Drug-Resistant Tuberculosis: New Regimens Offer Hope Against MDR-TB and XDR-TB

Why Is Drug-Resistant Tuberculosis a Growing Global Crisis?

The World Health Organization's 2024 Global Tuberculosis Report revealed that TB killed approximately 1.25 million people in 2023, surpassing both HIV/AIDS and malaria. An estimated 10.8 million people fell ill with TB in 2023, with approximately 410,000 cases of multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB). Only about one in three people with drug-resistant TB currently access treatment, and treatment outcomes remain suboptimal in many settings.

Drug-resistant TB arises primarily through inadequate treatment of drug-susceptible TB, including incomplete courses, incorrect drug combinations, or poor drug quality. MDR-TB is defined as resistance to at least isoniazid and rifampicin, the two most important first-line drugs. Extensively drug-resistant TB (XDR-TB) is further resistant to fluoroquinolones and at least one additional Group A drug (bedaquiline or linezolid). Pre-XDR-TB, resistant to fluoroquinolones in addition to MDR-TB, represents an intermediate category.

The burden falls disproportionately on low- and middle-income countries. India alone accounts for approximately 27% of global TB cases, followed by Indonesia (10%), China (7%), and the Philippines (7%). The COVID-19 pandemic severely disrupted TB services, causing an estimated 1.3 million additional TB deaths between 2020 and 2023 compared to pre-pandemic trends. The Global Fund to Fight AIDS, Tuberculosis and Malaria has pledged $15.7 billion for 2024-2026 to accelerate the response.

What Is the BPaL Regimen and How Has It Changed XDR-TB Treatment?

The BPaL regimen represents perhaps the most significant advance in TB treatment in decades. Developed by the TB Alliance, it combines three drugs: bedaquiline (an ATP synthase inhibitor), pretomanid (a nitroimidazole), and linezolid (an oxazolidinone antibiotic). Pretomanid received FDA approval in August 2019 under the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD), specifically as part of the BPaL combination for XDR-TB or treatment-intolerant/nonresponsive MDR-TB.

The TB-PRACTECAL trial, a randomized, controlled, open-label trial conducted across sites in Belarus, South Africa, and Uzbekistan, compared BPaL-based regimens to locally accepted standard of care for MDR-TB. Published in the New England Journal of Medicine in 2022, the trial demonstrated 89% favorable outcomes with BPaL-containing regimens over 39 weeks, compared to 52% with the standard of care. The dramatically shorter treatment duration (6-9 months vs. 18-24 months), all-oral administration, and superior efficacy marked a paradigm shift in drug-resistant TB management.

The earlier Nix-TB trial, a single-arm study published in the New England Journal of Medicine in 2020, had initially demonstrated 90% favorable outcomes with BPaL in 109 patients with XDR-TB or treatment-intolerant MDR-TB at 6 months post-treatment. The primary safety concern is linezolid-associated toxicity, including peripheral neuropathy (81% of participants) and myelosuppression, which can be managed with dose reduction. Research into optimized linezolid dosing and the addition of a fourth drug is ongoing.

What Other New TB Treatment Regimens Are Being Developed?

For drug-susceptible TB, the landmark TBTC Study 31/ACTG A5349 (published in the New England Journal of Medicine in 2021) demonstrated that a 4-month regimen of rifapentine, moxifloxacin, isoniazid, and pyrazinamide was noninferior to the standard 6-month regimen. This shorter treatment, now endorsed by WHO, could improve treatment completion rates and reduce the burden on health systems, particularly in high-incidence settings.

For MDR-TB, the STREAM Stage 2 trial evaluated a 9-month all-oral bedaquiline-containing regimen, while the endTB trial tested multiple novel 9-month combinations. WHO updated its MDR-TB guidelines in 2022 to recommend a 6-month BPaLM regimen (BPaL plus moxifloxacin) as the preferred treatment for MDR/RR-TB, contingent on fluoroquinolone susceptibility. This recommendation was based on the TB-PRACTECAL results and has the potential to dramatically simplify and improve MDR-TB treatment globally.

The TB drug pipeline includes several promising candidates in clinical trials. BTZ-043 and macozinone (MCZ) target the DprE1 enzyme involved in cell wall synthesis. Delpazolid, a next-generation oxazolidinone, aims to provide linezolid-like efficacy with reduced toxicity. Telacebec (Q203), targeting the cytochrome bc1 complex, and sudapyridine (WX-081), a bedaquiline analog, are also in advanced clinical testing. These drugs could form the basis of future regimens with improved efficacy and tolerability.