Intrapatient variability of efavirenz concentrations as a predictor of virologic response to antiretroviral therapy

Intrapatient variability of drug concentrations over time has not been evaluated as a predictor of drug response but may provide information on the onset and maintenance of response and a patient's adherence to therapy. Our objective was to develop a pharmacologically based measure of intrapatient variability of concentrations and investigate its association with a patient's response to antiretroviral therapy. Efavirenz concentrations were obtained for 50 children enrolled in Pediatric AIDS Clinical Trials Group study 382, a concentration-controlled trial of efavirenz plus nelfinavir and at least one nucleoside reverse transcriptase inhibitor. Efavirenz pharmacokinetic parameters were determined from 24-h concentration-time profiles at weeks 2 and 6 and used to predict trough concentrations obtained during I year of therapy. A concentration predictability score, defined as the fraction of measured trough concentrations that fell within a +/-50% range of the predicted concentration, was used to place subjects into high and low concentration predictability groups. Relationships between this score and human immunodeficiency virus RNA levels in plasma were investigated. Eight of 33 children (24%) in the high-predictability group experienced viral rebound, compared with 9 of 17 children (53%) in the low-predictability group (P = 0.042). Children with low predictability scores exhibited a significantly shorter time to their first viral rebounds and were significantly more likely to experience viral rebound; the latter finding persisted after adjustment for baseline viral load and efavirenz exposure at week 6. This novel method for the quantitation of intrapatient concentration variability was independently predictive of virologic rebound. This measure may allow interventions to minimize therapeutic failure and is applicable to other drugs.