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Observational Study
. 2017 Apr;83(4):801-811.
doi: 10.1111/bcp.13172. Epub 2016 Dec 9.

Isoniazid clearance is impaired among human immunodeficiency virus/tuberculosis patients with high levels of immune activation

Christopher Vinnard  1 , Shruthi Ravimohan  2 , Neo Tamuhla  3 , Vijay Ivaturi  4 , Jotam Pasipanodya  5 , Shashikant Srivastava  5 , Chawangwa Modongo  3 , Nicola M Zetola  3 , Drew Weissman  2 , Tawanda Gumbo  5 , Gregory P Bisson  2
Affiliations
Observational Study

Isoniazid clearance is impaired among human immunodeficiency virus/tuberculosis patients with high levels of immune activation

Christopher Vinnard et al. Br J Clin Pharmacol. 2017 Apr.

Abstract

Aims: Immune activation, which is characteristic of both tuberculosis (TB) and human immunodeficiency virus (HIV) infection, is associated with impaired drug metabolism. We tested the hypothesis that elevated levels of systemic immune activation among adults with HIV/TB initiating antiretroviral therapy (ART) would be associated with impaired clearance of isoniazid.

Methods: We conducted a prospective observational study of isoniazid pharmacokinetics (PK) and systemic immune activation prior to and 1 month after ART initiation. Nonlinear mixed effects analysis was performed to measure the covariate effect of immune activation on isoniazid clearance in a model that also included N-acetyltransferase-2 (NAT-2) genotype and interoccasional variability on clearance (thereby analyzing the PK data before and after ART initiation in a single model).

Results: We enrolled 40 patients in the PK visit prior to ART, and 24 patients returned for the second visit a median of 33 days after initiating antiretroviral therapy. The isoniazid concentration data were best described by a two-compartment model with first-order elimination. After accounting for NAT-2 genotype, increasing levels of CD38 and HLA-DR expression on CD8+ T cells (CD38+ DR+ CD8+ ) were associated with decreasing isoniazid clearance.

Conclusion: HIV/TB patients with high levels of immune activation demonstrated impaired isoniazid clearance. Future efforts should determine the role of this relationship in clinical hepatotoxicity events.

Keywords: human immunodeficiency virus; immune activation; isoniazid; n-acetyltransferse-2; pharmacokinetics; tuberculosis.

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Figures

Figure 1
Figure 1
Changes in immunological parameters between pharmacokinetic study visits. (A) %CD38 + HLADR + CD8+ T cells; (B) Log IL‐6; (C) C‐reactive protein; (D) CD4+ T cell count. ART, antiretroviral therapy; IL, interleukin
Figure 2
Figure 2
Plots of covariate relationships of between‐subject variability (η) in isoniazid clearance. (A) NAT‐2 genotype; (B) %CD38+DR+CD8+
Figure 3
Figure 3
Model estimated clearance and AUC0–inf before and after antiretroviral therapy initiation, stratified by NAT‐2 genotype. (A) Changes in individual isoniazid clearance; (B) Changes in individual predicted AUC0–inf
See this image and copyright information in PMC

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