Participants in the START treatment-timing trial who took antiretroviral
regimens containing efavirenz had an increased risk of suicidal and
self-injuring behaviour than those not using efavirenz, though the number of
events was small and the effect was mainly seen among people with a prior
psychiatric diagnosis, according to research presented at
the 21st International AIDS Conference
(AIDS 2016) last month in
Durban, South Africa.
Efavirenz (Sustiva or Stocrin, also in the Atripla combination pill) has been one
of the most widely used antiretrovirals, but it has fallen out of favour due to
its well-known association with central nervous system side-effects such as
dizziness and unusual dreams. Studies of the link between efavirenz and suicide
have produced conflicting findings. The Sustiva package insert states that suicide, delusions and
psychosis-like behaviour have been reported among people taking the drug, but
"a causal relationship to the use of Sustiva cannot be determined from
Alejandro Arenas-Pinto of
University College London and colleagues compared the likelihood of suicidal behaviour among people taking
efavirenz-containing and efavirenz-free antiretroviral
in the START trial.
Briefly, START was designed to evaluate the optimal timing of
HIV treatment. A total of 4685 previously untreated participants entered the
trial with CD4 T-cell counts above 500 cells/mm3 and were
randomly assigned to either start ART immediately or delay treatment until
their CD4 count fell below 350 cells/mm3 or they
developed HIV-related symptoms. START investigators reported last year that people randomised to receive immediate ART had a 57% lower risk of AIDS events, serious non-AIDS
events or death.
The START team previously reported that there were 27
cases of suicidal or self-harming behaviour in the immediate ART arm and 24 in
the deferred treatment arm – not a significant difference. But what about according
to ART regimen?
ART regimens in START were pre-specified before
randomisation. Three-quarters of participants (3516) were pre-specified to use
efavirenz-containing regimens, while 1169 used efavirenz-free combinations.
These groups were generally similar at baseline. About
three-quarters were men, the median age was 36 years and the median CD4 count
was approximately 650 cells/mm3. However, people in low- and
middle-income countries were more likely to use efavirenz than those in
high-income countries, and people with a prior psychiatric diagnosis, use of
psychiatric drugs or recreational drug use were more likely to take efavirenz-free
regimens. A total of 270 participants (5.8%) had prior psychiatric diagnoses and 316 used
psychiatric drugs such as antidepressants or antipsychotics.
Events defined as suicidal behaviour, based on the
Medical Dictionary for Regulatory Activities, included suicidal ideation (10 in
the immediate and 6 in the deferred arm), suicide attempts (17 and 13,
respectively), completed suicides (0 and 3), self-injurious ideation (0 and 1)
and intentional self-injury (0 and 1).
In the efavirenz-containing ART group there were 18
such events in the immediate treatment arm and 11 in the deferred arm, for a
hazard ratio (HR) of 1.42. In the efavirenz-free group there were 9 events in
the immediate arm and 13 in the deferred arm, for an HR of 0.74; these
differences did not reach statistical significance.
Regardless of regimen, suicidal events were more
common among people with a prior psychiatric diagnosis. In the
efavirenz-containing group, looking at immediate and deferred arms combined, 7
events occurred among people with a prior diagnosis (2.0 per 100
person-years) and 22 (0.2 per 100 PY) among people without a diagnosis. In the
efavirenz-free group there were 8 (1.7 per 100 PY) among people with and 14
(0.5 per 100 PY) among people without a prior diagnosis. Taken together,
overall suicidal event rates were 0.28 per 100 PY for the efavirenz-containing
group compared to 0.63 per 100 PY in the efavirenz-free group.
the lower overall rate could be due to the fact that people with
psychiatric conditions were more likely to avoid efavirenz. The researchers
noted that the rate of suicidal events was higher for efavirenz-treated participants
in the immediate versus deferred arm. In the efavirenz group these events
mostly occurred within the first year after starting ART, whereas in the
efavirenz-free group events occurred with similar frequency before and after
In a multivariate analysis, factors significantly
associated with suicidal or self-harming behaviour were older age (HR 0.52;
p = 0.02), recreational drug use (HR 2.9; 0.04) and heavy alcohol use (HR 6.1;
p = 0.003). But the biggest risk factor was a prior psychiatric diagnosis, which
raised the likelihood by 13-fold (HR12.8; p < 0.001).
"In the START trial,
participants using efavirenz in the immediate ART group had an increased risk
of suicidal behaviour compared to their ART-naive controls," the
researchers concluded. "The impact of efavirenz exposure was particularly
high in those with a prior psychiatric diagnosis."
Based on these findings, Arena-Pinto said screening
for pre-existing psychiatric conditions including depression is
"advisable" before starting efavirenz-containing ART.