Ignoring basic TB control fuels drug-resistance: Call for shorter, effective therapies!

Dr Mario Raviglione, WHO
Drug-resistant tuberculosis (TB) besides being a brewing public health emergency, is also a sordid reminder of what happens when most effective drugs, become ineffective - and - alarming number of people die of diseases which were much simpler to prevent, treat and cure in the past. "480,000 people developed multidrug-resistant TB (MDR-TB) in 2013, with 210,000 associated deaths. India, China, Russia, Pakistan and Ukraine have 60% of all MDR-TB cases in the world. Former USSR countries have highest percentage of new TB cases with MDR-TB" said Dr Mario Raviglione, Director of the World Health Organization (WHO)'s Global TB Programme, who was speaking at the 5th Asia Pacific Region Conference on Lung Health in Sydney, Australia.

MDR-TB happens when a person becomes resistant to two of the most powerful anti-TB drugs (isoniazid and rifampicin)- so treatment choices are severely limited, and treatment outcomes are not as good.

Dr Lee B Reichman, RUTGERS
[CNS Video] Agrees Dr Lee B Reichman, Adjunct Professor of Medicine, Preventive Medicine and Community Health at Rutgers New Jersey Medical School (NJMS), and Executive Director of NJMS Global Tuberculosis Institute: "Drug resistance in the world, as well as in Asia Pacific region, is a gigantic problem. It is preventable and treatable but it occurs because basic TB control is ignored. The burden of drug-resistant TB is huge and growing! TB is an easy disease to treat, but takes a long time, and drugs sometimes cause toxicity. If people are not treated properly or do not take their medicines properly they get drug resistance. Drug-resistant TB is difficult and expensive to treat."

"It is important to realize that drug resistance is ubiquitous – it is everywhere! Difference is that in places which have a good basic TB control programme we do not have whole lot of drug resistance. In our setting in USA, which is not comparable to many parts of the world, we have 99% adherence to anti-TB therapy - patients take their medicines under direct supervision and we do our best not to cause any drug resistance. But places like Papua New Guinea (PNG) have alarming levels of drug resistance – because – basic TB control programme for drug sensitive TB is so poor. In some places in PNG about 30% of patients are lost to follow up or half of them do not have their TB diagnosis made properly. This is also what creates drug resistance."

Detect drug-resistance upfront at the time of TB diagnosis

A recent study with over 100,000 patients, assessed the impact of upfront Gene Xpert testing on detection of pulmonary TB and rifampicin-resistant pulmonary TB cases in India. Gene Xpert is one of the state-of-the-art molecular test for diagnosing TB and at the same time as assessing resistance to at least one of the main drugs used to treat the disease (rifampicin). This study showed two important results: When implemented on a large scale in India the Xpert test significantly increased case-notification rates of all bacteriologically confirmed TB cases (39%) and increased rifampicin-resistant TB case detection by over five-fold compared to conventional drug sensitivity testing.

So diagnosing TB accurately and treating with drugs that are effective and sensitive for an individual, are important steps to ensure favourable treatment outcome.

Waiting list?

"There are few places where although we are detecting drug-resistant TB with new tools such as Gene Xpert but there is no capacity to treat all those diagnosed with drug-resistant forms of TB. This results in a waiting list of people to get treated for MDR-TB which to me is unconscionable. Everybody should have access to care they need" rightly said Dr Lee Reichman.

He added: "Everybody needs to have accurate drug susceptibility testing (DST) upfront at the time of TB diagnosis. For countries where standard MDR-TB treatment regimen works well and does not cause more drug resistance, it is okay to treat patients with standard therapies. But in countries or settings where standard regimens may amplify more drug resistance we need specific diagnosis for individualized treatment which is effective for that person. This is a human rights issue. Everybody deserves a proper diagnosis with TB, everybody deserves free, proper and appropriate treatment for TB, and not to do so in abridgement of human rights."

Why do we need new drugs for TB?

There is no doubt that we need shorter and effective treatment regimens for MDR-TB. While we wait for better and shorter therapies, we need to do as best and rationally as possible with tools we have on hand.

Before 1940s we had no drugs for TB and people were treated with bed rest and fresh air which worked half the time. Since anti-TB drugs became a reality, no one needed to die of TB. However irrational use of these drugs and several other factors that interact with health security, have pushed us in an era where most powerful anti-TB drugs have stopped working on some of the TB patients with drug resistance. TB deaths continue to be a reality even today.

TB bacteria grow slowly and drugs work in rapidly growing phase, so it takes months to treat a TB patient. "If someone has a streptococcal throat we can treat in 10 days. But with TB drugs basic treatment is 6-9 months and if drug resistance occurs, then as second-line drugs are less good, treatment might be for 20-24 months. We had no new anti-TB drug for fifty years but very recently now, we got two new drugs for drug-resistant TB, which are known as Bedaquiline (made by Janssen) and Delamanid (made by Otsuka). We have to use these new drugs very carefully to ensure that patients do not develop resistance to them and drugs are used rationally. So we are walking a fine line, people are just learning now how to use Bedaquiline which is more available than Delamanid" said Dr Reichman.

"Several studies show 80% cure rate for patients who were treated with regimens that included Bedaquiline but has to be done very carefully and we do not want to cause side effects or other problems. Investigators from the International Union Against Tuberculosis and Lung Disease (The Union) did research with existing anti-TB drugs including those that were not used that very often to see if shorten regimens will work for MDR-TB. This research was carried out in Bangladesh and few other places (such as Cambodia). The Union researchers found excellent results with this shorter 9 months regimen with over 80% cure rate for patients with MDR-TB. Previously MDR-TB cure rate in those settings using standard 20-24 months therapy, have been around 50%. WHO has taken this evidence into account and a long-term clinical trial is currently taking place to provide even stronger evidence base. The clinical trial results may come out in 2017-2018."

Dr Reichman could not have been more on-spot with his remark: "If we have drug-resistant TB regimens with cure rate like 50% that is like ancient medicine. We need new and better drugs, new and better diagnostics and we need to turn this around. It is unconscionable in 2015 for anyone to die of preventable, curable and treatable disease."

Dr Chen-Yuan Chiang
Photo credit: CNS, Hanoi/2013
Dr Chen-Yuan Chiang, senior consultant with the International Union Against Tuberculosis and Lung Disease (The Union) and also affiliated with the Centers for Disease Control and Prevention (CDC) in Taiwan, listed five conditions for the inclusion of Bedaquiline in the adult treatment regimen of MDR-TB:
  1. Treatment is administered under closely monitored conditions,
  2. Proper patient inclusion,
  3. Patient informed consent obtained,
  4. Adherence to principles of designing a WHO-recommended MDR-TB regimen, and
  5. Pharmacovigilance and proper management of adverse drug reactions and prevention of drug-drug interaction.
Side effects and adverse reactions with drugs are not uncommon. It is always good to be aware of possible adverse reactions related to a particular drug. Dr Chiang shed more light on possible adverse reactions related to Bedaquiline. Some of the common adverse reactions include: gastrointestinal distress (nausea, vomiting, abdominal pain, loss of appetite), joint pain (arthralgia), and headache. Some of the less common adverse reactions include: QT prolongation (although studies have not shown direct correlation between using Bedaquiline and cardiac effect but QT prolongation was observed in 2 patients in the study), hyperuricaemia, phospholipidosis (the accumulation of phospholipids in the body's tissues), elevated aminotransferases, and possibly an increased risk of pancreatitis.

Dr Chiang suggested a three-fold cascade of MDR-TB treatment regimens: For susceptible TB, treatment approach should be first-line anti-TB treatment; for Rifampicin-resistant TB but susceptible to quinolones, treatment approach should be to use second-line anti-TB treatment (9 months regimen); and for Rifampicin-resistant TB but resistant to quinolones, new drugs and potential group 5 drugs should be to used.

Put our 'house in order' before the 'window' closes

Anti-TB drug resistance is a human-made disaster. With multiple cross-cutting development challenges, structural drivers for TB, and weak and fragile health systems, the task to accelerate progress towards ending TB does not become any easier. But we have no choice but to put our 'house in order', and ensure all components of comprehensive and integrated TB control programmes are working well and efficiently, and TB rates, including those of drug resistant strains, are declining faster than currently projected.

Bobby Ramakant, Citizen News Service - CNS
2 September 2015
(The author is providing thematic coverage from the 5th Asia Pacific Region Conference on Lung Health, of the International Union Against Tuberculosis and Lung Disease (The Union). He is supported by the Lilly MDR TB Partnership. Follow him on Twitter: @CNS_Health and @bobbyramakant)