The results of the world’s largest clinical trial for MDR-TB treatment pertaining to the fully oral nine-month and six-month hybrid regimens were published in The Lancet on November 8. They were even announced at the ongoing Union World Conference on Lung Health 2022 (WCOLH). The new treatment regimens are also less expensive, lowering patient bills. However, lung health experts in the country, while agreeing that the study may be a step in the right direction, are already flagging concerns over its applicability in Indian MDR-TB patients.

What is the study about?

It is the first large-scale multi-country clinical trial to examine shortened regimens for treating the lung infection. It is also the first phase-III trial to test the efficacy and safety of Bedaquiline, a new drug with a novel mechanism of action within a shortened treatment regimen. The efficacy of the treatment regimen was assessed through the Standardised Treatment Regimen of Anti-Tuberculosis Drugs for patients with MDR-TB (STREAM) trials. Having recruited more than 1,000 patients since 2012, STREAM is now the world’s largest recruited clinical trial for MDR-TB. As part of the phase III trials, a total of 1,436 participants were screened between March 28, 2016, and January 28, 2020, and 588 of them were randomly assigned to the long regimen (32), control regimen (202), oral regimen (211), or six-month regimen (143). Participants were recruited in Ethiopia (67), Georgia (32), India (148), Moldova (63), Mongolia (130), South Africa (92), and Uganda (56).

What were the study trial results?

The study showed that both Bedaquiline-containing regimens – a nine-month oral regimen and a six-month regimen with eight weeks of second line injectables — had superior efficacy. The nine-month injectable-containing regimen reported fewer cases of hearing loss. The fully-oral nine-month regimen was more effective than the control regimen with 82.7 per cent of participants of the former showing a favourable outcome compared to 71.1 percent of the latter. The results also showed that the six-month regimen, which contained Bedaquiline and an injectable medicine for an abbreviated period of two months, was also more effective than the control regimen. Ninety one per cent of participants on a six-month regimen had a favourable outcome compared to 68.5 per cent in concurrent controls. Study authors Dr Ruth Goodall from University College London and others have said that these two regimens offer promising treatment options for patients with MDR or rifampicin-resistant tuberculosis.

Why is MDR-TB challenging to treat? What is the present regimen?

MDR-TB is a form of TB caused by bacteria that do not respond to isoniazid and rifampicin – the two most effective first line TB drugs, according to WHO. MDR-TB is treatable and curable by using second line drugs. However, the treatment options are limited and require medicines that have to be administered for at least nine months and up to 20 months. These medicines are expensive and toxic. Worldwide in 2019, the treatment success of MDR-TB patients was 60 per cent. Globally, only one in three persons, who developed MDR or rifampicin-resistant tuberculosis in 2020, were started on treatment, according to the study authors. Research shows that patients find it easier to complete the regimen compared with longer ones that last up to 20 months.

How feasible is the short course strategy for India?

The six-to-nine month regimen is a step in the right direction, says Dr Zarir Udwadia, consulting chest physician, PD Hinduja Hospital, Mumbai. “However, there are questions about the applicability of this regimen to the majority of Indian MDR-TB patients. Most of our MDR strains are also FQ (fluoroquinolone)-resistant where this regimen cannot be considered,” the doctor adds. “Both STREAM regimens include high dose INH (isoniazid). Yet most Indian INH-resistant strains have katG mutations (INH resistance commonly occurs due to mutations in the katG gene). High- dose INH will not overcome this resistance. We have also shown (in studies) that many of the individual components of the regimen are resistant to the strains encountered at the Hinduja Hospital. Treatment decisions for MDR-TB are complex,” admits Dr Udwadia.

In their study published in the BMC Infectious Diseases journal in January 2019, Dr Udwadia and his researchers had found that few were eligible for WHO’s newly-recommended short course for MDR-TB at a large Mumbai private clinic.

What are the concerns about relapse cases? What public health measures are required to be intensified?

India accounts for 28 per cent of the 10.6 million new TB cases, according to WHO. The country also has a large burden of MDR-TB (resistant to both isoniazid and rifampicin). Drug resistance can impact treatment, says Mumbai-based pulmonologist, Dr Vikas Oswal, who pointed out that some patients may require a longer period of treatment. A blanket rule here pertaining to a short course regimen may not apply, he says, adding that studies are required to gauge the relapse rates. According to Dr Sanjay Gaikwad, zonal task force chairperson for National TB Elimination Programme (West Zone) the use of shorter regimens can improve adherence apart from reducing costs. However, each patient has to be screened to assess whether he/she is suitable for the shorter regimen.

The good part though is oral intake and less use of injectables, Dr Gaikwad adds. He, however, insists that lessons need to be learnt from the Covid pandemic. “The health system should take proactive action and screen contact persons of the TB patient be it in the family or office setting. Let’s be mature enough to protect our families, colleagues and country,” he says.

Why are shorter regimens required? Will they be cost-effective?

Given the global burden of TB, effective, short and well-tolerated regimens that are easy to administer are urgently needed, says Guy Marks, president of The Union and convenor of the WCOLH. “Prior to Covid, tuberculosis killed more people than any other infectious disease in the world and still kills 1.5 million people a year, and there are 10 million cases every year. This research fills an important gap in evidence on shortened regimens for MDR-TB. Globally, there were an estimated 450,000 incident cases of MDR-TB or rifampicin-resistant TB in 2021, up 3.1 per cent from 437,000 in 2020,” he adds.