Pretomanid 200mg tablets

Novel anti-tuberculosis (TB) drugs have been shown to effectively treat drug-resistant TB (DR-TB). However, there is a risk of hepatotoxicity. We aimed to evaluate the incidence of hepatotoxicity in TB patients receiving bedaquiline (BDQ), delamanid (DLM), and/or pretomanid (Pa). This meta-analysis (PROSPERO: CRD42024564922) systematically explored electronic databases (i.e., Clinicaltrials.gov, Cochrane CENTRAL, Embase, PROQUEST, PubMed, ScienceDirect, and SinoMed) for clinical trials reporting the incidence of hepatotoxicity upon administering BDQ, DLM, and/or Pa. Primary endpoints were the overall incidence of elevated liver enzymes, particularly alanine transferase (ALT), aspartate transferase (AST), and gamma-glutamyl transferase (GGT). Proportion meta-analysis was performed for each outcome of interest. Sixteen trials with pooled 4086 participants. The combination of BDQ + Pa was associated with increased ALT (10.6%) and AST (10.4%). Among the individual drugs, Pa-containing regimens had the highest incidence of elevated liver enzymes (ALT [18.9%], AST [20.3%], and GGT [12.8%]). DLM-containing regimens had the lowest incidence (ALT [0.2%], AST [0.7%], and GGT [1%]). For BDQ-containing regimens, the incidence of elevated liver enzymes was similar to the standard of care (SOC): ALT (5.5%) vs. (6.9%) and AST (7.5%) vs. (10.8%), respectively. GGT elevation was more common among the groups receiving BDQ compared to SOC (10% vs. 3.1%). Overall, all the included trials were of high or fair quality. Among all the studied drugs, DLM alone demonstrated the highest hepatic safety, while regimens containing BDQ, Pa, or their combination showed higher hepatotoxic risks compared to SOC. We recommend regular liver function monitoring for DR-TB patients receiving these novel anti-TB drugs.

Abstract licence: CC BY-NC-SA

OBJECTIVE: To evaluate the available evidence comparing the use of the bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) regimen for 6 months with that of standard-of-care regimens for patients with multidrug-resistant or rifampin-resistant tuberculosis (MDR/RR-TB). METHODS: This was a systematic review of clinical trials comparing the use of the BPaLM regimen with the standard of care in patients with MDR/RR-TB. The main outcome measure was an unfavorable endpoint (a composite of death, treatment failure, treatment discontinuation, loss to follow-up, and recurrence), and secondary outcome measures included adverse events and serious adverse events. We searched the MEDLINE, EMBASE, Google Scholar, LILACS, and ClinicalTrials.gov databases, from their inception to January 31, 2024, with no limitation as to language or year of publication. The risk of bias was assessed by using the Cochrane risk-of-bias tool, and the quality of evidence was based on the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: A total of 3,668 studies were retrieved; only one (a randomized clinical trial) met the inclusion criteria and was included. In patients with MDR/RR-TB, treatment with the BPaLM regimen, when compared with the standard of care, reduced the risk of an unfavorable outcome (composite, number needed to treat [NNT] = 7); early treatment discontinuation (NNT = 8); adverse events and discontinuation (NNT = 12); and serious adverse events (NNT = 5). CONCLUSIONS: This systematic review of the use of BPaLM in patients with MDR/RR-TB, although it included only one study, showed that BPaLM is more effective than is the standard of care and has a better safety profile. That has major implications for guidelines on the treatment of MDR/RR-TB.

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BACKGROUND: Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes. METHODS: In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated. RESULTS: A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid. CONCLUSIONS: The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.).

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OBJECTIVE: To summarise the efficacy and safety of pretomanid (Pa) based regimens in patients with drug-resistant TB (DR-TB). METHODS: We included clinical trials, operational research and observational studies reporting the efficacy and safety of Pa-based regimens in DR-TB. The duration of the treatment was at least 24 weeks. Efficacy was reported as a favourable/unfavourable outcome and culture conversion. Safety was reported in terms of death and frequency of adverse events of special interest. RESULTS: Of the 127 articles identified, 13 were included. The proportion of favourable outcomes reported was 76-100%, and the median time to culture conversion was 4-6 weeks. Culture conversion rates ranged from 80-100% by the end of 3 months of treatment, regardless of the type of drug resistance. Treatment completion rates in the operational research studies varied between 18-93%. Safety events were not proportionate among the studies included, possibly due to the differing linezolid dosing (more frequent in the 1,200 mg dose regimen). CONCLUSION: Our review supports the use of Pa-based regimens in patients with DR-TB. The results indicate that Pa-based regimens are efficacious with tolerable safety profile in DR-TB patients.

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