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Clinical Trial
. 2019 May 16;14(5):e0216868.
doi: 10.1371/journal.pone.0216868. eCollection 2019.

Role of efavirenz plasma concentrations on long-term HIV suppression and immune restoration in HIV-infected children

Nontiya Homkham  1   2   3   4 , Tim R Cressey  5   6   7 , Naim Bouazza  8   9 , Lily Ingsrisawang  3 , Pornchai Techakunakorn  10 , Jutarat Mekmullica  11 , Thitiporn Borkird  12 , Achara Puangsombat  13 , Sathaporn Na-Rajsima  14 , Jean Marc Treluyer  8   9 , Saik Urien  8   9 , Gonzague Jourdain  1   5   6
Affiliations
Clinical Trial

Role of efavirenz plasma concentrations on long-term HIV suppression and immune restoration in HIV-infected children

Nontiya Homkham et al. PLoS One. .

Abstract

Background: To access the long term relationship between efavirenz plasma concentrations and evolution of HIV RNA loads and CD4 cell counts in children.

Methods: Retrospective analysis of data from HIV-infected children on first line efavirenz-containing regimen. A population pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the evolution of HIV RNA load and CD4 cell count (efficacy outcomes) in relation to efavirenz plasma concentration. Individual CYP2B6 516 G>T genotype data were not available for this analysis. A score (ISEFV) quantifying the effect of efavirenz concentrations on the long-term HIV replication was calculated from efavirenz concentrations and PD parameters and, a value of ISEFV below which HIV replication is likely not suppressed was determined. Cox proportional hazards regression models were used to assess the association of the risk of viral replication with ISEFV, and with efavirenz mid-dose concentration(C12).

Results: At treatment initiation, median (interquartile range, IQR) age was 8 years (5 to 10), body weight 17 kg (14 to 23), HIV RNA load 5.1 log10 copies/mL (4.6 to 5.4), and CD4 cell count 71 cells/mm3. A model of PK-PD viral dynamics assuming that efavirenz decreases the rate of infected host cells adequately described the relationship of interest. After adjusting for age, baseline HIV RNA load and CD4 cell counts an ISEFV <85% was significantly associated with a higher risk of viral replication (p-value <0.001) while no significant association was observed with C12 <1.0 mg/L.

Conclusion: The ISEFV score was a good predictor of viral replication in children on efavirenz-based treatment.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Pharmacokinetic-pharmacodynamic (PK-PD) viral dynamic model in which efavirenz decreases the rate of infected host cells.
Abbreviations: T; Target cells; T*, infected cells; V, free virions; λ, production rate constant of uninfected target cells; d, elimination rate constant of uninfected target cells; β, infected rate constant of target cells; δ, elimination rate constant of infected cells; p, virion production rate constant; C, elimination rate constant of free virions.
Fig 2
Fig 2
Cumulative probability of viral replication as a function of treatment duration between C12 below and above 1.0 mg/L (A), and ISEFV below and above 85% (B). Abbreviations: C12, efavirenz mid-dose concentration; ISEFV, inhibitory score.
See this image and copyright information in PMC

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