title: Importance of ethnicity, CYP2B6 and ABCB1 genotype for efavirenz pharmacokinetics and treatment outcomes: a parallel-group prospective cohort study in two sub-Saharan Africa populations.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Eliford
authors.initials: E
authors.lastname: Ngaimisi
authors.forename: Abiy
authors.initials: A
authors.lastname: Habtewold
authors.forename: Omary
authors.initials: O
authors.lastname: Minzi
authors.forename: Eyasu
authors.initials: E
authors.lastname: Makonnen
authors.forename: Sabina
authors.initials: S
authors.lastname: Mugusi
authors.forename: Wondwossen
authors.initials: W
authors.lastname: Amogne
authors.forename: Getnet
authors.initials: G
authors.lastname: Yimer
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Riedel
authors.forename: Mohammed
authors.initials: M
authors.lastname: Janabi
authors.forename: Getachew
authors.initials: G
authors.lastname: Aderaye
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Mugusi
authors.forename: Leif
authors.initials: L
authors.lastname: Bertilsson
authors.forename: Eleni
authors.initials: E
authors.lastname: Aklillu
authors.forename: Juergen
authors.initials: J
authors.lastname: Burhenne
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D017954:Africa South of the Sahara / Q000208:ethnology; D000480:Alkynes; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D048588:Benzoxazines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics; D010597:Pharmacogenetics; D011446:Prospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C510164:CYP3A5 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; C098320:efavirenz