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Efavirenz Linked to Higher Suicide Risk, May Be Falling Out of Favor

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The widely used NNRTI efavirenz was associated with a 2-fold increase in the likelihood of suicidal thoughts, attempted suicides, and suicide deaths, though the absolute risk remained small, according to a study described in the July 1 Annals of Internal Medicine. A related review article questioned whether efavirenz should still be considered a preferred option for initial HIV treatment, given its side effects and the development of equally effective and better-tolerated alternatives.

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 Center for Biostatistics in AIDS Research at Harvard School of Public Health and colleagues compared suicidal thoughts, attempts, and completed suicides among people taking efavirenz-containing versus efavirenz-free antiretroviral therapy (ART) regimens for initial HIV treatment. Findings were previously presented in part at the 2013 IDWeek conference in San Francisco.

This retrospectiveanalysis included 3241 treatment-naive adults with HIVwho were randomly assigned to efavirenz-containing regimens, and 2091 people assigned to efavirenz-free combinationsin AIDS Clinical Trials Group (ACTG) studies conducted between 2001 and 2010.

The 4 trials in the analysis (A5095, A5142, A5175, and A5202) tested efavirenz in combination with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) including zidovudine (AZT or Retrovir), lamivudine (3TC or 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.

Baseline characteristics were similar in the groups that took and did not take efavirenz. Nearly three-quarters were men and the median age was 37 years. About 75% were from the U.S., and within this group similar proportions were white (39%) and black (36%). About 15% had a prior AIDS diagnosis, 8% had a history of injection drug use, and one-third had a history of a psychiatric diagnosis or had used psychiatric medications within the past month.

Participants were followed for a median of 96 weeks. Suicidality was defined as a composite of suicidal ideation or thoughts, suicide attempts, and completed suicides.

Results

  • There were 47 total suicidality events in the efavirenz-containing arms compared with 15 in the efavirenz-free arms.
  • Suicidality event rates were 8.08 vs 3.66 per 1000 person-years, respectively, in an intent-to-treat analysis, with a hazard ratio (HR) of 2.28 -- slightly more than twice the risk.
  • There were 17 attempted or completed suicides in the efavirenz-containing arms and 5 in the efavirenz-free arms.
  • Attempted or completed suicide rates were 2.90 vs 1.22 per 1000 person-years, respectively, with a HR of 2.58.
  • There were 8 completed suicides in the efavirenz-containingarms compared with just 1 in the efavirenz-free arms -- that is, 8 of the 9 total suicides were people taking efavirenz.
  • In a broader secondary analysis that also included deaths attributed to substance abuse, homicide, accidents, or unknown causes -- which actually could have been suicides -- incidence rates were 9.28 vs 4.64 per 1000 person-years, with a HR of 2.06.
  • Time to suicidality was shorter in the efavirenz arms, while time to non-suicide deaths did not differ significantly between groups.
  • In both the efavirenz and placebo groups the incidence of suicidality rose most steeply within the first 24 months after starting antiretroviral therapy, and the excess risk in the efavirenz-containing arms was greater during this period (HR 3.69).
  • Factors significantly associated with suicidality in a multivariate analysis included:

o   Use of efavirenz: HR 2.08;

o   History of injection drug use: HR 2.26;

o   Psychiatric diagnosis or use of psychiatric medications: HR 4.07.

Initial treatment with an efavirenz-containing antiretroviral regimen was associated with a 2-fold increased hazard of suicidality compared with a regimen without efavirenz," the study authors concluded. "When efavirenz is used as a component of antiretroviral therapy, patients should be monitored carefully for exacerbation of depression or evidence of suicidal thoughts or behavior."

Limitations of this study include the fact that the trials were not designed to look at suicide, they did not use a standardized questionnaire about suicidality or depression, 3 of the trials in the analysis were open-label (meaning patients and researchers knew what drugs were used), and people with a psychiatric history might have been selectively excluded from efavirenz trials due to concerns about potential adverse events.

Time to Abandon Efavirenz?

In a related review in the July 2014 Journal of Antimicrobial ChemotherapyFrancois Raffi of Nantes University Hospital in France, Anton Pozniak of Chelsea and Westminster Hospital in London, and Mark Wainberg of McGill University in Montreal asked whether the time has come to abandon efavirenz for first-line antiretroviral therapy.

Efavirenz, and the efavirenz-containing Atripla single-tablet regimen, are preferred initial treatment options in U.S., European, and World Health Organization global HIV guidelines.

However, the authors argue, "because of (i) adverse events associated with efavirenz, (ii) a poorer overall efficacy of efavirenz compared with newer antiretrovirals, (iii) the ranking of efavirenz as FDA Pregnancy Category D [evidence of human fetal risk] and (iv) the relatively high prevalence of transmitted drug-resistance mutations, there is a need to reconsider the role of efavirenz in first-line ART."

They included in their evidence the increased risk of suicidality associated with efavirenz as compared with other antiretroviral drugs. Looking at effectiveness, they noted that "efavirenz has demonstrated overall inferior efficacy to various comparator drugs" for treatment-naive patients, including rilpivirine (Edurant, also in the Complera coformulation) and the HIV integrase inhibitors raltegravir (Isentress) and dolutegravir (Tivicay).

"Based on considerations of efficacy, toxicity and resistance, it is time to reconsider the routine use of efavirenz in ART," the authors concluded. "This, of course, presupposes that other antiretrovirals will be available in place of efavirenz, and may not be applicable in certain developing country settings where this is not the case."

"We acknowledge that cost, availability and acceptability are issues that drive much antiretroviral use, but we should continually re-evaluate what we recommend and challenge current paradigms," they elaborated. "Treatment advances have now resulted in safer and even superior alternatives to efavirenz...In order for the success of ART to become a reality in all countries, we need always to use the safest and most effective antiretroviral combinations."

Yet everyone is not convinced that time is running out for efavirenz, and some are concerned about the timing of calls to abandon it.

After Mollan presented her team's suicidality findings at IDWeek last year, long-time HIV physician Joel Gallant from the Southwest Care Center observed that more reports about neuropsychiatric side effects and suicide related to efavirenz are coming out just 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 at Birmingham made a similar observation, adding that efavirenz has worked well for a lot of people for a long time.

7/3/14

References

KR Mollan, M Smurzynski, JJ Eron, 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 161(1):1-10. July 1, 2014.

F Raffi, AL Pozniak, and MA Wainberg. Has the Time Come to Abandon Efavirenz for First-line Antiretroviral Therapy? Journal of Antimicrobial Chemotherapy 69(7):1742-1747. July 2014.