title: Effect of rifampicin-based antitubercular therapy and the cytochrome P450 2B6 516G>T polymorphism on efavirenz concentrations in adults in South Africa.
abstract: BACKGROUND
  Rifampicin induces expression of the cytochrome P450 isoenzyme 2B6 (CYP2B6), which metabolizes efavirenz. The CYP2B6 516G>T polymorphism impairs efavirenz metabolism and occurs more commonly in Africans than in Caucasians. We explored the effect of rifampicin-based antitubercular therapy and the 516G>T polymorphism on efavirenz concentrations in HIV-infected patients in South Africa.
  
  
  METHODS
  Between-patient and within-patient comparisons were made of mid-dosing interval efavirenz plasma concentrations in adults on antiretroviral therapy including efavirenz 600 mg daily, with and without antitubercular therapy.
  
  
  RESULTS
  There were 142 participants (40 were on antitubercular therapy and 102 were controls), the mean weight was 66 kg. Median efavirenz concentration was 2.4 mg/l (interquartile range [IQR] 1.3-3.1) and 1.8 mg/l (IQR 1.4-4.4) in participants on antitubercular therapy and controls, respectively (P=0.734). Paired efavirenz concentrations during and after antitubercular therapy in 17 participants were also similar (P=0.113). Genotyping results were 60 (49%) G/G homozygotes, 46 (38%) G/T heterozygotes and 16 (13%) T/T homozygotes. In a multivariate logistic regression model adjusted for sex, weight and concomitant antitubercular therapy, the 516G>T polymorphism was strongly associated with high (>4 mg/l) efavirenz concentrations: odds ratio (OR) 4.4 (95% confidence interval [CI] 1.3-14.9) for G/T versus G/G and 31.1 (95% CI 6.6-146.6) for T/T versus G/G. High efavirenz concentrations were associated with severe sleep disturbance (P=0.048). Low (<1 mg/l) efavirenz concentrations were associated with virological failure (OR 12.5, 95% CI 2.7-57.3).
  
  
  CONCLUSIONS
  Efavirenz can be used together with rifampicin-based antitubercular therapy without dose adjustment in this population. The 516G>T polymorphism occurred commonly and was associated with high efavirenz concentrations.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. karen.cohen@uct.ac.za
authors.forename: Karen
authors.initials: K
authors.lastname: Cohen
authors.forename: Alison
authors.initials: A
authors.lastname: Grant
authors.forename: Collet
authors.initials: C
authors.lastname: Dandara
authors.forename: Helen
authors.initials: H
authors.lastname: McIlleron
authors.forename: Lindiwe
authors.initials: L
authors.lastname: Pemba
authors.forename: Katherine
authors.initials: K
authors.lastname: Fielding
authors.forename: Salome
authors.initials: S
authors.lastname: Charalombous
authors.forename: Gavin
authors.initials: G
authors.lastname: Churchyard
authors.forename: Peter
authors.initials: P
authors.lastname: Smith
authors.forename: Gary
authors.initials: G
authors.lastname: Maartens
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D048588:Benzoxazines / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use; D003521:Cyclopropanes; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012307:Risk Factors; D013019:South Africa; D014376:Tuberculosis / Q000150:complications / Q000188:drug therapy*
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D003577:Cytochrome P-450 Enzyme System; C098320:efavirenz; D012293:Rifampin
references.citation: AIDS. 2005 Sep 23;19(14):1481-6
references.pmid: 16135901
references.citation: J Acquir Immune Defic Syndr. 2001 Dec 1;28(4):399-400
references.pmid: 11707679
references.citation: Clin Infect Dis. 2004 Feb 1;38(3):430-2
references.pmid: 14727217
references.citation: Pharmacogenet Genomics. 2005 Jan;15(1):1-5
references.pmid: 15864119
references.citation: J Pharm Biomed Anal. 2002 Oct 15;30(3):675-84
references.pmid: 12367693
references.citation: Ther Drug Monit. 2004 Jun;26(3):267-70
references.pmid: 15167626
references.citation: Biochem Biophys Res Commun. 2004 Jul 9;319(4):1322-6
references.pmid: 15194512
references.citation: Clin Infect Dis. 2005 May 1;40(9):1358-61
references.pmid: 15825040
references.citation: Clin Pharmacol Ther. 2007 Apr;81(4):557-66
references.pmid: 17235330
references.citation: J Pharmacol Exp Ther. 2003 Jul;306(1):287-300
references.pmid: 12676886
references.citation: AIDS. 2006 Jan 2;20(1):131-2
references.pmid: 16327334
references.citation: Clin Pharmacokinet. 2002;41(9):681-90
references.pmid: 12126459
references.citation: Ann Intern Med. 2005 Nov 15;143(10):714-21
references.pmid: 16287792
references.citation: AIDS Care. 2000 Jun;12(3):255-66
references.pmid: 10928201
references.citation: JAMA. 2008 Aug 6;300(5):530-9
references.pmid: 18677025
references.citation: Clin Pharmacokinet. 2005;44(8):849-61
references.pmid: 16029069
references.citation: Pharmacogenet Genomics. 2005 Dec;15(12):861-73
references.pmid: 16272958
references.citation: Antivir Ther. 2005;10(1):145-55
references.pmid: 15751772
references.citation: AIDS. 2004 Dec 3;18(18):2391-400
references.pmid: 15622315
references.citation: J Pharmacol Exp Ther. 2001 Dec;299(3):849-57
references.pmid: 11714868
references.citation: J Acquir Immune Defic Syndr. 2007 Jun 1;45(2):133-6
references.pmid: 17417100
references.citation: J Infect Dis. 2005 Dec 1;192(11):1931-42
references.pmid: 16267764
references.citation: Eur J Clin Pharmacol. 2008 Apr;64(4):357-65
references.pmid: 18057928
references.citation: J Acquir Immune Defic Syndr. 2008 Nov 1;49(3):336-7
references.pmid: 18978480
references.citation: AIDS Res Hum Retroviruses. 2006 Mar;22(3):232-9
references.pmid: 16545009
references.citation: AIDS. 2001 Jan 5;15(1):71-5
references.pmid: 11192870