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:

  • abnormal dreams
  • changes in mood
  • irritability
  • difficulty falling asleep
  • anxiety
  • dizziness

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.

Study Details

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:

  • efavirenz-containing regimens -- 3,241 participants
  • efavirenz-free regimens -- 2,091 participants

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:

  • 8% disclosed a history of injecting street drugs
  • 10% had received an antidepressant in the past
  • 32% had a history of mental health and emotional issues or had recently received what doctors called "psychoactive" medicines prior to entering the study. Such medicines would include treatments for anxiety, depression, bipolar illness, psychosis, schizophrenia and difficulty sleeping.

Most participants were monitored for up to three years.

Results

Researchers assessed participants for suicidality, which they defined as any of the following:

  • thoughts of suicide
  • attempted suicide
  • completed suicide

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:

  • efavirenz-containing regimens -- 47 events
  • efavirenz-free regimens -- 15 events

The distribution of attempted suicides was as follows:

  • efavirenz-containing regimens -- 17 events
  • efavirenz-free regimens -- 5 events

The distribution of completed suicides was as follows:

  • efavirenz-containing regimens -- 8 events
  • efavirenz-free regimens -- 1 event

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.

Missing or Misjudged

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.

Additional Risk Factors

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:

  • taking efavirenz
  • having a history of injecting street drugs
  • having a documented history of mental health and severe emotional disorders, including thoughts of or attempts at suicide

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:

  • efavirenz-containing regimens -- 0.5% of participants (16 people)
  • efavirenz-free regimens -- 0.4% of participants (nine people)

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.

Bear in Mind

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:

  • exposure to efavirenz
  • history of injecting street drugs
  • prior to entering the studies analysed, a recent history of using medicines for treating anxiety, depression, bipolar illness or psychosis

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:

  • aggravated or severe depression
  • hallucinations
  • thoughts of suicide
  • attempted suicide
  • outbursts of anger
  • paranoia
  • mania

Other Studies

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.

Strengths and Weaknesses

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.

Recommendations

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:

  • Such patients "should be monitored carefully for [signs or symptoms of worsening] depression or evidence of suicidal thoughts or behaviour."

Furthermore, the editors of the journal The Annals of Internal Medicine, in which the ACTG report was published, made this statement:

  • "An increased risk for suicidality should be considered when choosing efavirenz as part of an initial antiretroviral regimen."

References

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  2. Mollan KR, Smurzynski M, Eron JJ, et al. Association between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data. Annals of Internal Medicine. 2014 Jul 1;161(1):1-10.
  3. Raffi F, Pozniak AL, Wainberg MA. Has the time come to abandon efavirenz for first-line antiretroviral therapy? Journal of Antimicrobial Chemotherapy. 2014 Jul;69(7):1742-7.
  4. Ciccarelli N, Fabbiani M, Di Giambenedetto S, et al. Efavirenz associated with cognitive disorders in otherwise asymptomatic HIV-infected patients. Neurology. 2011 Apr 19;76(16):1403-9.
  5. Nguyen A, Calmy A, Delhumeau C, et al. A randomized crossover study to compare efavirenz and etravirine treatment. AIDS. 2011 Jan 2;25(1):57-63.
  6. Waters L, Fisher M, Winston A, et al. A phase IV, double-blind, multicentre, randomized, placebo-controlled, pilot study to assess the feasibility of switching individuals receiving efavirenz with continuing central nervous system adverse events to etravirine. AIDS. 2011 Jan 2;25(1):65-71.