Breaking the drug-resistant TB transmission cycle important

GeneXpert

Nearly two months after the Health Ministry set a highly ambitious target of working towards elimination of tuberculosis by 2025, a study published in The Lancet Infectious Diseases indicates that India’s TB crisis is all set to snowball by 2040 when one in 10 cases could be drug-resistant. What is even more alarming is that the increased number of drug-resistant cases — both multidrug-resistant TB (resistant to more than one of the first-line drugs) and extensively drug-resistant TB (additionally resistant to fluoroquinolones and at least one of the second-line injectable drugs) — will come from direct transmission from infected people to others rather than by strains acquiring resistance to TB drugs during treatment due to inappropriate treatment or discontinuation of treatment midway. The study found that “most incident” MDR cases are “not caused” by acquired drug resistance, and that acquired drug resistance will become a “decreasing cause” of drug-resistant TB. The increased availability of drugs to fight drug-sensitive TB has led to the emergence of MDR-TB strains. With increasing number of MDR-TB cases, there has been a shift in the way people get infected with drug-resistant TB — from strains acquiring drug resistance during treatment to direct transmission of MDR-TB strains from an infected person. The same trend is seen in the case of XDR-TB too. As a result, in high MDR-TB burden countries such as India, improved treatment outcomes in people might only reduce and not eliminate drug-resistant TB. Till 2015, only about 93,000 people with MDR-TB have been diagnosed and put on treatment.

The study, based on a mathematical model to forecast how TB is likely to progress in the four most-affected countries (Russia, the Philippines and South Africa, India), suggests that the number of new MDR-TB cases in a year in India will touch 12.4% by 2040, up from 7.9% in 2000. In the case of XDR-TB, the incident cases will rise to 8.9%, up from 0.9% in 2000. In 2015, the four countries accounted for about 40% (more than 230,000) of all drug-resistant TB cases in the world. Besides increasing the number of people who are diagnosed early and successfully treated, India’s TB control programme has come up with enhanced interventions to break the transmission cycle of the bacteria in the community. One of the ways this can be achieved is by carrying out immediate screening of all family members of a patient who has been diagnosed with the disease. Contact screening of family members and preventive treatment of all children below the age of five years who have not developed TB disease are already a part of the Revised National Tuberculosis Control Program (RNTCP) but is rarely done. Another important strategy that has to be adopted is making drug susceptibility testing universal and mandatory. Developing more accurate, cheaper and effective diagnostic tests and improved treatment regimens that are less expensive and of shorter duration will also go a long way in winning the war against the disease.

Published in The Hindu on May 12, 2017

Working towards personalised TB treatment

Three major global research centres in India will receive funding coming out of collaboration between the UK Medical Research Council (MRC) and the Department for Biotechnology (DBT), India. The Department for Biotechnology will match the funding provided by UK through MRC and Newton Fund.

The Chennai-based National Institute for Research in Tuberculosis (NIRT) will get one million pounds in funding from UK and DBT will provide an equivalent amount over a three-year period to develop new diagnostic tools and new treatments to address the sharp rise in cases of multi-drug resistant tuberculosis (MTB). The initiative will start in May/June this year.

“We will be undertaking whole genome sequencing of the TB bacterium to see the pattern of drug resistance in the community,” said Dr. Soumya Swaminathan, Director of NIRT. “As of now, there is limited information on drug resistance for second-line drugs and newer drugs.”

A UK company has already developed a cheap, hand-held, robust tool that has the capacity to carry out whole genome sequencing. The testing and validation of the chip-based technology will be done in India. “Within three years, we will be using this technology in India to sequence the genome of patients so that personalised TB treatment can be offered for better outcomes,” she said.

Many patients with MDR-TB and XDR-TB are resistant to second-line drugs. The new technology will help in finding out the mutations in a patient and decide a treatment that is tailor-made for him.

The second part of the funding will be for translational work. “It will mainly focus on host-directed therapies to improve the host’s immune system,” Dr. Swaminathan said.

Cambridge University has already identified some available drugs used for other diseases to target different pathways in immune response to fight the TB bacteria. The basic work has already been done.

A drug (verapamil) used for treating BP effectively blocks the efflux pump of the TB bacteria. Efflux pump pushes out a drug from the bacteria thus making the drug ineffective. Other drugs target TB bacteria by increasing autophagy, thereby killing them.

The second collaboration is between the Hyderabad-based L.V. Prasad Eye Institute and University of Sheffield. The collaboration is for developing and testing a technology that can be used for treating ocular infections.

“This technology has the potential to be used for other infections as well,” said Dr. Proshant Garg, Director and G. Chandrasekhar distinguished Chair of Education at the Institute.

The technology uses a highly functionalised polymer that can bind to specific microorganisms. Nanoparticles containing the antibiotics will be first tagged to the polymer with the hope that the polymer will deliver the nanoparticles to the site of infection. Once the polymer binds to the bacteria, the nanoparticles will release the antibiotics into the immediate environment of the microorganism.

“It’s a kind of missile technology for targeted drug delivery,” Dr. Garg said. The polymer, which will act as a drug carrier, has already been developed by the Institute in 2010-11 and its specificity to binding on microorganisms has also been verified.

“The collaboration will develop the technology to attach the nanoparticle to the smart polymer,” he said. The other pending work is to develop nanoparticles of different antibiotics and attach them to the polymer and ensure that the combination moves into the tissue and reaches the site of infection.

MRC will be providing Rs.9 crore and DBT’s share will be Rs.3 crore. The grant duration is four years.

Published in The Hindu on February 19, 2015

Editorial: An ominous situation

That the medicine chest is bereft of effective new drugs to fight the extremely drug-resistant tuberculosis (XDR-TB) strain has once again become frighteningly clear. According to a study published recently in The Lancet, while only 16 per cent (17 of the 107) of a South African patient cohort had either treatment cure or completion at the end of two years of follow-up, as many as 49 patients died and 25 failed treatment. With the strain remaining resistant to at least four of the most potent anti-TB drugs available today, XDR-TB patients have virtually exhausted all treatment options. Hence, despite long, complicated and prohibitively expensive treatment using toxic drugs, the outcome is at best poor. The dire urgency to bring immediate focus on the discovery of efficacious anti-TB drugs to treat all forms of drug-resistant strains becomes clear as hospitals in South Africa, for want of beds, are being forced to discharge XDR-TB patients who are yet to be cured. This is particularly ominous as they can spread the disease with equal ease as those with drug-sensitive TB. With the median survival period from the time of discharge being nearly 20 months, the threat of the dangerous form of TB spiralling out of control is real as many patients are culture-positive and about a third are smear-positive at the time of discharge; smear-positive patients have a higher bacterial load and hence a greater potential for spreading the disease. If this situation is allowed to continue for a few more years, the XDR-TB strain would spread to all countries.

There is also an immediate and pressing need for the high-burden countries to increase the number of beds for treating drug-resistant cases. It is time to come up with acceptable and workable solutions to isolate XDR-TB treatment failure or incurable cases to cut the transmission chain. Reducing the reservoir of TB-infected people through a simple, cheap and effective isoniazid preventive therapy in children under five years of age exposed to adults with pulmonary TB, will pay significant dividends in the long run. Next in priority should be ensuring that most drug-sensitive patients are diagnosed early, treatment using the correct drug regimen is initiated without delay, and the default rate is greatly reduced. This would automatically prevent the emergence of drug-resistant forms. The importance of this becomes all the more clear as all the parameters that go into the successful completion of drug-resistant TB treatment are fraught with problems. India, which is now expanding and equipping MDR-TB diagnostic centres with GeneXpert, has already detected 64,000 cases, the highest in the world.

Published in The Hindu on January 24, 2014

‘Long-term outcomes in South African patients with XDR-TB poor’

Long-term outcomes in South African patients who have extremely-drug resistant tuberculosis (XDR-TB) are “poor” immaterial of HIV status, notes a paper published on January 17 in The Lancet . Despite treatment outcomes being poor, “substantial number” of XDR-TB patients who were still infected were discharged from hospitals in spite of failing treatment. With the median survival period of these patients being nearly 20 months, the patients are “likely” to spread drug-resistant TB in the community, notes the study by Elize Pietersen et al from the University of Cape Town, South Africa.

“Many patients … who were discharged from hospital had positive sputum cultures, had failed treatment, and had no further therapeutic options. These patients survive for long periods living in the community and are likely to contribute to community-based spread of XDR tuberculosis,” the authors write.

According to them, a third of discharged patients were smear-positive and hence continued to be infected with XDR-TB, suggesting “high transmission potential.” Of the 45 patients who were discharged from the hospital into the community, 19 (42 per cent) continued to be XDR-TB culture-positive.

They cite lack of bed space in designated tuberculosis hospitals, scarce alternative long-term residential and palliative care facilities, and inadequate resources to support proper home-based care when appropriate as reasons for discharging the patients into the community.

The situation is likely to be similar in countries like India where XDR-TB and totally drug-resistant TB are present, they warn. “The findings we have outlined are likely to be relevant in several settings where XDR or totally drug-resistant tuberculosis has been described, such as … India,” they note.

Even with a multidrug regimen that includes capreomycin and fairly good adherence, the long-term treatment outcomes in XDR-TB patients are “poor.”

A cohort of 107 patients with XDR-TB was followed up between March 2008 and August 2012. At the end of two years, only 17 patients (16 per cent) had favourable outcomes (treatment cure or completion), while 25 patients (23 per cent) failed treatment. Forty-nine patients died and seven defaulted on treatment.

At the end of five years, only 12 patients (11 per cent) had favourable outcomes (treatment cure or completion), while 11 patients (10 per cent) had failed treatment.

Published in The Hindu on January 17, 2014

TB: ‘There is a clearly higher risk of mortality in children of 0-4 years’

X-ray

With 8.6 million people across the world developing tuberculosis in 2012 and nearly 1.3 million succumbing to the disease, and with the number of people with multi-drug resistant TB (MDR-TB) and extremely-drug resistant TB (XDR-TB) increasing every year, the focus has been on increasing case-detection and improving treatment rates.

In the process, no significant measures have been undertaken to prevent the disease. This is true in the case of developing countries, particularly in high-burden countries, including India.

This is despite the fact that we know one third of the global population (and nearly 40 per cent of the Indian population) is estimated to be latently infected with TB. Since 5-20 per cent of these latently infected people develop the disease at some point in their lifetime, the infected people serve as a huge reservoir.

One more glaring blind spot in our war against TB has been the near-neglect of children. This is despite ample evidence that many children who are infected when young become diseased as they age, even if they do not become diseased soon after infection.

But the focus is now shifting, and childhood TB is slowly getting its due attention. For the last two years, WHO in its annual report has been including the estimates of global TB burden in children below 15 years. And for the first time ever, WHO recently came up with a Roadmap for Childhood Tuberculosis. In 2010, WHO had come out with Rapid Advice for Treatment of Tuberculosis in Children. The global health body had earlier come out with guidelines for implementing contact tracing of children belonging to the most vulnerable group — under five years from families where an adult had been diagnosed with active pulmonary TB.

But countries, especially the developing ones, have shown little inclination in undertaking contact tracing despite knowing that many of the infected children become diseased in a matter of weeks and the mortality rate is also significantly high.

In a long-winding interview over email, Dr Greg Fox, Post-doctoral Research Fellow at McGill University, Montreal explains to me why and how important contact tracing of children aged under five is to win the war against TB.

How high are the chances of children below five years becoming diseased in households where a person has been recently diagnosed with active pulmonary TB?

See our meta-analysis (2013 paper in the European Respiratory Journal by Gregory J. Fox et al.,) with data for children for the rates of disease and infection in children. Our study found: “In 95 studies from low- and middle-income settings, the prevalence of active TB in all contacts was 3.1 per cent, microbiologically proven TB was 1.2 per cent, and latent TB infection was 51.5 per cent.”

What is the minimum time for a child below five years to get infected with TB when an adult in the household with active pulmonary TB is yet to start treatment?

If you define infection as the time from exposure to tuberculin skin test (TST) positivity, then there can be a delay of 8-12 weeks before TST becomes positive.

Compared with an adult, how vulnerable are children in this age group to TB infection when an adult in the household who is infected with active pulmonary TB is yet to start treatment?

In terms of disease, young children under five have a higher risk of disease than older children. A 2010 paper by Brooks-Pollock in PLoS ONE journal shows the age distribution of mortality in Ukraine. Young children are therefore very susceptible, and probably more susceptible than younger adults.

The susceptibility to infection is a different question. It is difficult to say, since the lifetime cumulative incidence of TST positivity increases over the lifetime. By the time a person is in the 30s, in a high prevalence country, he/she will usually have a high prevalence of latent TB infection (LTBI). The incremental effect of additional life-time exposure in this group [under five years of age] is small.

Aren’t children who have taken BCG vaccine on time naturally protected against TB, particularly in the first few years after vaccination?

[BCG vaccine does not prevent primary TB infection.] A 2010 paper in Clinical Infectious Diseases journal by Soumya Swaminathan and Banu Rekha states: “BCG vaccine has been shown to be protective against disseminated forms of TB in young children, with a summary protective estimate of 73 per cent (range, 67 per cent –79 per cent) against TB meningitis and 77 per cent (range, 58 per cent–87 per cent) against miliary disease.”

In a TB-endemic setting like India, will children not be at risk of getting infected with TB from contacts outside the household?

Yes. Community transmission is probably the bulk of transmission in high prevalence settings. The evidence of the proportion of transmission that occurs in the household is limited to a few small studies using molecular epidemiology in the context of household contact investigation. For example, a January 17, 2004 paper by Suzanne Verver in The Lancet shows this. The evidence is limited in India, to my knowledge.

What is the rationale for having a cut-off age of five years? Will children older than five years not gain from preventive therapy?

The WHO guidelines recommend that children under five years (i.e. 0-4 years) should be a priority for contact investigation. As in studies such as those by Brooks-Pollard, there is a clearly higher risk of mortality in children of 0-4 years. Hence this is a priority for screening. Of course, there is still benefit for all other ages — however the ages 5-18 have a substantially lower rate of mortality.

How effective is isoniazid as a prophylactic? For how long does the protective effect last?

The sustained effect is primarily related to the reduction in transmission that occurs as a result of the latent TB infection (LTBI) treatment in the community, but depends upon factors including treatment completion rates, the uptake of LTBI therapy in the community etc.

Is the six-month treatment a standard treatment regimen across the world or are there different timeframes depending on how endemic TB is in a region?

Six months is inferior to 12 months. Many countries use nine months. It also depends upon the proportion of treatment that is actually taken (completion of >80 per cent of a 12-month course results in a 90 per cent reduction, compared to a 60 per cent overall observed effect in real life setting.

Does the isoniazid drug cause any side-effects in children, especially those who are one year and two years of age?

The risk of complications of isoniazid is lower in younger children, but nonetheless they do occur.

How accurately is the dosage of 10 mg per kg calculated in reality? Are there any problems when the dosage is more?

This depends on how accurately the child is weighed. The theoretical risk of drug induced liver injury increases with dose, which has been shown in animal models.

[WHO “Rapid advice for TB treatment in children” for current dosing guidelines states: “Infants (aged 0–3 months) with suspected or confirmed pulmonary tuberculosis should be promptly treated with the standard treatment regimens. The treatment may require adjustment of dosages to reconcile the effect of age and possible toxicity in young infants. The decision to adjust dosages should be taken by a clinician experienced in managing paediatric tuberculosis.”]

How prudent is it to expose young children, especially one-year-old and two-year-old children, to X-rays when they don’t even have the disease?

Child contacts with suspected TB (on the basis of symptoms) should have a chest X-ray. The risk of a single chest X-ray is minimal. The advantage of diagnosing potentially life-threatening TB is substantial. Given the high risk of TB disease in child contacts, the risk-benefit calculus strongly favours an X-ray. In child contacts, where available, chest X-ray is a useful screening test for active TB (note that TST is often not available in many settings). However, symptom screening alone has been shown to be effective if this is all that is available.

How aware are health-care workers and doctors of the need for undertaking contact screening of children aged under five in high-burden countries?

Contact investigation is not frequently undertaken. A 2011 paper in the International Journal of Tuberculosis and Lung Diseases by T.J. Hwang et al., states: “Contact investigation contributes to improving early case detection of tuberculosis (TB). However, its implementation in low-income, high TB-burden countries remains limited.”

As a norm, are children in the developing countries on prophylactic treatment regularly followed-up for any symptoms of TB disease? How frequent are such follow-ups?

Follow-up depends on the setting. Generally, most programmes have single screening interventions near the time of exposure. The WHO recommends only a single-screening intervention.

On average what is the default rate? Which developing country has the highest adherence rate to drug treatment (six months)?

A 2012 paper in Cochrane Database Systems Review has some good examples. In countries like Canada, the U.S. and Australia, treatment completion rates can be very good because there is close supervision and regular follow-up during the entire treatment.

When children with latent TB default after some time, do they become more vulnerable to developing resistance to isoniazid?

The risk of developing isoniazid resistance is very low and not clinically significant in the treatment of children with latent TB infection where active disease is excluded. If a child stops taking isoniazid, then there is no selective pressure to develop isoniazid resistance again. If they repeatedly stop and start isoniazid during active disease, then yes, this would predispose them to increased risk — but that is why active disease should be excluded (clinically and/or radiologically).

On average, what is the success rate of putting children on prophylactic treatment for the number of children contacted, both in the developing and developed countries?

There is little information on this as no data is routinely collected by different national TB programmes. A 2012 paper in BMC Research Notes by Merrin E. Rutherford et al., is a good illustration of how this can be done (in Indonesia, they found compliance was only about 25 per cent).

How much do poor nutrition, small dwellings and crowded settings facilitate children developing the disease when an adult in the household has been recently diagnosed with active pulmonary TB?

The risk of infection and disease will vary depending upon the local epidemiology. If the prevalence of active disease is higher, then the risk of TB would also be higher.

The risk factors you identify (poor nutrition, overcrowding) are certainly recognised to be associated with increased incidence of TB. Social determinants of disease are important. An April 2011 paper in the American Journal of Public Health is informative.

How cost effective is contact screening of children and putting them on treatment?

Cost-effectiveness of treating latent TB infection varies substantially depending upon local factors. One study in Canada (2008 paper in Value Health journal) is informative.

Is there a difference in children easily developing latent/active TB when an adult is infected either with drug-resistant TB or drug-sensitive TB?

The rate of infection in contacts of MDR-TB and drug susceptible tuberculosis appears to be similar (see September 24, 2013 paper in Clinical Infectious Diseases journal by Shah et al.,). However, there are arguments about the fitness cost of drug resistance (see 2009 paper by Borrell et al). However, as MDR-TB typically has a prolonged period of infectiousness, relating to delayed diagnosis, probably overall contacts have a higher risk of developing infection and disease.

Do you think mass awareness campaign like what was done in the case of HIV/AIDS would help in increasing the awareness level of contact screening in the community and increase/change the health-seeking attitude of people?

Mass awareness campaigns need to be carefully designed, or they can reinforce the stigma associated with TB. Generally speaking, childhood TB contact investigation should be seen as a part of the broader approach to TB control — with the message that there can be benefit to the children from being assessed. World TB Day often provides a time for countries to focus upon TB in high-risk groups, such as child contacts, although I cannot quantify what proportion of countries make children a focus. Certainly the WHO Roadmap for Childhood TB is a part of an attempt to raise awareness of this issue. It is as much a challenge to educate policy makers and TB services about childhood TB as it is to educate patients, their contacts and the general public.

(The Correspondent is a recipient of the 2013 REACH Lilly MDR-TB Partnership National Media Fellowship for Reporting on TB.)

Published in The Hindu on November 8, 2013

Editorial: No time to lose

Published in The Hindu on march 20, 2008

If globally containing tuberculosis, the incidence of which is estimated to be growing at one per cent a year, is proving to be a big challenge, the  spread of multi-drug resistant tuberculosis (MDR-TB) — caused by a bacterial strain that is resistant to at least two of the best first-line drugs — is not making things easy. According to the latest report of the World Health Organisation on anti-tuberculosis drug resistance surveillance, the fourth by the world body, the number of drug resistant TB cases that had emerged in 2006 was about 4.9 lakhs. That translates to 4.8 per cent of the global population affected by drug resistant TB. Sadly, India and China alone account for half the global burden of multi-drug resistant TB.  The percentage of people affected by MDR-TB is likely to increase in India as the DOTS Plus programme to treat such cases was started only in August last year. Unlike detecting TB, diagnosing MDR-TB can be done only by specialised laboratories and not clinically. Though the plan is to have 24 regional laboratories (one for each State) capable of identifying such cases and managing 5,000 cases annually by 2010, in reality only five laboratories are now equipped to undertake testing and three more will be ready by the end of the year.   “Insufficient laboratory capacity is seen as the primary limitation in implementation of these plans,” notes the report.  This is of great concern as “…unless MDR-TB management develops rapidly in the public sector, an increasing number will be managed by the unregulated private sector.”

Though tuberculosis is endemic in the country, which is one of the high TB burden countries in the world, it was only two years ago that the Revised National TB Control Programme succeeded in achieving population coverage of directly observed treatment, short-course (DOTS) in all districts. Despite a detection rate of 61 per cent and treatment success rate of 86 per cent, the prevalence of drug resistance in new cases is about 3 per cent and over 17 per cent in the previously treated cases. Apart from the well known reason of patients not completing the full course of treatment, the indiscriminate use of second-line drugs by private practitioners is a major factor in the increasing number of drug resistant patients. More efforts have to be directed at educating healthcare providers on correct prescribing methods as some of the MDR-TB cases would eventually become drug resistant to three or more of the six classes of second-line drugs leading to extremely drug resistant TB (XDR-TB). Though estimates are not available, extremely drug resistant cases have already been reported in the country. A multi-pronged strategy is imperative to tackle MDR, lest the number of extremely drug resistant forms, for which there is no treatment at present, escalates.

Editorial: A warning signal

Published in the Hindu on October 12, 2006

The discovery of a highly virulent strain — extremely drug resistant tuberculosis (XDR-TB)–in KwaZulu-Natal province in South Africa, and presented last month at the XVI international AIDS conference in Toronto, has dramatically changed our perception of the way tuberculosis can create havoc for humanity.  According to the data presented at the conference, of the 536 patients tested, 53 were found infected with XDR-TB; 52 of the these, many of whom tested positive for HIV, had fallen prey to the new strain within 25 days.  This is not the first time that such strains have been identified.  A survey carried out between 2000 and 2004 by the World Health Organisation and the Atlanta based Centers for Disease Control and Prevention, which identified these strains in all regions of the world, conforms their prevalence.  As an editorial in a recent issue of the British Medical Journal points out, the emergence of such strains was only to be expected, given the poor control practices.  If the global incidence of tuberculosis is estimated to be growing at one per cent a year, about 4.5 lakh new cases are caused by multi-drug resistant tuberculosis (MDR-TB)—clearly the result of the failure of  all stakeholders to adhere to correct strategies for fighting TB despite the directly observed treatment, short-course (DOTS) being widely adopted.

While treating multi-drug resistant TB is possible by using at least four second-line drugs, treating patients suffering from extremely drug-resistant TB is currently not possible as the bacilli are resistant to three or more of the six classes of second-line drugs. That the possibility of developing a new class of TB drugs is at least four years away further compounds the tragedy.  Though “… a strain resistant to so many drugs is not virulent enough to make healthy people seriously ill,” as reported in Nature, is comforting, it can prove lethal to those who are HIV positive, estimated to number over five million in India. The only recourse, therefore, is to ensure that the incidence of multi drug resistant TB is reversed.  Adoption of incorrect prescription practices by many private practitioners is one of the biggest contributing factors. Despite the DOTS programme being in place throughout the country, and the prevalence of multidrug-resistant TB well known, estimates on a national scale are not available.  With the emergence of XDR-TB, the original roadmap to have these estimates by 2010 covering nearly 50 per cent of the population has to be revisited.  Concerted efforts are needed to make the DOTS-Plus programme, to address the management of multi drug resistant TB, operational quickly. In the wake of XDR-TB there is no room for complacency.