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IDWeek 2013: Does Efavirenz Use Raise the Risk of Suicide Among People with HIV?

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Suicidal thoughts, attempted suicide, and death by suicide were more than twice as common among people with HIV who started treatment with efavirenz, but the overall risk was quite low, according to a combined analysis of 4 ACTG trials with more than 5000 participants presented at the Second IDWeek meeting last week in San Francisco.

Efavirenz (Sustiva or Stocrin, also in the Atripla combination pill) 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 among people taking efavirenz, but its frequency has not been determined. The Sustiva package insert states that suicide, delusions, and psychosis-like behavior have been reported among 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 at Chapel Hill and colleagues designed a study to estimate the incidence of suicidality and compare the time to suicidality among 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 randomized to efavirenz-containing regimens and 2091 assigned to efavirenz-free combinations. Baseline characteristics were similar in the 2 groups. Nearly three-quarters were men and the median age was about 36 years. About 75% were from the U.S.; within this group 39% were white and 36% were black. About 15% had a prior AIDS diagnosis, 8% had a history of injection drug use, one-third had a history of a psychiatric diagnosis or psychiatric medication prescription, and 10% had been prescribed antidepressants.

The 4 trials in the analysis (A5095, A5142, A5175, and A5202) -- 3 of which were open-label -- tested efavirenz in combination with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) including zidovudine (AZT, Retrovir), lamivudine (3TC, Epivir), abacavir (Ziagen), emtricitabine (Emtriva), and/or tenofovir (Viread, or with emtricitabine in Truvada); 1 trial combined efavirenz with lopinavir/ritonavir (Kaletra). Efavirenz-free comparison regimens included 3 NRTIs, or lopinavir/ritonavir or boosted atazanavir (Reyataz) plus 2 NRTIs.

Participants were followed for a median of 150 weeks, or about 3 years. For 2 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 a maximum of 184 weeks.

Results

  • 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 6 months after starting antiretroviral therapy.
  • Among people taking efavirenz, the incidence rose steadily, but there was another jump around 2.5 years; in the efavirenz-free group, suicidality leveled off around 30 weeks, with another increase around 2 years.
  • Leaving out suicidal thoughts or ideation, there were 17 attempted or completed suicides among people randomized to efavirenz-containing regimens, compared with 5 among those taking efavirenz-free combos.
  • Event rates were 2.90 and 1.22 per 1000 person-years, respectively, with 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 2 trials), the total number of attempted or completed suicides reached 27 among efavirenz recipients and 7 among 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: HR 2.15;

o   Younger age: HR 2.80 for age <30 years;

o   History of injection drug use: HR 2.18;

o   Prior psychiatric diagnosis or use of psychiatric medications: HR 3.90, or nearly 4-fold higher risk.

The researchers concluded that initial treatment with an efavirenz-containing regimen was associated with a 2-fold increase in risk of suicidality and about a 2.5-fold higher risk of attempted or completed suicide.

"Suicidality was uncommon, but reported in each study and subgroup evaluated," they added.

They also noted that death from suicide, injury or unknown causes -- which are sometimes combined when reported study findings, especially if numbers are small -- paralleled the results for suicidality, and recommended that "careful attention should be paid to cause of death ascertainment in all clinical trials."

As a 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. Michael Saag from the University of Alabama made a similar observation, adding that efavirenz has worked well for a lot of people for a long time.

10/7/13

Reference

K Mollan, M Smurzynski, L Na, et al. Hazard of suicidality in patients randomly assigned to efavirenz for initial treatment of HIV-1: a cross-study analysis conducted by the AIDS Clinical Trials Group (ACTG). 2nd ID Week Conference (IDWeek 2013). San Francisco. October 2-6, 2013. Abstract 670.