title: CYP2B6 c.983T>C polymorphism is associated with nevirapine hypersensitivity in Malawian and Ugandan HIV populations.
abstract: BACKGROUND
  Nevirapine, an NNRTI used in HIV treatment, can cause hypersensitivity reactions in 6%-10% of patients. In the most serious cases (1.3%) this can manifest as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).
  
  
  METHODS
  DNA samples were obtained and analysed from a total of 209 adult patients with nevirapine hypersensitivity (57 from a prospective cohort and 152 routine clinic patients) and compared with 463 control patients on nevirapine without any hypersensitivity. The case group included 70 patients with SJS/TEN. All individuals were genotyped for two SNPs in the CYP2B6 gene [c.516G>T (CYP2B6*9) and c.983T>C (CYP2B6*18)] using the TaqMan real-time genotyping platform. The replication cohort comprised 29 controls and 55 nevirapine hypersensitive patients, including 8 SJS/TEN cases.
  
  
  RESULTS
  An association between the CYP2B6 c.983T>C polymorphism and nevirapine-induced SJS/TEN was observed. In the SJS/TEN group, 30% of individuals possessed at least one c.983T>C versus 16% in the tolerant group [P = 0.006; OR (95% CI) 2.24 (1.27-3.94)]. This association was not significant in the replication cohort [P = 0.075; OR (95% CI) 4.33 (0.80-23.57)]. Combined analysis resulted in an OR of 2.52 (95% CI 1.48-4.20; P = 0.0005) for the association of c.983T>C with SJS/TEN. No association was observed for c.983T>C with other hypersensitivity phenotypes and for CYP2B6 c.516G>T with any hypersensitivity phenotypes.
  
  
  CONCLUSIONS
  Our data show an association between the c.983T>C polymorphism and nevirapine-induced SJS/TEN. CYP2B6 c.983T>C has a frequency of 5%-10% in a variety of African populations, but is not observed in Caucasians, thus representing an ethnic-specific predisposing factor.
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Carr
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Malawi.
authors.forename: Mas
authors.initials: M
authors.lastname: Chaponda
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Elena M
authors.initials: EM
authors.lastname: Cornejo Castro
authors.affiliation: Department of Biostatistics, University of Liverpool, Liverpool, UK.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Jorgensen
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Malawi Dignitas International, Zomba, Malawi.
authors.forename: Joep J
authors.initials: JJ
authors.lastname: Van Oosterhout
authors.affiliation: Division of Human Genetics, University of Cape Town, Cape Town, South Africa.
authors.forename: Collet
authors.initials: C
authors.lastname: Dandara
authors.affiliation: Division of Human Genetics, University of Cape Town, Cape Town, South Africa Department of Pathology, College of Medicine, Blantyre, Malawi.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kampira
authors.affiliation: Joint Clinical Research Centre, Kampala, Uganda.
authors.forename: Francis
authors.initials: F
authors.lastname: Ssali
authors.affiliation: UVRI/MRC Uganda Research Unit on AIDS, Entebbe, Uganda.
authors.forename: Paula
authors.initials: P
authors.lastname: Munderi
authors.affiliation: Liverpool School of Tropical Medicine, Liverpool, UK.
authors.forename: David G
authors.initials: DG
authors.lastname: Lalloo
authors.affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Malawi Liverpool School of Tropical Medicine, Liverpool, UK.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Heyderman
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK munirp@liv.ac.uk.
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D016022:Case-Control Studies; D015331:Cohort Studies; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D004342:Drug Hypersensitivity / Q000235:genetics*; D005260:Female; D005838:Genotype; D060005:Genotyping Techniques; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D008295:Malawi; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000009:adverse effects* / Q000627:therapeutic use; D011446:Prospective Studies; D014454:Uganda
chemical_list: D019380:Anti-HIV Agents; D019829:Nevirapine; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6
keywords: Stevens–Johnson syndrome; adverse drug reactions; antiretroviral; pharmacogenetics