thoughts, attempted suicide and death by suicide were more than twice as common
amongst people with HIV who started treatment with efavirenz (Sustiva or Stocrin, also in the combination pill Atripla), but the overall risk was quite low, according to a
combined analysis of four ACTG trials presented on Friday at the IDWeek 2013
meeting in San Francisco.
has a well-known association with central nervous system side-effects that may
include abnormal dreams, depression and anxiety. Several studies have reported
cases of suicide amongst people taking efavirenz, but its frequency has not
been determined. The Sustiva package insert states that suicide, delusions and
psychosis-like behaviour have been reported amongst people taking the drug but
"a causal relationship to the use of Sustiva
cannot be determined from these reports".
Katie Mollan from the University of North
Carolina and colleagues designed a study to estimate the incidence of
'suicidality' and compare the time to suicidality amongst treatment-naive adults
with HIV who were randomly assigned to receive efavirenz-containing or
efavirenz-free regimens in AIDS
Clinical Trials Group (ACTG) studies conducted between 2001 and 2010. Suicidality was defined as a composite of
suicidal thoughts (ideation), attempts or completed suicides.
This retrospective analysis
included 3241 study participants randomised to efavirenz-containing regimens
and 2091 assigned to efavirenz-free combinations. Baseline characteristics
were similar in the two groups. Nearly three-quarters were men and the median
age was about 36 years. About 75% were from the US; within this group, 39% were
white and 36% were black. About 15% had a prior AIDS diagnosis, 8% had a
history of injecting drug use, one-third had a history of a psychiatric
diagnosis or psychiatric prescription, and 10% had been prescribed
The four trials in the
analysis (A5095, A5142, A5175 and A5202) – three of which were open-label – tested
efavirenz in combination with nucleoside/nucleotide reverse transcriptase inhibitors
(NRTIs) including AZT (zidovudine, Retrovir),
3TC (lamivudine, Epivir), abacavir (Ziagen), emtricitabine (Emtriva) and/or tenofovir
(Viread, or with emtricitabine in Truvada); one trial combined efavirenz
with lopinavir/ritonavir (Kaletra). Efavirenz-free
comparison regimens included three NRTIs or lopinavir/ritonavir or boosted
atazanavir (Reyataz) plus two NRTIs.
Participants were followed
for a median of 150 weeks, or about three years. For two trials, the primary
analysis included results up until data safety and monitoring boards
recommended stopping the efavirenz-free arms due to inferior efficacy;
efavirenz recipients continued treatment and follow-up through to a maximum of 184
A total of 47 suicidality
events occurred in the efavirenz-containing arms, compared with 15 in the
efavirenz-free arms, during the comparison period, for event rates of 8.08 and
3.66 per 1000 person-years, respectively. The hazard ratio (HR) for
suicidality was 2.28 – or more than twice the risk – in an intent-to-treat
analysis and the difference was statistically significant. An as-treated
analysis showed a similar pattern with a hazard ratio of 2.16.
In both groups, the incidence
of suicidality rose most steeply within the first six months after starting
antiretroviral therapy. Amongst people taking efavirenz, the incidence rose
steadily, with another jump at around two and a half years. In the efavirenz-free
group, suicidality levelled off around 30 weeks, with another increase at around
Leaving out suicidal
thoughts or ideation, there were 17 attempted or completed suicides amongst
people randomised to efavirenz-containing regimens, compared with five amongst
those taking efavirenz-free combinations. This gave hazard ratios of 2.58 for the intent-to-treat
analysis and 2.30 for the as-treated analysis.
Looking beyond the primary
comparison period, after the efavirenz-free arms were halted in two trials, the
total number of attempted or completed suicides reached 27 amongst efavirenz
recipients and seven amongst those previously in the efavirenz-free arms, for a
hazard ratio of 2.60.
Factors significantly associated with suicidality in a
multivariate analysis included use of efavirenz, younger age (HR 2.80 for age <30) and history of injecting drug use (HR 2.18). But the biggest risk
factor was prior psychiatric diagnosis or use of psychiatric medications, with
a hazard ratio of 3.90 – a nearly four-fold higher risk.
researchers concluded that initial treatment with an efavirenz-containing regimen
was associated with a two-fold increase in risk of suicidality and about a 2.5-fold higher
risk of attempted or completed suicide.
was uncommon, but reported in each study and subgroup evaluated," they
also noted that death from suicide, injury or unknown causes – which are
sometimes combined when reporting study findings – paralleled the results for
suicidality, and recommended that "careful attention should be paid to
cause of death ascertainment in all clinical trials".
cautionary note, Joel Gallant from the Southwest Care Center observed that more
reports about neuropsychiatric side-effects and suicide related to efavirenz
are now coming out as the drug is about to go off patent. "Just at the
time it becomes generic, people are finding a lot of reasons why we shouldn't
use it," he said.