The non-nuke efavirenz -- sold as Sustiva, Stocrin and found in Atripla -- has been commonly used as part of HIV treatment since the late 1990s. Efavirenz can be taken in a single dose and has potent anti-HIV activity when used as part of combination therapy (commonly called ART or HAART) in many studies. When used as directed, efavirenz is generally safe. However, this drug can cause side effects that affect the brain, including the following:
Researchers refer to these and other side effects that affect the brain as neuropsychiatric symptoms. These side effects are supposed to fade within the first two to four weeks of initiating therapy with efavirenz. However, several studies from Europe suggest that efavirenz-related side effects can persist. Furthermore, a UK study found that about 20% of participants given the efavirenz-containing medicine Atripla quit because of side effects that affected their brain.
A robustly designed (randomized, placebo-controlled, cross-over) clinical trial in Switzerland found that 50% of participants who were taking an efavirenz-based regimen preferred to switch to a combination that was better tolerated, in this case with the integrase inhibitor raltegravir (Isentress).
A less common side effect associated with efavirenz is the development of depression. For many years in high-income countries, the prescribing information for efavirenz has included warnings about the possibility, in rare cases, of self-harm and attempted suicide.
Researchers with the U.S. AIDS Clinical Trials Group (ACTG) decided to investigate any possible link between the use of efavirenz and suicidal thoughts or behaviour in several well-designed clinical trials that they conducted. In their work, the researchers focused on four randomized clinical trials and found that the use of efavirenz was associated with a two-fold increased risk of suicidal thoughts or behaviours.
The ACTG team reviewed data from four studies comparing efavirenz-based regimens to efavirenz-free regimens involving 5,332 participants. None of these people had previously been exposed to anti-HIV drugs. They were distributed as follows:
Although these four trials were held in different countries, nearly three-quarters of participants were from the U.S. Half of the participants were between the ages of 18 and 37 years; 73% were men and 27% were women.
Here are key points related to the mental health of participants:
Most participants were monitored for up to three years.
Researchers assessed participants for suicidality, which they defined as any of the following:
In their analysis, the researchers found that 83 participants had reported suicidal thoughts or behaviours. The overall distribution of people who had thoughts of, attempted or completed suicide was as follows:
The distribution of attempted suicides was as follows:
The distribution of completed suicides was as follows:
Statistical analysis revealed that participants taking efavirenz were at least twice as likely as participants not taking this drug to have thoughts of or attempted or completed suicide. This difference was statistically significant; that is, not likely due to chance alone.
In general, the length of time it took for a participant to develop thoughts of suicidal behaviours was shorter among people taking efavirenz than among people who did not take this drug.
Sometimes death due to suicide may be misclassified or attributed to drug overdose, accidents or murder. When researchers reanalyzed the data taking into account these other possible misclassifications, exposure to efavirenz was still associated with a two-fold increased risk of death.
Taking into account several factors and their relationship to thoughts of or suicidal behaviours, the researchers found that the following factors were linked to an increased risk for suicidality in participants:
Note that the researchers found that participants with a documented history of mental and severe emotional disorders were not common in these studies. They were limited to 25 people and distributed as follows:
Furthermore, among these 25 people (particularly five of the 16 who were taking efavirenz and one of the nine on an efavirenz-free regimen), thoughts of suicide or suicidal behaviour occurred.
Rates of suicidality were similar whether or not analyses were restricted to participants based in the U.S. or elsewhere.
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