Optimal management of drug-resistant tuberculosis: Can India lead the way?

The past decades have witnessed a revolution in the diagnosis and treatment of rifampicin-resistant/multidrug-resistant tuberculosis (RR/MDR-TB). Rapid molecular diagnostic tests can confirm a bacteriologic diagnosis of TB and determine resistance to key medications within hours of specimen submission. Once diagnosed, the vast majority of people living with RR/MDR-TB can be successfully treated using all-oral regimens in as little as six months. Despite the tremendous setbacks experienced in the global management of TB caused by the COVID-19 pandemic, the future holds great promise for innovative management of RR/MDR-TB. More and more evidence is being generated by researchers on new drugs and regimens and is being reviewed by the World Health Organization (WHO) in a timely manner to inform evidence-based guideline updates. Globally, countries have shown the ability to efficiently adopt and adapt such guidelines to their local settings. In India, TB remains a major health problem: India is amongst the eight countries that accounted for more than two-thirds of the global TB cases occurring in 2020. Moreover, the majority of the world’s drug-resistant TB cases reside in India: in 2021, one of every four MDR-TB cases globally from India. Thus, in 2021, there were an estimated 119,000 (93,000-145,000) MDR-TB cases in India, though these figures are considerably underestimated as only 76 per cent of new TB cases and 73 per cent of previously treated TB patients were even tested for rifampicin resistance1. The estimated number of MDR- and extensively drug-resistant (XDR)-TB patients who were started on treatment in India was a paltry 4/100,000 and 1/100,000 population, respectively, with suboptimal overall success rates of 57 per cent in 20191. Several challenges still persist in the country in terms of the optimal management of RR/MDR-TB. The most daunting ones are: (i) increasing levels of resistance to WHO recommended group A and B drugs2,3, (ii) substantial rates of catastrophic costs being faced by people with RR/MDR-TB in the country, (iii) marked heterogeneity in the roles of private providers in TB management and, (iv) lack of a strong engagement with the private sector. These obstacles are exacerbated by the lack of adequate investment in health at the national level4. Indeed, on any given day, far more Indian TB patients are still treated in the private sector than in the public sector. Even in India’s poorest state, Bihar, the private sector treats three times as many patients as the public sector5. When the prescriptions of 106 private practitioners in Dharavi, a vast, overcrowded slum in the centre of Mumbai, were audited, only 3 of 106 were found appropriate6. On the other hand, reporting of data is very poor in the private sector. There is also limited access to counselling and support services for people living with the disease. In addition, as in many other countries across the globe, the COVID-19 pandemic further exacerbated some of these issues, reversing years of progress in the management of TB in the country. During the pandemic, a significant reduction was observed in the number of DR-TB patients in India started on treatment. As compared to 2019, there was a 14 per cent reduction in the number of MDR-TB patients commenced on treatment7. While these issues could be seen as being insurmountable barriers to the optimal care of people living with RR/MDR-TB, facing them head-on also provides multiple opportunities for innovation which India is poised to embrace. India is also home to cadres of high-quality researchers, research institutions and healthcare providers who have the potential to propel the country forward in the struggle to solve the country’s RR/MDR-TB crisis. Moreover, there are glimmers pointing to cause for optimism in the country, including the effective implementation of a national RR/MDR-TB registry (Nikshay); availability of a nutritional support programme for all RR/MDR-TB patients (Nikshay Poshan Yojana); access to whole genome sequencing/next generation sequencing of Mycobacterium tuberculosis strains in selected sites and the growing implication in both national and international clinical trials testing new regimens for RR/MDR-TB (including BEAT-TB8, endTB9, endTB-Q and STREAM 210). Compassionate use is an early access channel allowed by the Indian Drug Law (which is referred to as ‘patient name-based importation’ in the national drug law) and can potentially facilitate the availability of new drugs, as they successfully complete phase II trials11–13. Such mechanisms have been used to enable early access to bedaquiline and delamanid14. Having such a mechanism in place is particularly important, as the TB pipeline has never been richer and many new compounds with new mechanisms of action are being evaluated in phase II. Civil society actors in India have also emerged as key players in the country’s efforts to tackle RR/MDR-TB. India is one of the first countries to have developed a strategy to end stigma and discrimination associated with TB15. In 2019, two DR-TB survivors in India - who have lost their hearing because of the toxicity of older treatment and lack of access to better-tolerated drugs such as bedaquiline – have challenged the patent application on the fumarate salt of bedaquiline, which would prevent development of generic versions of this key medicine, in turn delaying the scale-up of more affordable bedaquiline-containing regimens. When looking at how India has managed innovation in recent years, however, there is also cause for concern. First, the update and revision of national guidelines has often not kept pace with new evidence-based recommendations published by the WHO. In a landscape of continuous and vertiginous evolution, this poses unacceptable hurdles to practitioners struggling to offer optimal care to RR/MDR-TB patients. This issue is particularly relevant in view of the major changes introduced by the latest WHO recommendation on the treatment of RR/MDR-TB16. The gradual introduction of new regimens, through pilot studies in a few selected centres in India, has led to delays in access to optimal care. This strategy would not be adequate for newly approved shorter treatment regimens that have proven to be effective in randomized controlled clinical trials (i.e. TB-PRACTECAL) and that are expected to be rolled out following recent WHO endorsement. Second, specific populations have not received the attention they need. For instance, paediatric RR/MDR-TB is still severely underdiagnosed. Furthermore, children with RR/MDR-TB are often receiving second-line injectable agents as part of their treatment, while all oral regimens are now the WHO standard of care and even newer drugs such as bedaquiline and delamanid can be given to children irrespective of age, with formulations that are suitable for them. Third, the concerningly high rates of resistance to key second line drugs in the country have not been addressed by sufficient efforts to improve diagnostic resources. Access to rapid molecular testing for second line drugs including fluoroquinolones, including the new Xpert XDR assay, and the capacity for detection of resistance to key new drugs such as bedaquiline, clofazimine, linezolid and nitroimidazoles (delamanid and pretomanid) are still not universally available in the country. While there has been progress on the availability of bedaquiline across the country, RR/MDR-TB patients with higher level resistance to WHO group A and B drugs have still limited access to salvage treatment regimens, including delamanid and carbapenems that represent their only hope of achieving cure17. What would it take for India to pivot towards a more leading role in the global approach to RR/MDR-TB and become a driver of innovation as opposed to a late adopter? A revised, more agile process for guideline revision is needed to prompt timely implementation of new all-oral regimens, as additional evidence is being generated on shorter, safer treatment. Advances in RR/MDR-TB treatment, including new drugs belonging to new chemical classes or with new mechanisms of action, should be accompanied by universal roll out of drug susceptibility testing for new drugs, including, when available, rapid molecular tests18. Establishing targeted plans for vulnerable patient populations, such as children, and implementing differentiated models of care that place people at the centre of care should be a priority19. Finally, more attempts should be made to include and educate private practitioners. Far more public-private mix (PPM) partnerships need to be established than the few pilot sites currently available. This is key to increase notifications and ensure that accurate estimates on TB cases are available to develop strategies and allocate funding and resources. Establishing partnerships with impacted communities will also be instrumental to develop comprehensive strategies to tackle TB in the country. All these activities will urgently need to be supported with adequate, dedicated funding. In conclusion, India has the golden opportunity to take on a key leadership role in the global fight against RR/MDR-TB. The inspirational goal of making India a ‘TB-free country’ by 2025 - five years ahead of the target set by the United Nation’s sustainable development goals - is a testimony of the country’s commitment to tackle TB, a preventable and treatable disease, building on the plethora of existing actors and initiatives that constitute a unique resource for the country. Financial support & sponsorship: None. Conflicts of Interest: Author (LG) is Principal Investigator of two phase III clinical trials (endTB and endTB-Q) sponsored by [Médecins sans frontiers], testing shorter MDR-TB regimens. Author (JF) received funding from the Stop TB Partnership’s Global Drug Facility to support the roll-out of paediatric formulations of second line drugs.