August 28, 2013
A daily dose of 400 mg of efavirenz (Sustiva, Stocrin) has been found non-inferior to the standard 600-mg dose in treatment-naive, HIV-infected individuals.
The investigators from the ENCORE1 study reported the final, 48-week results from this randomized, double-blind, placebo-controlled, non-inferiority trial (with a non-inferiority margin of 10%) done in Africa, Asia, Australia, Europe and the Americas. A total of 636 participants with a viral load greater than 1,000 copies/mL and a CD4+ cell count between 50 and 500 cells/mm3 were randomly assigned to efavirenz 400 mg (two 200-mg pills taken once daily, N = 324) or 600 mg (three 200-mg pills taken once daily, N = 312), both with tenofovir/emtricitabine (Truvada).
At baseline, 34% of patients had a viral load greater than 100,000 copies/mL, and 74% had a CD4+ cell count between 100 and 350 cells/mm3. At 48 weeks, the proportion of participants with a plasma viral load below 200 copies/mL (the main endpoint) in the intent-to-treat (missing = failure) population was incredibly high: 94.1% for the 400-mg arm and 92.2% for the 600-mg arm, respectively (treatment difference 1.8, 95% CI -2.1, 5.8). This met the non-inferiority criteria, which was also met in a non-completer = failure analysis and a per = protocol analysis -- and in the subset of patients with a baseline plasma viral load above 100,000 copies/mL as well. The presenter said that efavirenz 400 mg also met non-inferiority criteria in terms of a plasma viral load below 50 copies/mL, but did not show the results.
Only 1.6% of patients in the 400-mg arm and 2.3% in the 600-mg arm developed virological failure, defined as a plasma viral load above 200 copies/mL. The viral load decay was similar between arms (P = .350), but surprisingly, CD4+ cell recovery was greater in the 400-mg arm than the 600-mg arm by 25 cells (95% CI 6, 44; P = .009).
There were no differences in the rates of serious adverse events or related to the study drug. However, not surprisingly, those on the 400-mg dose had lower rates of drug-related adverse events (36.8% vs. 47.2%, P = .008) and less frequently stopped the drug due to drug-related adverse events (1.9% vs. 5.8%, P = .010).
It is obvious that these trial results, though breathtaking, arrive somewhat late. The authors and some experts have claimed that a dose reduction of antiretrovirals can reduce drug costs, and there is no doubt that efavirenz is globally a preferred third drug in the standard antiretroviral regimen. However, the reduction in cost from lowering the dose of generic efavirenz is minimal. In a recent estimation, the cost of brand-name efavirenz could potentially be reduced from $63 per patient per year to somewhat more than $31 per patient per year. However, the cost of the generic drug is already minimal.
Furthermore, it remains to be seen if the high efficacy and poor-adherence forgiveness that the 600-mg provides in real-practice conditions within low-income countries can be maintained with the 400-mg dose, particularly when threatened by potential pharmacokinetic interactions.
Which other studies presented at IAS 2013 will have lasting impact long after memories of the conference itself have faded? Read more of Dr. Llibre and Dr. Young's top picks.