High plasma efavirenz level and CYP2B6*6 are associated with efavirenz-based HAART-induced liver injury in the treatment of naïve HIV patients from Ethiopia: a prospective cohort study

Pharmacogenomics J. 2012 Dec;12(6):499-506. doi: 10.1038/tpj.2011.34. Epub 2011 Aug 23.


The objective of this study was to assess the incidence, timing and identify pharmacogenetic, efavirenz (EFV) pharmacokinetic and biochemical predictors of EFV-based antiretroviral therapy (ART) drug-induced liver injury (DILI). ART-naïve HIV patients (n = 285) were prospectively enrolled. Pretreatment laboratory evaluations included hepatitis B surface antigen and C antibody, CD4 count and viral load. Liver tests were done at baseline, 1st, 2nd, 4th, 8th, 12th, 24th and 48th weeks during ART. Plasma EFV and 8-hydroxyefvairenz concentration was determined at week 4 using liquid chromatography-mass spectrometry. CYP2B6, CYP3A5, ABCB1 3435C/T and UGT2B7*2 genotyping was done using Taqman genotyping assay. Data were analyzed using survival analysis and Cox proportional hazards model. The incidence of DILI was 15.7% or 27.9 per 100 person-years and that of severe injury was 3.4% or 6.13 per 100 person-years. The median time for the development of DILI and severe injury was 2 and 4 weeks after initiation of ART, respectively. There was significant association of DILI with lower baseline platelet, albumin, log plasma viral load and CD4 count (P = 0.031, 0.037, 0.06 and 0.019, respectively). Elevated baseline alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, plasma EFV level and CYP2B6*6 were good predictors for the development of DILI (P = 0.03, 0.01, 0.016, 0.017 and 0.04, respectively). We report for the first time CYP2B6*6 as a putative genetic marker and high plasma EFV concentration as intermediate biomarker for vulnerability to EFV-induced liver injury in HIV patients. CYP2B6 genotyping and/or regular monitoring of EFV and lever enzymes level during early therapy is advised for early diagnosis and management of DILI.

Publication types

  • 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
  • Alkynes
  • Antiretroviral Therapy, Highly Active / adverse effects*
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Benzoxazines / adverse effects*
  • Benzoxazines / blood
  • Chemical and Drug Induced Liver Injury / genetics*
  • Cohort Studies
  • Cyclopropanes
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A / genetics
  • Female
  • Genotype
  • HIV Infections / drug therapy*
  • Humans
  • Male
  • Oxidoreductases, N-Demethylating / genetics*
  • Proportional Hazards Models
  • Prospective Studies


  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Alkynes
  • Benzoxazines
  • Cyclopropanes
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A
  • Oxidoreductases, N-Demethylating
  • efavirenz
  • 8-hydroxyefavirenz