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Background There are potential benefits to individualizing dosage in patients treated with efavirenz (EFV). We tested a simplified algorithm based on a Bayesian pharmacokinetic approach for guiding dose reduction in patients with EFV concentrations above the 75th percentile (P75) with documented virological efficacy. Methods We designed a prospective, open-label, multi-centre study. All consenting participants with EFV concentrations above P75 on standard dosage were included in a dose-reduction cycle. Primary end point was the number of patients who reached plasma concentrations within target (1,000–4,000 ng/ml) after, at most, two cycles of dose reduction at 3 and 6 months. CYP2B6 genetic characterization was performed. Results Seventy-two patients were screened and 13 ful-filled selection criteria. These patients, with undetectable viraemia on a stable 600 mg EFV-based regimen, had a median (interquartile range) EFV plasma level of 8,112 ng/ml (5,993–10,278) at baseline; 38% (between P75 and P95) qualified for a 400 mg EFV dose, and 62% (above P95) qualified for a 200 mg EFV dose. After one to two dose-reduction cycles, all patients reached targets for EFV plasma concentration at 24 weeks. The predictive dose reduction based on genetic profile differed from dose reduction according to therapeutic drug monitoring (TDM) in three patients. All patients maintained viral suppression at 6 months. Conclusions A standardized TDM-guided EFV dose-reduction strategy over a 24-week period was successful, safe and yielded EFV plasma concentrations within the recommended therapeutic range. In addition to improving neuropsychiatric tolerability, EFV dose reduction has the potential to substantially decrease treatment cost.

Background Physiological changes associated with pregnancy may alter antiretroviral plasma concentrations and might jeopardize prevention of mother-to-child HIV transmission. Lopinavir is one of the protease inhibitors more frequently prescribed during pregnancy in Europe. We described the free and total pharmacokinetics of lopinavir in HIV-infected pregnant and non-pregnant women, and evaluated whether significant alterations in its disposition and protein binding warrant systematic dosage adjustment. Methods Plasma samples were collected at first, second and third trimester of pregnancy, at delivery, in umbilical cord and postpartum. Lopinavir free and total plasma concentrations were measured by HPLC-MS/MS. Bayesian calculations were used to extrapolate total concentrations to trough (Cmin). Results A total of 42 HIV-positive pregnant women and 37 non-pregnant women on lopinavir/ritonavir were included in the study. Compared to postpartum and control values, total lopinavir Cmin was decreased moderately (31–39%) during pregnancy, and free Cmin minimally, showing significant alteration only at delivery (-35%). However, total and free Cmin remained in all patients above the target concentrations for wild-type virus of 1,000 ng/ml, and above the unbound IC50WT of 0.64–0.77 ng/ml of lopinavir, respectively. Lopinavir free fractions remained higher during pregnancy compared to post-partum and controls, and were influenced by α-1-acid-glycoprotein and albumin decrease. Free cord-to-mother ratio (0.43) was 2.7-fold higher than total cord-to-mother ratio (0.16), suggesting higher fetal exposure. Conclusions The moderate decrease of total lopinavir concentrations during pregnancy is not associated with proportional decrease in free concentrations. Both reach a nadir at delivery, albeit not to an extent that would put treatment-naive women at risk of insufficient exposure to the free, pharmacologically active concentrations of lopinavir. No dosage adjustment is therefore needed during pregnancy as it is unlikely to further enhance treatment efficacy but could potentially increase the risk of maternal and fetal toxicity. Nonetheless, in case of viral resistance in treatment-experienced pregnant women, loss of virological control or questionable adherence, it is justified to consider lopinavir dosage adjustment based on total plasma concentration measurement.