Did Udwadia et al do the right thing with their reports of TDR-TB?

Theo Smart
Published: 28 February 2012

In the last post, we reviewed the backstory regarding a report in Clinical Infectious Diseases by Udwadia et al on the detection of TB cases at a hospital in Mumbai, India, that lab tests suggested were resistant to all of the anti-TB medications the hospital could get hold of, and which were thus classified as being totally drug resistant-TB (TDR-TB).

Subsequently, however, after sending down a team to investigate the cases, the Ministry of Health in India seemed to downplay the gravity of the report, on one hand, while they announced a more aggressive response to drug-resistant TB on the other — sending out rather mixed messages about whether Udwadia et al did the right thing publishing their findings or not.

“It was inappropriate on PD Hinduja’s part to use the term TDR-TB because no such TB exists,” Dr S.K. Jindal, chief of Revised National Tuberculosis Control Programme (RNTCP) was quoted as saying in one article, making reference to the fact that there is no agreed upon definition of TDR-TB (or at least one that is demonstrable in a lab) and that therefore this was only XDR-TB.

In addition, according to the Ministry of Health and Family Welfare’s press release, the hospital hadn’t followed the appropriate RNCTCP protocol for  “quality diagnosis and management of XDR TB: Diagnosis of XDR TB must be based on microbiological confirmation from the accredited national reference laboratories namely National Institute of Research in TB/Chennai, National TB Institute/Bangalore and LRS Institute of TB and Respiratory Diseases/New Delhi.”

Indeed, statements to the press suggested that the lab wasn’t certified to perform such complicated drug sensitivity tests. While WHO guidelines do recommend that laboratories need to go through a certification process to demonstrate that they can do second line DST, according to India’s Daily New and Analysis, the lab at Hinduja National Hospital functions as Mumbai’s primary TB reference lab, and other reports we’ve heard suggest it is probably technically proficient at performing DST for many of the second-line drugs. For instance, according to Nature Magazine’s blog, Tanjore Balganesh, who until recently headed AstraZeneca’s TB research centre in Bangalore was quoted as saying the TDR-TB reports “raise concern, because the results have come from a really good lab.”

And the researchers weren’t off base when they said they performed DST using the critical concentrations for many of first-line and second-line drugs as per WHO recommendations. Such concentrations are listed for many second-line anti-TB medications in WHO’s Policy guidance on drug-susceptibility testing (DST) of second-line anti-tuberculosis drugs.1 However the guidelines also categorise or grade the recommendations for DST with each drug, in order to show how much weight to give the DST results when considering how to construct a potentially effective second or third-line regimen for drug resistant TB. Consequently, the guidance stresses, using the DST guidance for some of the drugs may be of little practical use. Thus the researchers could have over-interpreted the significance of their findings.

Dr Karin Weyer of WHO’s STOP TB Department provided some additional background to HATIP underscoring how unreliable and difficult to interpret these tests can be.

“The reliability and reproducibility of phenotypic second-line DST (in particular) are hampered by intrinsic differences in the various available methods, in vitro technical difficulties due to drug powder instability, protein binding, heat inactivation, filter sterilisation, and incomplete dissolution. In addition, for many second-line drugs the critical concentration defining resistance is often very close to the minimal inhibitory concentration (MIC) required to achieve anti-mycobacterial activity, increasing the probability of misclassification of resistance/susceptibility,” she told HATIP.

In light of this, the lack of circumspection from the team at Hinduja Hospital about the conclusiveness of their lab findings is troubling on a certain level. What we don’t want are some other TB teams trying to perform DST tests in a similar way for these drugs, and concluding mistakenly that a person is untreatable, when in fact, the drugs might indeed work for them. Such mistakes could wind up being deadly.

The clinical findings

The proof is in the clinical pudding — in other words, does the clinical outcome match the resistance profile?

“These patients were already exposed to these drugs and they did not work in them,” Udwadia said in one report.

However, according to the Central Team’s investigation, although three of the patients were dead, the nine remaining patients diagnosed recently at Hinduja Hospital (including seven from Mumbai) could be traced and were ‘found to be stable on treatment.’ In fact, according to a report in Gulf News, Chief Minister Prithviraj Chavan said people need not panic over the "so-called incurable disease," because the patients diagnosed were responding well to treatment, he said.

But unless the patient dies, it can be difficult to know for certain whether treatment for drug-resistance is working adequately.

According to a report in the Times of India, they used “sputum microscopy” to see if the surviving patients were responding to treatment. Smear-positive cases are considered still highly infectious and are usually have either failed to respond to treatment, or are not responding to treatment yet. Of the seven surviving cases from Mumbai (the Times did not include an account of the other two cases), four had become smear-negative, while three remained smear positive. But given people with M/XDR-TB may go back and forth between being smear-negative or smear-positive while on treatment, smear microscopy is not on its own a reliable indication of long-term outcome in such patients. WHO’s recommends checking culture results to help identify, whether an individuals bacteriology remains positive or reverts to positive following initial smear negative results.2

In fact, since it takes weeks to allow a culture to grow and at least a few weeks to be certain of a negative culture (even with liquid culture), there was really no way for a team of experts to make a visit and a day or two later announce with any surety that these patients did not have ‘incurable TB,’ unless negative culture results were already available for these patients (which seems highly unlikely given Udwadia’s statements).  

This is especially worrisome considering what some reports said was being used to treat them. For instance, a report in Scientific American highlighted just two anti-TB drugs including rifabutin (which is generally cross-resistant and weaker than rifampicin which the patients would have been resistant to by definition), and clofazimine, which according to WHO’s 2011 update on the programmatic management of MDR-TB, is included among ‘Group 5 drugs’ that “should not be counted among the main drugs making up the MDR-TB regimen, given the inconclusive evidence on their effectiveness.“3 In fact, in a review that the 2011 update is largely based upon, people with MDR-TB taking clofazimine had worse outcomes.

However, according to the Lancet:

Udwadia is trying any treatment he thinks might work,” In addition to clofazimine (probably only thrown in for good measure), this included double-dose isoniazid (which may over-ride common isoniazid resistance which is usually of a low order), the harsh antibiotic linezolid, the anti-psychotic drug thioridazine, and meropenem and clavulunate. The choice of the latter two drugs, which have little anti-TB activity on their own, is based upon a study showing they were profoundly effective when combined against TB in mice, though as yet, there are only limited data in humans.4, 5

 “We are clutching at straws here”, Dr Udwadia told The Lancet.

This is somewhat less than reassuring.

Preventing panic

Reassurance appears to be primarily what the Central Team was aiming at. In an article in the Times of India on the 20th, following the central team's conclusion that there were no cases of TDR TB in Mumbai, [Chief Minister Prithviraj] Chavan said citizens had no reason to worry.

“There is no doomsday situation in India,” the Delhi health ministry team said, according to another Times of India article. It quoted Dr Ashok Kumar, deputy director general for TB in Health Ministry "There should be no panic with regard to TDR-TB."

According to a report by Ganapati Muder in BMJ Indian “pulmonary and public health specialists believe the government’s response, particularly its focus on the terminology of resistance, seems intended to turn the spotlight away from India’s growing problem of drug resistant tuberculosis."6 Critics such as Maryn Miller in the Wired Science blog have concluded that this is:

“Fair enough, from the lab point of view. But from the political one, this is clearly blame-shifting. Within India, media reports are quite clear about what is really going on: The health ministry is looking for leverage to silence these physicians in order to spare the country further embarrassment.”

Perhaps, but they also may have wanted to avert panic, which was indeed a serious concern of public health significance. According to one particularly thoughtful report by Ramesh Menon in India Together:

It is frightening to think of how the new drug resistant strain is going to spread in crowded, unhygienic, urban India. Doctors are worried. In fact, many doctors at the TB Hospital in Sewri at Mumbai who are supposed to treat TB patients are now threatening to quit or are asking for a transfer. As many as 37 doctors at the hospital have died due to TB. In the last five years, 53 other doctors have contracted the disease. The fear is real."

 Moreover, they are not happy with the safety provisions at the hospital, which was never known for its infrastructure. It is also under-staffed. With the crisis looming large, the BMC [Brihanmumbai Municipal Corporation] wants to revamp the TB Hospital and convert it to a Centre of Excellence for TB Management. But with its staff now desperate to leave, this will be a long haul.”

Panic must be avoided, and perhaps the best way of doing that is to take decisive action to address the problem. While the reliability of their evidence of virtually untreatable TB is subject to debate, Udwadia et al got the Indian media and their government to finally pay attention to what is without a doubt a disaster in the making. “We expect the government authorities to admit that a decade of neglect of MDR-TB patients has resulted in TDR-TB,” Dr Zarir Udwadia of Hinduja Hospital told DNA India.

Citing somewhat dated WHO surveillance estimates of around 110,000 Indians with drug-resistant TB, Udwadia et al wrote in CID that only about 1% of Indians with drug-resistant TB get diagnosed and receive a standardised second-line treatment regimen through the country’s public health system. However, WHO’s most recent surveillance update stresses that the number of people with M/XDR-TB in India is simply unknown. Globally, there are close to half a million MDR-TB cases each year.

According to the most recent update from WHO, India, the Russian Federation, and China contribute more than 50% of the estimated worldwide burden of MDR-TB, but only China have reliable survey data on their national burden.7 RNTCP officials suggest that there are around 50,000 new MDR-TB cases each year, and assuming they survive a couple of years, the 100, 000 figure is close to right.

So that’s tens of thousands of cases with MDR-TB in India. But what happens to them next is even more frightening in the wilds of the private sector.

“Patients in India are trapped between an unregulated private sector and a government sector with limited capacity for drug sensitivity and treatment,” Dr Madhukar Pai, of McGill University in Canada, told BMJ.8

All of these people who are not accessing appropriate diagnosis and treatment from RNTCP have to pay out of pocket to seek treatment from private practitioners, many of whom are not adequately trained, including pharmacists who will sell them medications without a prescription. As Udwadia et al described in another study, only 5 out of 106 of private practitioners were able to write appropriate scripts for drug-sensitive TB in Mumbai, leading the researchers to worry that India was in danger of exchanging its drug-sensitive TB epidemic for a drug resistant one.9

What is even stranger is that the 106 doctors in TB didn’t just make common mistakes, instead they prescribed 63 different drug regimens.

If that is how health care providers treat drug-sensitive TB, imagine how they manage drug resistant TB.  As a result, a person with MDR-TB might get some of the right medications but in the wrong combinations, without proper follow-up. Given the high cost of second-line TB drugs, there is also a good chance that they may take effective medications for a while, and then quit when their money runs out.

"Additional drug resistance is therefore expected in these circumstances. We allowed it to happen. The problem has been neglected for long," Dr. Puneet Dewan, medical officer TB, WHO, said in the India Together article.

Treated this way, increasing drug resistance is inevitable. Something indeed must be done or a growing proportion of the MDR-TB cases will essentially become untreatable, and many probably already are.

TDR-TB is nothing new

As Dr Raviglione pointed out in the last post, however, this is nothing new. In a sense, virtually TDR-TB really happens whenever treatment for XDR-TB fails in a patient as another MDR-TB expert, Professor Edward Nardell of Harvard University is quoted as saying on New TB Drugs Working Group’s Website:

“While the emergence and spread of highly drug resistant strains has been a long-standing concern, strains resistant to all drugs is not new, and has been a by-product of introducing treatment for MDR TB long before XDR TB.  Having been engaged early on in the treatment of MDR TB in Peru, Haiti, and Russia, PIH has encountered highly drug resistant strains, now called XDR and TDR, long before there were any headlines about them.  Others have seen the same. Such cases were simply called MDR treatment failures and became chronic cases.”

Similarly, reporter John Donnelly, wrote in a blog post: “Whether the dozen people in India have a type of tuberculosis worthy of a new acronym — “TDR-TB” — there is no doubt that thousands of people with serious drug-resistant TB (including some who may be resistant to all drugs) aren’t getting treatment at all, or getting treatment that isn’t working.”

Donnelly cites WHO statistics that only a quarter of MDR-TB patients get appropriate treatment, and only half complete the full course successfully; while ”among patients with XDR-TB, death is more common than successful treatment,” he wrote.

Every country where XDR-TB has been detected, including in southern Africa, has had cases of XDR-TB that treatment fails to control. Many of these die, others remain alive for years, and capable of spreading the infection.

The question is, how to manage these cases in India and elsewhere, if not effectively, then at least humanely. Moreover, how can they be prevented from ever happening?

References

[1] Policy guidance on drug susceptibility testing (DST) of second-line anti-tuberculosis drugs. Geneva, World Health Organization, 2008. (WHO/HTM/TB/2008.392). Available from: whqlibdoc.who.int/hq/2008/WHO_HTM_TB_2008.392_eng.pdf.

[2] WHO. Guidelines for the programmatic management of drug resistant Tuberculosis. 2011 Update. Geneve, 2011.

[3] Falzon D et al. WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. ERJ Express. Published on August 2, 2011 as doi: 10.1183/09031936.00073611.

[4] Hugonnet JM et al. Meropenem-clavanulate is effective against extensively drug-resistant Mycobacterium tubeculosis. Science 323: 1215-1218, 2009.

[5] Dauby, N et al. Meropenem/clavulanate and linezolid treatment for extensively drug-resistant tuberculosis. Pediatric Infectious Disease Journal:(30):9:812-813, 2011.

[6] Mudur G. Indian health ministry challenges report of totally drug resistant tuberculosis. BMJ, 344:3702 doi:10.1136, bmj.e.702, 2012.

[7] Zignol M et al. Surveillance of anti-tuberculosis drug resistance in the world: an updated analysis, 2007–2010. Bull World Health Organ 90:111–119D, 2012.

[8] Mudur et al. op cit.

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

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