Relationship between efficacy, tolerance, and plasma drug concentration ofritonavir in children with advanced HIV infection

The relationship between ritonavir plasma concentration, efficacy, and tole rance was evaluated in 31 children with advanced HIV infection who were rec eiving a triple therapy with ritonavir as protease inhibitor. Median CD4(+) lymphocyte count and median viral load before the initiation of ritonavir- containing combination therapy were 1320 cells/mL and 5 log10 copies/mL, re spectively. Ritonavir was given at a dose ranging from 300 to 450 mg/m(2) t wice daily. The median follow-up of triple therapy was 19 months. Response was defined as a drop of viremia of more than 1 log. Plasma drug levels wer e determined twice during the observation period: after at least 4 weeks an d after 3 months of combined treatment. Samples were collected before (resi dual) and 2 hours (T2) after drug intake. Cholesterol, triglycerides, alani ne transaminase, aspartate transaminase, and gamma-glutamyl transpeptidase were assessed at the same time. The median values of rilonavir residual and T2 levels were 1.63 mgn and 5.9 mg/L at observation 1 and 3.35 mg/L and 6. 29 mg/L at observation 2, respectively. According to virologic response, me dian residual concentrations of ritonavir were 3.17, 2.52, and 1.04 mg/L fo r the complete, the partial, and the no-response groups. The authors observ ed a wide intersubject variability of ritonavir concentrations with an incr ease in residual levels between the two observation periods. Residual level s were correlated with virologic response whereas there was no direct assoc iation between T2 levels and long-term response. Patients with complete or partial response displayed statistically significantly higher residual conc entrations than the no-response group. No correlation could be demonstrated between elevated plasma drug concentrations and abnormal cholesterol or tr iglycerides values. These results emphasize the importance of a sustained h igh ritonavir concentration to achieve optimal treatment efficacy. Furtherm ore, these results prove the clinical benefit of therapeutic drug monitorin g and could potentially improve patient evaluation in terms of treatment ef ficacy. compliance, and viral resistance.