A Systematic Review on the Effect of HIV Infection on the Pharmacokinetics of First-Line Tuberculosis Drugs

Abstract

Introduction: Contrasting findings have been published regarding the effect of human immunodeficiency virus (HIV) on tuberculosis (TB) drug pharmacokinetics (PK).

Objectives: The aim of this systematic review was to investigate the effect of HIV infection on the PK of the first-line TB drugs (FLDs) rifampicin, isoniazid, pyrazinamide and ethambutol by assessing all published literature.

Methods: Searches were performed in MEDLINE (through PubMed) and EMBASE to find original studies evaluating the effect of HIV infection on the PK of FLDs. The included studies were assessed for bias and clinical relevance. PK data were extracted to provide insight into the difference of FLD PK between HIV-positive and HIV-negative TB patients. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and its protocol was registered at PROSPERO (registration number CRD42017067250).

Results: Overall, 27 studies were eligible for inclusion. The available studies provide a heterogeneous dataset from which consistent results could not be obtained. In both HIV-positive and HIV-negative TB groups, rifampicin (13 of 15) and ethambutol (4 of 8) peak concentration (C_max) often did not achieve the minimum reference values. More than half of the studies (11 of 20) that included both HIV-positive and HIV-negative TB groups showed statistically significantly altered FLD area under the concentration-time curve and/or C_max for at least one FLD.

Conclusions: HIV infection may be one of several factors that reduce FLD exposure. We could not make general recommendations with respect to the role of dosing. There is a need for consistent and homogeneous studies to be conducted.

Fig. 1

Study search and selection process

Fig. 2

Histograms of the mean or median area under the concentration–time curve for the HIV-negative and HIV-positive TB groups per study for a rifampicin, b isoniazid, c pyrazinamide and d ethambutol. Asterisk indicates statistical significance; 0–24/0–inf: AUC₂₄ and AUC_∞; 0–8/0–12: AUC₈ and AUC₁₂; 0–4/0–6; AUC₄ and AUC₆. The study by Sahai et al. [33] compared HIV-infected individuals without TB with healthy HIV-uninfected volunteers (healthy volunteers). INH isoniazid, RIF rifampicin, PZA pyrazinamide, EMB ethambutol, TB tuberculosis

Fig. 3

Histograms of the mean or median peak drug concentration for the HIV-negative and HIV-positive TB groups per study for a rifampicin, b isoniazid, c pyrazinamide and d ethambutol. Asterisk indicates statistical significance. The dashed lines represent the generally cited reference ranges by Peloquin [27]: rifampicin 8–24 µg/mL; isoniazid 3–6 µg/mL; pyrazinamide 20–50 µg/mL; ethambutol 2–6 µg/mL. The study by Sahai et al. [33] compared HIV-infected individuals without TB with healthy HIV-uninfected volunteers (healthy volunteers). INH isoniazid, RIF rifampicin, PZA pyrazinamide, EMB ethambutol, TB tuberculosis

Fig. 4

Ratio between the AUCs of HIV-positive and HIV-negative TB patients for studies showing a statistically significant alteration in first-line TB drug AUCs, stratified per drug. The dashed lines represent the 80–125% (0.8–1.25) cut-off values for clinical relevance; all studies with a ratio outside this range were considered clinically relevant. RIF rifampicin, PZA pyrazinamide, EMB ethambutol, TB tuberculosis, AUC area under the concentration–time curve