The results of the ACTG analysis show that in four clinical trials where regimens were randomly assigned, exposure to efavirenz was linked to a two-fold increased risk of suicidal thoughts or behaviours. Furthermore, eight out of nine participants who completed suicide were taking efavirenz.
Factors associated with an increased risk of thoughts of suicide or suicidal behaviour included the following:
The findings from the ACTG analysis should not be entirely surprising. Initial studies with efavirenz suggested that about 0.7% of 1,008 participants taking this drug vs. 0.3% of 635 participants who took an efavirenz-free regimen reported thoughts of suicide.
The ACTG researchers found and reviewed publicly available data used by the U.S. Food and Drug Administration (FDA) when reviewing the emerging data from efavirenz in clinical trials many years ago. In these early clinical trials, there were cases of "serious nervous system or psychiatric experiences" that could include the following outcomes arising from exposure to efavirenz:
The overall level of suicidality found in the ACTG's analysis is similar to that seen in an earlier French study. Bear in mind that in either the ACTG or French study, it is possible that given the stigma surrounding mental health issues, including suicide, some participants may have chosen not to report such suicidality.
Suicidality occurred throughout the monitoring period of the ACTG's trials -- three years.
The analysis by the ACTG was done on four randomized clinical trials. The number of participants was large and diverse.
However, the ACTG's methods did have some relative weaknesses. Three of the four studies were not double blind; that is, participants and their doctors and nurses knew who was taking which regimens.
Another important weakness was that the trials were not originally designed to assess the potential for suicide. Bear in mind that clinical trials for HIV drugs are generally not designed for the purpose of assessing the potential of anti-HIV drugs for suicidality. Such trials would have to be very large (several thousand people) and run for many years and would therefore be very expensive. Furthermore, as safer, better tolerated and more potent regimens than efavirenz are available today, clinical trials exploring the adverse effects of efavirenz are unlikely to be launched in high-income countries.
Despite the previously mentioned weaknesses of the ACTG's reanalysis of clinical trial data, it is likely that there is a relationship between exposure to efavirenz and an increased risk for suicide in a relatively small number of people who use it. The U.S. researchers stated that the risk for suicidality that they found associated with efavirenz is "clinically relevant." They therefore encourage doctors and nurses treating HIV-positive patients who use efavirenz to do the following:
Furthermore, the editors of the journal The Annals of Internal Medicine, in which the ACTG report was published, made this statement:
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