‘TDR-TB’ is nothing new, unless it stands for `Triggering Dramatic Responses` to tuberculosis becoming harder to treat

In what is by now old news, a little more than a month ago, a report in the journal Clinical Infectious Diseases from a hospital in Mumbai, India, described several cases of tuberculosis that drug sensitivity testing (DST) in the facility’s lab suggested were resistant to pretty much any anti-TB medication they could throw at it (12 first and second line TB drugs in all).¹

Consequently, the researcher/clinicians decided to classify the cases as being ‘totally drug-resistant TB’ (TDR-TB). Once the Indian media got a hold of that name, and discovered the hospital had since identified more cases, they had a field day with the story, alerting the public to the risks of this new apparently untreatable drug resistant TB strain spreading ‘in the air’ in the streets of its most populous city and possibly elsewhere in India.

This caused a degree of panic in the country —almost certainly a considerable increase in TB-related stigma — and recriminations between researchers and the Health Ministry over the validity of the findings and whether ‘TDR-TB’ was a misnomer— as well as much excitement in the global health social media/blogosphere. Whether the episode could lead to long overdue and appropriate attention being paid to the problem, commensurate to the scale and seriousness of the TB drug resistance that is  increasing in India and much of the world, is unclear; as is whether the threat of TDR-TB helps convince governments and donors that now is not the time to retrench support for TB research and control.

TDR-TB spreads quickly though the press and social media

The first time the story came to our attention was on 9 January, via a reference on twitter to an article in the Times of India, published two days earlier.

Tweets about ‘totally drug resistant TB’ were spreading rapidly on twitter, so we jotted off a quick email to a handful of people, including a number of experts at WHO, to quickly determine whether this was bad journalism based on bad science.

In a very short while, and much to our surprise, Dr Mario Raviglione himself, head of WHO’s STOP TB Department, wrote us back.

“Indeed, this issue of TDR is a very concerning one, yet anticipated and still uncertain in its reliability regardless of the quality of the lab. Nothing totally new, however. I am aware of an old study in Iran, as the piece says, reporting “TDR” but also of cases in Italy and Germany (we reported back 2-3 years ago in the European Respiratory Journal),” he said.

From Dr Raviglione’s response, this was clearly more than a muddled press report.

The report in CID had actually been published online (ahead of print) in late December. In the brief correspondence, Dr Zarir Udwadia and colleagues of the Hinduja National Hospital and Medical Research Centre in Mumbai, described troubling data on TB drug resistance in four patients at their facility.

After culturing specimens from the patients, they performed DST by exposing the mycobacteria in the cultures (in Mycobacterial Growth Indicator Tube 960) to all the first- and second-line TB drugs, at critical drug concentrations that should have stopped all the TB from growing — but didn’t. (The drugs tested included isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin, amikacin, kanamycin, capreomycin, moxifloxacin, ofloxacin, paraaminosalisylate,

and ethionamide. Molecular tests (using the MTBDRplus and MTBDRsl line probe assays) on samples from three of the four patients were in agreement.

This resistance was almost certainly the result of muddled TB management and a chaotic history that Udwadia et al were able to document in three patients who had been given 1) second-line drugs added sequentially to failing regimens, 2) often at wrong doses and 3) without adequate adherence support over the course of the previous 18 months. During that period, each patient had tried out various private practitioners —on average 4 — looking desperately for effective treatment.

The team from Hinduja National Hospital noted that Velayati et al had first coined TDR-TB when they had described 15 such cases in Iran a few years earlier.² But the problem in India looks far more frightening, and unless the system changes, probably inevitable, given that WHO’s global resistance report estimated that India had over 110,000 cases of multi-drug resistant (MDR)-TB in 2006 (20% of the world’s MDR-TB burden), but is only providing access through the national TB programme (which does a rather impressive job managing drug-sensitive TB) to about 1% of the drug-resistant population. The inadequate public scale-up of MDR-TB treatment has sadly forced people with MDR-TB to seek care from unregulated private practitioners who rarely know what they are doing. Udwadia et al demonstrated this in a previous study in Mumbai that found only 5 of 106 private practitioners practicing in one crowded part of the city could prescribe a correct prescription for a hypothetical patient with MDR-TB.³

Evolution of the TDR-TB story

By the time the “Times of India” published the story, Hinduja National Hospital had identified more cases — a total of 12 in the previous three months. The article reported that ten of the 12 cases were from Mumbai, while the other two are patients from Ratnagiri and Uttar Pradesh — with an average age of just 32.3 years. One of the 12 patients had already died.

The article described the personal costs of the illness for one patient, a 35-year-old woman, married to a farmer from Deveria, Uttar Pradesh, who had been ill for over five years. Her husband told the newspaper that her treatment had begun in a local hospital for a year, but they had moved several times looking for treatment before coming to Hinduya National Hospital. "I have sold major portions of my farm in this period and have taken up work in Mumbai,'' he told the reporter.

The article notes that she has been on an MDR-TB treatment for more than two years and is now very ill. Her doctors are awaiting a CT scan before they deciding whether lung surgery can provide some relief to her — about the only intervention they have yet to try.

The article notes that Dr Amita Athawale, head of the King Edward Memorial Hospital's chest department, agreed that TDR-TB is in fact a reality in India. "The cases we clinically isolate are just the tip of the iceberg," she told the paper.

A week later, the Times of India subsequently reported two more cases had been identified at the JJ Hospital in Byculla, South Mumbai, one of whom was dead and the other untraceable. In addition, another one of the 12 at Hinduya had passed away, and another case had been identified, which appeared to document transmission of TB between a mother and her daughter.

Elsewhere in the country, a few days after the initial Times of India Report, another broadsheet, the Daily News and Analysis (DNA) India, reported two more cases in Bangalore. According to the report, a young woman and an older man at Rajiv Gandhi Institute of Chest Diseases, had sequentially failed on MDR-TB treatment and were failing to respond to extensively drug resistant (XDR)-TB treatment — more than two years after initiating MDR-TB treatment, sputum specimens were sent for DST to the reference laboratory in Chennai that determined that these cases were also ‘TDR.’

These reports spread alarm about the fact that one of the cases had since absconded from treatment, and thus represented a threat to the community. More disturbing however was that the hospital had not reported the cases to the state authorities. When the state authorities learned of the reports in the press, they reportedly made a surprise visit to the facility and later told the press that there was no laboratory confirmation of ‘TDR.’ DNA India, however, reported that the hospital directors continued to stand by their story saying that they had eight more suspected cases and were awaiting laboratory confirmation. 

Similarly, the whole episode has been characterised by a mix of cooperation and tension between the team in Mumbai and the Indian Health Ministry. According to the Times of India, the Health Minister Ghulam Nabi Azad flew down to Mumbai on June 14 for an unrelated meeting, and quickly approved a quarantine plan that the officials in Mumbai State had drawn up, but he announced that a central team would arrive on 16 January to investigate the episode in Mumbai more closely.  A day or two after that the team announced that there actually was no such thing as TDR-TB, these were probably just extra XDR-TB cases, and that besides, the hospital in Mumbai was not really certified to perform DST for second-line TB resistance. This was largely portrayed by the press, and by many in the blogosphere as the Indian government burying its head in the ground.

 But about those DST tests and that terminology…

Technically, however, the Health Ministry was correct, and in agreement with WHO.

“The main problem remains that of confirming that these are truly totally resistant as the reliability of drug susceptibility testing (DST) for many second-line drugs is never certain 100% like it may be for INH or RMP,” Dr Raviglione told HATIP.

Indeed, the issue had come up when WHO was first trying to standardise the definition of XDR-TB. Some of the first cases of XDR-TB that were reported appeared to have resistance to a number of second line drugs, but WHO decided to restrict the definition of XDR-TB to TB with DST evidence of resistance to at least isoniazid and rifampicin, and to any fluoroquinolone, and to any of the three second-line injectables (amikacin, capreomycin, and kanamycin) — since DST was agreed to only be reliable, and reproducible for those drugs.

The WHO posted its official position on TDR-TB in a FAQ on 13 January, subsequently updated for clarity on 24 January. It stated that while the concept of totally drug resistant TB is simple enough, there is no consensus on how to document it with DST results.

“Data on the reproducibility and reliability of DST for the remaining second line drugs are either much more limited or have not been established, or the methodology for testing does not exist. Most importantly, correlation of DST results with clinical response to treatment has not yet been adequately established. Thus, a strain of TB with in vitro DST results showing resistance could in fact, in the patient, be susceptible to these drugs. The prognostic relevance of in vitro resistance to drugs without an internationally accepted and standardised drug susceptibility test therefore remains unclear and current WHO recommendations advise against the use of these results to guide treatment.”

Therefore TDR-TB cases can only be defined as XDR-TB at present, although it is quite likely, given the treatment histories, that it is indeed more resistant.

References

[1] Udwadia ZF et al. Totally Drug-Resistant Tuberculosis in India. Clinical Infectious Diseases Advance Access published December 21, 2011.

[2] Velayati AA, Masjedi MR, Farnia P, et al.Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug- resistant strains in Iran. Chest 136:420–5, 2009.

[3] Udwadia ZF, Pinto LM, Uplekar MW. Tuberculosis control by private practitioners in Mumbai, India: has anything changed in two decades? PloS One; 5:e1203, 2010.

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