Long overdue, short-term regimen for TB set to be a game changer Premium
Long overdue, short-term regimen for TB set to be a game changer Premium
Multidrug resistant tuberculosis (MDR-TB) is a strain of the TB disease in which the infecting tuberculosis germs are resistant to the effects of rifampicin and isoniazid, two of the most potent drugs available for TB treatment. Being infected with such TB strains carries up to a 30-40% risk of death, making MDR TB a serious, life-threatening illness. India bears a significant burden of TB and has a growing burden of MDR TB; of the 1,75,923 persons reported to the World Health Organization in 2023, 27% were from India.
For years, the evolution of such resistant germs was largely attributed to the lack of adherence to TB treatment and misuse of TB drugs, especially through improper drug regimens, both of which aid the selection of mutant strains of the bacterium. This is common in India, and often the duration of treatment (six months) and the number of drugs (typically four at the start of treatment) made treatment adherence for drug-sensitive (DS) TB challenging. It is therefore ironic that until recently, the treatment of DR TB involved even more drugs (at least 5), which were far more toxic than drugs used for drug-sensitive TB, for a longer duration (18 months or more). It is not surprising then that TB-affected communities globally have for years been advocating and asking for shorter, less toxic treatments, but were often ignored.
The health research and delivery system systematically deprioritised these demands. Perhaps it was because TB-affected populations lived largely in the global south. Physicians were taught to advise patients to ignore these side-effects and have often gaslighted patients for complaining about these side-effects. Intramuscular injections were prescribed to be taken daily, leading to painful swellings, making even being seated a challenge, making work, school, and leisure constantly painful and often impossible. Hearing loss, a side-effect of injectables, was dismissed with “better deaf than dead.” Skin discolouration, a common adverse effect of clofazimine added to the TB stigma but was termed a “minor adverse effect,” without really appreciating what the affected individual went through. Menstrual cycles were disrupted, appetites were lost and people suffered, dealing with severe depression and suicidal ideation. All were termed secondary to medications, which they had to endure for at least 18 months.
Shorter regimens have for long been the need of the hour. The most important and obvious advantages of the regimens are the duration of treatment, improved ability to complete treatment, and hopefully, less economic burden. These were envisaged as all-oral regimens with a low overall pill burden.
Among the most recent of these is the BPaL regimen, which has three oral drugs — bedaquiline, pretonamid and linezolid (BPaL/M has four drugs, along with moxifloxacin) — prescribed for 6 months. The Nix-TB trial proved the efficacy of the regimen in 109 patients enrolled in three South African centres. The ZeNix trial, conducted across four countries (South Africa, Georgia, Moldova, and Russia,) enrolled 181 participants and found that a lower dose of linezolid (600 mg once a day instead of twice) was better tolerated with similar outcomes.
While these new regimens can be game changers, caveats need to be kept in mind. First, adherence needs to be closely monitored, as bedaquiline resistance has been reported in a high proportion among those failing treatment. Several phone-based and digital devices have been used to improve adherence, in addition to counselling, and these need to be an integral part of treatment. Currently, these are missing in high-burden countries. Second, drug-susceptibility testing needs to be widely accessible to know whether the regimen is appropriate for a given patient. We should not treat these as silver bullets to be used indiscriminately. It only makes sense to prescribe a drug when one is certain that the drug works, and this is likely to get more relevant as treatment is widely prescribed.
There is also the development of antimicrobial resistance that is an inevitable consequence of such use in a subset of patients. Finally, shorter regimens are not devoid of adverse effects. Linezolid is notorious for causing disabling sensory neuropathy in a proportion of patients, and such adverse effects need to be watched for, and alternative regimens clearly defined for those who may not tolerate these regimens. We also must evaluate these regimens on the basis of individual experience and adverse events that affect the quality of the affected individual during, and post treatment.
The other key issue is health system preparedness, which remains low. Training of physicians in how to manage such situations has to be a part of the rollout. If we truly want to prevent MDR-TB, we must arrest the spread. This can only be achieved by universal molecular diagnostics to detect drug-resistant TB at an early stage. Since a majority of patients with TB access private healthcare as their first point of contact, we need large-scale efficient, and reliable private-public partnerships to ensure access to these regimens while preventing their abuse by making them indiscriminately available.
Shorter regimens are likely to be more expensive for the programme. However, continuing inexpensive but toxic regimens would be myopic, and will cause patient suffering, which often leads to them giving up. While the government must be lauded for taking this step forward to roll out new regimens, even if the move was delayed, preparedness, community education, and supportive services such as counselling and side effects management are key.
While new regimens are critical, it is also important not to forget the critical role of stigma reduction, economic and nutritional support, and better living environments for TB-affected populations. TB can be cured more quickly, but are we doing enough to prevent it? New regimens with only a focus on pill burden should not make us overlook the structural social, economic, and gender determinants in TB. Nor should we forget that what we need is person-centred, high quality care that informs, engages, and works with the affected individual and their families to address why some groups get TB in larger proportions and why some others give up on treatment. A shorter regimen is transformative, but is not the answer to all the issues that persist in TB.
Keeping in mind many such intervening factors, systems need to think of a more person-centred view of care and delivery. Under this, a quick rollout, with systemic preparedness and the above caveats, would help clinicians offer more humane treatment, cure patients faster, and allow them to return to their lives without huge disruptions. The answer to controlling TB, though, is not new regimens alone but a broader systemic transformation that may still be missing.
(Chapal Mehra is an independent public health consultant: chapal@piconsulting.in; Lancelot Pinto is a consultant pulmonologist and an epidemiologist at P.D. Hinduja National Hospital, Mumbai: lance.pinto@gmail.com)
