Abstract:
Objectives: We evaluated the importance of ethnicity and pharmacogenetic variations in determining efavirenz
pharmacokinetics, auto-induction and immunological outcomes in two African populations.
Methods: ART naı¨ve HIV patients from Ethiopia (n = 285) and Tanzania (n = 209) were prospectively enrolled in parallel to
start efavirenz based HAART. CD4+ cell counts were determined at baseline, 12, 24 and 48 weeks. Plasma and intracellular
efavirenz and 8-hydroxyefvairenz concentrations were determined at week 4 and 16. Genotyping for common functional
CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 variant alleles were done.
Result: Patient country, CYP2B6*6 and ABCB1 c.4036A.G (rs3842A.G) genotype were significant predictors of plasma and
intracellular efavirenz concentration. CYP2B6*6 and ABCB1 c.4036A.G (rs3842) genotype were significantly associated with
higher plasma efavirenz concentration and their allele frequencies were significantly higher in Tanzanians than Ethiopians.
Tanzanians displayed significantly higher efavirenz plasma concentration at week 4 (p,0.0002) and week 16 (p = 0.006)
compared to Ethiopians. Efavirenz plasma concentrations remained significantly higher in Tanzanians even after controlling
for the effect of CYP2B6*6 and ABCB1 c.4036A.G genotype. Within country analyses indicated a significant decrease in the
mean plasma efavirenz concentration by week 16 compared to week 4 in Tanzanians (p = 0.006), whereas no significant
differences in plasma concentration over time was observed in Ethiopians (p = 0.84). Intracellular efavirenz concentration
and patient country were significant predictors of CD4 gain during HAART.
Conclusion: We report substantial differences in efavirenz pharmacokinetics, extent of auto-induction and immunologic
recovery between Ethiopian and Tanzanian HIV patients, partly but not solely, due to pharmacogenetic variations. The
observed inter-ethnic variations in efavirenz plasma exposure may possibly result in varying clinical treatment outcome or
adverse event profiles between populations.
