Comprehensive Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Evaluation of Once-Daily Efavirenz 400 and 600 mg in Treatment-Naïve HIV-Infected Patients at 96 Weeks: Results of the ENCORE1 Study

Abstract

BackgroundENCORE1 demonstrated non-inferiority of daily efavirenz 400 mg (EFV400) versus 600 mg (EFV600) to 96 weeks in treatment-naïve, HIV-infected adults but concerns regarding lower EFV400 concentrations remained. Therefore, relationships between EFV pharmacokinetics (PK) and key genetic polymorphisms with 96-week efficacy and safety were investigated.MethodsRelationships between EFV PK parameters and single nucleotide polymorphisms (SNP; CYP2B6,CYP2A6, CYP3A4, NR1I3, NR1I2, ABCB1) with plasma HIV-RNA (pVL) <200 copies/mL and EFV discontinuation and adverse events at 96 weeks were explored. Receiver operating characteristic curve analysis evaluated the predictability of mid-dose interval (C12) cutoffs and 96-week pVL.ResultsA total of 606 patients (32 % female; 37 % African, 33 % Asian; n = 311 EFV400, n = 295 EFV600) were included. EFV PK parameters, including C12, were not associated with pVL <200 copies/mL at 96 weeks (odds ratio [OR] 5.25, 95 % confidence interval [CI] 0.41–67.90, p = 0.204). Lower risk of CNS-related adverse events was associated with CYP2B6 983TC/CC (OR 0.35, 95 % CI 0.15–0.81, p = 0.015) and higher risk was associated with CYP2B6 15582CT/TT and ABCB1 3435TT (OR 1.46, 95 % CI 1.02–2.09, p = 0.040; OR 2.31, 95 % CI 1.33–4.02, p = 0.003, respectively). Discontinuation due to adverse events (clinician decision) was independently associated with dose (OR 2.54, 95 % CI 1.19–5.43, p = 0.016). C12 between 0.47 and 0.76 mg/L provided sensitivity/specificity >90 % (100 %/92.3 to 98.9 %/92.3 %) for achieving pVL <200 copies/mL at 96 weeks.ConclusionsA higher rate of EFV-related adverse events and discontinuations due to these events for EFV600 were not driven by polymorphisms assessed. Although a single threshold concentration associated with HIV suppression may be clinically useful, it was not viable for ENCORE1. Implementation of EFV400 would improve toxicity management whilst still maintaining good efficacy.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-015-0360-5) contains supplementary material, which is available to authorized users.

Efavirenz Therapeutic Range in HIV-1 Treatment-Naive Participants

“…27,28 However, studies such as ENCORE1, which compared the efficacy of 400 mg of efavirenz to the standard dose of 600 mg at 48 and 96 weeks in treatment-naive patients, suggest that 1,000 ng/mL does not necessarily represent the optimal efficacy concentration cutoff based on the proportion of subjects with both a plasma viral load level ≥200 copies/mL and predicted efavirenz mid-dosing concentrations <1,000 ng/mL compared to >1,000 ng/mL (p = 0.059). 29,30 However, caution is recommended in interpretation based on the limited number of virologic failures and projection of pharmacokinetic parameters to a pharmacodynamic outcome at a much later time point. 30 In addition, a range of possible minimum effective concentrations were suggested (470–760 ng/mL), but additional analysis would be required to confirm this.…”

“…29,30 However, caution is recommended in interpretation based on the limited number of virologic failures and projection of pharmacokinetic parameters to a pharmacodynamic outcome at a much later time point. 30 In addition, a range of possible minimum effective concentrations were suggested (470–760 ng/mL), but additional analysis would be required to confirm this. 30 Other studies have reported no correlation between viral suppression and efavirenz exposure.…”

“…30 In addition, a range of possible minimum effective concentrations were suggested (470–760 ng/mL), but additional analysis would be required to confirm this. 30 Other studies have reported no correlation between viral suppression and efavirenz exposure. 31 In a study comparing the efficacy of three-times-a-week dosing to daily dosing of the combined antiretroviral medication efavirenz, emtricitabine, and tenofovir disoproxil fumarate in HIV-1 patients, with no history of virologic failure or resistance mutations to study drugs, all subjects (in both arms) maintained HIV-1 RNA <37 copies/mL for 24 weeks.…”

Over Exposure to Efavirenz Plasma Concentrations among Beninese HIV Patients Treated by A 600 mg Daily Dose

“…Patients having high plasma concentration of EFV should be subjected to closely follow-up. A recent study has shown that once-daily EFV 400 mg dose was so effective than once-daily EFV 600 mg despite lower plasma concentrations obtained, even if this study was probably critical because it compared pharmacokinetic parameters and plasma concentrations obtained at week 4 or 8 and clinical outcome at week 96 [30]. This study included 606 patients with 37% of African and 33% of Asian people.…”

Brief Report: CYP2B6 516G>T Minor Allele Protective of Late Virologic Failure in Efavirenz-Treated HIV-Infected Patients in Botswana

“…Understanding the clinical relevance of slow EFV metabolism on virologic response is of particular importance for populations in which the minor allele of CYPB2B6 516G>T is common, including patients of African descent. 9-11 Our goal was to determine whether the CYP2B6 516G>T genotype is associated with differential rates of undetectable viral load after having achieved initial HIV suppression. We hypothesized that the 516G>T genotype would be associated with differences in late virologic failure, e.g., either increased rates due to greater CNS toxicity or lower rates due to higher drug concentrations being more permissive of missed doses.…”