March 24th 2013

Another World TB Day - the anniversary of when Robert Koch announced his discovery of the Mycobaterium tuberculosis in Berlin in 1882.

It's the day when we look at what's being announced by the institutions and agencies who are monitoring the developments in this disease. This year has proved more eventful than usual. We therefore offer below a comprehensive and rigorous analysis of the information that is available to us, collated from a range of sources. Since we are anxious that any such analysis is fair and accurate, we would invite any party who finds the content below in any way challengable to please contact us so that we can amend it if necessary.

So it's World TB Day again, and the strap line for today is (as it was last year): to “stop TB in my lifetime”. And again we can’t help but wonder in the context of exactly whose lifetimes we should consider such a wonderful idea – those at most immediate threat from this disease (whose life expectancy is rather frighteningly being shortened by it), or those of us who are privileged enough to be more protected and removed from the emerging epidemics of drug resistant disease.

We also genuinely wonder just how realistic such an aspiration might really be…, for example, reported this week that: “TB is so widespread in South Africa that simply breathing carries a risk.”

Despite South Africa's status as a middle-income developing country and substantial spending on health, TB levels in South Africa continue to rise. "When something is out of control it's exactly that - one can't get away from it," says Professor Nulda Beyers, director of the Desmond Tutu TB Centre at Stellenbosch University. "Here in the Western Cape one in every three minibus taxis has a person with infectious TB in that taxi. Once it has reached those proportions it's very difficult to unravel what was the reason the figures got so very high,"

Poverty, the prevalence of HIV/Aids, the legacy of apartheid, and individual health-seeking behaviour are all among the factors that Professor Beyers cites when discussing the TB epidemic in South Africa.

The lack of beds in dedicated TB hospitals mean that not only are people in need of treatment being turned away and left to die in the community, but without isolation they remain infectious and able to spread MDR-TB to anyone with whom they came in contact. “Regular” drug susceptible TB cases, meanwhile, are generally treated more quickly and more effectively, meaning that the proportion of drug resistant cases will inevitably continue to rise. Worse still, the antiquated drug regimen available for DR-TB treatment poses a crude - and cruel - conundrum to both patient and doctor: take the treatment, hope for a cure that's about 50% likely and risk deafness or psychosis; or refuse the treatment and die – and inevitably (without isolation) either choice necessarily involves spreading the resistant strain of disease...

"I can talk about side effects until the cows come home, it's just terrible," says Dr Jenny Hughes, a DR-TB expert with MSF. "These drugs were first produced decades ago for normal TB. They have developed better drugs since then [in the 1960’s], which they now use for normal TB, but because DR-TB is resistant to those drugs, we have nothing else and so we have to use these older drugs against DR-TB and they're horrendous.” As many as a third of her patients default on treatment at some point in their two years. "It's complex, there are lots of different reasons" says Hughes. "You can try to think of all sorts of different strategies to help people take their treatment, but in the end, you need a better drug regimen."

Four days ago on 20th March, a group of Health Ministers from several African countries, as well as leaders of international agencies, launched a fresh offensive against tuberculosis in Africa. They signed what has been named the “Swaziland Statement”. (Swaziland carries a terrible burden: it has the world’s highest incidence of tuberculosis (TB) superimposed with high levels of co-infection with HIV and the country has a terrifyingly low life expectancy as a consequence – of just 31.8 years.)

This document effectively commits these African governments to accelerate progress against the two diseases over the next 1000 days until 2015, and to work with the Southern African Development Community (SADC) countries to achieve the original international millennium targets of cutting deaths from TB and HIV-associated TB by half by 2015, compared to 1990 levels.

This “1000 day push” is intended ”to achieve the [original] international targets of cutting deaths from TB and HIV-associated TB by half by 2015, compared to 1990 levels.” We have to wonder exactly how realistic such a drive might be, since we see it as a massively ambitious task -  to complete in the period’s final 1000 days the aims of the previous ten years during which Africa has seen rates not reduce at all, but rather actually to rise by at least a factor of four…

“We did not gather here today to underline the problem – we know the problem very well,” cautioned Benedict Xaba, the Minister of Health of Swaziland . “TB and HIV have combined together in a perfect storm and what we need to mobilise is an emergency response to this storm.” There is even a new word that has been coined this year to define this perfect storm – a “syndemic”. Somehow the word doesn’t sound nearly as dreadful as it should do.

The African region is actually not just currently off track from hitting the international TB and HIV-associated TB mortality targets by 2015 – it is massively off-track. Africa already had the highest mortality rates from TB, but it has now chillingly overtaken Asia – with its much higher population and number of TB cases – as the region with the greatest number of TB deaths as well.

There are long standing reasons behind this beyond the HIV/TB syndemic itself. Dr Aaron Motsoaledi, Minister of Health of South Africa, tellingly observed that: “If HIV/AIDS and TB were a snake, I can assure you the head would be in here South Africa. And I’m repeating this to the mining sector – because mineworkers come from the whole sub-region; they come here to our mines to catch TB and HIV and take it back home.”

Aggressively addressing the mining sector has to be good news, because the South African mining industry has been the fuel for the epidemic of TB in Southern Africa for over a century, and shamefully little has been done about it, either before, during or since apartheid - except to continue to recruit labour from all over the region – men who live and work in the most conducive conditions imaginable to engender the spread of TB, and then to cynically send them back home if they sicken as so many do - to die in their homelands and to infect their nearest and dearest in the process – an anticipated twelve to fifteen new cases if the miner survives for as long as a year. It’s been estimated that in this way the South African mining industry casually churns out an appalling 760,000 new TB cases each year.

We have to recognise that these leaders have committed to a massive task. Seven years ago in 2006, “Part II” of the Global Plan’s “Global and Regional Scenarios of TB Control ” speculated as to just how hard it is to halve the death rate in Africa as planned for 2015. It identified “serious constraints” that hamper this goal; the report stated that overcoming these constraints would require necessary but frankly quite unlikely “massive improvements in general health systems”, and an equally unlikely “reduction of 50% in HIV incidence” -  these in addition to powerful new diagnostic tools and substantially shortened treatment regimes. Unsurprisingly, given this sober analysis, they concluded that: “It is unlikely that even massive additional funding or even greater effort would be successful in overcoming the constraints”.

So what can have changed? 

On 13 November 2012 in Kuala Lumpur,  MSF presented the results from the largest multi-country implementation of the new GeneXpert rapid tuberculosis diagnostic test (a much-needed new diagnostic tool). This has rightly been hailed as a major step forward, but MSF simultaneously reported an urgent need to address an emerging global crisis of TB and drug-resistant TB which was also being revealed by the device. They showed an overall 50% increase in laboratory-based diagnosis of TB compared to the standard sputum TB test (which is still most the most commonly used diagnosis but which is well known to be only 50% reliable and less than 10% reliable in children). This 50% increase in detection logically suggests that current TB estimates may be similarly underestimated, and that the tool will reveal a much higher pool of infectious disease – experts in Mozambique, for instance, suggest a 100% rise in numbers and in workload. But, worse still, the MSF results also suggest that the scale of the drug-resistant  epidemic may reveal itself to be even more desperately underestimated (the device identifies resistance to the strongest TB drug so gives immediate indication of drug resistance which was previously impossible). The new diagnostic will definitely help to get people on treatment faster but, as observed by Dr. Helen Bygrave, an HIV/TB Specialist with MSF in South Africa, This new TB test is helping expose the true size of the drug-resistant TB epidemic.”

That surely is good news – but it’s also very bad news, because until now the scale of the drug resistant epidemic has been treated with simple circumspection, at best, and with denial at worst, and has not been propery planned for. Bizarrely it appears that only one country in Africa has high coverage TB surveillance – bizarre because this country is Egypt. None of the emerging BRICS economy countries have this high coverage either, despite a WHO estimate that 60% of new cases on MDR-TB were occurring in these countries in 2011 (their most recent estimate).

A widely unrecognised limitation of this test is that it has been validated only for sputum for the diagnosis of pulmonary tuberculosis. But some patients - like children for example - are unable to produce sputum. Nor will this test diagnose extra-pulmonary forms of the disease – forms of TB that are found elsewhere than in the lungs – which are far more common when there is HIV co-infection and is the hallmark of African TB, as well as also being more common in children. The ideal test, therefore, still needs development for the world to truly be able to meet those ambitions for 2015 – and it would have to be one that detects TB in an easier sample, like urine or blood.

New drugs are also emerging after a hiatus of almost fifty years. Two new drugs to treat TB are expected to come to market in 2013 and both are active against drug-resistant forms of the disease. Their introduction represents a critical opportunity to improve DR-TB treatment, hopefully to ensure that treatment is shortened and made more tolerable for patients. But, as importantly, they have to be made affordable and accessible to patients in developing countries where the problem is most acute. This last issue, unfortunately, may be the thorniest of all.

“The first new drug to treat TB in 50 years is an immense milestone. The fact that the drug is active against drug-resistant forms of the disease makes it a potential game changer.” says Dr. Manica Balasegaram, Executive Director of MSF’s Access Campaign in December.  “With new medicines for drug-resistant TB at the doorstep for the first time in half a century, the global health community can’t afford not to seize the opportunity of a lifetime by stopping drug-resistant TB from spiralling out of control.”

One of these drugs has now been approved for “compassionate use” in Bangladesh, Belgium, Germany, Georgia, Greece, Italy, Nepal, Peru, Switzerland, the United Kingdom, and France. South Africa, however, has refused its use, for reasons that are not clear. It may well be on account of its recognised dangerous side-effects.

Dr. Unni Karunakara, International President, Médecins Sans Frontières (MSF), whilst accepting the William Fulbright Prize for International Understanding in 2012, described the current endemic problems with drug development: “There is increasingly widespread recognition that the existing R&D system is failing – [particularly] failing patients with neglected or rare diseases… neglected diseases target the bottom billion – those living in the most rural areas, with poor or no access to healthcare, and often living on less than a dollar a day. Why don’t we have better tools available to combat neglected diseases? It is precisely because they are poor that the patients who are affected by these diseases are neglected. Let me explain.

The current system that we have to develop new drugs, diagnostics and vaccines, is driven by commercial rewards. A company develops a drug or diagnostic tool, receives a patent that allows the sale of the product at high prices, and the high prices in turn are expected to cover the costs of research and development, and generate substantial profit. This system fails miserably to incentivize R&D if patients cannot pay high prices – either because they are too poor or too few. That is why, between 1975 and 2004, only 1.3% of all new drugs were developed for tropical diseases and [none for] tuberculosis.”

He continues: “What has been incredibly alarming for our doctors in the field has been new data from our projects that suggest that the global scope of multidrug-resistant tuberculosis (MDR-TB) is much more vast than previously estimated, requiring a concerted international effort to combat this deadlier form of the disease.  Wherever we look for drug resistant TB we are finding it in alarming numbers, suggesting current statistics may only be scratching the surface of the problem. And with 95 percent of TB patients worldwide lacking access to proper diagnosis, efforts to scale up detection of MDR-TB are being severely undermined by a retreat in donor funding.  Precisely when increased funding is needed most.”

Data collected from MSF projects around the world have shocked doctors tackling the disease. In the north of the Central Asian country of Uzbekistan, 65 percent of patients treated by MSF in 2011 were diagnosed with MDR-TB – most with their first diagnosis— indicating that drug resistant TB is not only fuelled by incorrect treatment, but that it is also transmitting in its own right.

MSF identify that this global crisis of MDR-TB is exacerbated by another “perfect storm”  - this one the lengthy treatment regimens (around two years) with highly toxic drugs, most of which were developed mid-last century and which have unpleasant side effects. The small TB drug market, which features few manufacturers, has kept the costs of some drugs prohibitively high. Reduced funds, notably the recent Global Fund cuts, only exacerbate the situation. So there is a very realistic fear that – as with the development of the first antiretroviral drugs for treating HIV – these newest medicines will be by definition reserved for only those that can afford them.

“The challenge.. is not ours alone,” bemoans MSF. “It is also for governments, International Government Institutions, the Pharmaceutical Industry and other NGOs to confront this injustice.Dr. James Orbinski, as president of  MSF’s International Council back in 1999 in his acceptance speech on behalf of MSF for the Nobel Peace prize said that “What we as a civil society movement [should] demand is change, not charity.

Another key “constraint” delaying the further proper roll-out of HIV and TB treatment is the chronic shortage of health staff, particularly in Africa. A Canadian study this year suggested that Sub-Saharan countries that invest in training doctors have ended up losing as much as $2 billion as their expert clinicians leave home to find work in more prosperous developed nations. This study shows that these governments spend between $21,000 (the figure for Uganda) and $59,000 (for South Africa) in order to train a doctor, only to see them migrate to richer countries (in Uganda, even just across the border to Rwanda where doctors are paid more…).

 "Among the nine sub-Saharan African countries most affected by HIV/AIDS, more than $2 billion of investment was lost through the emigration of trained doctors," these researchers tell us. "Our results indicate that South Africa incurs the highest costs for medical education and the greatest lost returns on investment."

These findings, incidentally, suggest that the benefit to Britain was around $2.7 billion, and to the United States around $846 million. It’s already been estimated elsewhere that there is a global shortage of 4 million health workers, with a serious shortage in fifty-seven countries, thirty-six of which are in Sub-Saharan Africa where the TB epidemic is raging at its worst. 

Dr Margaret Chan, the Director General of the WHO gave a press briefing on TB last week in Geneva. It’s a general characteristic of WHO reports that you sometimes have to look perhaps a little harder than you should need to for the real news… and this one is no exception.

“On many levels”, she began, “TB control is a glowing success story…. The epidemic which, in 1993, looked set to spiral out of control, peaked ten years ago and began a slow but steady decline. The Millennium Development target of halting and reversing the TB epidemic by 2015 has already been achieved. Overall, the world is on track to meet the target of a 50% reduction in deaths compared with 1990. An unprecedented number of vaccines are now at various stages of development. The end of last year saw regulatory approval of the first new TB drug in 50 years.”

So far so good (although the accuracy of this summary is quite challengeable using the WHO’s own data – since new cases in 2012 compared to 1990 appear globally to be about the same at around 8 million, and deaths also at around 1.5 million each year). But she so far fails to identify the lack of targets missed in Africa or to mention the fundamental problems of drug resistance which had hopelessly insufficient focus in those original Millennium Goals but which pose such a problem now. But she continues:

“The negative side [however] has three dimensions.

 “The first dimension is scale. Despite recent success in shrinking the epidemic, the global TB burden remains enormous.

“The second dimension is the rise of TB strains that are resistant to multiple first-line drugs or extensively resistant to second-line drugs as well…. In some countries, as many as 35% of new cases have MDR-TB at the start. This gives you an idea of the powder keg we are sitting on.

“The final dimension is financial. The funding gap for TB care and control is substantial.”

The WHO and the Global Fund have identified an anticipated gap of US$ 1.6 billion in annual international support for the fight against tuberculosis in 118 low- and middle-income countries – this is on top of an estimated US$ 3.2 billion that could be provided by the countries themselves. Filling this gap would enable full treatment for 17 million TB and multidrug-resistant TB patients and save an estimated 6 million lives between 2014-2016.

60% of this funding gap (around a billion dollars) is identified as being directly needed in Africa. It’s not all bad news, however. The percentage proportion of the Global Fund that is being specifically directed to TB (as against HIV and Malaria) has risen from a measly 16% to a more realistic 25%.

 In addition to the $1.6 billion annual gap in international financing for critical implementation interventions, the WHO and its partners also estimate that there is also a US$ 1.3 billion annual gap for TB research and development for the period 2014-2016, research which includes clinical trials for new TB drugs, diagnostics and vaccines. These don’t come cheap, and the characteristic so far has been to possibly exaggerate each trial’s possibilities in order to maximise the potential for vital investment for Phase III trials.

 “It is critical that we raise the funding that is urgently needed to control this disease,” said the Head of the Global Fund Dr Mark Dybul, speaking at Dr Chan’s side at the briefing. “If we don’t act now, our costs could skyrocket. It is invest now or pay forever.” 

So what else might be potentially being missed on this March 24th in these reports?

Last May, the Indian Journal of Medical Research casually reported that the country was on target to meet the millennium goals and added that - “The prevalence of MDR-TB is not increasing in the country”. This turned out to be somewhat at odds to some frightening revelations later last year twhich suggested that as many as 10% of new TB cases in populous Mumbai, Bihar and Uttar Pradesh are MDR-TB and also that there are increasing cases that are resistant to all currently available TB drugs (controversially termed TDR-TB, or totally resistant). Both of these latter reports suggest a well-entrenched drug resistant epidemic in India, where existing numbers of TB cases are huge – a factor for drug resistant disease spread which is barely touched upon in the current World TB Day summaries, and appears to be a new potential blind spot.

Dr Zarir Udwadia, a TB expert in Mumbai, who was initially vilified for identifying the problem by the Indian Health Minsitry, recently described his current normal reaction to a confirmation of a case of MDR-TB: “Ten years ago, you would have been horrified. Now we say, ‘At least she’s only MDR…’.”

This flare-up of drug resistant disease in India is put down to the unregulated nature of Indian medicine and of its drug provision (its private sector). These allow patients to literally "graze" TB drugs - including second line ones - without a proper programme to control, reduce or eliminate the risks of increased resistance.

But there are further worrying indicators of contributing factors which emerged last month. A survey was conducted of available TB drugs in the unregulated private marketplaces of 17 countries (including India and several in Africa). The survey identified that 16% of available TB drugs in African countries failed quality control tests. Overall 9% of the tested drugs in the survey failed, and approximately half of these were assessed to be sufficiently deficient to actually contribute to drug resistance. It's important to recognise that these drugs were NOT a part of any proper TB control program (although there is a risk that drugs like this percolate the approved supply chain through fraud), but they are readily available to TB patients when there are supply problems or when patients believe that their treatments are failing. It is even suggested that they may actually be cheaper for patients in some countries, including in Zambia.

Furthermore, a study published in October in the Lancet identified that amongst 1200 confirmed MDR-TB patients from various countries (by definition resistant to two of the four first line drugs) 47% were also resistant to at least one of the second line drugs. This is very bad news. There can, unfortunately, be no doubt that the evolution of the bacillus is marching well ahead of the campaign to combat it despite it being ramped up, and that the devastation caused by this foul ancient disease is of course still by far at the worst amongst the poor. We would tentatively suggest that the problem is even now still being under-estimated, and that the whole project of globally controlling TB in the 21st century remains very much in the balance, and may already be lost in some hot spots.

It’s worth reviewing what the original millennium goals for reducing the global TB burden were – specifically to halve prevalence and mortality rates by 2015 to what were current at 1990, and to develop programs which could eliminate TB by 2050. The first goal was unfortunately always problematic given that there was a generally undocumented baseline in most of the countries worst affected by the disease. The second goal was laudable but may have always been unrealistic. The current rate of decline (after several years of rising) is about 1.6% per year - but the decline required to be near elimination by 2050 is nearly 20%. So the goal of elimination by 2050 is currently not much more than a pipe dream without massive developments and changes of fortune.

The mortality rate itself presents its own set of problems. The figures for the numbers of deaths from TB actually exclude the those who have both TB and HIV aty the time of their death (in other words those who are confirmed HIV+ but who die of TB). These are all internationally classified as HIV deaths and are missed off the TB mortality rates. This means that the recorded mortality rates for TB are at best misleading, and at worst worthless, particularly given the high percentage of co-infected cases in Africa who actually die from TB.

Last year, the World Health Organization working with the Stop TB Partnership began the process of developing a “post-2015” TB strategy with the final proposed strategy and targets planned to be presented to the World Health Assembly in 2014. We will be watching out for this. The 50% mortality target, at least, is now almost certainly going to be extended to 2025, and it looks like the elimination target of 2050 will most probably be retained.

Dramatic changes” are identified as being needed to have a chance of eliminating this disease by 2050 – one of which would definitely include a post-exposure vaccine. The standard BCG vaccine is now over ninety years old, and is less than effective. It has been termed the most widely used vaccine in the history of medicine, and yet, unlike polio or smallpox, it has had little impact on eliminating the disease – around 2.3 billion people are currently estimated to be latently or actively infected.  So a new vaccine is absolutely vital.

Only a month ago, the most promising new vaccine candidate failed in its trials in South Africa. The results had been highly anticipated because it’s so well recognised how important a new vaccine could be. There are possibly six more candidates in the pipeline so all is not lost, but as a way of eradicating the disease by 2050 they hold out little hope unless they astonish. With 80% of Africans estimated as being latently infected (and 32% of humanity), no normal vaccine could truly touch the disease for probably two generations – so the only real candidate that could make any short term difference has to be a post-exposure vaccine. These vaccines are effectively used for rabies or for tetanus, for instance, immediately after infection. But it’s quite clear, of course, when you’ve been bitten by a dog or trod on a rusty nail that you are at risk of either disease – but for the slow-burn latent plague of tuberculosis? It will be the medical discovery of the century if it can be achieved. Our understanding is that best progress so far has seen a slight delay in disease development in animals so nothing realsitic can be expected in the shorter term.

Extreme weather events have been a commonplace this last year, so we support the metaphorical analysis that a perfect storm of disease is out there – one that has already been fed by earlier storms of neglect and complacency, but which is now being further  fed by a bunch of hurricane strength storms of their own. They make for a depressing list: the original “hurricane Mycobacterium tuberculosis”, combined with “hurricane HIV/AIDS”, and “hurricane ever-developing drug resistance” rampaging alongside "hurricane challenging-older-drug regimes". These in turn are being fed inxorably by fed by “cyclone poverty”, by “cyclone insufficient infrastructures”, by “cyclone medical brain drain”, by “cyclone inhumanity-in-the-field-of-drug research and development”, by “cyclone funding gaps”, by “hurricane lack-of-vaccine”, and by “tropical storm under-reporting and under-diagnosis”.

The strategic targets described above are more than troublesome in the light of all of this. The idea that death rates can still be halved in Southern Africa in a thousand days, for instance, seems fanciful at best if not ludicrous; the idea that the disease can be eradicated within 37 years is laudable but currently fantastic without seriously cheap new drugs, a post exposure vaccine, the implementation of a worldwide fully regulated TB control program resourced by a motivated workforce,  and a significant reduction in poverty.

Can simple moxa make a difference with so many complexities making progress so challenging… actually we’d still suggest that maybe it can if we see the results we anticipate in Kampala - at least in the short to medium term while (hopefully) the research manages to catch up with the disease – particularly so in those environments with the worst deficiencies of infrastructure where this appalling drug resistant “syndemic” is on the loose.