The Possible Future for Africa if rates of TB continue to grow

If things don’t change, the future for most of the continent is unfortunately already mapped out for us in a small country in Southern Africa.

Swaziland is the country with the highest incidence rates of TB in the world. According to the WHO’s most recent figures, this runs at a terrifying 1,287/100,000.

(The United States has a comparatively tiny incidence rate of 4/100,000, by the way. The World Health Organisation (WHO) declares a health emergency when the TB incidence exceeds 250/100 000 per year or higher – whilst an estimated incidence rate of a mere 40/100,000 or greater is considered to be a “high incidence of tuberculosis” in the UK.)

The United Nations identifies Swaziland as being at the forefront of the HIV/TB epidemic. The two diseases have effectively stopped its economic and social progress, and it s now at a point where it endangers the existence of its society as a whole. The United Nations Development Program has suggested that, if the expansion continues unabated, the "longer term existence of Swaziland as a country will be seriously threatened.”

And life expectancy in Swaziland is now 32 years – 6 years less than any other country on our planet…..

South Africa follows not that far behind in the TB stakes (at 981/100,000). There’s a big difference, however, between South Africa and Swaziland. South Africa is a BRICS economy with an outlook of economic growth and an estimated $2.5 trillion in mineral reserves. Its health service is throwing some of its financial might at the problem of drug-resistant TB, but it still appears to be losing the battle to the disease with incidence rates rising year on year. One has to even ask whether these efforts are sustainable in the longer term: In 2008 only 2.5% of treated TB cases in South Africa were confirmed as MDR-TB, yet this 2.5% of patients took a massive 94% of the overall TB drug budget. That gives a proper idea of how expensive it is to treat drug-resistant TB when treatment is available and helps explain why it’s unavailable in so much of Africa.

Why is the situation so much worse in Southern Africa?

Two reasons: one is that rates of HIV are also higher. The other is that the standard first line TB drugs have been more widely available for longer than in the rest of the continent. You cannot create drug-resistant TB without drugs; but more importantly drug resistance is only likely to develop where drugs are not complied to, are in short or intermittent supply, or where diagnostic deficiencies mean that they are serially misapplied. The simple truth is that, in respect of all of these factors, the rest of Africa is probably around ten to fifteen years behind South Africa and Swaziland.

In other words countries with a low per-capita gross domestic product (GDP) can all be reasonably predictably expected to experience something similar to what is happening so desperately in Swaziland unless new drugs or treatments are found fast – specifically ones that are cost-effective.

(Almost all Sub-Saharan countries have a GDP that is a tenth or less of South Africa’s.)

The key to unlocking the TB problem in Africa is finding new treatments that work quickly, that are compatible with HIV medication and which are cost effective.

The Economics

The WHO considers any intervention with a cost-effectiveness ratio which is more than the respective country’s GDP to be less than desirably cost-effective. What this means is that a treatment regime costing $11,100 can be considered highly cost-effective in South Africa, whilst it could be considered totally non-cost-effective in Uganda – by a factor of ten. So a new treatment that costs more than, say, $1,300, based on current figures, would be extremely cost effective in South Africa, but would be borderline in Uganda. Current treatment costs for MDR-TB in South Africa cost between $4,500 and $9,000 per patient – in other words way beyond the limit of cost-effectiveness for most Sub-Saharan countries.

These are the economic realities of medical interventions in the developing world.

That is, of course, also if the treatments are effective…..

The Effectiveness

Success rates for treating MDR-TB in South Africa (where resources are at their best in Africa) run at around 50% (in other words the drugs fail every other patient who undergoes treatment and they die). This is, by any standards, a dreadful survival rate.

The World Health Organisation (WHO) guidelines recommend a 20 month minimum treatment regimen for MDR-TB. All their associated recommendations are graded as having a very low quality of evidence (which is the WHO's lowest level of evidence), a grading which effectively means that "Any estimate of effect is very uncertain.”

In a nutshell, patients currently on MDR TB regimens typically take a side-effect-ridden regimen with a poor evidence base for more than a year and a half and still only have a slightly better than half chance of a successful treatment outcome.

 Here’s some shocking reasons why this is the case – a selective list of the evidence base of five commonly used second- line drugs used for treating MDR-TB:

 Kanamycin: It’s been possible to find just one clinical trial of kanamycin in people with TB, though it is more accurate to describe it as a prospective case-controlled study. It was published in 1958.

 Ethionamide: One tiny clinical trial of 27 people compared ethionamide against thiacetazone in 1963.

 Levofloxacin: Besides a seven day early bactericidal activity trial, there are no identifiable clinical trials of levofloxacin that have considered the drug for the treatment of MDR TB.

 Terizidone: There is just one reference to a possible clinical trial in a 1972 paper.

 Linezolid: Linezolid has been used in South Africa for drug-resistant TB for some time. Yet despite this the first randomized controlled trial of linezolid in patients with drug-resistant TB was only published in October 2012. It was, incidentally, a substantially smaller trial (41 patients) than the Phase II RCT we are conducting in Uganda. The results were promising, but the drug was also associated with serious adverse events.

 The side-effects of the standard drugs used to compose MDR TB regimens are awful. In one South African MDR TB cohort, more than half the patients taking one drug became hearing impaired. In another, 28% had severe adverse events. In a Turkish cohort, side effects were severe enough to cause drug changes in more than half the patients.

 The Numbers

Over the last decade, roughly five million people developed drug resistant TB, but less than 1% had access to appropriate treatment and 1.5 million died.

 The number of MDR-TB cases notified in the 27 recognised high MDR-TB burden countries doubled between 2009 and 2011. These are the patients who were actually diagnosed and counted. Almost all African countries remain out of this net simply because there are no diagnostics to measure the amount of drug resistance in the community.

 Currently, less than 20% of the estimated global burden of multidrug-resistant tuberculosis (MDR-TB) patients are being detected and treated (a figure that may be far lower since this is estimated on the total notified cases of TB, not the total estimated number). Lack of laboratory capacity and slow technology transfer to resource-limited settings remain a crucial barrier. Assuming that such an estimate is accurate, what exactly does it mean?

It means that at the very least 80% of drug resistant TB go uncounted, undiagnosed and untreated (and most will die); but it also means that 80% of drug resistant cases will infect others with their strain of disease at the rate of about one a month until the day they stop breathing. Epidemiology is a complex field of medical science, but, if you care to think about this for only a minute, it’s fairly obvious that there is one enormous problem developing here. If patients infected with drug resistant disease live for more than a month after they become infectious (TB is normally a slow-burner taking months or even years to take its final toll - and even in cases of HIV co-infection they can be expected to live at least two months) then the epidemic will inevitably grow in size year on year unless something major can be done.

The proof of this, unfortunately, is already out there, and it’s not just in Africa. This year as many as one in ten new cases of TB were identified in China as being drug-resistant. This effectively upsets “the old dogma" that drug-resistant TB occurs mostly in people who did not respond to first-line treatments, or in infected people who relapsed after previous drug treatment. Smaller studies in Mumbai and in Uttar Pradesh, India's most-populous state, show  even higher rates with 13% of newly diagnosed TB patients infected with multi-drug-resistant strains.

The Funding Gap

The WHO estimate that, between 2013 and 2015, up to $8 billion per year is needed in low- and middle-income countries merely to implement existing interventions, with a current funding gap of up to $3 billion per year. The funding gap for research and development was $1.4 billion in 2010.

This is the world that Moxafrica is tentatively stepping into. By any stretch of the imagination it is a desperate one, well removed from the world most of us know and inhabit. Assessed collectively, this is why the RCT in Kampala could be so important.