Breakthrough in Tuberculosis Treatment: Shorter, Safer Regimens Offer New Hope
In a landmark progress for global health, a randomized clinical trial conducted across seven countries has unveiled three new, shorter, all-oral treatment options for drug-resistant tuberculosis (TB). Published in the New england Journal of Medicine,the findings mark a significant step forward in the fight against multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB),a disease that affects an estimated 410,000 people annually,primarily in low- and middle-income countries.
The phase 3 trial, led by the endTB project, compared five 9-month, all-oral drug regimens to the standard 18- to 24-month therapy, which includes injectable drugs and medications wiht severe side effects. Historically,the standard regimen has shown only a 65% success rate. In contrast, the trial revealed that three of the new regimens were noninferior, achieving favorable outcomes in 85% to 90% of participants.
“Customary MDR/RR-TB treatment is frequently enough a long and difficult battle with considerable side effects,” said Lorenzo Guglielmetti, PhD, MSc, co-principal investigator and director of the endTB project, in an interview posted on the project’s website. “The new regimens tested in the endTB trial can drastically improve the patients’ quality of life. They make it easier for patients to complete the full treatment and ultimately increase the chances of full recovery.”
The Trial: A Closer Look
The study enrolled participants aged 15 and older with confirmed fluoroquinolone-susceptible,rifampicin-resistant TB from Georgia,India,Kazakhstan,Lesotho,Pakistan,Peru,and South Africa. Participants were randomly assigned to receive either the standard therapy or one of five 9-month regimens containing combinations of bedaquiline (B),delamanid (D),linezolid (L),levofloxacin (Lfx) or moxifloxacin (M),clofazimine (C),and pyrazinamide (Z).
Among the 754 participants, 699 were included in the modified intention-to-treat (mITT) analysis. The primary endpoint was a favorable outcome at week 73,defined by two negative sputum culture results or favorable bacteriologic,clinical,and radiologic evolution.
Key Findings
The results showed that four of the five choice regimens were noninferior to standard therapy in the mITT analysis:
- BCLLfxZ: 9.8 percentage points (95% CI, 0.9 to 18.7)
- BLMZ: 8.3 percentage points (95% CI, −0.8 to 17.4)
- BDLLfxZ: 4.6 percentage points (95% CI,−4.9 to 14.1)
- DCMZ: 2.5 percentage points (95% CI, −7.5 to 12.5)
Though, in the per-protocol analysis, DCMZ was not found to be noninferior. Adverse events were similar across regimens, with grade 3 or higher hepatotoxic events more common in the experimental groups, except for the BDLLfxZ group.
WHO Endorsement and Broader Implications
The study authors noted that the 85% to 90% treatment success rate with the alternative regimens mirrors the 89% success rate observed in trials for the 6-month, all-oral BPaLM regimen, which the World Health Institution (WHO) recommended in 2022. Unlike BPaLM, which is limited to nonpregnant individuals aged 14 and older, the three new regimens (BLMZ, BCLLfxD, and BDLLfxZ) can be used in nearly all adults, children, and pregnant women, with pediatric formulations available for all drugs.
“These findings support the use of three new, all-oral, shorter-duration regimens for rifampin-resistant tuberculosis along with BPaLM,” the authors wrote. The WHO officially endorsed these regimens in August 2024.
A Milestone in TB Treatment
The endTB trial is part of a broader effort to evaluate the safety and efficacy of bedaquiline and delamanid, the first new TB drugs developed in nearly 50 years. As Guglielmetti explained,these drugs represent a “great promise for the fight against TB,” but their development was initially stalled due to limited interest from pharmaceutical companies.
This breakthrough not only offers hope to patients but also underscores the importance of global collaboration in addressing diseases that disproportionately affect vulnerable populations.
| Regimen | risk Difference (95% CI) | Noninferiority |
|————-|—————————–|——————–|
| BCLLfxZ | 9.8 (0.9 to 18.7) | Yes |
| BLMZ | 8.3 (−0.8 to 17.4) | Yes |
| BDLLfxZ | 4.6 (−4.9 to 14.1) | Yes |
| DCMZ | 2.5 (−7.5 to 12.5) | No (per-protocol) |
The endTB trial results are a testament to the power of innovation and perseverance in the fight against TB. With shorter, safer, and more effective treatments now available, the global health community is one step closer to ending this devastating disease.
Breakthrough in Tuberculosis Treatment: Shorter, safer Regimens Offer New Hope
In a landmark progress for global health, a randomized clinical trial conducted across seven countries has unveiled three new, shorter, all-oral treatment options for drug-resistant tuberculosis (TB). Published in the New England Journal of Medicine, the findings mark a importent step forward in the fight against multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB), a disease that affects an estimated 410,000 people annually, primarily in low- and middle-income countries. the phase 3 trial, led by the endTB project, compared five 9-month, all-oral drug regimens to the standard 18- to 24-month therapy, which includes injectable drugs and medications with severe side effects. The trial revealed that three of the new regimens were noninferior, achieving favorable outcomes in 85% to 90% of participants.
the Trial: A Closer Look
Editor: Could you provide an overview of the endTB trial and its significance in the fight against MDR/RR-TB?
Guest: Absolutely. The endTB trial was a phase 3 clinical trial conducted across seven countries, including Georgia, India, Kazakhstan, Lesotho, Pakistan, Peru, and South Africa. It enrolled participants aged 15 and older with confirmed fluoroquinolone-susceptible, rifampicin-resistant TB. The trial compared five 9-month, all-oral drug regimens to the standard 18- to 24-month therapy, which has historically shown only a 65% success rate. The primary endpoint was a favorable outcome at week 73, defined by two negative sputum culture results or favorable bacteriologic, clinical, and radiologic evolution. The trial’s significance lies in its potential to drastically improve the quality of life for patients by offering shorter, safer, and more effective treatment options.
Key findings
Editor: What were the key findings of the trial, and how do they compare to the standard therapy?
Guest: The trial found that four of the five experimental regimens were noninferior to the standard therapy in the modified intention-to-treat (mITT) analysis. Specifically, the regimens BCLLfxZ, BLMZ, and BDLLfxZ showed treatment success rates of 85% to 90%, compared to the standard therapy’s 65% success rate. The risk differences for these regimens were 9.8 percentage points, 8.3 percentage points, and 4.6 percentage points, respectively. Although the DCMZ regimen was not found to be noninferior in the per-protocol analysis, it still showed promise. Adverse events were similar across regimens,with grade 3 or higher hepatotoxic events more common in the experimental groups,except for the BDLLfxZ group.
WHO Endorsement and Broader Implications
Editor: How does this trial align with the WHO’s recent recommendations, and what are the broader implications for TB treatment?
Guest: The trial’s findings align closely with the WHO’s endorsement of the 6-month, all-oral BPaLM regimen in 2022. The three new regimens—BLMZ, BCLLfxD, and BDLLfxZ—can be used in nearly all adults, children, and pregnant women, with pediatric formulations available for all drugs. This broad applicability is a significant improvement over BPaLM, which is limited to nonpregnant individuals aged 14 and older. The WHO officially endorsed these regimens in August 2024, marking a pivotal moment in the global fight against TB. These findings support the use of shorter-duration, all-oral regimens for rifampin-resistant tuberculosis, offering hope to millions of patients worldwide.
A Milestone in TB Treatment
Editor: What does this breakthrough meen for the future of TB treatment, and how does it reflect on global collaboration in healthcare?
Guest: This breakthrough is a milestone in the fight against TB, notably for drug-resistant strains. The endTB trial is part of a broader effort to evaluate the safety and efficacy of bedaquiline and delamanid, the first new TB drugs developed in nearly 50 years. These drugs represent a great promise for addressing TB, but their development was initially stalled due to limited interest from pharmaceutical companies. the trial’s success underscores the importance of global collaboration in tackling diseases that disproportionately affect vulnerable populations. with shorter, safer, and more effective treatments now available, we are one step closer to ending this devastating disease.
Conclusion
The endTB trial marks a significant advancement in the treatment of multidrug-resistant/rifampicin-resistant TB. The findings demonstrate that shorter, all-oral regimens can achieve favorable outcomes in 85% to 90% of patients, compared to the standard therapy’s 65% success rate.With the WHO’s endorsement and the potential for broader submission, these new regimens offer hope to millions of patients worldwide. This breakthrough highlights the importance of innovation, perseverance, and global collaboration in the fight against TB, bringing us closer to ending this devastating disease.