Tuberculosis (TB) remains a significant global health concern, affecting individuals both with and without HIV. The standard treatment regimens for TB often involve the use of isoniazid, but the drug can sometimes lead to serious adverse effects and tolerability issues. In a recent phase II randomized controlled trial, a novel fixed-dose combination of alpibectir-ethionamide has shown comparable bactericidal activity to isoniazid, without the same level of adverse events. This new combination has the potential to address the challenges posed by the current treatment options for TB.
Ethionamide, a drug recommended for drug-resistant TB and TB meningitis, is known for its high dose requirements which can lead to intolerable side effects, particularly gastrointestinal issues. However, alpibectir, a new activator, enhances the bioactivation of ethionamide through alternative pathways. By combining alpibectir with ethionamide, it may be possible to use lower doses of the drug and reduce the occurrence of adverse events. This innovative approach could potentially expand the range of effective treatments available for both drug-susceptible and drug-resistant tuberculosis cases.
Kelly Dooley, MD, PhD, MPH, an infectious disease expert not involved in the study, expressed optimism about the alpibectir-ethionamide combination. She highlighted the importance of finding new drugs for TB and commended the strategy of repurposing existing drugs with known effectiveness but poor safety profiles. The need for multiple-drug combinations to combat increasingly prevalent drug resistance, particularly in cases of bedaquiline resistance, underscores the significance of exploring alternative treatment options like alpibectir-ethionamide. However, further research is needed to evaluate the efficacy of this combination against specific TB strains with inhA mutations.
The phase II trial enrolled 17 adults with new, untreated pulmonary TB. Participants were divided into two groups, with one receiving alpibectir-ethionamide and the other isoniazid for 7 days. The study measured bactericidal activity by analyzing the time to positivity in liquid cultures from sputum samples collected daily throughout the treatment period. Both groups showed similar baseline characteristics, with no significant differences in terms of efficacy between the two regimens. Adverse events were generally mild, with gastrointestinal and nervous system disorders being the most commonly reported issues. Plasma concentration analysis revealed comparable levels of ethionamide and its metabolite, indicating the potential for effective bioactivation.
The study team is now focused on evaluating various doses of alpibectir and ethionamide to determine the optimal combination for treating TB. The promising results of this trial suggest that the alpibectir-ethionamide combination could be a valuable addition to the arsenal of treatments available for tuberculosis. By addressing the limitations of current drugs and offering a potentially safer and more tolerable option, this novel approach holds great promise in improving outcomes for individuals affected by TB worldwide. Ongoing research and clinical trials will be essential in further establishing the efficacy and safety of this innovative treatment strategy.
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