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Meta-Analysis
. 2020 Jan 1;24(1):48-64.
doi: 10.5588/ijtld.19.0025.

A systematic review and meta-analysis of first-line tuberculosis drug concentrations and treatment outcomes

R Perumal  1 , K Naidoo  2 , A Naidoo  3 , G Ramachandran  4 , A Requena-Mendez  5 , C Sekaggya-Wiltshire, S G Mpagama, A Matteelli  6 , J Fehr  7 , S K Heysell  8 , N Padayatchi  2
Affiliations
Meta-Analysis

A systematic review and meta-analysis of first-line tuberculosis drug concentrations and treatment outcomes

R Perumal et al. Int J Tuberc Lung Dis. .

Abstract
in English, French, Spanish

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.

Des concentrations sériques faibles de médicaments antituberculeux de première ligne ont été largement rapportées, mais leur impact sur le résultats du traitement est moins étudié. Une recherche systématique sur Medline/PubMed et le registre central des essais contrôlés de Cochrane a été réalisée, depuis le démarrage jusqu’au 31 mars 2018, pour des articles décrivant les concentrations de médicaments pour la tuberculose (TB) de première ligne et les résultats du traitement de patients adultes atteints de TB pharmacosensible. La recherche a identifié 3073 abstracts de publications dont le caractère approprié a été vérifié ; 21 articles ont été acceptés pour leur inclusion dans l’analyse qualitative et ont consisté en 13 cohortes d’observation prospective, 4 cohortes d’observation rétrospective, 1 étude cas témoins et 3 essais randomisés contrôlés. Les données de 15 études ont été disponibles pour un méta analyse ; 13 études de la rifampicine (RMP), 10 études de l’isoniazide (INH), 8 études du pyrazinamide (PZA) et 4 études dé l’éthambutol (EMB). Cette méta analyse a découvert qu’une concentration faible du PZA augmentait probablement le risque de résultat médiocre (8 études, n = 2727 ; RR 1,73 ; IC95% 1,10–2,72), qu’une faible concentration de RMP pouvait légèrement augmenter le risque de mauvais résultats (13 études, n = 2753 ; RR 1,40 ; IC95% 0,91–2,16), tandis que des concentrations faibles d’INH (10 études, n = 2640 ; RR 1,32 ; IC95% 0,66–2,63) et d’EMB (4 études, n = 551 ; RR 1,12 ; IC95% 0,41–3,05) n’induisaient pas de différence évidente en matière de résultat du traitement. Il n’y a pas eu de biais de publication significatifs ni d’hétérogénéité entre études dans aucune des analyses. L’impact clinique potentiel des concentrations du PZA et de la RMP justifie d’autres évaluations. Il est urgent de réaliser des évaluations poussées des relations complexes entre pharmacocinétique et pharmacodynamique dans le traitement de la TB.

La concentración sérica baja de fármacos antituberculosos de primera línea ha sido objeto de múltiples comunicaciones, sin embargo, su efecto sobre los desenlaces terapéuticos se ha estudiado menos. Se llevó a cabo una búsqueda sistemática en la base de datos MEDLINE/PubMed y el Registro Central de Cochrane de Ensayos Clínicos Controlados desde su comienzo hasta el 31 de marzo del 2018 de artículos que describían la concentración de los fármacos antituberculosos de primera línea y el desenlace terapéutico en pacientes adultos con tuberculosis (TB) normosensible. Se encontraron 3073 resúmenes de publicaciones únicas, de las cuales se evaluaron los criterios de selección; 21 artículos fueron aptos para inclusión en el análisis cualitativo; se incluyeron 13 estudios de cohortes observacionales prospectivos, 4 estudios de cohortes observacionales retrospectivos, 1 estudio de casos y testigos y 3 ensayos clínicos aleatorizados. Quince estudios contaban con datos para el metanálisis; 13 estudios examinaban la rifampicina (RMP), 10 la isoniazida (INH), 8 la pirazinamida (PZA) y 4 el etambutol (EMB). En el metanálisis se encontró que la concentración baja de PZA probablemente aumenta el riesgo de alcanzar un desenlace desfavorable (ocho estudios; n = 2727; RR 1,73; IC95% 1,10–2,72), una concentración baja de RMP puede causar un leve aumento del riesgo de desenlace desfavorable (13 estudios, n = 2753; RR 1,40; IC95% 0,91–2,16), pero no se observó una clara diferencia en el desenlace terapéutico con concentraciones bajas de INH (10 estudios, n = 2640; RR 1,32; IC95% 0,66–2,63) ni EMB (4 estudios, n = 551; RR 1,12; IC95% 0,41–3,05). No se observó un sesgo de publicación importante ni heterogeneidad entre los estudios en ninguno de los análisis. La posible significación clínica de las concentraciones bajas de PZA y RMP justifica realizar nuevas investigaciones. Asimismo, se precisan con urgencia evaluaciones exhaustivas de las complejas relaciones farmacocinéticas y farmacodinámicas en el tratamiento de la TB.

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Conflict of interest statement

Conflicts of interest: none declared.

Figures

Figure 1
Figure 1
PRISMA flow chart of literature search for studies which described drug pharmacokinetics of first-line tuberculosis drugs and treatment outcomes. TB = tuberculosis; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Figure 2
Figure 2
Forrest plot of the effect of low vs. normal serum RMP concentrations on treatment outcome–random effects risk ratio. RMP = rifampicin; CI = confidence interval; M-H = Mantel-Haenszel test; df = degree of freedom.
Figure 3
Figure 3
Forest plot of the effect of low vs. normal serum INH concentrations on treatment outcome–random effects risk ratio. INH = isoniazid; CI = confidence interval; M-H = Mantel-Haenszel test; df = degree of freedom.
Figure 4
Figure 4
Forest plot of the effect of low vs. normal serum PZA concentrations on treatment outcome–random effects risk ratio. PZA = pyrazinamide; CI = confidence interval; M-H = Mantel-Haenszel test; df = degree of freedom.
Figure 5
Figure 5
Forest plot of the effect of low vs. normal serum EMB concentrations on treatment outcome–random effects risk ratio. EMB = ethambutol; CI = confidence interval; M-H = Mantel-Haenszel test; df = degree of freedom.
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Comment in

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