Impact of Pharmacogenetics on CNS Side Effects Related to Efavirenz

Abstract

Aim: This article evaluates which genetic factors are involved in CNS toxicity related to long-term treatment with efavirenz (EFV) standard doses and their relationship with plasma concentrations. Patients & methods: A total of 119 HIV-positive patients, in which 1350 EFV plasma concentrations, 68 SNPs and 14 EFV-related adverse effects (AEs) were analyzed. Results: Overall, 32.77% of patients reported CNS toxicity and 8.40% had concentrations above the therapeutic range. A correlation was mainly found between patients with global CNS AEs and high EFV maximum steady-state plasma concentration (p = 1.47 × 10^-6). A preliminary analysis confirmed that CYP2B6*6 (516G>T and 785A>G) was the most highly correlated (p = 0.005) with AEs and high plasma concentrations. In a second analysis adjusting for maximum steady-state plasma concentration, suggestive genetic associations were found between BCRP 421C>A, MRP1 816G>A, 5-HT2A 102C>T and different AEs. Conclusion: The finding of the involvement of these SNPs in EFV toxicity opens the door for further studies to confirm their validity and for their application in the future clinical practice.

Original submitted 18 February 2013; Revision submitted 17 May 2013

KEYWORDS::

• adverse effects
• CNS
• efavirenz
• HIV
• metabolism enzymes
• neurotransmitter systems
• pharmacogenetics
• pharmacokinetics
• SNPs
• transporter proteins

Acknowledgements

The authors would like to thank the Europharma Foundation under an agreement of collaboration between the University of Salamanca and the University Austral of Chile, and to the SNP genotyping services, which were provided by the Spanish ‘Centro Nacional de Genotipado‘ CEGEN-USC in the Fundación Galega Medicina Xenómica.

Financial & competing interests disclosure

This research was supported by funding granted by the Europharma Foundation under an agreement of collaboration between the University of Salamanca and the University Austral of Chile. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This research was supported by funding granted by the Europharma Foundation under an agreement of collaboration between the University of Salamanca and the University Austral of Chile. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.