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 therapeutic drug monitoring laboratories in the US that were experienced in antiretroviral drug assays, and a lack of familiarity with the principles of pharmacokinetic monitoring at participating clinical sites. This manuscript 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.

A Randomized Clinical Trial Evaluating Therapeutic Drug Monitoring (TDM) for Protease Inhibitor–Based Regimens in Antiretroviral-Experienced HIV-Infected Individuals: Week 48 Results of the A5146 Study

“…The heterogeneity of the diverse number of PI-containing regimens initiated at study entry and the different PI dose escalation algorithms stipulated for each PI regimen 30,34 may have negatively impacted the ability to detect a long-term viral load difference between the randomized arms. In subgroup analysis, there was evidence of a differential treatment effect by number of active PIs in the regimen.…”

“…The NIQ was based upon a predicted IC 50 fold change from a virtual phenotype report 34 and was shown to correlate with virologic outcome in treatment-experienced patients in retrospective studies. 25,29 The A5146 study design could have incorporated an alternative modality with the use of a genotypic inhibitory quotient (GIQ) in which the number of resistance mutations determines the extent of drug resistance, rather than the IC 50 fold change.…”

“…The reference IQs for the specific PIs used were derived from patient populations evaluated in prior studies 18,19,31–33 and incorporated the ratio of patient trough concentrations to the fold change in IC 50 of their virus isolate that was correlated with virologic success for that given PI. 34 An NIQ ≤1 indicated that the subject’s IQ was below the threshold associated with virologic suppression for that given PI. The study identified subjects with NIQ ≤1 as having low likelihood of virologic response who potentially could benefit from PI dose escalation.…”

“…34 Implementation of PI dose escalation was not allowed if nonadherence or dose-related toxicity was identified.…”

Instantaneous Inhibitory Potential and Inhibitory Quotient Show a Modest Association with Virologic Outcome: Is Either a Useful Surrogate for Clinical Drug Efficacy?

“…In fact, adjustment of drug doses (therapeutic drug monitoring) to achieve a higher trough concentration in randomized clinical trials has failed to give any better results overall, compared with not making such an adjustment [7,9]. Thus, despite the popularity of therapeutic drug monitoring in Europe, this approach has not become the standard of care in the United States and is filled with challenges, such as a relative lack of commercially available therapeutic drug-monitoring facilities and lack of familiarity with the principles of pharmacokinetic monitoring in routine clinical practice [10].…”