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

Abstract

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 (Cmin) 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 Cmin 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, χ(2), Fisher exact tests and logistic regression (5% type I error rate).

Results: Seven hundred eighty patients received EFV; 543 provided ≥1 EFV Cmin. 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, 29-41); 63% were male, 74% black. Median Cmin was 1.96 µg/mL on-RIF versus 1.80 off-RIF (P = .067). Cmin 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 Cmin (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 Cmin compared to EFV alone. Patients weighing ≥60 kg had lower median EFV Cmin 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.

Keywords: HIV/AIDS; efavirenz; pharmacokinetics; rifampin; tuberculosis.

Figure 1.

Statistical summaries of within-participant mean efavirenz (EFV) trough concentrations (C_min), log₁₀ µg/mL. EFV C_min from 324 participants with at least 1 on-rifampin (RIF; open triangles) and off-RIF (open circles) C_min values. EFV C_min from participants with EFV C_min from multiple timepoints have values summarized as the within-participant mean EFV concentration on-RIF and off-RIF. Heavy horizontal lines indicate medians; light horizontal lines indicate Q1 and Q3. P values are obtained from a Wilcoxon signed-rank test of within-participant differences, on-RIF minus off-RIF EFV C_min (within off-RIF quintile). *Statistically significant difference (P ≤ .05). Abbreviations: C_min, trough concentrations; EFV, efavirenz; RIF, rifampin.

Figure 2.

Comparison of on- and off-rifampin (RIF) efavirenz (EFV) trough concentrations (C_min) by race/ethnicity and by weight. On-RIF (closed triangle, solid line) and off-RIF (closed circle, dashed line) participant-specific mean EFV C_min are presented as medians and 95% confidence intervals (CIs) around the medians. Data from 324 participants with both on- and off-RIF EFV C_min values are plotted. The median within-participant on-RIF versus off-RIF EFV C_min difference, number of participants contributing to each CI and a Wilcoxon signed-rank P value is shown. *Statistically significant difference (P ≤ 0.05). Two Asian male participants were omitted from the by-race/ethnicity comparison. Horizontal dashed lines at 1 and 4 µg/mL mark the commonly cited thresholds for sub- and supraoptimal EFV C_min. Abbreviation: RIF, rifampin.

Figure 3.

Human immunodeficiency virus RNA suppression at week 48, by weight. P values are obtained from a Pearson χ² test. Missing RNA and participants lost to follow-up are considered not suppressed. Abbreviation: HIV, human immunodeficiency virus.