title: High predictive value of CYP2B6 SNPs for steady-state plasma efavirenz levels in South African HIV/AIDS patients.
abstract: BACKGROUND
  Efavirenz is primarily metabolized by CYP2B6, with a minor contribution from CYP1A2, CYP2A6, CYP3A4 and CYP3A5. Genetic variability in these genes contributes towards differences in plasma efavirenz concentration, which ultimately leads to either development of adverse drug events or emergence of virus resistance. However, the clinical utility or validity of introducing genotype-assisted dosing is not known. The aim of this study was therefore to evaluate the effects of 14 single-nucleotide polymorphisms (SNPs) in five drug-metabolizing enzyme genes on steady-state plasma efavirenz levels in South African HIV/AIDS patients as well as their clinical validity.
  
  
  METHODS
  HIV/AIDS patients were recruited from Themba Lethu Clinic, at Helen Joseph Hospital, Johannesburg. Blood samples for plasma drug levels and DNA extraction were obtained from each participant. PCR/RFLP and SNaPshot genotyping were used for SNPs in CYP1A2, CYP2A6, CYP2B6, CYP3A4 and CYP3A5 among 464 Bantu-speaking South Africans. Plasma efavirenz concentrations were measured using LC/MS/MS. Genotypes and plasma efavirenz levels were used to calculate predictive values. Multivariate analysis was used to select the minimal set of SNPs with significant clinical validity.
  
  
  RESULTS
  Qualitative and quantitative differences in allele frequencies were observed when comparing South Africans with African, Caucasian and Asian populations. CYP2B6 516T and 785G (*6) and CYP2B6 983C (*18) alleles were significantly associated with high plasma efavirenz levels. CYP2B6 A-G-A-C-C and A-T-G-T-C haplotypes (with respect to CYP2B6 136A>G; CYP2B6 516G>T; CYP2B6 785A>G; CYP2B6 983T>C; and CYP2B6 1459C>T) were associated with higher levels of efavirenz, whereas G-G-A-T-C and A-G-A-T-C haplotypes showed significantly lower levels of efavirenz. The CYP2B6*1/*6 genotype was significantly associated with an increased risk of loss to follow-up. The sensitivity, specificity and positive predictive values for the CYP2B6*6/*6 genotype in predicting efavirenz levels above 4 µg/ml were 46, 97 and 88%, respectively. However, these values improved to 49, 100 and 100%, respectively, when either the CYP1A2 -163A (*1F) allele or the NR1I3 8784C/C genotype was present.
  
  
  CONCLUSIONS
  Screening for CYP2B6 516G>T SNP has a high specificity and positive predictive value for efavirenz levels above 4 µg/ml and could be used in deciding on efavirenz dosage among individuals homozygous for this variant, which could lead to better precision medication.
authors.affiliation: Department of Clinical Laboratory Science, Division of Human Genetics, University of Cape Town, Cape Town, South Africa.
authors.forename: Marelize
authors.initials: M
authors.lastname: Swart
authors.forename: Michelle
authors.initials: M
authors.lastname: Skelton
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ren
authors.forename: Peter
authors.initials: P
authors.lastname: Smith
authors.forename: Simbabrashe
authors.initials: S
authors.lastname: Takuva
authors.forename: Collet
authors.initials: C
authors.lastname: Dandara
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000235:genetics*; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000097:blood* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D048588:Benzoxazines / Q000097:blood* / Q000627:therapeutic use; D044383:Black People / Q000235:genetics*; D016022:Case-Control Studies; D000090702:Constitutive Androstane Receptor; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005787:Gene Frequency; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D015999:Multivariate Analysis; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D013019:South Africa; D044465:White People / Q000235:genetics
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D000090702:Constitutive Androstane Receptor; D003521:Cyclopropanes; C000716327:NR1I3 protein, human; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C510164:CYP3A5 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C098320:efavirenz