title: Therapeutic drug monitoring of protease inhibitors and efavirenz in HIV-infected individuals with active substance-related disorders.
abstract: BACKGROUND
  Achieving targeted antiretroviral (ARV) plasma concentrations during long-term treatment in human immunodeficiency virus (HIV)-infected patients with substance-related disorders (SRDs) may be challenging due to a number of factors, including medication adherence, coinfection with hepatitis B or C virus, medication intolerance, and drug interactions. One approach to investigate these factors is to conduct therapeutic drug monitoring to measure ARV exposure during treatment. The objective of this study was to utilize therapeutic drug monitoring to compare efavirenz (EFV) and protease inhibitor pharmacokinetics in patients with and without SRDs.
  
  
  METHODS
  This was a multicenter, cross-sectional open-label study in patients with HIV-1 infection receiving antiretroviral therapy (ART), with active (n=129) or without (n=146) SRD according to National Institute on Drug Abuse criteria. Two hundred seventy-five subjects who were receiving either protease inhibitor-based or EFV-based ART regimens for >6 months were enrolled at 4 HIV treatment centers with an equal distribution of SRD and non-SRD at each site. The patients were instructed during enrollment visits with regard to the importance of adherence before and after study visits. Demographics and routine clinical laboratory tests were recorded.
  
  
  RESULTS
  Among the 275 patients, 47% had SRD with at least 1 substance. There were no significant differences between SRD and non-SRD groups for race, gender, age, or CD4 count at entry. A significantly higher proportion of patients with SRD had an entry HIV RNA plasma concentration>75 copies per milliliter compared with patients without SRD (40% vs 28%, P=0.044). Logistic regression modeling revealed an association between HIV RNA plasma concentration and African American race (P=0.017). A significantly higher proportion of SRDs also had an EFV or protease inhibitor trough concentration below the desired range (23% vs 9%, P=0.048). Significantly lower trough concentrations were noted in patients with SRDs receiving atazanavir (0.290 vs 0.976 μg/mL) or lopinavir (3.75 vs 5.30 μg/mL).
  
  
  CONCLUSIONS
  The pharmacokinetic data indicate differences between HIV-infected patients with and without SRDs that may influence viral load suppression during long-term ART. These findings require additional investigation in a randomized design with more intensive pharmacokinetic assessment to identify individual factors that are contributing to suboptimal ARV exposure in patients with SRDs.
authors.affiliation: Translational Pharmacology Research Core, NYS Center of Excellence in Bioinformatics and Life Sciences, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14203, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ma
authors.forename: Barry S
authors.initials: BS
authors.lastname: Zingman
authors.forename: Amneris E
authors.initials: AE
authors.lastname: Luque
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Fischl
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Gripshover
authors.forename: Charles S
authors.initials: CS
authors.lastname: Venuto
authors.forename: Robin
authors.initials: R
authors.lastname: DiFrancesco
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.forename: Gene D
authors.initials: GD
authors.lastname: Morse
mesh_terms: D000480:Alkynes; D048588:Benzoxazines / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003430:Cross-Sectional Studies; D003521:Cyclopropanes; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006678:HIV / Q000302:isolation & purification; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D019966:Substance-Related Disorders / Q000097:blood* / Q000821:virology*
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D017320:HIV Protease Inhibitors; D012367:RNA, Viral; C098320:efavirenz