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

PLoS One. 2013 Jul 5;8(7):e67946. doi: 10.1371/journal.pone.0067946. Print 2013.

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.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
  • Adult
  • Africa South of the Sahara / ethnology
  • Alkynes
  • Anti-HIV Agents / pharmacokinetics
  • Anti-HIV Agents / therapeutic use*
  • Antiretroviral Therapy, Highly Active
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Benzoxazines / pharmacokinetics
  • Benzoxazines / therapeutic use*
  • CD4 Lymphocyte Count
  • Cyclopropanes
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A / genetics
  • Ethnicity / genetics*
  • Female
  • Genotype*
  • Glucuronosyltransferase / genetics
  • HIV Infections / drug therapy*
  • HIV Infections / genetics*
  • Humans
  • Liver-Specific Organic Anion Transporter 1
  • Male
  • Middle Aged
  • Organic Anion Transporters / genetics
  • Pharmacogenetics
  • Prospective Studies
  • Treatment Outcome
  • Young Adult

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Alkynes
  • Anti-HIV Agents
  • Benzoxazines
  • Cyclopropanes
  • Liver-Specific Organic Anion Transporter 1
  • Organic Anion Transporters
  • SLCO1B1 protein, human
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A
  • UGT2B7 protein, human
  • Glucuronosyltransferase
  • efavirenz

Grants and funding

This study is supported by grant from EDCTP (grant No. CT.2005.32030.001), Swedish research council (grant No. VR 3902, 521-2011-3437, 348-2011-7383), the Swedish International Development Cooperation Agency SIDA (grant No. SWE 2004–098, HIV-2006-031, SWE 2007–270) and Karolinska Institutet. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.