Relationship Between Weight, Efavirenz Exposure, and Virologic Suppression in HIV-Infected Patients on Rifampin-Based Tuberculosis Treatment in the AIDS Clinical Trials Group A5221 STRIDE Study

Background. Rifampin (RIF) upregulates CYP 450 isoenzymes, potentially lowering efavirenz (EFV) exposure. The US EFV package insert recommends an EFV dose increase for patients on RIF weighing >= 50 kg. We conducted a pharmacokinetic study to evaluate EFV trough concentrations (C-min) and human immunodeficiency virus (HIV) virologic suppression in patients on EFV (600 mg) and RIF-based tuberculosis treatment in the multicenter randomized trial (ACTG A5221). Methods. EFV C-min was measured 20-28 hours post-EFV dose at weeks 4, 8, 16, 24 on-RIF and weeks 4, 8 off-RIF. Results were evaluated with 2-sided Wilcoxon rank-sum, chi(2), Fisher exact tests and logistic regression (5% type I error rate). Results. Seven hundred eighty patients received EFV; 543 provided >= 1 EFV C-min. Median weight was 52.8 kg (interquartile range [IQR], 48.0-59.5), body mass index 19.4 kg/m(2) (IQR, 17.5-21.6), and age 34 years (IQR, 2941); 63% were male, 74% black. Median C-min was 1.96 mu g/mL on-RIF versus 1.80 off-RIF (P = .067). C-min were significantly higher on-RIF versus off-RIF in blacks (2.08 vs 1.75, P = .005). Weight >= 60 kg on-RIF, compared to <60 kg, was associated with lower EFV C-min (1.68 vs 2.02, P = .021). However, weight >= 60 kg was associated with more frequent HIV RNA < 400 copies/mL at week 48, compared to weight <60 kg (81.9% vs 73.8%, P = .023). Conclusions. EFV and RIF-based tuberculosis therapy coadministration was associated with a trend toward higher, not lower, EFV C-min compared to EFV alone. Patients weighing >= 60 kg had lower median EFV C-min versus those <60 kg, but there was no association of higher weight with reduced virologic suppression. These data do not support weight-based dosing of EFV with RIF.