The virologic responses with reduced-dose efavirenz at 48 weeks have proven durable out to 96 weeks, ENCORE1 study results show.
The finding, presented at the HIV Drug Therapy Congress in Glasgow, United Kingdom, supports the use of a lower dose of the drug in combination with tenofovir plus emtricitabine as first-line therapy for HIV.
"Efavirenz has been an incredibly important drug, but there has always been a tendency to err on the side of caution with the antiretrovirals in general, and to push for something that looks like the maximally tolerated dose rather than a dose that looks more like the minimum effective concentration," Sean Emery, PhD, from the Kirby Institute at the University of New South Wales in Sydney, Australia.
At 96 weeks, the rate of viral loads below 200 copies/mL was virtually identical for the 400 mg reduced dose of efavirenz and the 600 mg approved dose (90.0% vs 90.6%), when used in combination with tenofovir plus emtricitabine.
"I wouldn't be critical about the decision made some 20 years ago to use the higher dose," said Dr Emery. "But I would be concerned going forward were there to be any substantial pushback to the adoption of a clearly evidentiary sound decision to use efavirenz at a dose of 400 mg rather than 600 mg a day."
ENCORE1 was a multinational, double-blind, placebo-controlled, noninferiority trial of treatment-naive HIV-positive adults. In the intent-to-treat population, about one-third of the patients were female and roughly equal proportions were white, of African descent, and of Asian descent.
Of the 585 patients who completed 96 weeks of therapy, 299 were randomized to reduced-dose efavirenz and 286 to standard dose efavirenz.
At 96 weeks, noninferiority of the two doses was demonstrated for virologic response, defined as a viral load below 200 copies/mL. It was also demonstrated for viral loads below 50 copies/mL and below 400 copies/mL, irrespective of baseline viral load.
There was no difference between the two groups in time to loss of virologic response, defined as a viral load above 200 copies/mL, or in the mean change in viral load from baseline.
ENCORE Call for Lower Dose
The mean change in CD4 cell count from baseline to week 96 remained significantly higher in the reduced-dose group than in the standard-dose group. The difference in favor of the reduced dose was 25 cells/uL (P = .03).
One of the reasons Dr Emery's team conducted the trial was to see if the tolerability and safety profile of reduced-dose efavirenz was better than standard-dose efavirenz.
"Adverse events were not dissimilar numerically between the two randomly assigned treatment groups," he acknowledged.
When the investigators attributed causality to adverse events they suspected were triggered by efavirenz, "you do see a difference that is statistically significant between the group that received 400 mg and the group that received 600 mg," Dr Emery reported. The frequency of events was lower in the reduced-dose group.
"Clearly, we would have liked a much stronger signal for the tolerability and safety profile of reduced-dose efavirenz than we were able to show," he noted. "Having said that, the fact that we were able to preserve therapeutic efficacy in almost 600 patients over 2 years of treatment has to be a very strong signal that 400 mg is efficacious. On that basis, why would you not recommend using 400 mg in routine clinical care?"
The 96-week results of the ENCORE1 trial provide reassuring data regarding the robustness of reduced-dose efavirenz in a first-line regimen, said Alexandra Calmy, MD, PhD, from Geneva University Hospital.
"Small-scale studies had already suggested that efavirenz 400 mg (or even 200 mg in studies guided by therapeutic drug monitoring) was safe and efficient, but the 'gold standard' of a randomized clinical trial was lacking," Dr Calmy told Medscape Medical News.
She suggested that physicians might now want to question whether other trials need to be done to confirm optimal drug doses for all antiretrovirals, and cited the d4T "saga" that demonstrated that dose selection is not a trivial question.
"Certainly, the right balance between efficacy and safety warrant careful evaluation earlier in the drug-development scheme for all populations of concern," Dr. Calmy observed. "But results of ENCORE1 give us confidence that efavirenz 400 mg is robust enough to be recommended as first-line therapy for the general adult population."
She cautioned, however, that the scope of this recommendation needs to be defined, and that the therapy has to be shown to be safe and efficient when used with anti-TB drugs, in people with very high baseline viral loads, and in pregnant women before the World Health Organization can change current guidelines.
"With these data in hand, low-dose efavirenz may be broadly recommended as a safe, efficient, and relatively cheap option in our current formulary," Dr. Calmy concluded.
HIV Drug Therapy: Abstracts 0421 and 0422.Presented November 6, 2014.
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Cite this: Viral Load Reductions Persist With Less Efavirenz for HIV - Medscape - Nov 06, 2014.