December 8, 2013
With better tolerated and even more convenient antiretrovirals coming to market, there has been the beginning of a shift away from the use of fixed-dose efavirenz/tenofovir/emtricitabine. A new study from researchers within the U.S. NIAID-funded AIDS Clinical Trials Group (ACTG) linking efavirenz use to an increased risk of suicidality (suicidal ideation and/or attempted/completed suicide) may further hasten reduced reliance of our all-time favorite NNRTI.
Data collected during four ACTG randomized trials comparing efavirenz-based regimens to other antiretroviral combinations in treatment-naive patients were examined. In all, 5,332 patients were included; most were enrolled at U.S. sites and were men. A third had a documented history of psychiatric disorder and 10% were on an antidepressant at study baseline. These characteristics were well balanced between those randomized to efavirenz-containing (N = 3,241) and efavirenz-free (N = 2,091) regimens.
While suicidality was rare overall (62 events), there was a significantly higher risk for those receiving efavirenz (hazard ratio [HR] = 2.16, 95% CI: 1.16 - 4.00) and this increased risk was apparent almost immediately after randomization. Younger age (less than 30 years), a history of injection drug use, and a psychiatric history all were significant factors associated with suicidality. There was a trend (P = .06) for greater risk of attempted or completed suicide in the efavirenz-assigned group and a significant greater risk in this group of untimely death (suicide, accidents, overdose and homicide).
There have been suspicions that efavirenz has lasting effects on mood, despite the results of a substudy of one of the included trials that found the impact of the drug on neuropsychiatric assessments to be transient. This latest analysis suggests otherwise. Some will point to the small number of events to justify unmodified prescription of efavirenz, although the rarity of myocardial infarctions in the D:A:D study did not temper the furor that resulted when abacavir was reported to be a major risk factor. That three of the four studies included in the analysis were open-label could contribute bias and increased reporting of psychological outcomes among those known to be taking efavirenz is possible. The trend in attempted/completed suicide argues, however, that the results are not entirely a function of heightened sensitivity among participants and investigators to the potential neuropsychiatric effects of efavirenz.
Complicating the issue is that efavirenz is on the verge of going generic. A provocative cost analysis estimates savings on the order of US$1 billion with the use of generic versions of efavirenz and lamivudine (3TC, Epivir) along with brand name tenofovir (Viread) in place of the fixed-dose efavirenz/tenofovir/emtricitabine. Prying efavirenz completely from our prescribing hands may be hard if it becomes cheap, but this study, despite its limitations, raises important concerns that will affect the future use of this antiretroviral.
What are some other top clinical developments of 2013? Read more of Dr. Wohl's picks.
David Alain Wohl, M.D., is an associate professor of medicine in the Division of Infectious Diseases at the University of North Carolina and site leader of the University of North Carolina AIDS Clinical Trials Unit at Chapel Hill.
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