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Efavirenz Dose and Genotype Do Not Affect 48-Week Response in Low/Standard-Dose Trial
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15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, May 19- 21, 2014, Washington, DC
Mark Mascolini
After 48 weeks of treatment in the 630-person ENCORE 1 trial of 400 versus 600 mg of efavirenz daily, very few people had virologic failure [1-3]. Dose, CYP2B6 genotype, and pretreatment viral load did not affect 48-week virologic response in these previously untreated people [1].
This double-blind, noninferiority trial randomized antiretroviral-naive people in 13 countries in Europe, Africa, the Asia-Pacific region, and Latin America to 400 or 600 mg of efavirenz daily plus tenofovir/emtricitabine. Study participants gave single blood samples 8 and 16 hours after dosing on weeks 4 and 12, and 46 people underwent intensive sampling on weeks 4 and 8.
One third of study participants were women, 37% African, 33% Asian, 17% Hispanic, and 13% Caucasian. Median age stood at 35 years (range 18 to 69), median weight at 65 kg (range 39 to 149), median CD4 count at 270 (range 40 to 679), and median viral load at 56,803 copies (range 162 to 10,000,000). Rates of adverse events and serious adverse events did not differ between study arms.
Compared with wild-type CYP2B6 516GG/983TT genotype, efavirenz clearance (CL/F) decreased 34%, 27%, 71%, and 65% for genotypes 516GG/983TC or CC, GT/TT, GT/TC or CC and TT/TT.
As expected, 400 mg of efavirenz daily yielded lower exposures than 600 mg. But at week 48, 97% of participants randomized to 400 mg and 98% randomized to 600 mg had a viral load below 200 copies. Proportions of people with a viral load below 200 copies did not differ in a modified intention-to-treat analysis, a noncompleter-equals-failure analysis, or a per-protocol analysis [3]. Response rates did not differ between arms with a 50-copy cutoff.
Because virologic failure rates were so low in each study arm, the researchers could not perform multivariate analyses of factors related to failure. But in univariate analyses, neither efavirenz dose, genotype, nor pretreatment viral load predicted virologic response (P > 0.05).
In an analysis adjusted for weight, age, sex, ethnicity, and genotype, mean individual log-transformed 24-hour concentration of efavirenz was associated with nearly quadrupled chances of having a week-48 viral load below 200 copies (odds ratio 3.8, 95% confidence interval 2.0 to 7.0, P = 0.001).
Among study participants with an efavirenz 12-hour concentration below versus above 1.0 mg/L (the reported minimum effective concentration), 21% (4 of 19) versus 2% (12 of 574) had a week-48 viral load at or above 200 copies (P = 0.001). Of the 19 people who had a 12-hour concentration below 1.0 mg/L, 14 were taking 400 mg and 5 were taking 600 mg. One of 14 taking 400 mg and 3 of 5 taking 600 mg had a week-48 viral load above 200 copies.
Because "virological outcomes were not related to dose allocation," the researchers suggested, "other drivers of virological response such as adherence may be involved."
References
1. Dickinson L, Amin J, Else L, et al. Population PK-PD analysis of 400 mg vs. 600 mg efavirenz once daily in treatment-naive HIV patients at 48 weeks: results of the ENCORE1 study. 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. 19- 21 May 2014. Washington, DC. Abstract O_01.
2. Safety and efficacy of reduced dose efavirenz (EFV) with standard dose EFV plus two nucleotide reverse transcriptase inhibitors (N(t)RTI) in antiretroviral-naive HIV-infected individuals. (ENCORE1). ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/NCT01011413
3. ENCORE1 Study Group, Puls R, Amin J, et al. Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, double-blind, placebo-controlled, non-inferiority trial. Lancet. 2014;383:1474-1482. Erratum in Lancet. 2014;383:1464. http://www.ncbi.nlm.nih.gov/pubmed/24522178
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