Atazanavir (ATV) plasma concentrations at different times after drug uptake: associations with virologic response and hyperbilirubinemia
KeywordsBilirubin Viral Load Drug Intake Virologic Response Interindividual Variability
Purpose of the study
To explore the clinical significance of morning ATV plasma concentrations in HIV+ patients taking drugs at different day times.
HIV-infected patients on an ATV-containing cART regimen since >2 weeks, with an available ATV concentration obtained by a validated HPLC-UV (group i) 12 ± 2 hours (C12 h) and (group ii) 24 ± 2 hours (C24 h) after drug intake and 24 weeks subsequent virological follow-up, were retrospectively selected. Patients with genotypic resistance to ATV were excluded. Virological failure was defined as HIV-RNA >50 copies/ml after 24 weeks.
Summary of results
A total of 171 plasma samples from 112 patients (56% males, median age 46 years IQR 40–51) were analyzed. Median time from ATV initiation was 8.9 months (IQR 1.9–17.2). At ATV dosing, 79.5% of patients had a viral load <50 copies/ml. Overall, 27 (24.1%) showed virological failure at 24 weeks. No significant differences in terms of virological failures were seen between ritonavir-boosted and unboosted regimens. Median ATV plasma concentration was higher in patients using boosted regimens: 1.5 mg/L (IQR 0.58–2.30) vs. 0.27 mg/L (IQR 0.05–1.15), p < 0.01.
C12 h ATV concentrations were measured in 115 instances while C24 h in 56 samples. Median ATV plasma concentration was significantly higher in group (i) compared to group (ii): 1.5 mg/L (IQR 0.7–2.3) vs. 0.26 mg/L (IQR 0.07–0.67), p < 0.01. Plasma concentration showed a high interindividual variability in both groups (co-efficient of variation 83.3% and 146.8%, respectively).
In group (i), ROC curve test provided an ATV concentration cut-off of 0.23 mg/L to predict virological response at 24 weeks: instances (n = 17) with a C12 h ≤0.23 mg/L showed virological failure in 41.2%, whereas instances (n = 98) with a C12 h >0.23 mg/L failed in 16.3% of cases (p = 0.042). A total of 22.5% (20/89) of patients developed grade III/IV hyperbilirubinaemia. ATV C12 h correlated with concomitant unconjugated bilirubin (r = 0.223, p = 0.037). A concentration cut-off predictive of >grade III total bilirubin toxicity could not be identified. No correlations were identified between C24 h and virologic response or bilirubinemia.
Identification of an ATV C12 h efficacy threshold can be useful for the clinical application of morning TDM in patients receiving ATV at night.
This article is published under license to BioMed Central Ltd.