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Variability in Efavirenz (EFV) Concentrations Predicts Virologic Outcome in HIV-Infected Children R. C. BRUNDAGE*1, F. H. YONG2, T. FENTON2, S. A. SPECTOR3, S. E. STARR4, and C. V. FLETCHER1.
1Univ. of Minnesota, Minneapolis; 2Harvard Sch. of Publ. Hlth., Boston, MA; 3Univ. of California, San Diego; and 4Univ. of Pennsylvania, Philadelphia Introduction: Nonadherence is a major cause of inadequate drug exposure leading to therapeutic failure. As a consequence of decreased adherence, measured drug concentrations are expected to be lower and less predictable.
Objective: To develop an integrated pharmacokinetic-adherence measure (IPAM) of drug exposure and investigate its association with virologic failure.
Methods: Data were available from 50 subjects enrolled in PACTG 382, an open-label, multi-center, AUC-controlled Phase I/II trial in HIV-infected children receiving EFV, nelfinavir and at least one NRTI. EFV pharmacokinetic parameters were estimated in each subject from AUCs obtained at weeks 2 and 6. These parameters were used to predict routinely collected EFV concentrations (up to 12) obtained during the first year of the study. A measured concentration within a ±40% range of the predicted concentration was considered acceptable. The fraction of all observations within this acceptable region was defined as the IPAM (range 0-1) for each subject. Subjects were classified as low IPAM (<33rd percentile) or high IPAM (³33rd percentile). Viral rebound (VR) was defined as having >400 copies/mL after at least two consecutive RNA <400 copies/mL or a >0.75 log10 increase from nadir otherwise. Results. The median IPAM was 0.20 and 0.67 in the low and high groups, respectively. 7 of 31 children (22.6%) in the high IPAM group experienced VR vs 10 of 19 children (52.6%) in the low IPAM group (P=0.037, Fisher's exact). The low IPAM group exhibited a significantly shorter time to first VR (P=0.008, log-rank test); this finding persisted in a Cox regression analysis, which controlled for baseline viral load (P=0.022).
Conclusions: The novel IPAM marker we developed was independently prognostic of virologic rebound. Measured drug concentrations and the application of this method may identify low adherence subjects, and could allow interventions to minimize therapeutic failure.
Key Words: adherence, pharmacokinetics, virologic response
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