title: The design and implementation of A5146, a prospective trial assessing the utility of therapeutic drug monitoring using an inhibitory quotient in antiretroviral-experienced HIV-infected patients.
abstract: The AIDS Clinical Trials Group designed and implemented a prospective, randomized, strategy trial in antiretroviral-experienced, HIV-infected patients to evaluate the virologic impact of protease inhibitor dose escalation in response to therapeutic drug monitoring (TDM) with an inhibitory quotient, which integrates both drug exposure and viral drug resistance. In the process of developing this clinical trial, several unique challenges were identified that required innovative solutions. The major challenge was the need to integrate resistance testing, pharmacokinetic data, medication adherence, toxicity data, clinical assessments, randomization assignment, and protocol-specified clinical management in a way that could be utilized in real time by the protocol team, communicated promptly to the clinical sites, and transmitted accurately to the study database. In addition, the protocol team had to address the relative lack of commercially available TDM laboratories in the United States that were experienced in antiretroviral drug assays and a lack of familiarity with the principles of pharmacokinetic monitoring at participating clinical sites. This article outlines the rationale for the design of this strategy trial, specific barriers to implementation that were identified, and solutions that were developed with the hope that these experiences will facilitate the design and conduct of future trials of TDM.
authors.affiliation: Infectious Diseases Division, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA. lisa_demeter@urmc.rochester.edu
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Demeter
authors.forename: A Lisa
authors.initials: AL
authors.lastname: Mukherjee
authors.forename: Robin
authors.initials: R
authors.lastname: DiFrancesco
authors.forename: Hongyu
authors.initials: H
authors.lastname: Jiang
authors.forename: Robert
authors.initials: R
authors.lastname: DiCenzo
authors.forename: Barbara
authors.initials: B
authors.lastname: Bastow
authors.forename: Alex R
authors.initials: AR
authors.lastname: Rinehart
authors.forename: Gene D
authors.initials: GD
authors.lastname: Morse
authors.forename: Mary
authors.initials: M
authors.lastname: Albrecht
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016903:Drug Monitoring; D006678:HIV / Q000187:drug effects / Q000502:physiology; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D012107:Research Design
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors