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

Tuberculosis is the leading cause of death in human immunodeficiency virus (HIV)–coinfected individuals worldwide. Concomitant treatment of HIV and tuberculosis is required to reduce the risk of death and HIV progression [1–3]. However, antiretroviral therapy (ART) can be complicated by drug–drug interactions with tuberculosis medications, particularly rifampin (RIF), which induces cytochrome (CYP) P450 enzymes. Efavirenz (EFV) is recommended as a component of first-line ART in HIV/tuberculosis coinfection [4] and is metabolized primarily through hepatic cytochrome P450 CYP2B6. EFV pharmacokinetic exposure is significantly increased by several genetic polymorphisms in CYP2B6 [5–9]. Slow-metabolizing CYP2B6 alleles are present in all populations at varying frequencies, with 516G→T (rs3745274) most frequent with African or Asian ancestry, 983T→C (rs28399499) most frequent with African ancestry, and 15582C→T (rs4803419) most frequent with Asian or European ancestry [6, 10–12]. In addition, patients taking multidrug therapy for tuberculosis also receive isoniazid, an inhibitor of CYP2A6 and other isoenzymes [13], potentially impacting EFV concentrations as well as rifampin. CYP2A6 is an alternative pathway for EFV elimination that may be of particular importance in patients with slow EFV metabolizer phenotypes [14, 15]. The appropriate EFV dose for HIV-infected patients receiving concomitant RIF continues to be debated because available data are conflicting. Traditional pharmacokinetic (PK) studies enrolling healthy volunteers in the United States combined with limited data from patients coinfected with HIV and tuberculosis have demonstrated a 30% decrease in plasma EFV area under the concentration time curve (AUC) with RIF coadministration [16–18]. In contrast, several larger, population-based studies in patients from primarily resource-limited settings indicate either that there is no effect of RIF on EFV concentrations [7, 19] or that RIF coadminstration increases EFV concentrations in African patients [20, 21]. Focusing on intensive PK data gathered primarily in developed settings, the US Food and Drug Administration (FDA) recently approved a revised EFV package insert to recommend that EFV be increased from a standard daily dose of 600 mg to 800 mg for patients taking concomitant RIF who weigh >50 kilograms [22], whereas the British HIV/tuberculosis treatment guidelines recommend EFV dose increase for those weighing >60 kg [23]. In contrast, based on clinical trial and observational data, the World Health Organization does not recommend increased EFV dosing based on weight in tuberculosis patients [4, 24]. Determining the appropriate dosing of EFV during tuberculosis treatment is essential because very high EFV concentrations may increase drug-related toxicity, while very low EFV concentrations may result in treatment failure with emergence of drug-resistant HIV [25, 26]. To evaluate the relationship between weight, EFV concentrations, and HIV RNA suppression, we conducted a population-based pharmacokinetic analysis in the STRIDE (A Strategy Study of Immediate Versus Deferred Initiation of Antiretroviral Therapy for AIDS Disease-Free Survival in HIV-Infected Persons Treated for Tuberculosis with CD4 < 250 Cells/mm3) study participants. The STRIDE study (A5221) was an open-label, randomized study comparing ART started earlier (within 2 weeks of tuberculosis treatment initiation) versus later (8–12 weeks after tuberculosis treatment initiation) in HIV-infected participants receiving RIF-based tuberculosis treatment [2]. The impact of weight ≥50 kg and ≥60 kg on EFV concentrations was evaluated, given the differing weight cutoffs for recommended EFV dose [22, 23, 27].