Discussion
TB, hepatotoxicity, adverse drug reactions, PRS
DRUG-INDUCED HEPATITIS, DRUG INTERACTIONS, DRUG MECHANISM, ADVERSE DRUG REACTIONS
In this open-label, pilot randomized clinical trial, the short-course (4-month) PRS regimen consisting of clofazimine, prothionamide, pyrazinamide and ethambutol appeared to have inferior efficacy in the modified intention-to-treat population and higher incidence of drug-induced hepatitis. Its inferior efficacy is mainly attributed to the higher rates of permanent regimen change due to adverse drug reactions and consent withdrawn during treatment. As per-protocol analysis showed, both groups achieved high rates of culture conversion, radiological improvement and sustained treatment success (all above 80%).Considering the complex drug mechanism of action and drug–drug interactions, how to properly select and combine available drugs for multidrug chemotherapy is always a question in clinical practice. Design of an optimal drug-dose combination among currently available drugs is challenging because of the exponentially large number of possible drug-dose combinations [Although not entirely unanticipated, the high incidence of drug-induced hepatitis, the main cause for permanent change of assigned regimen in this study, in the PRS regimen group was still surprising since neither clofazimine nor prothionamide are the usual TB drugs causing hepatotoxicity [There are several limitations of our study. Firstly, most comparisons in this study were underpowered and inconclusive due to the limited sample size. The Preclinical studies conducted subsequent to the start of this pilot human study identified much more potent PRS regimens than the one studied here. These ultra short-course regimens reduced the time needed to achieve relapse-free cure in mice by up to 85% compared with the standard regimen [In conclusion, the 4-month PRS regimen is a completely new drug combination for drug-susceptible TB treatment, breaking the traditional concept of first- and second-line drugs. Though the PRS regimen group was observed with inferior efficacy in the modified intention-to-treat population, both treatment groups appeared to have desired efficacy in per-protocol population. The unanticipated high incidence of drug-induced hepatitis in PRS regimen group underlines the importance of safety assessment for proof-of-concept studies. While future clinical studies are more likely to focus on newer more potent PRS regimens that include non-generic drugs, this study provides the first proof-of-concept in humans that the artificial intelligence-enabled PRS approach can identify drug regimens with the capacity to markedly shorten the duration of treatment required to cure patients with TB.