Presence of the CYP2B6 516G> T polymorphism, increased plasma Efavirenz concentrations and early neuropsychiatric side effects in South African HIV-infected patients.
BACKGROUND
The 516G > T polymorphism in exon 4 of the CYP2B6 gene has been associated with increased plasma Efavirenz (EFV) concentrations. EFV concentrations greater than the recommended therapeutic range have been associated with the increased likelihood of developing adverse CNS effects. The aims of this study were to a) determine the presence of the 516G > T and other CYP2B6 exon 4 polymorphisms in a South African group of HIV-infected individuals b) investigate the relationship between the EFV plasma concentrations, the CYP2B6 516G > T polymorphism and the occurrence of CNS related side effects in this group of patients and c) develop and validate a rapid method for determination of EFV in plasma.


METHODS
Data from 80 patients is presented. Genetic polymorphisms in exon 4 of the CYP2B6 gene were identified using PCR amplification of this region followed by sequencing of the amplification products. EFV concentrations were analysed by UPLC-MS/MS. Assessment of the presence of CNS related side effects following EFV initiation were elicited with the use of a questionnaire together with physical examination.


RESULTS
Plasma EFV concentrations displayed high inter-individual variability amongst subjects with concentrations ranging from 94 mug/l to 23227 mug/l at 2 weeks post initiation of treatment. For the 516G > T polymorphism the following frequencies were observed 23% of patients were TT homozygous, 36% GG and 41% GT. The TT homozygous patients had significantly higher EFV concentrations vs. those with the wild (GG) genotype (p < 0.05). Patients who experienced no side effects had significantly lower EFV plasma concentrations vs. the group of patients which experienced the most severe side effects (p < 0.05).


CONCLUSIONS
The significant association between the 516G > T polymorphism and plasma EFV concentrations has been demonstrated in this study. A rapid and sensitive method for the measurement of plasma EFV concentration was developed and validated.
Gounden
Verena
V
Department of Chemical Pathology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, 2001, Republic of South Africa. verenagounden@yahoo.com.
van Niekerk
Chantal
C
Snyman
Tracy
T
George
Jaya A
JA