TB – where are we now?

Characterised by persistent cough, night sweats, fever and cachexia, it is the second most common cause of death due to an infectious disease worldwide: variously called consumption, phthisis and the white plague, Tuberculosis (TB) is sometimes also thought of as the first disease known to humankind. Analysis of the DNA of TB’s causative agent, Mycobacterium tuberculosis (Mtb), dates its evolutionary divergence to around 40,000 years ago – around the time when modern humans were expanding out of Africa. The earliest evidence to-date that directly shows the interaction of Mycobacterium tuberculosis with humans comes from analysis of remains from the neolithic era; some of the earliest humans to have practised agriculture and domestication of animals showed skeletal changes and molecular markers consistent with infection by Mtb. Fast-forward through to present day, and even with the impressive sum of our technical and medical know-how, it’s clear that there is still much work to be done in addressing the huge numbers of those infected.

In 2012, there were 8.6 million new infections, and 1.3 million deaths attributable to TB. Most often occurring as an infection of the lung, Mtb has been characterised thus far by its persistence and ease of transmission; it is estimated that almost a third of humanity – more than 2 billion people – carry Mtb as a latent infection held in check by their immune systems. These can then progress to active TB, where immunological insults such as from exposure to smoke from tobacco or biomass fuels, or infection by immunosuppressive diseases like HIV, cause reactivation. The lifetime risk of progression from latent to active TB is around 10%, with a staggering 200 million at risk, but we are now at a point where attempts to control Mtb’s spread are gaining pace. As with any disease control program, putting together the necessary political will, service providers, and patient access are all essential and often difficult steps but it can, and does, work: for example, check out this photo essay from the World Health Organisation on a coordinated approach to TB control which was used in Swaziland (the country with the highest incidence of TB worldwide) last year.

TB TREATMENT AND ANTIBIOTIC RESISTANCE

The standard regimen for treatment of tuberculosis starts as a short course using four first-line drugs: isoniazid, rifampicin, pyrazinamide and ethambutol for two months, followed by four months on isoniazid and rifampicin. This use of multiple drugs as combination therapy is designed to reduce the risk of selecting for resistance, and several drugs, each with a different mode of action, have a much better chance at killing all of the bacteria present than a single drug. However, in spite of this precaution, treatment can still fail and antibiotic resistance has grown to be a significant problem across the globe, especially in cases where patient adherence is low, and  pharmaceutical regulation is poor (for a wealth of information, please take a look at this brilliant infographic from Médecins Sans Frontières). Patients infected with extensively drug resistant tuberculosis (XDR-TB), or multidrug resistant tuberculosis (MDR-TB) must then be treated using second line drugs, and if treatment in this manner fails, then third line drugs may be deployed. The third line drugs’ effectiveness may as yet be unproven, and apart from issues of bacterial resistance, other more mundane challenges can then come into play: for example, the medications may simply be unaffordable in many developing countries, yet ironically these are the regions which often have the greatest need.

LOOKING TO THE FUTURE OF TB TREATMENT

It’s still important to view the landscape with a small sense of optimism; currently, there are a number of promising drug candidates in development, which could revolutionise the treatment path for the millions worldwide who are currently suffering from active TB. Shorter treatment times, fewer side effects, and effective killing of the bacteria are the holy grail for TB drug development. All were features touched upon by Dr. Mel Spigelman, CEO of the Global Alliance for TB Drug Development when he visited Dublin in March, to give a talk on recent developments in the pharmaceutical arms race against Mtb. Newly-developed compounds, given in combination therapy alongside current antitubercular drugs have been shown in trials to possess greatly improved bactericidal effect, and could do so in much shorter times than current regimens. Some of these new combinations could be effective in clearing infection within 2-4 months, as opposed to the current 6-9 months, and an aspirational goal is to create a treatment that can be effective in 7-10 days. With more promising drug candidates than ever available for testing, we are now at an unprecedented stage of technical progress.

ONGOING CHALLENGES: REACHING THE MOST VULNERABLE AND UNDER-SERVED

When a person is infected with HIV, depletion of immune function prevents the body from adequately controlling infections, making these patients more susceptible to active TB, particularly those who have developed AIDS. Around 13% of persons living with HIV worldwide also suffer from TB, which remains the biggest killer infection in HIV patients. Additionally, there is still an ongoing problem of drug interactions and additive toxicity between antitubercular therapies and the antiretroviral drugs that HIV patients must take in order to remain healthy. The ability to co-administer these medications therefore still poses a significant challenge. In addition, side effects notwithstanding, the sheer number of pills that must be taken by HIV/TB co-infected patients can itself be a major barrier to compliance.

Tuberculosis is also still a prominent cause of infant mortality, causing as many as 70,000 deaths per year (pdf). However, it also often goes undiagnosed, and practical difficulties can impede diagnosis, such as obtaining proper sputum samples for testing. Furthermore, even though the risk factors for TB apply to everyone regardless of age, the youngest can often be more vulnerable than adults, for example in the case of malnutrition. Chronic undernourishment can lead to diminished immunity, which is an all too common concern in regions of extreme poverty. Added to this is the burden of poor sanitation, causing repeated bouts of diarrhoeal disease. These directly lead to undernourishment, but can also cause longer term damage to a child’s digestive system, further weakening their ability to absorb nutrients, and amplifying the risk to their immune system. A further consideration is the provision of child-friendly dosages for TB medications, and care must be taken to avoid side effects such as hepatotoxicity, yet still maintain the drugs’ effectiveness.

There are also simpler reasons why it is still difficult to fully control this killer disease. Although we know the best-practice when it comes to TB treatment regarding the medications, facilities and mechanisms needed, what happens in cases where patients simply do not have access to even the most basic medical care? This is the reality for as many as one billion people across the globe who currently have no access whatsoever, and will never see a health professional in their lifetime. Over 95% of deaths worldwide due to TB occur in developing countries, where for many patients even drug-sensitive TB is tantamount to a death sentence. Since the current global burden is geographically heterogeneous, it has definitely been possible to constructively focus efforts towards control: 80% of the world’s TB cases are localised to just 22 countries. However, many of these suffer from difficulties in healthcare provision and coverage, which have contributed to deaths that might otherwise have been prevented. It has been said that TB is inseparably linked with poverty, and without overcoming the ongoing challenges of economics and access, change will be slow.

LOOKING TOWARDS THE FUTURE

In spite of the current obstacles, progress has certainly occurred to-date: between 1990 and 2012, the TB mortality rate fell by 45%, and the MDG target of a 50% reduction is now a realistic and achievable target. Credit must also go to the international development organisations, governments, academics and civil society groups who are all working in a concerted effort to improve the lives of many throughout Low- and Middle-Income Countries. Even the most seemingly ‘ordinary’ of provisions, such as roads and telecommunications can go a long way towards improving access to healthcare, for example by speeding up diagnosis, ensuring the availability of medications, and helping connect trained health professionals to the communities who need them. It is now because of these developments, alongside proven treatment strategies, targeted funding through international initiatives like the Global Fund To Fight AIDS, Tuberculosis and Malaria, and making the best new medications available where they are most needed, that we are finally approaching a time where we can hope to permanently cut our ties with Tuberculosis.

Stephen Macdonald

For more information on Tuberculosis, please visit the Stop TB Partnership, as well as the World Health Organisation’s TB page.