The history of TB shows medicine at its worst and best. For all the bravery and brilliance of some physicians and scientists, there have been many others whose ignorance, incompetence and intransigence have made matters worse—Humanity came off the Magic Mountain, developed the Magic Bullets to kill the Magic Dragon—but ended up slaying itself. Christopher Holme. Trial By TB.
One hundred thirty years after Robert Koch's discovery of Mycobacterium tuberculosis as the cause of tuberculosis (TB) and 50 years after we had the means to control it, we have managed by a combination of complacency and incompetence to allow this bacillus to mutate to a virtually untreatable form. Squandering away almost every last available drug, we have, as a result of policy and practice failures, allowed drug-resistant TB to flourish through much of the developing world. We have only ourselves to blame for the ominous progression in resistance encountered in many of the high TB-burden countries; multi-drug-resistant (MDR) TB, being followed by extensively drug-resistant TB which in turn has been followed by totally drug-resistant (TDR) TB. TDR-TB, which represents the most extreme form of amplified resistance, caught the attention of the medical community in January 2012 with the description of the first four Indian cases in a short letter to Clinical Infectious Diseases.1 TB exists on such an epic scale in India (300 million Indians infected) and is indeed so endemic in this country (300 000 deaths annually) that this report would have passed unnoticed, had it not been first picked up by the lay press, initially in India, and then in the West. Since then, TDR-TB has become one of the most covered medical stories of the year.
In the original description, we described four cases encountered at an MDR-TB clinic in the Hinduja Hospital, Mumbai's busiest private hospital. These patients were resistant to all 12 of the first- and second-line drugs that could be tested for in the mycobacterial laboratory of the hospital. These drugs included all of the first-line drugs: isoniazid, rifampicin, ethambutol, pyrazinamide and streptomycin; all three of the second-line injectables (kanamycin, amikacin and capreomycin); both the fluoroquinolones tested for (levofloxacin and moxifloxacin); and the two main group 4 drugs (ethionamide and para-amino-salicylic acid).
TDR like MDR- and XDR-TB that preceded it is an iatrogenic disease arising under the selective pressure of inadequate treatment. It is caused by exposure to the wrong drugs, to the wrong regimen or to the wrong doses. Both the public and the private sectors are to blame in equal measure for these inadequacies. The public sector with its focus on Directly Observed Therapy Short–course (DOTS) to the exclusion of all else can offer patients who fail Cat 1 short-course chemotherapy, the wholly unacceptable Cat 2 regimen that merely adds on a single drug, streptomycin, to the original four first-line drugs. This contravenes the fundamental logic of offering these patients a drug susceptibility test at this stage and breaks the axiom of ‘never add a single drug to a failing regimen’.3 Currently, no more than 6000 Indian patients receive appropriate second-line drugs (SLD) in the public sector under a few pilot DOTS-Plus projects in 15 Indian states. The vast majority of these unfortunate patients have no option but to turn to India's large, unwieldy, unregulated and sometimes unqualified (non-allopathic ‘doctors’ practicing with impunity) private practitioners in desperate attempts to cure their MDR-TB. The prescribing standards of this group has been studied and commented on, with work by Udwadia et al. showing that only 3 of 106 private practitioners prescribed an appropriate regimen for a patient with MDR-TB.4 The vast majority of prescriptions were inappropriate and served only to amplify resistance converting MDR- to XDR-TB. Thus, decades of failure at public and private health level resulted in the spectre of TDR-TB. This was thus a disaster waiting to happen. In the words of Paul Nunn, coordinator of the Stop TB department: ‘a wake up call for countries to accelerate provision of proper care, particularly for MDR patients’.
The very prefix ‘totally’ was enough to stir up a huge controversy. While it was true that these patients did still have some available drug options, it was equally true that these were extremely limited. This form of TB was likely to be much more difficult to treat than XDR-TB where there was at least the option of some of the first-line drugs, a newer fluoroquinolone, one of the injectables and some of the group 4 drugs still retaining sensitivity.
The various responses, public, government and international, to the TDR outcry were also informative. The lay press in India seized this opportunity to galvanize public opinion, and for a month, TB never left the front pages of Indian newspapers. Decades of neglect were made up in that period, with TB suddenly thrust into the headlines. The Indian government went into initial denial mode and called the term TDR ‘misleading’ attempting to underplay the significance of the report, saying the term had not yet been endorsed by the World Health Organization (WHO). This tended to obfuscate attention from the fact that India has the world's largest MDR population: about a 100 000 ‘official’ new cases each year (privately treated cases are seldom if ever notified, and hence, these numbers are gross underestimates) yet less than 1% of these have ever had a drug susceptibility test.5 The WHO took the TDR report with much more serious intent and conducted a special meeting in Geneva on March 21st to discuss their terminology and treatment. After lively debate among 50 experts from across the globe over 2 days, WHO conceded that reports of TB patients with severe patterns of resistance, even worse than XDR-TB alone, were increasing and provided a formidable challenge. However, they concluded that the term ‘TDR-TB’ could not yet be recommended as an entity given that drug susceptibility test for drugs other than those that define XDR was problematic to interpret. They stressed that new drugs that might be effective were expected to enter clinical practice in the future and also pointed out the impact that a label such as ‘total’ drug resistance would have on the individual patient and his carers. The overall conclusion was that a new definition for drug-resistant TB was neither ‘feasible nor desirable’ at this stage. Several physicians in the developing and developed world actively involved in the care of MDR patients felt that the WHO had chosen the safe option and could have ideally used the opportunity India's TDR cases provided to focus global attention on the alarming spread of drug-resistant TB.
What options can we offer these desperately ill patients who have this form of amplified resistance and need some treatment? Compassionate use salvage regimens comprising completely new drugs with no pre-existing resistance have been proposed by Carl Mendel of the Global TB alliance, hypothetically combining TMC207, OPC67683, PA824 and PNU100480 in an all new regimen. Our patients do not have the luxury of time and will be dead, as they wait for the slow emergence of these novel agents through the drug pipeline. At the Hinduja hospital where we now have 14 patients with TDR-TB, we have attempted salvage regimens including combinations of toxic group 5 drugs like linezolid, weak agents like clofazamine, expensive antibiotics like meropenem-clavulanate and experimental, but cheap and off-patent agents like thioridazine, in a desperate attempt to cure these patients.6,7 Surgery has been aggressively offered whenever feasible, although sadly, most patients are so wasted from advanced bilateral disease that this is an option in only a minority.
Thus, TDR-TB is a sad but cautionary tale of how the tools available have been squandered, and resistance amplified until an almost untreatable form of TB has emerged. A few positives have emerged from the TDR-TB imbroglio with the Indian government having roused itself from its slumber. Notification of MDR- and XDR-TB has been made compulsory across all private clinics and labs in Mumbai, in itself no small feat in the world's most densely populated city with its 18 million residents. Laboratories, which have always been the Achilles heel of Indian TB programmes, have had their funding and equipment increased in the city's two major public hospitals. The annual Mumbai TB budget has increased sixfold to $5.7 million, while the Union TB budget has been increased countrywide by 70% to $136 million. Finally, the Union Health secretary has written to each state instructing them to rapidly scale-up DOTS-Plus programmes.
We have miles to go even if these promises are kept, however. India still has only 27 labs accredited to perform drug susceptibility test, a drop in the ocean of 1.21 billion inhabitants, and these numbers cry out to be increased. It is hoped that drug susceptibility test will be offered early, as it should, to all Cat 1 failures, as WHO has recommended. GeneXpert machines that were WHO-approved in 2010 and have the capacity to diagnose rifampicin resistance (a surrogate marker of MDR) within 6 h need to be rolled out across the country. The early diagnosis and treatment of MDR-TB would have great impact not just for the individual patient but also in reducing spread in crowded communities. Public–private partnerships and education of private practitioners need to gain momentum. Finally, it is to be hoped that legislation can be passed to ensure only qualified specialists prescribe SLD. All this will take political will and huge additional funding, but India's vast population of MDR-TB patients have been neglected for so long that their claims for justice can no longer be denied.