Dangerously low blood drugs levels may occur in nearly two-thirds of people on antiretroviral therapy over the course of a year, say researchers in the December 1st edition of the Journal of Acquired Immune Deficiency Syndromes. But, they add, using therapeutic drug monitoring as part of a well-tailored HIV care plan can approximately double the chances reaching target blood levels of medication.
Except for certain recommended situations, therapeutic drug monitoring (TDM) of antiretroviral drug blood levels is a tool that has seen limited clinical application. Many factors have blocked its acceptance, including natural variability in drug blood levels in a patient, a lack of reference standards for the different drugs, and a lack of solid data supporting who might best benefit from this expensive and unwieldy procedure.
To address some of these gaps, Best and colleagues of the California Collaborative Treatment Group 578, designed a study to explore two fundamental questions: 1) what proportion of patients have blood levels of protease inhibitor (PI) or NNRTI above or below target values; and, 2) what factors predict who will have non-target levels.
The randomised, controlled, open-label study recruited 230 patients who were either starting therapy for the first time or switching their regimen. Regimens were designed by clinician and patient with no trial constraints. Participants were then randomly assigned to either receive TDM or standard care. At week two, all patients had blood samples drawn for TDM. Samples were also drawn at all visits up to study end at week 48. However, only participants in the TDM arm had results and dosing recommendations provided to their clinician.
There are no standards for optimal drug blood levels, so a committee of specialists reviewed clinical, laboratory and modelled drug concentration data before making a recommendation on whether and how to alter drug dosing. The researchers chose as a target drug level an average concentration greater than the average concentration calculated from published oral clearance values for each drug. The committee included the participant’s broader health care plan when making recommendations.
Among the 199 participants entering the study, two thirds were treatment-experienced at study entry. The group had advanced disease, with a median viral load just under 160 000 copies/ml and a median CD4 cell count of 176 cells/mm3.
Of the 190 participants in the analysis, 74 (39%) had concentrations outside the target range at two week. Over the 48-week course of the study, 122 (64%) had non-target levels at least once.
During the study, the expert committee made 170 recommendations to change PI or NNRTI exposure in 122 patients. Almost all, 166 recommendations, were to increase drug exposure. The most common action was to increase drug dose, though the expert committee also recommended more specific actions, such as modifying diet, changing concomitant medications or improving adherence.
Clinicians followed recommendations in 76% of cases. The researchers attributed this high uptake due to the tailoring of the recommendations to individual patient cases.
Among TDM-arm participants who had non-target levels and whose clinician followed recommendations, 60% achieved target levels at the next visit. In contrast, target levels were achieved in 36% of standard-care patients who had recommendations that were not made available to their clinicians. Overall, TDM participants with non-target levels achieved target more often, 65% of the time, compared with 45% of the time for participants in the standard-care arm (a non-significant difference, p = 0.09).
Researchers identified three factors that independently predicted nontarget drug blood levels: greater body weight, use of efavirenz (Sustiva) and use of lopinavir/ritonavir (Kaletra). In multivariate analysis, the odds ratio was 1.019 for each 1-kg increase in body weight, 4.131 for efavirenz use and 4.102 for lopinavir use. Based on these findings, the researchers suggest that heavier patients and patients receiving efavirenz or lopinavir should be included as candidates for TDM.
Commenting on the two-thirds of participants who had a nontarget drug blood level during the study, researchers stated “TDM allows detection of these at-risk patients and provides a tool for the clinician to intervene before regimen failure.” They conclude that their study could be used as a starting point for further TDM studies exploring toxicity and efficacy.
Best BM et al. A randomized controlled trial of therapeutic drug monitoring in treatment-naïve and –experienced HIV-1–infected patients. J Acquir Immune Defic Syndr 46:433 – 442, 2007.