‘Your old road is rapidly aging - - for the times they are a-changing’- Bob Dylan.
Tuberculosis remains the world’s foremost infectious disease, killing an estimated 1.6 million people in 2021, up 14% in the last 2 years. This increase in the number of cases of TB and multi-drug resistant (MDR-TB) has unravelled decades of progress and reflects the profound impact COVID-19 has had on tuberculosis.
Despite this grim news, these are exciting times for doctors treating Drug Resistant TB (DR-TB) and for their patients suffering from this deadly disease. For too long had our patients been subjected to long, expensive, toxic and painful injection-based regimens. These regimens had been adopted despite sub-optimal evidence and without any RCTs to support their use. Little wonder then that global treatment success rates were only 60% for MDR-TB in 2019.
Over the last few years, the MDR-TB treatment landscape has moved with exhilarating speed. Data from multiple, large, good-quality RCTs support the efficacy of new, less toxic regimens with extremely encouraging cure rates. The regimens studied have combined new drugs (bedaquiline, delamanid and pretomanid) with highly effective, repurposed drugs (linezolid and moxifloxacin) to make up several novel, all-oral shorter regimens, poised to revolutionize the treatment of MDR-TB.
The initial, pivotal trial conducted by the TB Alliance (Nix-TB) was an open-label, single-group study from South Africa which showed that 6 months of BPaL (bedaquiline, pretomanid and linezolid) resulted in favorable outcomes in 90% of patients with XDR-TB and MDR-TB which was non-responsive or treatment intolerant. However, these astounding success rates came at the cost of considerable toxicity, as the dose of linezolid used in this study was 1200 mg a day. A follow-up study (ZeNix) by the same group across 11 sites in 4 countries showed that 600 mg of linezolid was an equally effective, but less toxic dose. Médecins Sans Frontières (MSF) took the unprecedented step of sponsoring and coordinating 3 multicenter clinical studies: TB PRACTECAL, endTB, and endTB-Q. TB PRACTECAL demonstrated that BPAL plus moxifloxacin (BPaLM) resulted in superior cure rates compared to the longer WHO standard of care regimen (89% vs 52%) with far less toxicity (20% vs 59%). The endTB and endTB-Q trials included bedaquiline (BDQ), linezolid (LZD) and delamanid (DLM) in both fluoroquinolone (FQ) susceptible and FQ resistant MDR-TB respectively and whilst data has yet to be published, preliminary cure rates are most encouraging. A major trial from India conducted by ICMR (BEAT India) showed that BDQ, DLM, LZD and clofazamine given for 9 months resulted in favorable outcomes in 91% of patients with pre-XDR-TB and 69% of those with XDR-TB, with median culture conversion times of 8 weeks. A trial called NExT from South Africa showed that just 6 months of an all-oral 5 drug regimen which included BDQ, LZD and FQ was superior and less toxic to the traditional 18 month WHO regimen in use at the time. Finally, the results of the STREAM Stage 2 study, just published, demonstrate that two short BDQ based regimens (one of 6 months including 2 months of injectable kanamycin, and the other, all-oral, of 9 months) were both superior to the longer regimen established to be effective in the earlier STREAM Stage 1 study.
More than 10 additional trials with catchy acronyms like TRUST, MDR-END, endTB, SimpliciTB, GRACE-TB, DRAMATIC, and BEAT-Tuberculosis are already under way and are likely to transform the way we treat DR-TB in the next decade. Current updated WHO recommended guidelines include 6 month regimens based on ZeNix and TB PRACTECAL data, a 9 month regimen based on STREAM STAGE 2 data, and longer individually designed 18 month regimens where shorter regimens cannot be applied. These regimens are summarized in Table 1 and for the first time the physician has several choices when it comes to treating DR-TB.
Eventually however, the success and sustainability of these new regimens depends upon scaling up their access and affordability in the developing world where they are most urgently needed. The high costs of BDQ (currently $270 for a 6 month course) and DLM ($1700 for 6 months) are a major hurdle to rapid scale up of the newer regimens by NTPs in the developing world. A recent MSF report estimates that these costs of production and profit are 3 times and 18 times higher for BDQ and DLM respectively than generic versions if their production were allowed.
Equally important is the responsible use of these drugs to prevent development of resistance to the newer drugs which form the backbone of these regimens. Already the specter of linezolid (LZD) and bedaquiline (BDQ) resistance looms ominously on the horizon. A meta-analysis of 25 studies from 14 countries showed a pooled frequency of LZD resistance of 4.2%. At our tertiary care center in Mumbai, 23 of 343 MDR strains (6.7%) had LZD-resistant MDR-TB. Prior linezolid use correlated with emergence of LZD resistance. Bedaquiline resistance is another emerging problem. The first case report of acquired resistance to BDQ was reported in 2014, less than a year after the introduction of this drug. BDQ resistance rates as high as 4% from South Africa and 15% from Moldova are already being reported. It is incumbent on all physicians treating DR-TB to prescribe these drugs prudently, avoiding the mistakes made in the past which lead to emergence of DR-TB in the first place.
In conclusion, the emergence of new drugs and new all-oral regimens for DR-TB signals an exciting renaissance in the management of this disease. M. tuberculosis is a wily and unforgiving foe and we owe it to the hundreds of thousands of MDR-TB patients across the globe to continue to strive to develop effective, safe, simple, and shorter regimens. The progress made in the last few years is reason for cautious optimism.
1. Global Tuberculosis report 2022. 2022.
2. World Health Organization. WHO operational handbook on tuberculosis. module 4: Treatment-drug-resistant tuberculosis treatment, 2022 update. https://www.who.int/publications/i/item/9789240065116
3. Conradie F, Diacon AH, Ngubane N, Howell P, Everitt D, Crook AM, et al. Treatment of Highly Drug-Resistant Pulmonary Tuberculosis. New England Journal of Medicine 2020;382:893–902.
4. Conradie F, Bagdasaryan TR, Borisov S, Howell P, Mikiashvili L, Ngubane N, et al. Bedaquiline–pretomanid–linezolid regimens for drug-resistant tuberculosis. New England Journal of Medicine 2022;387 9 810–23.
5. TB PRACTECAL | MSF UK n.d. https://msf.org.uk/tb-practecal
. accessed December 5, 2022.
6. Padmapriyadarsini C, Vohra V, Bhatnagar A, Solanki R, Sridhar R, Anande L, et al. Bedaquiline, Delamanid, Linezolid and Clofazimine for Treatment of Pre-extensively Drug-Resistant Tuberculosis. Clin Infect Dis 2022. https://doi.org/10.1093/CID/CIAC528
7. Esmail A, Oelofse S, Lombard C, Perumal R, Mbuthini L, Mahomed AG, et al. An All-Oral 6-Month Regimen for Multidrug-Resistant Tuberculosis: A Multicenter, Randomized Controlled Clinical Trial (the NExT Study). Https://DoiOrg/101164/Rccm202107-1779OC
8. Goodall RL, Meredith SK, Nunn AJ, Bayissa A, Bhatnagar AK, Bronson G, et al. Evaluation of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): an open-label, multicentre, randomised, non-inferiority trial. Lancet 2022;400. https://doi.org/10.1016/S0140-6736
9. Lange C, Barry CE, Horsburgh CR. Treatments of Multidrug-Resistant Tuberculosis: Light at the End of the Tunnel. Am J Respir Crit Care Med 2022;205:1142–4. https://doi.org/10.1164/RCCM.202202-0393ED
11. Azimi T, Khoshnood S, Asadi A, Heidary M, Mahmoudi H, Kaviar VH, et al. Linezolid resistance in multidrug-resistant mycobacterium tuberculosis: A systematic review and meta-analysis. Front Pharmacol 2022;13. https://doi.org/10.3389/fphar.20220.955050
12. Tornheim JA, Intini E, Gupta A, Udwadia ZF. Clinical features associated with linezolid resistance among multidrug resistant tuberculosis patients at a tertiary care hospital in Mumbai, India. J Clin Tuberc Other Mycobact Dis 2020;20:100175. https://doi.org/10.1016/j.jctube.20200.100175
13. Andries K, Villellas C, Coeck N, Thys K, Gevers T, Vranckx L, et al. Acquired Resistance of Mycobacterium tuberculosis to Bedaquiline. PLoS One 2014;9:e102135. https://doi.org/10.1371/JOURNAL
14. Ismail NA, Omar SV, Moultrie H, Bhyat Z, Conradie F, Enwerem M, et al. Assessment of epidemiological and genetic characteristics and clinical outcomes of resistance to bedaquiline in patients treated for rifampicin-resistant tuberculosis: A cross-sectional and longitudinal study. The Lancet Infectious Diseases 2022;22 4 496–506.
15. Chesov E, Chesov D, Maurer FP, Andres S, Utpatel C, Barilar I, et al. Emergence of bedaquiline resistance in a high tuberculosis burden country. European Respiratory Journal 2022;59:2100621. https://doi.org/10.1183/13993003.00621-2021