Importance of ethnicity, CYP2B6 and ABCB1 genotype for efavirenz pharmacokinetics and treatment outcomes

• Verfasst von: Ngaimisi, Eliford [VerfasserIn]
• Verfasst von: Habtewold, Abiy [VerfasserIn]
• Verfasst von: Minzi, Omary [VerfasserIn]
• Verfasst von: Makonnen, Eyasu [VerfasserIn]
• Verfasst von: Mugusi, Sabina [VerfasserIn]
• Verfasst von: Amogne, Wondwossen [VerfasserIn]
• Verfasst von: Yimer, Getnet [VerfasserIn]
• Verfasst von: Riedel, Klaus-Dieter [VerfasserIn]
• Verfasst von: Janabi, Mohammed [VerfasserIn]
• Verfasst von: Aderaye, Getachew [VerfasserIn]
• Verfasst von: Mugusi, Ferdinand [VerfasserIn]
• Verfasst von: Bertilsson, Leif [VerfasserIn]
• Verfasst von: Aklillu, Eleni [VerfasserIn]
• Verfasst von: Burhenne, Jürgen [VerfasserIn]
• Titel: Importance of ethnicity, CYP2B6 and ABCB1 genotype for efavirenz pharmacokinetics and treatment outcomes
• Titelzusatz: a parallel-group prospective cohort study in two sub-Saharan Africa populations
• Verf.angabe: Eliford Ngaimisi, Abiy Habtewold, Omary Minzi, Eyasu Makonnen, Sabina Mugusi, Wondwossen Amogne, Getnet Yimer, Klaus-Dieter Riedel, Mohammed Janabi, Getachew Aderaye, Ferdinand Mugusi, Leif Bertilsson, Eleni Aklillu, Juergen Burhenne
• E-Jahr: 2013
• Jahr: July 5, 2013
• Umfang: 13 S.
• Fussnoten: Gesehen am 22.11.2021
• Titel Quelle: Enthalten in: PLOS ONE
• Ort Quelle: San Francisco, California, US : PLOS, 2006
• Jahr Quelle: 2013
• Band/Heft Quelle: 8(2013), 7, Artikel-ID e67946, Seite 1-13
• ISSN Quelle: 1932-6203
• DOI: doi:10.1371/journal.pone.0067946
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Africa
• Sach-SW: African people
• Sach-SW: Alleles
• Sach-SW: Antiretroviral therapy
• Sach-SW: Highly-active antiretroviral therapy
• Sach-SW: HIV
• Sach-SW: Pharmacokinetics
• Sach-SW: Population genetics
• K10plus-PPN: 1778211321

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 naïve 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.