Pretomanid for tuberculosis: a systematic review.

Abstract

BACKGROUND\nOutcomes of treatment of tuberculosis patients with regimens including pretomanid have not yet been systematically reviewed.\n\n\nOBJECTIVES\nTo appraise existing evidence on efficacy and safety of pretomanid in tuberculosis.\n\n\nDATA SOURCES\nPubmed, clinicaltrials.gov. and Cochrane library.\n\n\nSTUDY ELIGIBILITY CRITERIA\nQuantitative studies presenting original data on clinical efficacy or safety of pretomanid.\n\n\nPARTICIPANTS\nPatients with tuberculosis.\n\n\nINTERVENTIONS\nTreatment with pretomanid or pretomanid-containing regimens in minimum one study group.\n\n\nMETHODS\nTwo authors independently extracted data and assessed risk of bias. Data on efficacy (early bactericidal activity, bactericidal activity, end-of treatment outcomes and acquired resistance) and safety were summarised in tables. Mean differences in efficacy outcomes between regimens across studies were calculated.\n\n\nRESULTS\nEight studies were included; four randomised controlled trials on 2-week early bactericidal activity in rifampicin-susceptible tuberculosis, three trials with randomised rifampicin-susceptible tuberculosis arms and a single rifampicin-resistant tuberculosis arm (two on 8-week bactericidal activity, one on end-of-treatment outcomes), one single-arm trial with end-of-treatment outcomes in highly resistant tuberculosis. Activity of pretomanid-moxifloxacin-pyrazinamide was superior to standard treatment on daily change in colony-forming units at days 0-2, 0-56 and 7-56 and time to culture conversion in rifampicin-susceptible tuberculosis (hazard ratio: 1.7 [95%CI:1.1-2.7]), but not at end of treatment in one study. This study was stopped due to serious hepatotoxic adverse events, including three deaths, in 4% [95%CI:2-8] patients on pretomanid-moxifloxacin-pyrazinamide and none in controls. In patients with uncomplicated rifampicin-resistant tuberculosis on pretomanid-moxifloxacin-pyrazinamide treatment, 91% [95%CI:59-100] had favourable end-of-treatment outcomes. In patients with highly resistant tuberculosis, 90% [95%CI:83-95] on pretomanid-bedaquiline-linezolid had favourable outcomes six months after treatment, but linezolid-related toxicity was frequent. No acquired resistance to pretomanid was reported.\n\n\nCONCLUSIONS\nEvidence suggests an important role for pretomanid in rifampicin-resistant and highly resistant tuberculosis. Trials comparing pretomanid to existing core and companion drugs are needed to further define that role.