In a recent publication Raffi et al. suggest that it may be time to drop efavirenz (Sustiva®) from 1st line HIV treatment recommendations [1]. The authors make the claim that efavirenz was inferior to rilpivirin (Edurant®) and dolutegravir (Tivicay®) in a total of 3 recent controlled studies. They review the CNS side effect profile of efavirenz and find the newer drugs superior regarding safety and tolerability. With similar once-a-day convenience and compliance, they feel that efavirenz should probably be relegated to 2nd tier status. This article makes a good case against efavirenz at first blush but the argumentation does not feel balanced. Let me make here the case for efavirenz without prejudice.
Efavirenz is the only representative of the NNRTI class with a long strong track record of clinical testing which neither etravirine nor rilpivirine nor dolutegravir can match. There is little evidence that efavirenz has lost efficacy over time as far as VL reduction is concerned. The authors present data suggesting superiority of rilpivirine over efavirenz in 3 studies but these studies were not designed to test superiority in the first place. Not being a statistician, I would still point out that the 95% confidence intervals of difference in efficacy at the primary endpoint includes 0 (zero) indicating that superiority cannot be claimed. There is only 1 exception: in the SINGLE study dolutegravir can claim superiority by a slim 2% margin.
As pointed out by the authors, CNS adverse events have a tendency to disappear over time. Indeed, most patients tolerate efavirenz and few need to be switched to another drug. Not to forget: Rilpivirine was not free of CNS issues in its much more limited study program. The Warnings and Precautions section in the package insert points mentions depressive disorders in 8-9% of study patients [2]. More importantly: Rilpivirine’s efficacy drops off in patients with high VL; it is therefore restricted to “patients with pre-ART plasma HIV RNA < 100,000 copies/mL” in the latest Guideline [3].
My take is that rilpivirine is not the greatest drug for all treatment-naive patients, either.
The better is always the enemy of the good. Integrase inhibitors are about to take the lead in the ART market, in preference to PIs or NNRTIs. Dolutegravir has a profile of excellent efficacy, excellent safety, once-a-day dosing, lack of drug-drug interactions and few resistance issues. Should everybody now be started on 2 nukes plus dolutegravir?
Efavirenz remains an excellent alternative, and so are the PIs. Efavirenz has some well-known safety issues which we have learned to manage. As long as efficacy remains almost identical to the newest, latest and most expensive antiretroviral, efavirenz should not be pushed aside too quickly.
Let me know where you come down on the issue. And leave a comment if you vehemently agree – or disagree.
References:
[1] Raffi. J Antimicrob Chemother 2014; 69: 1742
[2] Edurant Package Insert. http://www.edurant.com/sites/default/files/EDURANT-PI.pdf [3] Guidelines for Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents. 2014; http://aidsinfo.nih.gov/guidelines
