Effect of Rifampin-Isoniazid-Containing Antituberculosis Therapy on Efavirenz Pharmacokinetics in HIV-Infected Children 3 to 14 Years Old

Antimicrob Agents Chemother. 2018 Dec 21;63(1):e01657-18. doi: 10.1128/AAC.01657-18. Print 2019 Jan.

Abstract

We compared efavirenz pharmacokinetic (PK) parameters in children with tuberculosis (TB)/human immunodeficiency virus (HIV) coinfection on and off first-line antituberculosis therapy to that in HIV-infected children. Children 3 to 14 years old with HIV infection, with and without TB, were treated with standard efavirenz-based antiretroviral therapy without any efavirenz dose adjustments. The new World Health Organization-recommended antituberculosis drug dosages were used in the coinfected participants. Steady-state efavirenz concentrations after 4 weeks of antiretroviral therapy were measured using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) assays. Pharmacokinetic parameters were calculated using noncompartmental analysis. Between groups, PK parameters were compared by Wilcoxon rank-sum test and within group by signed-rank test. Of the 105 participants, 43 (41.0%) had TB coinfection. Children with TB/HIV coinfection compared to those with HIV infection were younger, had lower median weight-for-age Z score, and received a higher median efavirenz weight-adjusted dose. Geometric mean (GM) efavirenz peak concentration (Cmax), concentration at 12 h (C12h), Cmin, and total area under the curve from time 0 to 24 h (AUC0-24h) values were similar in children with HIV infection and those with TB/HIV coinfection during anti-TB therapy. Geometric mean efavirenz C12h, Cmin, and AUC0-24h values were lower in TB/HIV-coinfected patients off anti-TB therapy than in the children with HIV infection or TB/HIV coinfection on anti-TB therapy. Efavirenz clearance was lower and AUC0-24h was higher on than in patients off anti-TB therapy. Reduced efavirenz clearance by first-line anti-TB therapy at the population level led to similar PK parameters in HIV-infected children with and without TB coinfection. Our findings do not support modification of efavirenz weight-band dosing guidelines based on TB coinfection status in children. (The study was registered with ClinicalTrials.gov under registration number NCT01704144.).

Keywords: HIV; antituberculosis therapy; children; drug-drug interactions; efavirenz; tuberculosis; tuberculosis coinfection.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Alkynes
  • Anti-Retroviral Agents / blood*
  • Anti-Retroviral Agents / therapeutic use
  • Antitubercular Agents / therapeutic use*
  • Benzoxazines / blood*
  • Benzoxazines / pharmacokinetics
  • Benzoxazines / therapeutic use
  • Child
  • Child, Preschool
  • Chromatography, Liquid
  • Coinfection / drug therapy
  • Cyclopropanes
  • Drug Interactions
  • Female
  • HIV Infections / drug therapy*
  • Humans
  • Isoniazid / therapeutic use*
  • Male
  • Reverse Transcriptase Inhibitors / blood*
  • Reverse Transcriptase Inhibitors / therapeutic use
  • Rifampin / therapeutic use*
  • Tandem Mass Spectrometry
  • Tuberculosis, Pulmonary / drug therapy*

Substances

  • Alkynes
  • Anti-Retroviral Agents
  • Antitubercular Agents
  • Benzoxazines
  • Cyclopropanes
  • Reverse Transcriptase Inhibitors
  • efavirenz
  • Isoniazid
  • Rifampin

Associated data

  • ClinicalTrials.gov/NCT01704144