detection rate, however, the same calculation would be: 100 divided by 26, and then multiplied by 100. This makes a total of 384.  We can see from this exercise that factoring the number of notified cases by “the estimated amount of incident cases not identified by the surveillance system for all forms of TBthus makes a total that is only about 40% of what it might really be. The implication of this is immense – it could mean that a more accurate estimate of new cases of MDR-TB each year isn’t half a million – it’s actually nearer 1.2 million, and it would certainly mean that this pandemic is on the rise.

 So much for method I... But we already know that the two methods apparently corroborate each other, so maybe we’re wrong about this. So what about the second method?

Method II estimates MDR-TB incidence as “the ratio of the number of MDR-TB deaths divided by the MDR-TB case fatality rate (expressed as a proportion)”. The problem, of course, is that there still aren’t any decent measurements of MDR-TB deaths because there aren’t any reliable numbers of MDR cases being reported in the first place. Because of this a more indirect method of assessing this has total to be used instead. The WHO’s alternative  number-crunching is therefore done as follows: Method II total  is estimated by using the “ overall deaths from TB, [multiplied by] the overall proportion of TB cases that have MDR-TB (approximated by the weighted average of the proportion of new and retreated cases that have MDR-TB, as calculated from DR surveys or continuous surveillance), and [in turn multiplied by] the relative risk of dying among people with MDR-TB compared with those without MDR-TB (estimated from a systematic review that included data from twenty-five studies)”.

This is all a bit of a mouthful, but we can see from the parts we’ve highlighted in bold text is that the first factor that this second estimate is fundamentally dependent upon is the “proportion of cases that have MDR”. And of course this proportion was a part of Method I which means that any factor of error could be the same! In other words, the flaw in the first method is passed on to become the flaw in the second. The second method could similarly spit our an estimate that is just 40% of reality.

But there is another flaw with this second method because this calculation also includes the incorporation of ‘ICD-10’. ICD-10 is the international classification of diseases which was adopted by the WHO in 1992 in relation to reporting mortality statistics. It’s used by statisticians to code the underlying cause of every death with specific concern for matters relating to public health. Basically this means that a death can only ever be attributed (as far as this coding is concerned) to one disease – and, because of the threat of the HIV pandemic at the time the code was finalised, it was determined back in the 90s that if an individual died HIV-positive then their death should be coded only to HIV/AIDS whatever might have been the actual the cause of their death. By using ICD-10 the real reductions that have recently been recorded in TB deaths have been inevitably exaggerated (suggesting, for example, that the targets for reducing TB deaths by 2015 were nearly met, when they were actually far adrift of it because they didn’t include HIV/TB deaths).

In similar fashion the document states that its calculations of MDR-TB mortalities use TB mortality numbers “defined as the number of deaths caused by TB in HIV-negative people, according to the latest revision of the International classification of diseases (ICD-10).” Because of this the resulting calculations don’t include any TB deaths in individuals who are co-infected with HIV which inevitably further skews the final figures, especially where there are high rates of co-infection (i.e. in the African region where currently rates of MDR-TB are, perhaps unsurprisingly, being estimated to be so unexpectedly low...).

Actually, when classified using ICD-10, 26% of all estimated TB deaths worldwide must fall into this category of ‘HIV deaths’ (and most will be African). This amounts to 400,000 annual deaths from TB which don’t get coded as TB deaths at all – and so definitely won’t get counted as TB deaths in this second method described above.

There's one further issue relating to ICD-10, unfortunately. Using ICD-10 a death is only coded as one if the casualty was bacteriologically confirmed as sputum positive before death. This makes a TB coded death harder to maker than a TB diagnosis, simply because about half of all notified cases are diagnosed despite being sputum negative because of symptoms - because the sputum test is known to be so unreliable. Once again, we can predict a skewing of the numbers.

So can we conclude that the WHO’s suggestion that it has “no evidence” that the proportion of the pandemic that is MDR is on the rise is dundamenetally questionable? We think we can because it'sased on a system of reporting and estimating that is fundamentally flawed and which needs to be urgently revised if this pandemic is to be taken seriously.

The solution, of course, is to implement national drug-resistant surveys, though these are expensive and are, in any case, sometimes also far from as reliable as might be wished.

In the next blog we will explore exactly this. We’ll discuss a case study, reviewing the MDR-TB numbers that are both estimated and reported for South Africa – and we'll show show how terribly wrong things can go if they’re allowed to – even with the help of a national drug resistance survey. 

In hope for 2016...

Even an intermittent reader of these blogs will know that the underlying themes of our blogs revolve around our struggles to make coherent sense of all that’s evolving in the world of TB. We recently made special efforts to explain some of our confusions to the WHO itself in Geneva. Amongst other things we tried to describe what we experience as a ‘curtain’ existing between two specific types of stakeholders in the fight against this disease. On the inside of the curtain there are the likes of the WHO itself, the Stop TB Partnership, the Global Caucus (of parliamentarians), USAIDS,, and even the likes of MSF and PIH. All of these appear have a good handle on the precariousness of the situation and have good access to each other. On the outside we have the small NGOs, activist groups like the Treatment Action Group [TAG], charities like ourselves, individual clinicians and patients and their families – all of whom comprise so-called ‘civil society’ which is being invited to crucially engage itself in helping to turn the tide of this disease. And all of these agencies and individuals certainly have an instinctive idea of what’s unravelling with TB but we encounter nowhere near enough coherency in the facts that are presented for us to get a true picture of what’s happening and therefore how best we should respond.

In fact we believe that this ‘curtain’ is actually stymying the sort of quality of activism that’s now needed to help turn the tide of this pandemic. Whilst everyone on both sides of this imaginary ‘curtain’ certainly share the same fundamental goal (which is the earliest possible elimination of this curable disease) it’s certainly not the case that everyone is as privy to the same epidemiological intelligence. What worries us most, however, is that this gap of knowledge may be sometimes being deliberately engendered for reasons of political expediency.

Another thing that anyone who’s been reading these blogs will know is that far too much of the intelligence that is available is (at least on this side of the curtain if not on both) too incoherent for it to be appropriately useful.

Over this Christmas period, however, we’ve encountered some fresh incoherencies – but these aren’t appearing in the data this time. They're in the political sphere – specifically in relation to the recent publication of the U.S. public policy on tuberculosis.

Nearly two months ago (on 3rd November) 642 American TB experts wrote an open letter to President Obama. Co-ordinated by the Infectious Diseases Society of America and the American Thoracic Society, its message was pretty direct:  “We urge you [Mr President] to formally release the Plan to Combat Drug-Resistant Tuberculosis that your administration announced earlier this year … and to follow release of the Plan with a budget request that will support its implementation.”

We weren’t at all sure what this Plan was about but we were immediately interested so we read on.

It implored: “A plan is needed now, complete with research and development and programmatic goals and outcomes and a proposed budget, beginning in fiscal year 2017, that will ensure its implementation and success.” And their final message to the President was blunt: “Global leadership to respond to drug-resistant tuberculosis is long overdue.”

This all actually sounded very encouraging: some sort of ‘Plan’ must surely be in the pipeline but it sounded like it must be encountering some final delays so these doctors were trying to chivvy things along. There even seemed to be a possibility that President Obama was about to stake his political leadership in the struggle against TB! But once we started peering further around our fabled ‘curtain’ to find out more we came across something else which set our alarm bells ringing. It was a piece on the same subject of TB and relating to President Obama, and it was written by Joanne Carter of Results and it was published in the Washington Post just a week later on November 11th. She reported:

“The President’s proposed budget request has proposed slashing international funding for TB in each of the last four years including a planned cut for the year of $45 million from the previous budget level of $236 million.” [all bold type here and later is our own]

What?!! According to our numbers that pretty much amounted to an intended 20% cut in funding for TB, something which we found pretty shocking. Our concern was reinforced by a further sentence in Ms Carter’s piece which reported: “Public Health experts believe that … American government funding should be far higher than its current level.” Those public health experts clearly would include those 642 physicians who’s written that open letter, and we certainly agree with them.

“Fortunately,” Ms Carter continued, “Congress has recognised the essential role that the United States plays in combating the global threat of TB. Bipartisan opposition has rejected the proposed cuts.”  That at least was reassuring. But, while on December 16th it was reported that the USAID’s budget for TB for the 2016 financial year hadn’t been cut as had been intended by the President, it was still formally announced that it was being‘flatfunded’ at $236 million – i.e. set at the same level as in 2015 in spite of what those public health experts had said was needed.

We saw both a worrying an an encouraging picture emerging from all of this: here was a significant group of experts putting significant pressure on the U.S. President to reconsider his position. It’s something which could have given the whole world of TB activism a positive message for Christmas, but unfortunately it hardly gives us much cause to rejoice because the response amounted to a lot less than is needed. In fact the positive response that manifested had come from Congress and not from the President at all! So the critical issue for us all to consider as we enter 2016 is how public and how critical this sort of pressure can and should become for it to be as effective and game changing as it surely needs to be in the coming months.


The new National Plan for MDR-TB

Then a week ago, with three days to go before Christmas, the Obama administration finally got around to releasing its new Plan for MDR-TB. The White House PR department trumpeted it as “a comprehensive plan that identifies critical actions to be taken by key Federal departments and agencies to combat the global rise of multidrug-resistant tuberculosis”.

The Plan is organized around just three goals:

Goal 1: Strengthen Domestic Capacity to Combat MDR-TB. This goal relates to the efforts which are to be made within the United States itself. Each year just under 100 individuals are diagnosed with MDR-TB in the U.S., and the Plan’s aim for 2020 is to reduce this by 15%. Reducing a numerical incidence by just 15 cases-a-year over five years hardly seems much of an ambition when compared to the sort of challenges we’re contemplating elsewhere, but perhaps such a modest goal provides a reminder that the challenge of reducing incidence of this disease should never be underestimated.  

Goal 2: Improve International Capacity and Collaboration to Combat MDR-TB. This goal relates to the wider international efforts that are well recognised to be required from the United States (and other donor nations), particularly through strategic investments to broaden access to diagnosis and treatment. This surely should be seen as the most crucially important goal of the five year Plan.

Goal 3: Accelerate Basic and Applied Research and Development to Combat MDR-TB. This relates to R&D into new rapid diagnostics, into new shortened and less toxic drug regimens, and into new vaccines, all of which could and should be used both at home and abroad. 

It’s important to realise that this new Plan isn’t the first one that’s been developed by the U.S. government in order to combat MDR-TB. To date two other national action plans on MDR-TB have been published by the Center for Disease Control – one way back in 1992 and the other in 2009. Each one laid out its own goals for both prevention and for research -- but (and we feel it’s really very important to point this out since this is so relevant to the current Plan) they never got the funding to get off the ground for them to be implemented.

We feel we particularly need to stress this because the new Plan itself cautions that its own ultimate success will be “subject to budgetary constraints and other approvals, including the weighing of priorities and available resources by the Administration”. In other words, given the story of the previous Plans, and the administration’s own record of trying to cut its national TB budget in recent years, the new Plan comes with no guarantee at all that it will ever be usefully implemented.

But we also think that it’s worth recording what that very first National Action Plan to Combat Multidrug-Resistant Tuberculosis back in 1992 actually said. A full 23 years ago it made no bones at all about the threat that was faced – “At no time in recent history has tuberculosis (TB) been as great a concern as it is today. TB cases are on the increase, and the most serious aspect of the problem is the recent occurrence of outbreaks of multidrug-resistant (MDR) TB, which pose an urgent public health problem and require rapid intervention.”

The Plan itself then meticulously identified a full nine objectives that were believed needed to be met if MDR-TB was to be successfully contained (not just three like the current Plan). We think it’s worth listing them here exactly as they were listed nearly a quarter of a century ago because of what they collectively imply.

a)      surveillance and epidemiology -- determining the magnitude and nature of the problem;

b)      laboratory diagnosis -- improving the rapidity, sensitivity, and reliability of diagnostic methods for MDR-TB;

c)       patient management -- effectively managing patients who have MDR-TB and preventing patients with drug-susceptible TB from developing drug-resistant disease;

d)      screening and preventive therapy -- identifying persons who are infected with or at risk of developing MDR-TB and preventing them from developing clinically active TB;

e)      infection control -- minimizing the risk of transmission of MDR-TB to patients, workers, and others in institutional settings;

f)       outbreak control;

g)      program evaluation -- ensuring that TB programs are effective in managing patients and preventing MDR-TB;

h)      information dissemination/ training and education; and

i)        research to provide new, more effective tools with which to combat MDR-TB.

Not one of these objectives has yet been properly achieved. But for us it’s more striking still that the very first one is so bizarrely omitted from the current Plan (i.e. “the intention to determine the true magnitude and nature of the problem”). 

Surely, if there are just two things that we know about MDR-TB today, one is how little we still know about how much drug-resistant disease is really out there, and the other is where (or how) we should be properly starting to “improve International Capacity and Collaboration to Combat MDR-TB” (which is the second goal of last week’s National Plan). And such hapless lack of intelligence still persists a full twenty-three years down the road as much as the WHO may be quoting their 27 'high burden MDR-TB countries', so surely it should be the very first thing for the key donors now to be considering investing in if they want to see their money well spent. For us at least, the very first place to start (again) would be by implementing proper global surveillance and analysis.

Another part of the White House's proposal to deal with the disease is to “initiate treatment [by the end of 2016] for 25% of patients with MDR-TB in 10 countries with the highest burdens of MDR-TB”. Given that currently the WHO estimates (very optimistically indeed as far as we are concerned) that 20% of MDR-TB patients globally are already getting treatment, this hardly seems that ambitious or aggressive a target.

In fact, if we unpack this part of the proposal a little further, this offers us just another incoherence in the existing analyses of the estimated numbers (and in the consequent implementation of strategies): because what this appears to translate into (at least in terms of the new American National Plan) is an additional 200,000 MDR-TB cases being treated over the next five years, but these patients will mainly be in Russia, China and India–in three middle-income countries that currently self-fund most of their TB programs anyway. This is planned simply because these three countries are estimated to have the highest numerical burdens of MDR-TB (and they certainly all do have terrifying MDR epidemics). But none of these three huge nations (we believe) is among the ten nations where the highest proportional (not numerical) burdens of MDR-TB currently occur: all of these countries (we believe) are in southern Africa, and almost allare low-income ones. The problem, of course, is that no-one can either say or gainsay whether this opinion is true and this in turn is because the surveillance of MDR-TB (that very first item on the 1992 list of objectives) is still so appallingly deficient for this region.

Whether or not our suspicions about where the worst problems now lie are correct, this new National Action Plan (in its own words) also serves as a call to action for other bilateral and multilateral donors, private sector partners, and affected countries to further their investments in this critical area of worldwide concern”. Mario Raviglione, the WHO’s TB czar, has picked up on this. He’s described the new Plan as a bold move by the U.S. administration and he hopes that it will be followed “by a similar type of attitude and bold moves by other European countries. Especially in Europe, people are simply ignoring the fact that MDR-TB is at the border”. Let’s hope he’s right but with Europe confronting so many other acute problems on its borders, it’s difficult to be too confident in the broader judgement of Europe’s politicians.

Meanwhile for Joanne Carter, who wrote that piece in the Washington Post and who is also the executive director of Results, the National Plan that's emerged is much more than an example for countries in Europe or elsewhere. “We see it as a really important Christmas present,” she says now that she’s finally seen it. “We're really, honestly, just happy [it came out] ... in advance of final revisions of the 2017 budget.”

We guess we should be happy as well but we have to admit to being not quite so optimistic about those final revisions to the budgets. We know that the financial input, not just from the U.S. but from every other donor nation as well, is going to hold the key to any real success. We really hope that she’s right in how she sees it because otherwise in another twenty-three years we may be commenting on yet another National Plan responding to what has become an intractable drug-resistant pandemic that’s spiraled out of control because of lack of political will, which by then will almost certainly also have become the dominant part of the wider global tuberculosis pandemic.

We’re certain that it will now be down to the commitment and persistence of ‘civil society’ to maintain pressure on politicians to prise the appropriate funding out of their respective treasuries, and to ensure that this won’t be just turn out to be another empty pledge without proper implementation.

As Stop TB’s Lucica Ditiu advocates: “We can only end TB if we are willing to commit our hearts, minds, and resources to combating this terrible disease.” But we’re sure we first need to find out much, much more about where the problems really are, and then respond coherently and efficiently to what is found.

In hope for more progress in 2016!

World AIDS Day 2015 and those tricky '90-(90)-90' targets

Today is World AIDS Day.


Michel Sidibé, the Executive Director of UNAIDS, made an exciting announcement this week. He said:


The good news is that we now have what it takes to break this epidemic and keep it from rebounding—to prevent substantially more new HIV infections and AIDS-related deaths and to eliminate HIV-related stigma and discrimination.”


This is a fantastic achievement – the result of twenty years' consistent effort, tireless activism and heroic personal contributions. It’s no time for complacency, though, because there’s still a mountain to climb if the Sustainable Development Goal of “ending” HIV by 2030 is to be achieved. But today is surely a moment for HIV activists to both celebrate and be optimistic.


Unfortunately we can never help but compare the successes arising out of such concerted AIDS activism with the corresponding limited progress that’s been made with TB in the same period – and today is no different. Somehow TB has become the permanent poorer relative in relation to its deadly twin (remembering that these two diseases can work with a dreadful synergy, and that the majority of those who die HIV positive in Africa are actually dying of TB).


It’s so easy to forget this. In fact it’s easy to miss it completely because of a crazy but logical rule in the international classification of deaths. For epidemiological expediency it dictates that any human death can only ever be ascribed to one disease, and that, because of the historically-perceived global super-threat of HIV, if you die HIV positive you end up down in the books as dying of HIV even though it’s invariably another opportunist disease that actually kills you. This means that two-thirds of Africans who die each year finally consumed by their tuberculosis infections go down in the international tallies as dying from HIV (and not TB) simply because they lived and died HIV positive.


It’s easy to gloss over the implications of this even if you’re fully aware of them. It can tilt the numbers, for instance, to the extent that officially claims are made that TB deaths have reduced nearly 50% to targeted levels for 2015 when they haven’t.  It worries us as a result that even the WHO may be guilty, not just of glossing over the scale of the perpetuating problem of TB deaths, but also of ‘spinning’ their language in their Reports. Here’s the statement, for instance, that the organisation made about TB deaths in relation to HIV/AIDS in its most recent TB Report:


“TB now ranks alongside HIV as a leading cause of death worldwide.”  


But it doesn’t actually “rank alongside” it at all! TB is now unashamedly back at the top of the unholy tree of lethal infectious diseases despite its being one of mankind’s oldest enemies, despite its being a disease that’s been curable in most cases for nearly seventy years, and despite the fact that it’s been almost eradicated in most developed countries. In fact the WHO's own numbers show that TB’s estimated annual death-toll now significantly EXCEEDS the death-toll associated with HIV/AIDS – so what’s been a triumph for HIV activists has seen a reversal of fortune for those advocating for tuberculosis. It's all there in the WHO’s own reported numbers: there were estimated to be 1.5 million deaths from TB in 2014 (and we’d suggest quite probably a lot more..) whilst there were 1.2 million deaths logged for HIV/AIDS. (HIV was killing more than 2 million a year in its heyday so whilst 1.2 million annual deaths is still a huge number and still a tragic waste of lives, this should be recognised as huge progress. Tuberculosis, on the other hand, has being pretty consistently killing the same amount of human beings throughout this same period year on year.)


This simple graphic illustrates what’s been shaping up for years. In this illustration the middle section shows those co-infected with both diseases who often only get reported in the HIV numbers.


So we suggest that the WHO’s news about TB in October’s Report would have been better announced as follows:


“TB, mankind’s oldest bacteriological enemy, is now once again humanity’s most lethal infectious killer”.


The new '90–90–90' targets


Last year UNAIDS adopted a new and  rather catchy ‘90-90-90’ slogan as a part of their plan for ending HIV. According to this plan, by 2020 90% of all people living with HIV will know their HIV status; by 2020 90% of all people with diagnosed HIV infection will be receiving sustained antiretroviral therapy; and by 2020 90% of all people receiving antiretroviral therapy will have achieved viral suppression. (And what's more, by 2030 these same targets are intended to be ramped up to 95-95-95 driving HIV right into submission.)


Once again TB advocacy was looking outclassed and left behind, but right at the end of last year fresh efforts were made to match the undeniable ambition of these targets for HIV. In November in Brasilia the Ministers of Health from Brazil, Russia, India, China and South Africa announced almost identical commitments regarding tuberculosis at their BRICS Health Ministers Meeting.

They approved a co-operative plan that would include a common approach to universal access to first line tuberculosis medicines for all people with TB (not just in BRICS countries, but also in low- and other middle-income countries as well).


Perhaps a little unimaginatively they similarly called it ‘90-(90)-90’ (just a couple of brackets encouraging us to spot a difference.)


By this plan by 2020 90% of TB patients will be being diagnosed and started on first line drug treatment, 90% of the most vulnerable groups will be being screened, and a success rate in those receiving treatment of 90% will be being achieved. Furthermore they reckoned that meeting these targets will help see TB ended by 2035.


These targets for TB were originally suggested by Dr. Aaron Motsoaledi (who’s not just Chair of the Stop TB Partnership  but also Minister of Health for South Africa) back in October 2014 at the Union Lung Conference in Barcelona. This year's same Union Conference is being this week in Capetown, with special store being placed in launching the Partnership’s Plan for TB for 2016-20 with the 90-(90)-90 targets at its very heart. In fact, by coincidence, this Plan and its targets have been officially endorsed today (on World AIDS Day) by its delegates.


The BRICS ministers also agreed to cooperate on scientific research and innovations on diagnostics and treatment, including in relation to drug-resistance. They identified sharing technologies, identifying manufacturing capacities and TB financing as key priorities. But it’s the drug-resistant component that must now be the make-or-break factor within their ‘nineties’ targets, but the truth (at least as far as we can see it) is that they don’t allow for drug-resistance at all.


Getting 90% of drug-susceptible TB cases diagnosed and on treatment  is a big ask for sure, but it’s still achievable with concerted efforts given that currently 68% are believed to already be being found and treated. But with MDR-TB this same case detection rate is just 25% at best (and we’d suggest that even this percentage is optimistic). Anyone who seriously believes that this percentage can be improved nearly fourfold in as many years knows nothing about the challenges of diagnosing MDR-TB.


Meanwhile a 90% treatment success rate for drug-susceptible TB is even more achievable given that it’s already reported that an 87% success rate is being achieved. But with MDR-TB the related success rate is just 50% - and with XDR-TB it’s a terrible 25%. There’s little or no chance that these targets can be achieved in the timescale allotted for DR-TB.


There are possible knock-on consequences of these ‘nineties’ targets for TB. They're worrying and shouldn’t be underestimated. Individual health ministries are being increasingly pressured to do more to meet the targets set for them. If national TB programs are then put under the cosh to meet these targets they’ll do the obvious and concentrate almost all of their resources on achieving them – because otherwise they’ll be judged accordingly and may well lose their donor funding. But if they do so they’ll almost certainly do it at the expense of any existing MDR-TB problem that they have (because treating MDR-TB is so much more expensive and more challenging). In other words, meeting the very targets that are being seriously mooted to help end TB may paradoxically cut the drug-resistant component loose for the second time in twenty years.


What makes this all the more perplexing is that it was the ministers of the BRICS countries who came up with these targets, because four out of five of them are well-recognised to have drug-resistant TB epidemics that are the worst in the world. South Africa’s epidemic is well recognised to be out of control (though at least its extent is well recognised); China’s is known to be proportionately dangerous and is also reported to be occurring at frightening rates in newly infected cases; Russia’s (along, it should be added, with all of the former Soviet oblasts) DR epidemic is well entrenched and chronic (Mario Raviglione, the WHO’s TB czar, has euphemistically suggested that “something is not going well there”); and India’s is almost too terrifying to consider having been officially ignored and underestimated for far too long. Of the BRICS countries only Brazil seems to have escaped the curse of MDR-TB.


The fact that these five countries not only generally fund their own TB programs but also generate 25% of global GDP and have significant research infrastructure and capacity at least gives us cause for hope, but even Dr Motsoaledi must accept that his own country’s budgets for fighting MDR-TB (which are certainly more generously allocated than most) aren’t containing the problem and are already insufficient.


Somehow HIV trumps TB every time. It trumps it in the advocacy stakes. It trumps it in the resources stakes. It even trumps it in the coherency stakes. There’s enormous catching up to be done and we’re probably going to need the help of the HIV community to do it.


In contrast, the only thing that TB manages to trump HIV in is in its inherent complexities. There's unquestionably a long hard road ahead before we can claim we’re defeating this disease, and it's one which we're sure needs to be navigated not with catchy soundbite targets but with immense determination and unprecedented creative intelligence.

'Unchanged Melody (2)' ... further reflections on the 2015 Report

When it comes to measuring the progress of a disease three different methods of measurement are normally used: incidence, prevalence and mortality. In the case of TB these are invariably pegged against a consistent number of population – i.e. ‘per 100,000’ – so when we encounter such estimates we can understand them in terms of ‘how many per 100,000’.

Mortality rates are fairly obvious: it suggests how many individuals within an average 100,000 individuals might have been estimated to die of TB in the year in question.

Incidence and Prevalence, however, are slightly trickier. 

Incidence refers to the number of individuals who develop active TB during a particular time period (in the case of TB reports this period is normally a year) and once again it’s represented in terms of an average 100,000 population. More often than not this measurement is used to suggest the likelihood that an individual in a population might be affected by the condition, but with TB it’s not quite that simple because we have two stages ofdisease – the latent phase and the re-activated one. So with TB it’s a little different, though incidence does (as we will shortly see) at least offer a useful idea of the rate of re-activation from earlier infections which were latent.

Prevalence refers to the total number of individuals in a population who have an active disease or health condition. With TB once again it’s represented in relation to an average 100,000 population. Sometimes you’ll see prevalence as being estimated against a period of time, and sometimes as being estimated against a specific point of time (referred either as ‘period-prevalence’ or ‘point-prevalence’). It’s the latter which is the case with TB numbers in WHO Reports. Essentially prevalence offers us more an idea of proportion (of how much of the population is has active disease) at a specific point of time, rather than a rate of infection or re-activation (which is what incidence measures). It’s normally calculated by multiplying the estimated incidence rate and the estimated average duration of the disease

TB is a chronic disease that can last for years and years (the WHO reckons the average duration of untreated TB to be 3 years), but it can also take between 6 and 24 months to complete a course of treatment, so these two measures (incidence and prevalence) offer very different windows in terms of what’s happening in any community epidemic. Put simply, if we have a country population with an estimated incident rate of 100/100,000 at the same time as we have a global average was 25/100,000 we can say that the rate of re-activating TB is four times the global average; but at the same time we can also reasonably assume that we simultaneously have a local pool of TB-infected people without re-activated disease which may well also be four times higher than the global average (because this is where the new incident cases must be coming from).

Furthermore if there was no TB treatment available and we accept the WHO estimate that the average duration of untreated TB is 3 years, we would logically reckon that prevalence was 100x3 or  300/100,000 (effectively three times the incident rate). The ratio between prevalence and incidence would then be 3:1. But in some cases (in children for instance) TB can kill literally in days, so things are far from consistently simple. And with the intervention of effective drugs this ratio drops anyway substantially: instead of 3:1, globally it looks like it’s currently down to roughly 4:3.

You may have already realised that TB incidence tends to offer more an idea of comparison. Countries with higher incidence rates have more entrenched epidemics than those with lower ones. It also offers an idea of trend, however: if the incidence rate is rising it suggests that, for one reason or another, more individuals are developing active potentially infectious tuberculosis; if the incident rate is falling it suggests the opposite (and this could well be because of successful efforts at TB control). Prevalence, on the other hand, tends to offer us not just an idea of disease burden, but also of attributable community risk: if the prevalent proportion is high it suggests that the risk for an individual member of that community of being infected by TB is also high; if it’s low it similarly suggest that the individual risk of infection is low.

Unfortunately, TB isn’t a simple disease so these measurements are far from straightforward in application because many factors may be at play in a national epidemic. First of all, (thankfully) not all re-activated TB is infectious. Pulmonary TB (the most common type) is generally accepted to be the most infectious; extra-pulmonary TB (TB which has infected another organ and constitutes globally perhaps 10%-20% of the pandemic) generally isn’t; bovine TB (extra-pulmonary TB contracted from drinking unpasteurized milk or poorly cooked meat from an infected animal) generally isn’t infectious either. But even amongst pulmonary TB cases infectiousness is known to be highly variable. Generally ‘sputum-positive’ cases (those who are diagnosed by sputum microscopy when visible TB mycobacteria can be seen in a sample of their sputum by microscope) are predictably more infectious than ‘sputum-negative’ cases (those diagnosed either simply by symptoms or by X-ray because there are no signs of TB mycobacteria on their microscope slides) for instance. And such sputum-negative cases comprise about 40% of the estimated pandemic.

But to make things more complicated still, a TB infection doesn’t remotely mean automatic illness anyway. This is because not all of those infected by the disease go on to develop active (potentially infectious and lethal) TB – in fact normally only a small percentage do, between 5% and 10% of infected latent cases – and this re-activation can often take years to happen. For the vast majority the disease remains contained by the first response of the infected person’s immune system – in which case it’s called a ‘latent’ infection without illness or symptoms but with an on-going possibility of breaking out at some later date and re-activating into full-blown TB.  If one happens to be HIV-positive as well, however, the odds are very heavily stacked against the disease remaining in this latent condition for very long – in fact the current guesstimate is that it becomes a frightening 26 times more likely to re-activate. If you think about this for a moment it makes this possibility much more like a stone certainty.

So far so good, if that’s the only way to describe such a depressing summary.

The missing measurement for MDR disease

Strangely no estimated prevalence rates for either MDR- or XDR-TB yet appear in the annual Reports. Generally these Reports offer absolute estimated numbers of MDR cases calculated directly from percentages of the wider pandemic which have been estimated themselves from prior surveys of drug-resistance in the countries concerned. So if there are estimated to be 10,000 new cases of TB in a country in the year in question, and 5% of its TB disease is reckoned to be MDR, then 500 new MDR cases can be assumed to be arising. Sometimes these estimates are the results of national surveys, and sometimes they are extrapolated from sub-national ones. And sometimes these estimated percentages are from surveys that are a decade or more old.

One general problem with these incidence/prevalence indicators is that their value can fluctuate when the base numbers are low, and this may possibly be why they’ve been avoided with MDR-TB so far. This concern is only really relevant, however, if there are any inherent risks of ‘false positive’  diagnoses – in other words if a medical test for the disease in question is known to produce a proportion of false positive diagnoses because only a few can then really throw the numbers. With diagnostic tests for TB, however, this isn’t the case - actually it’s the opposite. TB tests generally are inherently unreliable and are far more likely to produce false negative results (hence the necessary categorisation of ‘sputum-negative’ disease for when the disease is clinically diagnosed despite the absence of any confirmation by bacteriological tests). All widely available approved tests for TB is statistically likely to provide some false negative diagnoses, so it really doesn’t seem that this particular caution should be being applied with this disease. So we’re really not sure why prevalence of MDR-TB isn’t being assessed.

The implications with MDR- and XDR-TB

Meanwhile, as we’ve already seen in the case of the wider pandemic ,the WHO hangs its hat on a prevalent-to-incident ratio of around 4:3. This is hardly controversial but it’s important to recognise that this only applies to drug-susceptible disease. Given the far lower detection rates with MDR-TB (at best a rate of 25% as opposed to 63% for DS-TB), along with the lower treatment success rates (50% as opposed to 86%) we think that it can be anticipated with some certainty that the existing ratio of prevalent to incident cases with MDR-TB must be much higher than the blanket 4:3. In fact we think that it could quite easily be 2:1. And if this is the case there could an awful lot more infectious prevalent MDR-TB cases out there than anyone is caring to discuss - possibly at least twice what anyone is reporting, and at least twice what anyone seems ready or willing  to plan for.

We’re prepared to take a rough punt in this blog at what we may be looking at. We fully accept that we may end up some way off the mark with our numbers, not least because we don’t have access to the necessary data, but we think that this is a worthwhile exercise at this point of time given what’s at stake.

We can make a start by looking at what the most recent Report had to say about treatment outcomes in MDR cases (from its 2012 cohort, their most recent data). Here’s what it had to say on the matter: 50% of MDR cases who started treatment successfully completed it; meanwhile of the other 50%, 16% were known to have died, 16% were lost to follow up, 10% were reported as having failed their treatment, and for the remaining 8% there was no outcome information available.

From an epidemiological perspective we can actually be rather relieved that those 16% died, because at least we can then say that they no longer pose an infectious threat to anyone. We can’t, unfortunately assume anything similar about the other 34% - but let’s be epidemiologically hopeful and assume that the 8% who had no available outcome information shared a similar fate (or assume that they spontaneously recovered which does sometimes happen). At least then our rough calculations can’t be accused of being incautious. So this leaves 26% of our original treatment cohort remaining potentially infectious for as long as they keep breathing.

It may be remembered from our earlier blog (‘Unchanged Melody (1)‘) that there were 123,000 MDR cases that were diagnosed and notified in 2014. Of these, however, only 110,000 were enrolled on treatment. So using our percentage we’ve just decided upon of cases who remained infectious, we have 26% of these 110,000 (or 28,600) as the first contribution to a cumulative woodpile of prevalent infectious cases to consider for this year. But we can also immediately add those 13,000 who were diagnosed but never enrolled (123,000 less 110,000). And we can also add those who were estimated to have been new cases of MDR disease but who never got notified at all (480,000 less 123,000 or 357,000).

So here’s the sum of prevalent cases rolling out from the 2014 cohort:




                                                398,600 prevalent potentially infectious MDR cases arising last year

Let’s just call this 400,000 for simplicity’s sake from here on. The million dollar question now is this: how long might they survive?

Well, let’s check back on the South African study which tracked XDR patients who were discharged from hospital after failing at least two years of all available treatment. These unhappy souls were then seen to survive for an average of 19 months before dying. This same survival period was recorded as being three years in Cambodia in another study. But we also know that these numbers should be treated with huge uncertainty if we are to view them globally, so let’s more conservatively suggest that the average survival rate of these 400,000 infectious cases might be just 12 months (once again because we don’t want to be seen as being incautious in our rough calculations).

On this basis we can anticipate our 400,000 potentially infectious cases from 2014 might just survive on average for the duration of 2015 – and in line with accepted infection-rates for TB (that a single infectious TB case infects 10-15 further cases in a twelve month period), they can thus be anticipated to infect roughly around 5 million people with their MDR strains in this period.

We should add at this point that some disease-duration calculations used by the WHO do seriously challenge this idea if the case concerned is also HIV positive. Without treatment such cases are reckoned by the WHO to last anywhere between a few days to two-and-a-half months, but since even treated HIV cases are only reckoned to have the disease for a maximum of a year when the treatment for MDR lasts for two we’d simply suggest that these numbers may need reviewing. Furthermore, given that South Africa (where those patients were seen to survive for 19 months) is a high incident HIV country, we think this is a reasonable viewpoint. 

So this is pretty serious stuff, although we also know that these prevalent cases won’t all be infectious which gives us cause to be careful what conclusions we might draw. It does suggest though (if the proportion of MDR disease is remaining essentially unchanged) that several million could be being added to the existing growing pool of MDR latent infection every year – the size of which we really still have absolutely no idea about at all. And between 5% and 10% of this pool can be expected to develop re-activated infectious MDR-TB in the course of time (though this will be a much higher percentage if there’s much HIV around).

If we’re thinking of 5 million new latent infections each year, however, then happily these numbers seem to roughly tally with the WHO’s estimate of 480,000 new MDR cases each year since 10% of 5 million is 500,000, or almost exactly the same number as the WHO estimate. In other words we can reasonably suggest that the cycle of MDR disease is indeed stable as is being reported by the WHO. But unfortunately the reality doesn’t tally with this reckoning because, whilst our 5 million new infections were calculated from those who were estimated to be new incident cases in 2014 they only relate to the number infected during 2015 (during the year which we are suggesting the 400,000 might survive). As such it needs to be added to by two other numbers:

  • one  is the possible number of people who would have been already infected by all 480,000 of these ‘new’ 2014 cases before they were ever likely to have presented themselves for diagnosis at a TB clinic;


  • and the other is the number who might have already been infected by them during the year in question (2014).

TB is well recognised to be a chronic disease, and the nature of those it most frequently infects (along with their general limited access to health care) means that the disease is frequently very well advanced before the sufferer presents for diagnosis, often only when he or she is finally really struggling to work. There are plenty of variables inherent in this for sure, but it’s been suggested that in low-income populations it can take as long as three years from onset of symptoms before patients even present themselves to a clinic.

Generally the WHO reckons that the duration of an average TB case is around 3 years from start to finish, either before dying or spontaneously recovering. So let’s stick with this estimate for now, and suggest that this “pre-presenting” period might be on average just a single year (much as we’ve suggested is the average survival time at the other end of the treatment period). In this case all of our 480,000 ‘new’ cases estimated to have appeared in 2014 may well have already latently infected over 5 million others before the calculations we’ve just run above have even come into play. And if so we can effectively quite easily double our 5 million number at a simple stroke, and then quite reasonably suggest that, unless only 5% of such latent infections re-activate, the WHO’s estimate of a stable 480,000 new cases of MDR-TB each year might not be quite such a reasonable number after all.

If the re-activation rate were a blanket 10% (still bearing in mind that the re-activation rate is reckoned to be 26 times higher amongst HIV co-infections this percentage hardly seems unreasonable in a country in southern Africa) then we can anticipate that, with a possible 5 million new DR latencies being spawned before the year in question and a further 5 million being spawned the year thereafter we’re looking at a prevalence of possibly 1 million potentially infectious cases. In other words, the prevalent:incident ratio of MDR could quite reasonably be assumed to be 2:1

But we should also consider how many might be have been infected by them during the year 2014 itself. In other words, if we just look at the last three years, we might even go so far as to suggest the following:

                                2012                       5 million new latent infections

                                2013                       5 million new latent infections

                                2014                       5 million new latent infections


So just in the last three reported years the pool of latent MDR-TB may have increased by 15 million cases just from the 2014 cohort (not even contemplating the inclusion of those infected by the survivors from the 2013 cohort which could be adding a further 5 million). In which case we might even be looking at a prevalence:incidence ratio that’s near to 3:1 which is what we originally reckoned for TB disease when it’s left untreated.

Of course it probably won’t be because we haven’t as yet factored in the fact that probably only half of these surviving MDR cases will be infectious (by having sputum-positive pulmonary TB). We can hope that the other half won’t be, which means that the real ratiomight be nearer 3:2 (at least if we ignore the HIV factor). But even 3:2 is significantly different to 4:3 which is the ratio of ‘all-TB’ which seems to amount to a stable pandemic.

The MDR-TB pandemic surely cannot be as stable as is being claimed, can it?

The risk of re-activation of a latent infection is sometimes calculated as follows: 5% for the first two years, and then 0.1% for each year thereafter (though we stress once again that these sorts of percentages in no way apply to the immune suppressed, and reiterate that this re-activation is reckoned to be a huge 26 times more likely if the patient is co-infected with HIV). But of course there are some other counter-balancing factors to this. One is infection control within the community – and of course this could make a huge difference to keep the re-infection rates down. Another is that these events are taking place in hotspots, so the pool of potential infectees has to become relatively more finite in the course of time as more and more might be infected. In other words it might even be that the rate of onward infection of 10-15 new cases will in the course of time reduce. But this should hardly be any cause for complacency.

But what this all suggests is something simple. It’s also a little terrifying: if there is any prevalent MDR disease in a country that also has high rates of HIV then the possibility of its drug-resistant epidemic rising alarmingly is significantly more than in a country with little HIV. In fact it’s as good as a stone certainty and it should be treated as such.

But let’s remember something else: the WHO believed that the estimates of MDR disease last year were “essentially unchanged from those published in recent global reports” (Global Tuberculosis Report 2015, page 56). Frankly, if any of the above is correct, this assessment does seem unlikely. Any conclusions we might be drawing from this year’s Report can equally be extrapolated backwards for the last few years as well, the only difference being that the numbers put on treatment were less each year making any final extrapolations a little worse than we’ve made them for the most recent 2014 cohort. This simple cumulative effect seems to be something which is currently simply being ignored which has to further suggest that the current estimate of unchanging numbers is mistaken.

But here’s a rather inconvenient question to consider: why is it that the estimated rates of MDR disease in new TB cases in South Africa are being published as being just half of the global average when there’s been an MDR (and XDR) epidemic of sizeable proportions in this country for well over a decade? South Africa is a high incident HIV country with a known MDR and XDR problem and it's also recognised as being the furnace for the African TB epidemic. These are the percentages that appeared in the WHO Report: the global estimated percentage of new cases of TB that were MDR in 2014 was 3.5% whilst the published estimate for South Africa was 1.8%; the global estimated percentage of retreatment cases that were MDR was 20%, whilst for South Africa it was just 6.7%.

Improbable percentages? We certainly think so. But then you may well not trust our calculations either because they’re too rough and ready. Truthfully we can’t be sure of them ourselves. But what we do know with absolute certainty is that most of the measurements of this disease are still far too fraught with uncertainty for anyone to be confident about what’s really going – and we think that these things need to change rather fast because there are an awful lot of lives at stake.

Unchanged melody... (1)

Well the WHO’s Global Report has been out for over a week, and it  turned out to contain pretty much the sort of numbers we were anticipating. Unfortunately we’re still struggling a little to make coherent sense out of all of them. While we wait for their expert response to some specific questions we’ve asked relating to what appear to be serious anomalies regarding some of the numbers relating specifically to South Africa, we’ve decided to share some of our other confusions.

To set the scene we’ve selected some specific individual sentences from the Report itself, and then compared them with some similarly selected sentences from the sobering statement made by MSF last week in response to the Report’s publication (‘Global TB report reveals rate of diagnosis for multi-drug resistant TB cases is heading in the wrong direction’).

We’ve chosen these sentences very deliberately, and make no apology for the fact that those of WHO which we’ve selected are not necessarily representative of the wider Report. We’ve chosen them because we suspect that they contain some discrepancies in statistical representation and in language choice which may merely be the tip of an epidemiological iceberg, the most dangerous part of which is unseen as we will further explain at the end of this particular first piece. As such we end this piece by suggesting that something rather important may be being missed – and naturally we welcome comments accordingly if others see otherwise.

In each instance below the first selected text is from the WHO’s Report, and it’s then followed immediately with a comparative text from MSF. Both of these are then followed by our own commentary which is intended to add context to each selection. Here is the first one.

WHO: “The advances are major: TB mortality has fallen 47% since 1990, with nearly all of that improvement taking place since 2000, when the MDGs were set.”

 MSF: “Yet another year of disheartening statistics, such as TB’s persistent annual 1.5 million death toll, should serve as a wake-up call that enormous work still needs to be done to reduce the burden of this ancient, yet curable disease.”

Our own commentary: First of all we have to admit that we strongly suspect that the annual toll of 1.5 million premature TB deaths may be an underestimation. But be that as it may, we simply can’t accept the claim that “TB mortality has fallen by 47%” anyway. This is because it deliberately omits from the body count all of those who died from TB but who were co-infected with HIV/AIDS at the time they died. For some curious reason best known to the folk in Geneva these 400,000 dead people just don’t get counted in this particular equation which relates to one of the targets set by the Stop TB Partnership back in 2006 – though they do get counted in the WHO’s estimated 1.5 million annual death toll referred to by MSF. If they were added into the falling-mortality equation as we believe they always should have been then the number of deaths that could be said to be directly caused by TB last year was actually not 47% – but about 9% less, and we can even use a WHO graph to demonstrate this.



You can see from this graph that two curves are separately tracked – one of deaths among HIV-negative people which peaked around 2000, the other among HIV-positive ones which peaked around 2005. You can also see that back in 1990 there were estimated to be 1.5 million deaths in the former and about 0.15 million deaths in the latter (totalling 1.65 million). In 2014 there were estimated to be 1.1 million deaths in the former, and 0.4 million in the latter (totalling 1.5 million). And this, any which way you may choose to look at it, represents a reduction in deaths of 9%, and not 47%.

So to the next selected sentences:

WHO: “More TB patients were tested for drug-resistance in 2014 than ever before.”

MSF: “When it comes to the deadlier forms of the disease – such as multidrug-resistant TB – the news is particularly bleak. Despite progress in rolling out better diagnostics such as rapid molecular tests, fewer people were detected with MDR-TB in 2014 than in 2013, even though the estimated number of new cases remained steady.”

Our commentary: Here we have examples of carefully selected words intending to promote quite different conclusions – with both statements being apparently correct. Fewer people were detected with MDR last year than the year before (something which MSF sees as being “particularly bleak”), and at the same time more TB patients were tested than ever before (which the WHO reports as being encouraging). If we accept both statements as they stand, however, and then put them together we can even draw a further conclusion still – and it’s one that also seems hopefully optimistic. If more patients were tested and in the same period fewer MDR cases were detected it suggests that the total number of cases of MDR disease hanging out among the majority host of drug-susceptible TB must somehow be on the wane. And if this were the case then it should surely have been the headline of the whole Report, since the WHO’s Director General herself stated a couple of years ago that the world is sitting on a “powder keg” of drug-resistant TB. So collating these two statements together offers a hopeful sign that the powder keg’s sizzling taper might actually be showing signs of fizzling out.

There was no such big headline however – the best the Report was prepared to offer was that they the proportion of DR-TB within the pandemic last year was “essentially unchanged” (on page 56) and/or that it has “changed little in recent years” (on page 2).

The trouble with this more sober reckoning though is that, as much as we might hope it might be true it really doesn’t make sense. If it really was such a struggle to see the rate of the whole TB pandemic (the vast majority of which is susceptible to the standard DOTS regimen of drugs) stall and then begin to decline (now dropping at a rate of about 1.5% a year) with the majority of cases getting treatment and the vast majority of these being successfully treated, then how can the same thing possibly be happening with MDR cases when everyone agrees that the vast majority of cases never see treatment at all and that those who do only complete treatment successfully half of the time?

So let’s try another selection, this one also relating to MDR-TB.

WHO: “The ratio of patients enrolled in treatment to patients newly notified as having MDR-TB … was 90% globally …”

MSF: “We’re losing ground in the battle to control drug-resistant forms of TB, and without considerable corrective action, the vast majority of people with MDR-TB won’t ever be diagnosed, put on treatment, or cured. Today, a person with multidrug-resistant TB has worse than a one-in-four chance of being properly diagnosed.”

Our commentary: Once again we can see some selective phrasing being used by both parties. MSF’s language in this instance is a little more emotive. It’s also quite explicit. At best only one-in-four cases are being properly diagnosed. (Whilst this proportion is taken directly from the data in the WHO Report, we have to add that we also think that this number is pretty optimistic). Meanwhile the WHO confirms from their data that a lucky 90% (or nine-out-of-ten) of these one-in-four MDR cases who get diagnosed will also get approved treatment (and do please note that by inference this computes to only nine-out-of-every-forty of all estimated MDR cases getting approved treatment). But the WHO also offers data in their Report that indicate that only half of these complete treatment successfully. So we have to factor this in as well – and so actually it looks like only nine out of every 80 MDR cases were successfully treated last year – or just over 10%. Under such a scenario it does look like MSF are right: ground must be being lost even though 90% of newly notified patients may have been being enrolled on treatment programs, and “considerable corrective action” does need to be implemented.

So let’s try a fourth and final comparison.

WHO: “Globally in 2014, 123,000 patients with MDR-TB or rifampicin resistant tuberculosis (RR-TB) were notified … This was equivalent to 41% of the 300,000 estimated TB patients who were estimated to have MDR-TB in 2014.”

MSF: “Worse, the total number of people diagnosed with MDR-TB globally in 2014 was actually lower than the previous year (123,000 in 2014 vs 136,000 in 2013), although the total estimated number of people who developed MDR-TB remained the same.”

Our commentary: Here we have two statements which use the same number (123,000 patients either notified or diagnosed as being MDR by national TB programs) to infer vastly different things. Broadly speaking one infers that this 123,000 tells us that some things are still going backwards; the other that it gives grounds for optimism.

But in relation to the WHO’s statement above there was one important word that was missed out from the WHO’s summary quoted above which does influence our possible interpretation of it. This was the word ‘pulmonary’. The WHO suggests above that there were 300,000 patients who were estimated to have MDR-TB in 2014 – when this was not actually their best guess for all cases of MDR-TB at all – it was only their best guess for new cases of pulmonary MDR-TB. On an entirely different page their estimate of the total burden of all types of new cases of MDR TB was actually 480,000 – a full 60% more. In fact on another page of the Report they even compute this number against the 123,000: “Of the 480,000 estimated to have occurred in 2014, only about a quarter of these – 123,000 – were detected and reported”. So 41% of “estimated TB patients” getting notified or 25% of them? You can take your pick depending on which section you read, on which page you open the document, or on which conclusion you prefer to draw, more positive or more negative.

The missing measure

But we have one ore thing to add to this blog and we believe it to be very important indeed. The number that’s never getting estimated (and we think it’s a rather important one) is the total number of MDR cases who might just be ‘out there’ now – not just the estimated number of new cases or the estimated annual number of missed MDR cases (if it’s even possible to remotely accurately estimate this given the terrible dearth of diagnostic surveillance). In order to estimate the number of living-breathing MDR cases that have to be out there we need to add in the number of missed cases from the year before who have survived, and also the number from the year before that who are still surviving as well, along with the number of MDR cases who fail treatment each year but who survive and remain infectious until they either spontaneously cure (as some do) or die – or continue to survive permanently infectious until they die of other causes. 

A survey in South Africa has suggested that XDR patients who fail all treatment are then discharged and survive for a median time of 19 months before dying; a similar one in Cambodia suggests that they may last for an average of three years. Such periods of time are far from epidemiologically insignificant. In three years a single infectious patient can be anticipated to infect a further forty patients with untreatable (albeit initially latent) disease. Of these forty latent cases, however, epidemiologists would only expect between two and four to re-activate and become infectious themselves in the course of time, but that’s certainly enough to both perpetuate and potentially increase a pandemic of functionally untreatable disease. (And these sorts of number would certainly be expected to be higher if there was much HIV in the community which is without question the case in South Africa).

In epidemiological parlance these unlucky folk are called ‘prevalent’ cases, and with a chronic and widely-disseminated disease like tuberculosis it’s expected that there will invariably be a higher number of ‘prevalent’ cases in any given period (let’s say during the 12 months of 2014) than there will be newly emerging ‘incident’ cases in the same year – if only because the incident cases have to be included amongst them. (With some significant misgivings, however, we note once again in this year's Report that several of the reported national numbers suggest the opposite for last year, including three of the 22 so-called ‘High Burden Countries’ where particular focus has been exerted on their epidemics for well over a decade, with a further four of the 22 improbably reporting prevalence:incidenceratios that were nearly equal at 1:1).

The WHO’s numbers for the whole pandemic support a more probable ratio, however: they estimate that there were 13 million prevalent cases in 2014, but that there were 9.6 million new incident ones. The year before it was 12 million and 9 million but the ratio is almost exactly the same – at 4:3.

But the WHO believes that there were 480,000 new incident cases of MDR in 2014, a number which we know can only represent a proportion of the prevalent MDR pandemic even if MDR-TB incidence really “has changed little in recent years”. So what about this slowly accumulating host of prevalent MDR cases (those who struggle on for two to three years before expiring – or even longer)? There’s no mention of them anywhere in the Report despite the fact that they possibly pose the biggest threat of all to the WHO’s best efforts to end the pandemic, not just because they are drug-resistant, but also because they are bound to also include untreatable infectious cases.

In the next blog we will try and explain why the general prevalence ratio of 4:3 for the TB pandemic has to be much higher in the MDR and XDR sub-pandemics, and we’ll try putting a few rough numbers together in the process of doing so.

So whose Plan is it anyway?

The last twelve months has seen the emergence of a new ‘post-2015’ Global Strategy for TB – one that’s intended to be rolled out over the next twenty years in the hope of seeing the ‘end’ of this pandemic.

Back in June 2013 a high level panel established by the Secretary General of the UN submitted its report to the WHO. It contained its own recommendations for this new plan for TB and the principle of universal health coverage was definitely included within them. Amongst other things this amounts to is the difference between aggressively treating drug-resistant TB (which is so expensive and requires such resource) and not doing so.

During the first phase of this Global Emergency (from 1993 till today) there has unquestionably been a shamefully inadequate response to the drug-resistant part of the pandemic – which is exactly why the problem is now so large.  What's alarming us is that we have yet to see one visible target set in this Plan for either MDR- or XDR-TB.

The aims of the new draft post-2015 strategy first showed its face in October 2013. Instead of the previous long-term aim of “eliminating” TB by 2050, it now surprisingly included the more ambitious goal of “ending the global TB epidemic by 2035”, with milestones and targets being set for 2020, 2025, and 2030. Things were starting to look astonishingly optimistic, but it was still intended for the plan to be reviewed by the WHO executive board in January 2014 and then for it to be discussed and hopefully ratified by the World Health Assembly in May.

And this is exactly what happened. The delegates of the 192 countries who were at Geneva in May 2014 unanimously and enthusiastically adopted the Plan and then passed it straight back to the WHO, with half of them surely knowing that its targets were impossible to be met in their own countries given their existing health resources, and surely all of them noting that a Plan which embraced the idea of universal health coverage failed to incorporate a single target for DR-TB that might actually help make this happen.

It’s important to appreciate that it’s the responsibility of national governments and their health ministries for the planning and execution of their own TB programmes at national levels. The efforts of such national TB programs (NTPs) are informed, if not largely directed, by the WHO’s strategies but it’s down to the NTPs themselves to implement them. Ideally these NTPs govern the equipping and functioning of diagnostic laboratories, providing a continuous supply of drugs to treatment outlets which are appropriately available, co-ordinating the efforts and activities of government and non-government health care operatives, and setting national policies relating to TB treatment. But of course we don’t live in an ideal world. We live in one where half of the countries in the world don't have the resource to diagnose MDR-TB let alone treat it at any scale, and without doing so there's not a prayer that TB can be 'ended' by 2035.

So whose responsibility then is this Plan that can't be met, and whose responsibility is it to see this disease being properly treated and the pandemic ended?

Well certainly the UN should put its hand up. After all it initiated the formation of the WHO in the first place, but its specialist committee also submitted its own report on TB to the WHO back in June 2013 which formally started the ball rolling with this new post-2015 Global Plan. The result – the current Plan to ‘end’ TB by 2035. Meanwhile back at the UN that same specialist committee was apparently also concurrently involved in developing the UN’s own Sustainable Development Goal no.3 for Health. This also includes the goal to ‘end’ the epidemic of TB, but this time by 2030, five years earlier than the WHO’s Global Plan!  Doubtless some regrettable semantics exist here, but it’s difficult not to believe that when the SDGs were officially adopted last month there wasn't serious consternation amongst those in the WHO who had worked so hard on their Plan for 2035 – which is ambitious enough after all.

Is this an example of some of the incoherence that appears to be endemic in TB control? Maybe it is.

But as far as implementing the Plan is concerned (whichever end-date one favours) it still has to be first and foremost the responsibilities of the governments of the countries themselves as part of their social contracts with their citizens. In other words, it actually amounts to the individual responsibilities of exactly those World Health Assembly delegates of the 192 countries who so merrily signed the new Plan in Geneva last year and then passed it back to the WHO before retiring for drinks and canapés. (Or similarly the delegates of the 193 countries of the UN General Assembly which adopted the 2030 Development Agenda titled Transforming our world last month – those SDGs).

But this is a global problem and TB is an airborne disease with no respect for borders, so such responsibility has also to be shared with the WHO itself, particularly if it recognises that its Global Plan simply can’t possibly be met by individual countries without outside help. In fact the WHO accepts this shared responsibility, with the prime responsibility normally resting on the shoulders of the governments themselves – but wherever resources are known to be particularly poor these responsibilities weight heavily in the direction of Geneva.

So it’s also the responsibility of those in Geneva to accurately assess the situation on the ground in each and every one of these countries, not just in terms of the burden of their disease, but also in terms of the resource available to counter it – and not just do this in terms of what the country may be ‘officially’ telling them, but also in relation to what is really happening on the ground because for many reasons this might be different. And they have an army of operatives worldwide to do exactly that.

But even this gets complicated because within Geneva itself there are divided responsibilities with two distinct organisations now working on the case, and they don’t always see eye to eye with each other.

One is the WHO and its Global TB Programme, and the other is the Stop TB Partnership. 


The Global TB Programme is a division of the WHO with its own Director, Mario Raviglione, who’s been in post since 2003.  They are the normative body who don't generally engage in advocacy but rather develop their general strategies based on the global data, the collection of which is under their general direction. It was the WHO’s Global TB Programme, for instance, which drafted the current WHO End TB Strategy.


The Stop TB Partnership, on the other hand, currently convenes what is known as ‘civil society’ and actively advocates for the disease worldwide, with the intention of accelerating social and political action in relation to controlling the disease.  Stop TB has its own separate funding with which to draw together its own plan as well – this one a more advocacy-focused 'five year plan' which takes us from 2016 until 2020. But Stop TB still has to stick to what the Global TB Programme has put into its post-2015 End TB Strategy so the parameters for their own plan are effectively set for them. They then have the challenge of pitching everything in a way that will keep donor governments interested.  It's not a simple situation to be in, and it surely helps a little if the picture isn’t too bleakly painted.


But the truth is that things don’t appear to be exactly all a bed of roses in Geneva, and today co-ordination and coherence seems to be on something of a knife-edge. What’s a little ironic is that the Stop TB Partenership was originally conceived back in 1998 in response to a recognised need to co-ordinate those involved in the prevention and treatment of TB. By 2006 the Partnership had even developed muscle enough to launch its own targets for TB for 2015, which were far more ambitious than those developed for the disease before this by either the UN or the WHO.


Was their 2006 Plan an early sign of the tensions that appear to have developed since? It’s hard to say because everyone is so cautious about what they state on the matter publicly. What’s certain is that until recently the Partnership’s secretariat was hosted by the WHO, but they've now moved out. It’s now hosted by UNOPS, with the Partnership officially recognising that “the Partnership in its current form will be better able to fulfil its mandate by moving its secretariat to … a specialized provider of administrative services.” It carefully added however that, “the decision was fully supported and facilitated by WHO”. What’s clear is that members of the Partnership were previously actively involved in drafting earlier global strategies. It’s not so clear how actively involved they are now.


What's acknowledged on the Partnership’s website, however, is that, “the Partnership draws on WHO's expertise, uses its global data and information as the base for its own advocacy material and coordinates its actions and initiatives closely with WHO.” It’s all very diplomatic stuff, particularly because it refers to what may be the root of the problem – the global data – because everyone who knows anything about TB knows that the numbers bear only a faint reflection of the reality on the ground – most particularly in respect to MDR- and XDR-TB.

And it's the WHO that has to accept the full responsibility for collecting the data from the countries themselves and representing it appropriately.

Without any question at all there’s been a desperate dearth of surveillance data in previous Reports, particularly in respect of drug-resistance, and this is unlikely to be different this year. In the last Report there was a “new analysis” of the extent of drug-resistance and as we have blogged already this analysis was unbelievably flawed. But it’s one thing publishing flawed data, it’s another entirely if you use it to inform global policies for the coming two decades.

And this is why we’re so worried about the content of the impending Report.

What exactly is it going to say about the proportion of drug-resistant disease within the wider pandemic?

What Global Emergency exactly?

In a few days’ time the WHO will publish its annual Global Tuberculosis Report. You may find some reference made to it in the media. If you do, then what you'll read about it will most probably reflect a press release crafted by the WHO, the organisation which has the unenviable responsibility of trying bring this disease under control. What you read will also probably depend on where you live because, despite tuberculosis being a truly immense humanitarian problem, astonishingly little gets properly discussed about it in the media of those countries where the disease has now been dramatically reduced. Unfortunately, however, the same extraordinary reductions were simply never achieved in those countries (or at least in their poorer quarters where those who are most vulnerable to this disease live) which is why today we have such a serious collective public health challenge on our hands.

And we really are worried about what this imminent Report may contain - not just because of what it might say, but also what it may NOT say. So this is the first of a short series of blogs to promote awareness of this important publication – comprising a couple of discussion pieces before its publication, followed byn one on the day of the publication itself, and probably one a day or two afterwards once we’ve had a chance to take a proper look at it. In truth we hope that much of what we have to say in these earlier blogs will be proved wrong or even grossly unfair – and you’ll understand why if you read on.

This Report comes at a critical moment – it will appear at the end of the ‘Millennium Development Goal’ period (which has run up to 2015) – at the moment when a set of new targets are being set in stone for the next 15 years in the hope of achieving what hasn’t yet been achieved – which is a significant reduction in the incessant death and destitution brought about by this terrible disease. If this Report tells the truth about this devastation then we believe that any strategy developed from it will stand a chance of success, but if it chooses not to (and we do recognise that many of the reasons for not doing so may seem to the authors of the Report to be politically good ones) then we’re not at all sure that it will do much at all. In fact we fear not just that this emergency will continue, but that this treatable disease is now going to get more and more difficult to both cure and control.

Here’s something that we believe that this Report is going to say: that TB has this year taken back its old title of being humanity’s most lethal infectious killer disease. For some years now it’s been believed that HIV/AIDS had stolen this particular crown away from it – but if you recognise that a majority of those who live with an HIV infection in Africa actually die of TB even this interpretation has always been challengeable.

The Report is also probably going to say that TB still activates in around 9 million new victims a year, and kills about 1.5 million of them. In fact we believe that it kills many more than this – probably as many as 2.5 million. We also have a hunch that one or more recently completed national prevalence surveys are going to force the WHO to suggest that the rates of TB (incidence, prevalence and mortality) are all a bit higher than previously estimated – but ten we even know of an eminent London expert who thinks that even this will be a gross underestimation.

How can this carnage possibly have been allowed to have happened when the disease is said to be treatable and is almost eradicated in so many developed countries? Or when the world appears to be able to tool up so readily to control and outbreak of SARS or swine ‘flu?

The Background

Back in the 19th century it was being reckoned that as many as one in seven deaths in Europe were down to tuberculosis. Such terrible death rates began to reduce in the 20th century, to the extent that when the first TB drugs arrived the 1940s they really could make a difference and it was quickly realised that the ancient killer disease really could be driven into submission. What happened next (with enormous effort it should be said) was an incredible public health initiative which saw rates of TB infections plummet in both North America and Western Europe and “man’s oldest bacteriological foe” driven nearly to extinction.

But in the rest of the world, unfortunately this wasn’t quite the case.

When the United Nations was formed in 1945, one of the first things that it proposed was the setting up of a global health organization. The result was the WHO whose constitution came into force on 7 April 1948 – a day which we now celebrate each year as World Health Day. The Organisation was initially directed to attack three specific diseases: venereal disease, malaria and tuberculosis – so right from the outset it was directed to keep TB securely in its sights.

Unfortunately, the first forty-plus years didn’t see the same sort of progress made in what were then referred to as the second and third worlds as had been seen in Europe and America. In fact rather the opposite, and this was partly because almost all of those many experts in lung disease who’s learnt plenty about TB now switched their focus on to treating lung cancer. TB was left to fester away in the slums and the barrios, killing at will - but that was until HIV arrived to stir things up and the Organisation at last woke up to the implications of its own neglect.

So in 1993, a full 45 years after it was first formed with a founding intention of driving TB into submission, the WHO found itself unprecedentedly officially declaring TB to be a Global Emergency. And 22 years later, that same Emergency still exists though with an added twist.

Sure the rates of the disease have now begun to reduce (though it took twelve years of struggle to see this begin to happen). It’s now reducing at a little less than 2% a year which means that at this rate the disease could finally give itself up to biomedicine some time in the middle of the 22nd century. So energies are now being directed towards accelerating this decline. But since this Global Emergency was first declared something else has developed which makes things a lot more complicated than they were in 1993: a proportion of the disease has been becoming increasingly drug-resistant, and is threatening to become untreatable just as these belated efforts have finally begun to take effect.

Drug-resistance isn’t simple. Clinically speaking with TB it comes in two basic forms – either multi-drug resistant (MDR-TB) or extensively drug-resistant (XDR-TB). With the former the disease is resistant to the two strongest anti-TB drugs, it’s difficult to treat successfully and it takes a lot of money to do so. With the latter it’s resistant even to some (or even all of the weaker drugs as well, and it’s REALLY difficult to treat successfully, and is REALLY expensive. Each type of TB requires vastly different resources, entirely different clinical strategies and different infrastructural resources as well. In other words, we have three pandemics where before we had one.

Effectively we can look back and see that we’ve had two phases of TB control. The first (1948-1993) when this treatable disease was allowed to fester and flourish in poorer countries while it was practically eradicated in the richer ones; and the second (1993-today) when it’s been allowed to morph into three distinct diseases, two of which are only treatable depending if local resource can afford to do so. And this epidemiological disaster hasn't just happed onits own - it's been allowed to happen  because drug-resistance develops through treatment mismanagement. It's a man-made disease in other words. What’s most astounding of all, though, is that this has been allowed to happen during 22 years of an official Global Emergency..

Is this all a gross oversimplification? Well some might argue that it is. But it’s at this particular point in this debatable history (when everything is undebatably on a knife edge) that this Report is going to be published.

Should we be interested in what it's gon to say? We think so, which is why we’re publishing this series of blogs.

The next blog in the series intends to discuss some of the responsibilities and what they imply.

The ‘Duke’ and the secondary stories behind this year’s Nobel Prize for Medicine

Duke Ellington was once asked what his favourite type of music was. “There are only two types of music”, he replied, “either good music and bad music”. And the same can surely be said of medicine.


The Nobel Award


This week an elderly and very modest Chinese researcher called Dr Tu Youyou has been belatedly co-awarded the Nobel Prize for Medicine for her meticulous research into the anti-malarial drug Artemisinin. This is a drug that has been subsequently hailed as the most important development in the treatment of malaria since quinine, so her story is surely one of good medicine – and so it’s been reported so in the media this week. In fact her own personal story is not just one of dedication, but also passion and bravery. There is also some very bad medicine that unravelled behind her discovery, however, and this hasn't been told this week, though it surely deserves telling just as much as her own one. It's a story of very bad medicine indeed and tells us a lot about the politics of global medicine today.


Artemisinin was first being identified outside China as a viable treatment for malaria back in 1979. But it was more than a decade earlier in 1967 that a group of Chinese researchers including Dr Tu Youyou had begun examining their culture’s traditional medical literature and realised that Qinghao, (Artemisia annua), or Sweet Wormwood had been being used in China as a tea to reduce malaria symptoms for sixteen hundred years right into the modern era. One of its chemical derivatives, Artemisinin, was then found by the same Chinese researchers to be even more powerful in its anti-malarial effects.

The ‘genocidal’ delays in the drug's roll-out

Their initial research coincided with America’s Vietnam War which provided reason enough, as far as Chinese politicians were concerned, to keep their researchers’ initial discoveries under wraps. Tu’s work wasn’t actually published until 1977 and, as was the custom in China at the time, the author of the study remained anonymous. It was a full six years after the end of the War, however, in 1979, when Dr Keith Arnold, a malaria researcher based in Hong Kong, first began hearing about the drug. He wangled his way into the PRC in the hope of finding out whether mefloquine, the drug which he had himself had helped develop with the U.S. Army (and which had been widely used in Vietnam), could outperform the artemisinin variants which he was hearing were still being developed within China. It turned out that all of his efforts on behalf of mefloquine failed - Artemisinin proving far more effective in every laboratory test. But the Chinese still stayed coy about their drug, leaving Arnold uncertain even as to what plant the drug had been derived from - ethically not good medicine at all. But then this type of bad medicine took a turn for the worse.

By 1982 Sweet Wormwood had been positively identified as the principal component for the drug’s synthesis and it had also been revealed to be an endemic plant in the U.S. (even growing on the banks of the Potomac in Washington DC). But, in spite of this, the desperately needed new drug for malaria ended up languishing on shelves because of conscious institutional neglect and inertia. The WHO actually failed to endorse the drug until as late as 2000, and even then it remained generally unavailable until 2006. So a full 26-year period went by between Arnold’s first encounter with it and its full availability – and 39 years had passed since this Nobel Prize winning research was first begun. If that’s not a story of very bad medicine indeed, it’s difficult to know what is.

The reasons for this delay may well have been complex, but they can’t possibly be excused given what was at stake. With nearly a million children a year at that time estimated to be dying from malaria in Africa, Arnold didn’t hold back on the matter, branding the delay “genocidal” (whether it was  caused by over-caution, negligent indecision or simple incompetence). Given that perhaps as many as 25 million children died in the hiatus period and the fact that the drug has since been hailed as the most important development in malaria since the introduction of quinine, his anger was surely understandable.

As far as we know, Dr Arnold never met Dr Tu, but they surely would have got on if they had. “It is scientists’ responsibility to continue fighting for the healthcare of all humans,” says Dr Tu, and Dr Arnold sang from the same hymn sheet. So good on Dr Arnold! – and congratulations to Dr Tu! – but shame upon shame on those politicians in the PRC, as well on those in Geneva who held up the roll-out of the drug for so long for whatever reasons.

Incidentally, it’s worth noting that the WHO was founded in 1948 with a global remit to tackle three specific diseases – venereal disease, malaria and TB. Their record on the latter two is still hardly yet worthy of any award and certainly doesn't make for atune the Duke might have tapped his feet to. In a couple of weeks the Organisation will be releasing this year’s Global Report on Tuberculosis and its possible contents fill us with trepidation because we already fear that it will contain evidence of similarly bad medicine. We will report on it as soon as we have full access to the Report and have been able to digest it.)

So what are the real costs of drugs today?

It’s unlikely you won’t have found yourself shocked these last few days by the story of the ex-hedge fund manager who bought the rights to a so-called ‘HIV drug’ and then “gouged” the price per pill from $13.50 to a staggering $750.

What you may have missed, though, is that something very similar was happening at almost exactly the same time to an old second-line TB drug. In this case it was hiked from US$500 for 30 tablets to $10,800 as the drug changed hands from Purdue to Rodelis Pharmaceuticals – and then was dropped back to $1,050 for 30 tablets as Purdue took the drug back after protest. (They reckon that they simply couldn’t make any profit manufacturing it at their original price.)

Aside from the fact that the hedge-funded ‘HIV’ drug (deraprim) is 62 years old and isn’t strictly speaking  an HIV drug at all (actually it’s a drug used for treating a serious pararastic infection that sometimes occurs in HIV patients) there seems to be something pretty weird afoot here and it’s all about manufacturing rights and prices in the U.S.

This second-line TB drug (cycloserine) is of a very similar age to the ‘HIV’ drug – it’s technically a year older having been discovered 63 years ago. As such both drugs are way out of their original patent periods, and original patents are anyway only intended to protect the interest of those who initially invest their intellect and effort in a new drug’s development. Subsequently their prices should generally reflect what the demand from the marketplace dictates. The cases of both deraprim and cycloserine seem to be examples of a relatively new and quite cynical American business strategy — of acquiring old, neglected drugs (often for rare diseases) and turning them into costly “specialty” drugs.

Of course TB is hardly a rare disease – but we’ll come back to that in a minute.

Cycloserine was acquired last month by Rodelis Therapeutics, a company which rather worryingly reveals almost no information about itself online. It promptly raised the price of the old TB drug more than twenty-fold. Rodelis justified this by announcing that it needed to “invest” in order to make sure the supply of the drug remained “reliable”. Not surprisingly this dubious excuse for what looked like out-and-out profiteering raised something of a storm of protest, and last Saturday the company bowed to the outrage and agreed to return the drug to its former owner, a non-profit organization affiliated with Purdue University.

“We discovered literally on Thursday the strategy that had been undertaken by Rodelis”, said Dan Hasler, the president of the Purdue Research Foundation, which had former oversight of the drug’s manufacturing operation. “We said this was not what we had intended.”

The Foundation now, however, will charge $1,050 for 30 capsules, twice what it charged before, though around a tenth of what Rodelis was trying to charge. Rodelis reckons that the new price is necessary to stem losses, but let’s take a closer look at this claim – because what’s happened is still a huge 100% hike in the former price of the drug.

Cycloserine is a so-called ‘second line’ drug used as part of a multi-drug regimen, usually of six drugs, to treat MDR-TB when the standard drugs don’t work. Originally it went on sale in 1955 when there was a lot more TB around in North America than there is today but still 30 years before any cases of MDR-TB were emerging. It’s not a nice drug. It has pernicious side-effects many of which involve variations of psychotic disorders. But it still has a part to play as one of the back-up drugs that can attack the TB mycobacterium when it’s resistant to first-line drugs. For a long time the drug was being produced by Eli Lilly and Company, but around 15 years ago it decided to drop it, largely because it was getting out of antibiotics as they were no longer seen as being sufficiently profitable. Lilly then transferred the rights along with the manufacturing skills to generic drug companies in India, China and South Africa in order to see the regions most affected by MDR-TB supplied with the drug. Then, in 2007, it gave the rights for the United States and Canada to the Chao Center for Industrial Pharmacy and Contract Manufacturing, which itself operates under the auspices of the Purdue Research Foundation. Its president, Dan Hasler, was himself a former Lilly executive before becoming President of the Purdue Foundation, and he reckons that the Chao Center has lost about $10 million on the drug since 2007 because of the small number of patients who need it and the high regulatory costs of its manufacture. So the Chao Center was hardly uninterested in making a deal when it was approached by Rodelis.

An adult patient with multidrug-resistant tuberculosis normally takes three 250mg capsules of cycloserine a day, along with other drugs, probably for 24 months and often longer. Under the price Rodelis intended to charge, a full course of cycloserine in the U.S. would thus cost $788,000 for cycloserine alone. With the new price from the Chao Center, it will now be $76,650. That’s quite a difference – but before Rodelis got involved it cost less than half that at $36,500.

During 2013 (the last year we have the numbers for) there were just 95 new MDR-TB cases notified in the U.S. (as opposed to an estimated 480,000 worldwide, which itself is almost certainly a gross under-estimation), and Dan Hasler reports that they sell pills for about 40 U.S. MDR patients each year. Given that cycloserine is used over a full two years, we can halve that original treatment cost of $36,500 (to $18,250) to give us an approximate annual cost per patient, and we can then multiply this by 40 patients – which gives us a rough annual turnover for Chao for this drug of $1,460,000 – so let’s call it one-and-a half million dollars.

But Chao took the drug on back in 2007, and so have been manufacturing it for eight years during which time they say they’ve lost $10,000,000 on the drug. So let’s see: 8 years x $1,460,000 = $11,680,000 (let’s call this 11 million). So they’ve taken $11 million in sales and still lost $10 million in the last eight years… it really must have been a no-brainer to see the back of the thing, because given these numbers it surely must be a very expensive drug to produce. In fact even now it looks like, having doubled their earlier price, they will still only just be breaking even on the drug!

But is it really that expensive to manufacture?

You’ll recall that Lilly transferred manufacturing rights and expertise to generic manufacturers in India, China and South Africa. So what sort of prices are now being charged by manufacturers in these countries? Well, as of today, here in the UK, you could buy a single box of 30 tablets of cycloserine online, imported into the UK by a Canadian company but manufactured by Mcleod Pharmaceuticals in Mumbai, for £120 (or around $200). But hang on – Purdue reckon they can barely clear their costs unless they charge $1,050 for the same amount of tablets (and our rough calculations based on their own numbers confirm this…).

Well of course there are two factors at play here that do complicate things a little. One is the bulk size of batch manufacture. Mcleod will surely be manufacturing an awful lot more tablets than Purdue. But in this case surely it would simply make infinitely more sense to just import the drug from abroad, rather than have it produced at all in America for so few patients at such high cost.

But of course there are also the costs of obtaining American regulatory approvals. This sounds like it could be expensive, but would they really be so high given that Mcleod’s tablets are already approved by both the WHO’s Expert Review Panel and its Stringent Regulatory Authority and that the drug itself was awarded FDA approval back in 1964 thanks to Eli Lilly? It seems highly unlikely.

But here’s the real kicker. The WHO’s Green Light Committee’s Global Drug Facility (GDF), which has been ordering second-line TB drugs in batches that have been small enough for them to have been seriously criticised for having been inefficient and uneconomical, pays just $0.14 for each tablet. Yes – less than a quarter of a dollar – or more than a two-hundredth of the new price being set by Purdue. So the GDF can buy a two-year course of cycloserine for a patient in South Africa for $310, while the same number of tablets in the U.S. cost $76,650.

Globalisation anyone?

You have to wonder what the hell the word really means since normal economic principles of supply and demand don’t seem to operate any more – especially as two huge global trading treaties are currently being negotiated (TTIP and TPP), both of which are being heavily lobbied by the pharmaceutical industry. The fact that much of the secret negotiations involve agreeing international principles of intellectual property rights (i.e. patents, which have huge implications for the prices of drugs anywhere), and given the industry’s self-evident capacity for outrageous greed, this should concern all of us anywhere.

... but then we'd never heard of Chuuk ...

If you know anything about TB you’ll be well aware that good news in the field of MDR-TB is hard to find. In fact we’d never really heard much at all - but then nor had we heard of Chuuk.

Chuuk is one of several US-affiliated island states among the so-called Federated States of Micronesia in the western Pacific. (It’s also, incidentally, one of the last places on earth where you can find the traditional Pacific master navigators who can make safe landfalls at distant oceanic islands just by using the stars, the clouds, wave patterns and the behaviours of seabirds). The Chuuk archipelago boasts a total population of 53 thousand people (pretty much equivalent to a small town), and, like many others in Micronesia, it has a TB problem.

Then, in 2007, one particular island in the archipelago, Weno, reported an outbreak of MDR-TB. It's a small island with just 15,000 inhabitants – but rather frighteningly it reported not one but two simultaneous outbreaks of different DR strains (one of which was resistant to three TB drugs, and the other to five). Exactly how these outbreaks occurred remains a mystery, but what happened next constitutes a story, not just of extraordinarily good treatment, but also of hope.

Satelllite photo of Weno

Satelllite photo of Weno

Because of Chuuk’s affiliation with the U.S. this double outbreak was fortunate enough to receive the immediate attention of the Center for Disease Control (CDC).

Bearing in mind that with TB things normally happen slowly this tiny outbreak grew fast: four of the first five cases died in the first eight months (including a two year-old child and its mother). Unfortunately because of the bureaucracy involved it almost always takes time to procure the necessary second line drugs to treat MDR-TB. In this instance even with the CDC aboard it still took more than a year during which the infected cases were sent home because of lack of facilities. As a result by July 2010, when things had swung into action properly, they had 25 cases under treatment.

Dr Richard Brostron of the CDC sums the outbreak up very simply:

“What happens when you have two MDR-TB cases and they don’t get treated for a year is that you end up with more – and in the end we had 41 cases of drug-resistant tuberculosis in addition to our contacts.” In the early stages this made for 6 new cases in the first year, and then 22 in the second Put this in epidemiology-speak and it means that the incident rate of MDR-TB (before treatment began to bite into the epidemic) had risen from 13 to 147 per 100,000 population in just two years. Apart from the 1,130% increase in new infections, the rate itself is pretty terrifying for MDR-TB. The increase offers us a clear picture (if one is needed) of how MDR-TB can take off when it finds an isolated environment that’s ideal for it.

The following graphic (which is the CDC’s) gives a complete picture of the waves of the disease – how it first took off (taking nearly all of its victims with it), then stalled once treatment was begun (presumably as community infection was reducing), and then offered up a lesser resurgence before it finally expired altogether.

What this shows beyond doubt is that concerted treatment of MDR-TB works, and (in TB terms) it can even work fast if it’s caught early.

The treatment outcomes recorded in Chuuk (which are shown below) are truly remarkable because, aside from those who died during the initial delay in getting treatment started, an astonishing 97% had successful outcomes. This percentage is almost exactly double the WHO’s globally reported current success rate of 48% (which as you’ll see in the next graphic hasn’t really changed since 2009). What’s more it’s even higher than the global target that’s just been set for much more easily treatable drug-susceptible tuberculosis (which is 90%).

So what went right for a change?

Well first of all a proper treatment programme was rolled out and this was then meticulously supported. Secondly the general approach was fundamentally patient-centred o as to maximise the chance that the patients kept taking their drugs. But probably most importantly of all, every possible contact of each and every infectious case was identified and evaluated (232 of them), then tested for latent infection and if necessary put on a special treatment programme to treat their latent disease. This approach is called ‘active case finding’ – getting out there out to look for potential new cases rather than waiting for them to present themselves after infecting others – and it looks like it’s an essential component of any MDR-TB programme if success is seriously intended. The patients who were enrolled in this secondary precautionary programme were then monitored for a further period of 36 months.

The results from the contact tracing efforts are also both extraordinary and exemplary. An encouraging 89% of those who began treatment for what was suspected latent drug-resistant disease completed it, with not one of them developing active disease. However 14 of those who had been found and tested positive for latent disease refused treatment – and of these two went on to develop MDR-TB. They may well, in fact, even have contributed to the secondary surge in the graphic above.

An obvious question arises: if an epidemic of such a challenging lethal disease was essentially wiped out in an out of the way place like Chuuk, why can’t it be done elsewhere?

(To put this in perspective, it was reckoned in the WHO’s most recent estimate of MDR-TB that there were 480,000 new cases of MDR-TB in 2013, but there were probably almost as many deaths. Globally it's as good as certain that the vast majority of MDR-TB cases are currently being lost to the disease.)

The answer to why this disease isn't yet under control is right here in the story of Chuuk. It's because appropriate help isn't yet being given where it's needed. In this instance it took the help of a global health superpower – America and its CDC - which threw a diminutive part of its resource at an otherwise insuperable problem on a tiny island – which then got sorted out in six years. But this particular response didn’t just treat the disease properly, it also went looking for every possible future case it could find and then treated each one it could to stop further disease breaking out. In other words, the health workers in Chuuk were helped to get ahead of the disease rather than the other way around.

So if those entrusted with protecting the health of mankind are really serious about responding to MDR-TB they now need to weigh up the world’s health resources and plan cording. The countries with the strongest health services are going to have to help those with the weakest – or the whole world will end up paying a lot more in the end and millions are going to have died along the way.

We've recently offered our opinions on this issue in a little more detail to the Stop TB Partnership in Geneva. We know that they’ve taken note of what we’ve offered but we’re hoping for further response in the coming months. Chuuk may be no more than a tiny dot in an immense ocean, but its story gives cause for hope - but only if world leaders and global agencies care to recognise it.