title: Relationship between weight, efavirenz exposure, and virologic suppression in HIV-infected patients on rifampin-based tuberculosis treatment in the AIDS Clinical Trials Group A5221 STRIDE Study.
abstract: BACKGROUND
  Rifampin (RIF) upregulates CYP 450 isoenzymes, potentially lowering efavirenz (EFV) exposure. The US EFV package insert recommends an EFV dose increase for patients on RIF weighing ≥50 kg. We conducted a pharmacokinetic study to evaluate EFV trough concentrations (Cmin) and human immunodeficiency virus (HIV) virologic suppression in patients on EFV (600 mg) and RIF-based tuberculosis treatment in the multicenter randomized trial (ACTG A5221).
  
  
  METHODS
  EFV Cmin was measured 20-28 hours post-EFV dose at weeks 4, 8, 16, 24 on-RIF and weeks 4, 8 off-RIF. Results were evaluated with 2-sided Wilcoxon rank-sum, χ(2), Fisher exact tests and logistic regression (5% type I error rate).
  
  
  RESULTS
  Seven hundred eighty patients received EFV; 543 provided ≥1 EFV Cmin. Median weight was 52.8 kg (interquartile range [IQR], 48.0-59.5), body mass index 19.4 kg/m(2) (IQR, 17.5-21.6), and age 34 years (IQR, 29-41); 63% were male, 74% black. Median Cmin was 1.96 µg/mL on-RIF versus 1.80 off-RIF (P = .067). Cmin were significantly higher on-RIF versus off-RIF in blacks (2.08 vs 1.75, P = .005). Weight ≥60 kg on-RIF, compared to <60 kg, was associated with lower EFV Cmin (1.68 vs 2.02, P = .021). However, weight ≥60 kg was associated with more frequent HIV RNA < 400 copies/mL at week 48, compared to weight <60 kg (81.9% vs 73.8%, P = .023).
  
  
  CONCLUSIONS
  EFV and RIF-based tuberculosis therapy coadministration was associated with a trend toward higher, not lower, EFV Cmin compared to EFV alone. Patients weighing ≥60 kg had lower median EFV Cmin versus those <60 kg, but there was no association of higher weight with reduced virologic suppression. These data do not support weight-based dosing of EFV with RIF.
authors.affiliation: HIV/AIDS Division, San Francisco General Hospital, University of California, San Francisco, CA 94110, USA. aluetkemeyer@php.ucsf.edu
authors.forename: Anne F
authors.initials: AF
authors.lastname: Luetkemeyer
authors.forename: Susan L
authors.initials: SL
authors.lastname: Rosenkranz
authors.forename: Darlene
authors.initials: D
authors.lastname: Lu
authors.forename: Florence
authors.initials: F
authors.lastname: Marzan
authors.forename: Prudence
authors.initials: P
authors.lastname: Ive
authors.forename: Evelyn
authors.initials: E
authors.lastname: Hogg
authors.forename: Susan
authors.initials: S
authors.lastname: Swindells
authors.forename: Constance A
authors.initials: CA
authors.lastname: Benson
authors.forename: Beatriz
authors.initials: B
authors.lastname: Grinsztejn
authors.forename: Ian M
authors.initials: IM
authors.lastname: Sanne
authors.forename: Diane V
authors.initials: DV
authors.lastname: Havlir
authors.forename: Francesca
authors.initials: F
authors.lastname: Aweeka
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000627:therapeutic use*; D048588:Benzoxazines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001835:Body Weight; D003521:Cyclopropanes; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D006801:Humans; D008297:Male; D012293:Rifampin / Q000627:therapeutic use*; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy*; D019562:Viral Load
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D048588:Benzoxazines; D003521:Cyclopropanes; C098320:efavirenz; D012293:Rifampin
keywords: HIV/AIDS; efavirenz; pharmacokinetics; rifampin; tuberculosis