Funding opportunity for proposals to increase access to TB, HIV and malaria medicines, treatment and diagnostics in low and middle-income countries — deadline 22 May 2012

 If you are a researcher, NGO, Product Development Partnership, or other group or individual working in TB, HIV or malaria, the deadline is quickly approaching to submit a letter of intent (LOI) explaining your project proposal to UNITAID.

UNITAID is an international facility that seeks to provide diagnostics and pharmaceuticals for AIDS, tuberculosis and malaria to developing countries at deeply reduced prices through market interventions. Launched on the government of France’s initiative, it is funded by innovative financing mechanisms — more than half the money comes from an airline ticket levy in participating countries (Cameroon, Chile, Congo, France, Madagascar, Mali, Mauritius, Niger and the Republic of Korea), and voluntary donations from airline travellers in other countries.

UNITAID’s key achievements have been to map the markets for antiretroviral products, project future demand and to work with the Clinton HIV/AIDS Initiative to help manufacturers re-engineer processes and supply chains to bring down prices and project future volumes.

ACTION (ACTION to Control TB Internationally) has put out an alert to TB researchers in particular. ACTION states that to date, UNITAID has granted $240 million towards TB projects, and that UNITAID is particularly interested in TB proposals that seek to:

• Improve diagnostic tools for MDR-TB, primarily through price reductions of GeneXpert, and developing linkages between new diagnostics and medicines markets.

• Develop quality assurance and delivery mechanisms for first line anti-TB drugs to improve standards and regulation, get rid of poor quality drugs, and prevent country supply shortages.

• Increase affordability and accessibility to second-line anti-TB drugs by reinforcing supply chain management and increasing diagnostics to drive demand.

• Address pediatric TB pharmaceuticals and diagnostics through developing a fixed-dose combination (FDC) drug for children, new diagnostics for pediatric TB, and improving the supply of currently available medication.

It is particularly encouraging that UNITAID is looking at how it can influence the development of a robust market for second-line TB drugs and for the diagnostics that will support the development of that market.(The most recent edition of HATIP looks in detail at one element of that process, the introduction of the GeneXpert platform and the Xpert MTB/RIF test, which can both detect TB and rifampicin resistance).

Indeed UNITAID held a meeting at the World Health Assembly in Geneva this week in order to get people talking about how the fragmented but very large markets for second-line TB drugs in the BRICS countries (Brazil, Russia, India, China and South Africa) can be brought together in order to deliver the same kinds of win-win developments for patients and industry that have already occurred in HIV.

How can you access these funds?

Please consult the Guidelines, Application Form, and background invitation below

• .LOI guidelines [PDF, 225KB]

• Annex A HIV diagnostics technology landscape (Jun 2011) [PDF, 1.3 MB]

• Annex B Update HIV diagnostics technology landscape (Oct 2011) [PDF, 800 KB]

• Annex C Malaria diagnostics landscape (Dec 2011) [PDF, 1.2 MB]

• Annex D Medicines landscape (Jan 2011) [PDF, 530 KB]

• Annex E LOI application form [DOC, 1.0 MB]

• Annex F Market impact framework [PDF, 110 KB]

• Questions and Answers [PDF, 170 KB]

Act fast: the Deadline: May 22, 2012

If the LOI is accepted, UNITAID will contact applicants and ask them to submit a full proposal in September 2012. Proposals will go through technical review in committee and then to the UNITAID board for final review and a vote to approve funding.

Contact: For further information, contact UNITAID via email at the following address: loiunitaid@who.int

Any setting where there is a significant burden of drug resistant TB would do well to adopt the key steps being taken in Mumbai.

These include strengthening the health system TB programme so that it can provide universal and free access to diagnosis and treatment for TB of any kind, scaling up better, systematic TB surveillance and reporting, and tracing and screening TB contacts (particularly for drug resistant TB) at a bare minimum. TB programmes also need toconsider other issues, such as TB infection control, education of other healthcare providers, community engagement and patient empowerment as mentioned above, and any of the other activities suggested in the Global Plan to Stop TB, 2006-2015, and in WHO’s Guidelines for the programmatic management of drug-resistant Tuberculosis. Update 2011, and its associated tools and field guides (see http://www.who.int/tb/challenges/mdr/programmatic_guidelines_for_mdrtb/en/index.html).

However, the threat of TDR-TB has underlined and highlighted the need for more research into TB vaccines, new drugs that are active against the emerging drug-resistant strains, and point-of-care tests for TB and for TB drug susceptibility. We hope there will be more to say about vaccines soon. HATIP addresses the TB control basics routinely.

However, there are some specific developments and needs pertaining to diagnosis and drug development that we should mention here.

Nucleic acid amplification tests do at least offer the promise of detecting some drug resistance much earlier than conventional culture — though in most settings they are not cheap enough or widely available enough to affect clinical practice. One potential exception is of course the GeneXpert TB/Rif test being scaled up fairly rapidly in South Africa and some other countries, although there is currently some confusion about how to integrate the resistance testing aspect of the assay. Especially because it is identifying three to four times as more rifampicin-resistant TB than the South African TB programme anticipated (and much more than the system can presently manage). The rate of scale-up in many countries may however be compromised by weakened financial support for laboratory infrastructure (with the trouble at the Global Fund).

However, it is not really the cheap point of care test we’ve all been waiting for. What’s needed is a test that every primary health clinic without reliable electricity could implement. It is widely hoped that recently announced funding from the Gates Foundation could speed up the development of such tools.

Less exciting perhaps — but needed none-the-less — are other types of diagnostics research, such as developing a large enough data set to be able to give definitive guidance regarding DST for some of the other second line drugs soon. According to Drs Raviglione and Weyer, Professor Dick Menzies is conducting some additional analyses on the individual patient data set that informed the recent update of the WHO guidelines on programmatic management of drug-resistant TB.

Unfortunately, Dr Weyer told HATIP that “Although probably the largest patient data set available, the number of patients with XDR plus/minus additional drug resistance is not sufficient to reach solid conclusions, also given the multitude of factors which have to be controlled for in such analyses.”

Prof Menzies analyses will be discussed at the upcoming Expert Group Meeting (EGM) on DST scheduled for 19-21 March in Geneva, as well as at a technical consultation on so-called ‘totally drug-resistant TB’ that is being organised by Dr Nunn’s team immediately afterwards.

Because of all the difficulties with culture-based methods of DST for second-line drugs, Dr Weyer believes genotypic DST is probably going to be the way forward. “However,” she told HATIP, “the genotypes associated with resistance have not been adequately described or are overlapping between different classes of drugs while MICs also vary across the different known molecular mutations.”

“In essence, there is a huge need for research investment in identifying the relevant molecular mutations, developing appropriate diagnostic tests for detecting resistance/susceptibility targeting these mutations, and linking the latter with clinical/patient outcomes in well-designed prospective studies. At present there is no global, coordinated research effort - nor funding - available to achieve this.”

New TB drugs

As for the new TB drugs, a few promising candidates are entering advanced clinical development — and there have been increasing calls for access to these medications for people who aren’t susceptible to enough currently available drugs with anti-TB activity to construct an effective regimen.

Dr Francesca Conradie, recently appointed head of the South African HIV Clinician’s Society, discussed this with us at the Union World Lung Health Conference in Lille France, last October. Her interest is primarily to get access through compassionate use to at least two of these new drugs at once, to increase chances of a response in a patient, and decrease the likelihood of resistance developing (clearly the drugs would be added to others that the patient may be susceptible to). However, even though what Dr Conradie is suggesting would be in a very controlled setting, with every reasonable precaution taken to prevent the spread of resistance, should these XDR - going on-TDR-TB cases fail on these drugs and become resistant to them, the spectre of losing these new classes of drugs by using them in treatment failures seems to alarm drug companies and policy makers alike.  At any rate, she said she was making very little headway and protested, ‘this is a matter of life or death for these patients, it represents his or her very last chance. Compassionate use of these two drugs could save their life, but without it, they are going to die.”

It occurred to us that the difficulty determining susceptibility to the other second-line drugs must make it more difficult to convince anyone that these drugs wouldn’t just be wasted. If DST for these drugs were more reliable and reproduceable, she could show that she could construct a potentially effective regimen for a patient, and bolster the case for compassionate use.

Dr Weyer told HATIP that she agrees DST complicates use of the new drugs in salvage regimens. She said:  “There is a long road ahead to address optimal regimen design, appropriate DST methods, and programmatic challenges around uptake and rational use. WHO is therefore accelerating policy development on these issues, and the outcomes of both the DST-EGM and the technical consultation will feed into this process and hopefully add impetus to the need for major research investment.”

Finally, while the TDR-TB scare makes a good case in more funding of TB research to prevent an unmanageable form of TB, it is also “happening just as the biggest international funder for TB is in crisis,” Kolleen Bouchane, Director of the TB advocacy organisation, ACTION wrote in the Huffington Post. Citing the Global Fund’s accomplishments, she notes that “just as the science tells us to scale up, donor governments tell us they are too broke -- they can't keep or make new commitments to fight these three diseases.” Without the support of a vibrant health Global Fund, the spectre of ‘TDR-TB’ becomes even more frightening.

“It is still possible for public health systems to take a pro-active step, as the Mumbai officials are now doing to stem the problem,” Dr Dewan told India Together. “TB Control in Mumbai can be transformed. The challenge is to ensure that all TB patients get the support they need and that would prevent the emergence of drug resistance strains."

Indeed, while health officials may want to downplay the notion that the TB cases Udwadia et al were totally drug resistant, they do at least appear to be taking the ‘threat’ of TDR-TB more seriously.

What is being done about the ‘TDR-TB cases identified in these reports?

Regarding the cases identified by Udwadia et al: the Central Team announced that the Revised National Tuberculosis Control Programme (RNTCP) Maharashtra would be adopting all these cases and offering them their entire course of treatment free of charge. [It is hoped that this treatment will at least include the medications devised by Udwadia et al, if the patients are indeed responding to treatment, but we have been un able to confirm this as of yet. Treatment for drug resistant TB in India is generally standardised, as access to second-line DST has been too limited to allow for individualised regimens).

Plans to isolate the ‘TDR-TB’ patients in a remote facility appear to have been put on hold for now. Shortly before the Central Team visit, an emergency plan had been approved to send the cases identified thus far to a 30 bed sanatorium facility in Jaysingpur, 400 kilometers (250 miles) south of Mumbai.

A number of experts and activists criticised isolation in a remote location as unnecessary and a kneejerk reaction — and potentially a violation of the patient’s human rights. Rather it was suggested that they would be better managed in the TB wards of their local hospital.

Others, such as Nerges Mistry, the director of the Foundation for Medical Research in Mumbai, voiced concerns in the Lancet about the lack of good infection control to prevent the spread of highly drug-resistant TB to staff and other patients.

Indeed, a more patient- and staff-centred approach would be to introduce good infection control in these facilities, given the fact that these cases probably represent the tip of the iceberg, in order to prevent the spread of difficult-to-treat TB strains that are probably already present but not yet detected in the facility — or deliver home-based care provided that infection control in the home can be established (and if not in the home, at least near to it).

(Some researchers believe that there are some circumstances where isolation in sanatoria might indeed be the best and most compassionate options for some patients, as long as certain criteria are in place, such as easy access for friends and family. This will be discussed in a future entry in the HATIP blog).

However, the Central Team advocated against isolation of these ‘TDR-TB’ cases, suggesting that treatment was greatly reducing their infectiousness — even though only some of the patients were smear-negative at the time of its visit. Of course, all of the cases probably spent at least some time infectious, so contact tracing for each of these patients and their families is underway.

What is being done to fight and prevent drug resistant TB in Mumbai?

After input from the Central Team, the Maharashtra state government, Brihanmumbai Municipal Corporation (BMC) and private hospitals came up with a plan to deal much more aggressively with drug-resistant TB in Mumbai. Several of these steps are described in a press release, though reports in the Times of India on 19 January and 20 January, and elsewhere in the Indian media have clarified a number of key points.[i]

1) Immediately and dramatically strengthening the TB control staff in Mumbai.

Each of Mumbai’s 24 wards are now designated as 24 RNTCP districts, each hiring its own district TB officer, coordinated by one senior TB officer for all of Mumbai. All 25 doctors hired as TB officers will be sent for training at Bengaluru's National TB Institute. They will be responsible for administration, and also follow up and monitoring of patients to ensure they do not drop out of treatment.

2) Dramatically strengthening the infrastructure to support the TB programme.

Each TB district will be supported with infrastructure including 24 district TB drug stores and one additional state level TB pharmacy. The TB programme will decentralise further so that that there will be a basis TB unit for every 200,000 people (rather than for every 500,000 people). Overall this will add 35 additional TB units, overseen by TB control officers, supported by 20 additional microscopy centres (and lab technicians to be hired immediately).

The number of TB beds at GTB hospital in Sewri will be increased from 45 to 90.

Three additional DOTS-Plus sites (for drug-resistant TB) will be established. Crucially, Mumbai’s public sector has lacked the laboratory infrastructure to identify and confirm the diagnosis of drug-resistant TB, so additional culture and second-line DST laboratories are to be established and accredited at GTB Hospital in Mumbai in the next five to six months, and at two private laboratories as soon as possible.

3) The programme will try to ensure case notification by implementing the notification system under the BMC Public Health Act for TB, which establishes with punitive measures for whenever healthcare providers fail to report TB cases (this should assist TB district officers keep track of patients going onto treatment.

Mandatory laboratory notification will be introduced for M/XDR TB from all public and private sector laboratories of Mumbai, with retesting and confirmation under RNTCP. 

4) Contract tracing will be performed for all patients diagnosed in Mumbai with M/XDR TB, and TB screening performed on all of their close contacts. A similar exercise will also be undertaken in other districts and municipal corporation areas in the state.

5) There will be universal access to MDR TB screening in Mumbai including those treated by the private sector (they no longer have to repeat a failed course of treatment in the public sector in order to qualify for DST).

6) And, last but not least, there will be universal access to treatment for patients diagnosed with drug-resistant TB in Mumbai, who will be treated free, with treatment support whether they have enrolled with RNTCP or not.

The high expense of second-line medication is one of the reasons why patients stop taking treatment and become even more resistant. While first-line treatment costs around US $45, treatment for drug resistant TB costs around $4000, while treatment for XDR-TB can cost at least 2 and a half times as much. Few Indians can afford appropriate M or XDR-TB treatment, but it has been decided, in Mumbai at least, that it would be more expensive not to treat it.

7) A publicity campaign will be launched widely in order to spread awareness of the availability of free diagnostic and treatment services for all types of TB.

Finally, according to a report in the Gulf News, a research project on the prevalence of TB in the congested slums of Dharavi will also be undertaken with technical assistance from the World Health Organisation.

Are these measures enough?

Whether these measures are enough will of course depend upon how well they are implemented — as well as whether estimates are accurate about how much drug-resistant TB there is in Mumbai.

There are some risks with implementation. Where and how people with drug-resistant TB are treated is an issue. Without addressing factors such as poor infection control, it is possible that bringing more people with drug-resistant TB into facilities could lead to its spread to other patients, and staff. This is less likely if treatment for drug resistant TB is ambulatory. Spreading drug resistance within a health facility has been the cause of other drug-resistant TB outbreaks (such as the initial XDR-TB outbreak in Tugela Ferry (Church of Scotland Hospital), KwaZulu-Natal, South Africa in 2005), and without good infection control, serious illness and  potential deaths among healthcare providers -  not to mention poor morale and staff retention - could undermine TB control efforts.

One issue HATIP is currently uncertain about is whether second-line TB treatment will be an empiric standardised regimen in Mumbai (second line is often standardised when there is inadequate access to second-line DST for individualised or optimised treatment) and if so, how well is it tailored to the local resistance patterns.

Constructing a standardised second line regimen that is effective in most of the TB cases in a population, can be difficult when people have very different treatment histories. According to the report in PLos Med, the poorly trained private practitioners in Mumbai prescribed a wide range of treatment regimens, and theirpatients, could have developed very different resistance profiles.

If that is the case, a standardised drug-resistant TB regimen may fail to adequately control the infections in many of the M/XDR-TB patients in Mumbai — and suboptimal treatment could thus lead to increased resistance.

On the other hand, when the resistance profiles in a population are relatively homogenous, a standardised empiric regimen that suits the population would be simpler and more cost-effective than performing all that DST testing, and procuring a wider array of anti-TB treatment medications. WHO recommends ongoing continuous resistance surveillance to inform these decisions.[ii]

In CID, Udwadia et al recommended that the public sector take over all treatment of drug-resistant TB. While the Global Plan to Stop TB recommends engaging all health care providers, is it wise to empower private practitioners to continue treating drug-resistant TB patients without first providing further training to make sure that treatment, care and support conforms to international standards? Or will enforcing the case notification system work well enough that district TB officers will be able to keep a close eye on all the people with M/XDR-TB treatment in their district?

Udwadia et al also suggested, as have others, that India needs to more tightly regulate access to TB medications. It is important to note that some TB drug resistance could be the result of inadvertent exposure to TB medications. Some second and third-line anti-TB drugs are also commonly used to treat other conditions. If a healthcare provider or pharmacist provides one of these medications, such as a fluoroquinolone without first screening the patient for TB or checking to see whether they are on TB treatment, it could foster drug resistance. WHO urges strict enforcement of regulations for the quality and dispensing of anti-TB drugs, particularly of the second-line drugs. Other steps, such as guidance to pharmacists and non-TB specialists might also help avoid such mishaps.

The initial steps being taken in Mumbai are primarily focused on traditional TB control programme elements but we have yet to see any mention of marginalised populations who tend to have a greater risk of drug-resistant TB and who can be difficult for the formal health sector to reach. Is the need to consider, reach out to, engage and address the needs of poor and vulnerable populations such as people living with HIV, the poor, low caste, migrants, and people who use drugs adequately addressed by the TB programme in Mumbai? Will universal access to M/XDR-TB diagnosis and treatment going to be extended to the prisons of Mumbai or will it be a blind spot - as in so many other settings?

One of the pillars of the Global Plan to Stop TB is that community engagement in the TB response is critical. For instance,  could accessing DR-TB treatment, even if free, jeopardise relationships, employment or housing because of TB-stigma; does it interfere with mobility or work? do people have to trade putting food on the table, for treatment?

Engagement with the various communities at risk can help identify these issues, lead to more effective outreach, support services, follow-up, contact tracing and so on. Empowered and informed patients and communities may also be able to influence national policy and help leverage more support for health systems and TB services. Service integration or collaboration with other health sectors is needed in order to guarantee that other essential care in these populations — such as HIV prevention, testing, treatment (especially early ART) and care, or substitution maintenance therapy for people who use drugs — is integrated at or effectively linked with TB service delivery points and vice versa.

Finally, and most glaringly, the reports describe these efforts as being Mumbai-specific. What about the rest of India?

As Dr Paul Nunn from WHO's Stop TB Department told The Lancet: “Until recently, care for MDR-TB was not available in the public sector in India. Thus those with MDR-TB were forced in to the private sector where availability of anti-TB drugs is effectively unregulated and care is uncoordinated and unsupervised…This problem was predictable, and indeed was predicted.”

It would be a fallacy to assume that serious TB drug resistance will only be limited to Mumbai and its slums when the conditions that lead to virtually untreatable TB exist in many other areas in India.

References

[1] Ministry of Health and Family Welfare. Central Team Submits Report on Drug Resistant Tuberculosis Mumbai Cases.  Centre Assures full Supply of DR-TB Drugs and Technical help. RNTCP Maharashtra to Adopt Identified Cases and Offer free Treatment. January 20, 2012.

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

To coincide with World TB Day, members of WHO’s STOP TB Department published a piece in a special Tuberculosis and TB/HIV Supplement of the Journal of Infectious Diseases that lays out the case for improving access to TB prevention, diagnosis and treatment services for pregnant women and their children. They call for the following “low-cost, effective interventions” to be made a routine part of the integrated management of pregnancy and child health in much the same way as TB collaborative activities are now part of standard of care for HIV programmes in resource-constrained settings.

Such collaborative activities have indeed become the standard of care for HIV programmes, though it took some time to happen, and in most resource-constrained settings, we still have a long way to go in implementing them. But there are also clearly a number of differences in how HIV services and maternal and child health services are structured and delivered, and HATIP will be querying experts working in the fields of HIV and maternal neonatal and child health (MNCH) on these questions in the months to come.

The discussion on integrating TB activities into MNCH platforms begins

Collaborative TB/HIV activities have indeed become the standard of care for HIV programmes, though it took some time to happen, and in many resource-constrained settings we still have a long way towards implementing them consistently.

As WHO has pointed out, women, especially pregnant women and their children, represent populations whose TB needs are underserved, and particularly in countries with a high burden of HIV co-infection, this results in serious morbidity and mortality.

Delivering some of those services where women of child-bearing age and their children access care seems to make sense. But is it really that easy? There are clearly a number of differences in how HIV services and the MCH services are structured and delivered. So HATIP asked experts working in the fields of HIV and maternal, neonatal and child health what they think of the STOP TB Department’s recommendations for TB integration.

Most of the discussion has been focused on two areas: feasibility, and whether IPT should really be the priority in pregnant women living with HIV.

“On my visits to the districts, visiting primary health centres there, I have been sensitising doctors on the need for screening of TB among pregnant women and it is obvious this is not done in practice,” Dr Beena Thomas of the Tuberculosis Research Centre in Chennai told HATIP. She noted that the focus of the MCH programme in India right now is on preventing maternal mortality and promoting institutional deliveries.

“To that end incentives are being given, the village health nurses are being trained to register and enter pregnant women’s data into a computerised data system. But with the statistics of TB among pregnant women and children, it is reasonable or doable to screen all pregnant women for symptoms.”

However, they probably won’t be using the WHO symptom screen to rule out TB in order to put women on IPT.

“There is no policy for INH among pregnant women. I am not sure if it will be accepted especially with the concerns of medication among pregnant women, when they have no symptoms and are afraid of any reactions affecting the foetus. We need to do a study on feasibility and acceptability of INH [IPT]among pregnant women who do not have symptoms – and if they have not been exposed to TB? I am not sure [it would be appropriate].”

She said the doctors she’s met don’t seem to consider asking whether the patient has TB symptoms, rather, they are more “concerned with ordering chest X-rays, and inducing sputum.”

In some settings, where women rarely go into the antenatal services, there are concerns that there may not even be much of an opportunity to do screening, let alone complete the diagnostic process.

“In our study there was a lot of difficulty in performing TB screening at delivery and postpartum", said Dr Jyoti Mathad, Fellow at Weill Cornell Medical College, who is doing studies on latent TB diagnostics and pregnant women in India with Dr Gupta.

“For delivery, women are discharged pretty quickly if they had vaginal deliveries and so it may be difficult to perform any kind of intervention besides a questionnaire and have them still be there for the outcome of the intervention (e.g. X-ray results, sputum microscopy, TST). For the postpartum period in India, many women stay at home or go to their mother's home with their child for essentially the whole first year. We thought intervention at the immunisation clinic would be an opportunity for screening, but even that proved to be difficult. We are not sure if children are just getting immunised elsewhere such as local community clinics,” Mathad said.

However, Dr Thomas thinks symptom screening could work in the context of the programme to prevent parent-to-child transmission – by relying on the community-based elements that facilitate that programme.

“We just need to sensitise health providers and also community workers (village health nurses, ASHA, etc.) during their visits to look out for TB symptoms and then be engaged in [making effective] referrals.”

She thinks using these community-based mechanisms would facilitate integration into the antenatal clinic. “Home-based monitoring, even collecting sputum and linking the patient to care should not be a problem, considering we have the village health nurses and the ASHAs who are on the job for the MCH programme. It could also be incorporated into the school health programme to screen all children for TB on a regular basis. That would be a good start as they do it for anaemia, eye problems, for example,” she said.

Professor Anthony Harries of the International Union Against Tuberculosis and Lung Disease gave his personal opinion about what interventions should be prioritised in HIV-infected pregnant women who have a high risk of TB.

“The best way to prevent this TB risk is to offer HIV testing and counselling to all pregnant women, and for those who are HIV-positive to offer Option B+ = this is triple ART for life for the pregnant women regardless of the CD4 count. This intervention will work first to reduce HIV transmission to the foetus and baby, and to the sexual partner, and to subsequent babies: a lower risk of HIV means a lower risk of TB. This intervention will work secondly to reduce maternal morbidity and mortality, maternal risk of TB and maternal hepatitis B infection,” said Dr Harries.

He noted all the challenges involved in getting a diagnosis of TB in pregnant women – which does not mean that it shouldn’t be done; it is just that the process is already labour intensive.

“If the pregnant woman is negative to the symptom screen, we know this does not completely exclude TB – some may have asymptomatic, culture-positive TB, but Steve Lawn and others in South Africa have shown that many of these persons develop symptoms in the subsequent few months. Thus, repeated screening is necessary if only to identify those who will develop symptoms later on. In the continuous asymptomatic pregnant woman, IPT is probably safe and should reduce further risk of TB, although the benefit of IPT is only in those with a positive tuberculin skin test. This conundrum may prevent health workers going ahead and starting IPT despite WHO guidelines that it is feasible and pragmatic to give IPT to all.”

“It’s not easy. However, ART works regardless of tuberculin skin status and I think this should be the priority. So, I would focus my TB prevention efforts around HIV counselling and testing. I would aggressively promote ART for HIV-positive pregnant women and for HIV-negative pregnant women I would demand vigilance for those who are coughing for > 2-3 weeks and investigate them accordingly for TB,” he concluded.

Dr Chewe Luo of UNICEF wrote to tell HATIP that she agreed with Professor Harries’ analysis. “We should be pragmatic and need to move forward with what he suggests. Many countries are moving forward with option B+ as the preferred regimen for PMTCT but are not thinking about TB symptom screening at follow-up visits. If we want to see how the different PMTCT regimen options impact TB we should look at this more systematically.”

Professor Ben Marais of University of Sydney Medical School stressed that making sure that women were screened for HIV and put on treatment to prevent HIV transmission may indeed be the most important anti-TB intervention.

“It is amazing how HIV testing is not standard of care for pregnant women in South East Asia (though I can only speak for Vietnam, Indonesia and Bangladesh). It seems as if there are many cultural and stigma barriers and most doctors I’ve spoken to say they will offer it only to mothers who confess to be sex workers or IV drug users. Even then access to care is very limited, with strict CD4 criteria applied by the few HIV treatment centres that are in existence. The same applies to TB patients.

“But as a paediatrician, I can only echo that paediatric HIV is a preventable disease and every infected child in essence represents a failure of the “system, though I realise there are many practical hurdles.”

There is certainly no doubt that getting pregnant women living with HIV on ART is the higher priority – it prevents TB and vertical transmission of HIV. But whether IPT can be given safely on top of it, depends upon the ability to continue monthly symptom screening and keeping a close eye out for side-effects that are more common in women – and perhaps to perform TSTs in settings where fewer women are latently infected with TB. 

However, as Dr Thomas suggested, community health workers or expert patients may be able to manage some of these activities outside the clinical setting, perhaps in the home, though they would need to be trained and have those services integrated with their other responsibilities. But, as Dr Yassin’s study showed in Ethiopia showed, health extension workers can do a great job of increasing case detection by introducing screening strategies (contact tracing) into their routine activities, and could also scale-up IPT delivery.  

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.