A systematic review and meta-analysis of first-line tuberculosis drug concentrations and treatment outcomes
Rubeshan Perumal, Kogieleum Naidoo, Anushka Naidoo, Geetha Ramachandran, Ana Requena‐Méndez, Christine Sekaggya‐Wiltshire, Stellah Mpagama, Alberto Matteelli, Jan Fehr, Scott K. Heysell, Nesri Padayatchi
Abstract
Low serum concentrations of first-line tuberculosis (TB) drugs have been widely reported. However, the impact of low serum concentrations on treatment outcome is less well studied. A systematic search of MEDLINE/Pubmed and the Cochrane Central Register of Controlled Trials up to 31 March 2018 was conducted for articles describing drug concentrations of first-line TB drugs and treatment outcome in adult patients with drug-susceptible TB. The search identified 3073 unique publication abstracts, which were reviewed for suitability: 21 articles were acceptable for inclusion in the qualitative analysis comprising 13 prospective observational cohorts, 4 retrospective observational cohorts, 1 case-control study and 3 randomised controlled trials. Data for meta-analysis were available for 15 studies, 13 studies of rifampicin (RMP), 10 of isoniazid (INH), 8 of pyrazinamide (PZA) and 4 of ethambutol (EMB). This meta-analysis revealed that low PZA concentration appears to increase the risk of poor outcomes (8 studies, n = 2727; RR 1.73, 95%CI 1.10–2.72), low RMP concentrations may slightly increase the risk of poor outcomes (13 studies, n = 2753; RR 1.40, 95%CI 0.91–2.16), whereas low concentrations of INH (10 studies, n = 2640; RR 1.32, 95%CI 0.66–2.63) and EMB (4 studies, n = 551; RR 1.12, 95%CI 0.41–3.05) appear to make no difference to treatment outcome. There was no significant publication bias or between-study heterogeneity in any of the analyses. The potential clinical impact of low concentrations of PZA and RMP warrants further evaluation. Also, comprehensive assessments of the complex pharmacokinetic-pharmacodynamic relationships in the treatment of TB are urgently needed.