Efavirenz Updates: Bone Mineral Density & Suicidality

Efavirenz and Bone Mineral Density

Persons with HIV infection have a number of risk factors for decreased bone mineral density (BMD), related not just to effects of HIV or resulting illness but also to ART. For example, BMD decreases by as much as 5-6% after initiation of ART, and certain ARVs (eg, tenofovir, protease inhibitors) cause greater losses over time than do others. It also is becoming clearer that vitamin D deficiency or insufficiency is common among HIV-infected persons, and that efavirenz can further lower levels of vitamin D.

A recent study evaluated the effects of vitamin D + calcium supplementation on bone metabolism in ARV-naive patients who were starting efavirenz/tenofovir/emtricitabine (Atripla). ACTG 5290 randomized 165 patients to receive vitamin D 4,000 IU daily + calcium 1,000 mg daily or to placebo. Subjects had 25-OH D levels ranging from 10 ng/mL to <75 ng/mL. They were relatively well matched for baseline criteria including age (36 and 31 in the two groups, respectively) race, BMI, HIV RNA, CD4 count, and estimated daily dietary vitamin D and calcium intake.

After 48 weeks, BMD decreased 50% less in the vitamin D + calcium group than in the placebo group:

  • Total hip-to-waist ratio: 1.46% vs 3.19%; p < .001
  • Lumbar spine: 1.41% vs 2.91%; p = .085

The 25-OH D levels rose significantly in the supplemented group but did not rise in the placebo group (p < .001 for difference between groups).

Echoing the BMD results, elevations in markers of bone turnover and parathyroid were attenuated in the vitamin D + calcium group (though there were no significant differences in changes in inflammatory markers).

Clinical Bottom Line

Importantly, this small study showed that supplementation with vitamin D + calcium attenuates bone loss in patients initiating EFV/TDF/FTC. Left unanswered by this study are many questions, including whether lower dosages of vitamin D would be effective, whether patients with normal vitamin D levels would benefit, whether supplementation would be effective in persons on different ARV regimens, and how long vitamin D should be continued; these questions merit further study.


  • Overton ET, Chan ES, Brown TT, et al. High-dose vitamin D and calcium attenuates bone loss with ART initiation: results from ACTG A5280. In: Programs and abstracts of the 2014 Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston. Abstract 133.

Efavirenz and Suicidality

Efavirenz (EFV) commonly causes neuropsychiatric adverse effects in the early days and weeks after initiation, though these generally are mild to moderate in intensity and lessen with time. Many clinicians have been cautious about prescribing EFV for patients with serious psychiatric conditions, though serious adverse effects in these patients have not been well studied. A new analysis of suicidality among patients taking EFV helps characterize the risk of suicidality in persons on EFV-based regimens.

This is a combined analysis of data from 4 ACTG studies of initial treatment that included an EFV-containing arm (A5095, A5142, A5175, and A5202). 3241patients were randomized to regimens containing EFV (n = 3,241) or regimens without EFV (n = 2,091). The individual studies had somewhat different eligibility criteria (including differences in screening for suicidality) but the two groups were quite well matched at baseline for most factors including depression and use of antidepressant medications. Median follow-up was 96 weeks.

The main findings of the study are:

  • The incidence of suicidality, defined as suicidal ideation or attempted or completed suicide, was about twice as high in EFV-treated groups, and this held true in a variety of sensitivity analyses (other causes of death were present at essentially the same rate in the EFV and no-EFV groups).
  • Suicidality incidence (per 1,000 person-years): 8.08 in the EFV group, 3.66 in the no-EFV group (hazard ratio [HR]: 2.28, 95% confidence interval [CI]: 1.27 to 4.10; p = .006).
  • Attempted or completed suicide: 2.90 vs 1.22 in EFV and no-EFV groups, respectively (HR: 2.58, CI: 0.94 to 7.06; p = .065).
  • Completed suicides: 8 in the EFV group, 1 in the no-EFV group.
  • Other factors for increased hazard of suicidality were history of injection drug use (IDU), documented psychiatric history or recent psychoactive medication IDU, young age (on multivariate analysis).

Clinical Bottom Line

Although this study comes with several important limitations, including the facts that there was no standardized screening for suicidality and that some of the constituent studies were open label, its findings offer an important and sobering caution. It is important to screen carefully for risk of suicidality before prescribing EFV and to monitor regularly during treatment with EFV. This is particularly true for patients who have other risk factors for depression or suicidality.


  • 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. Ann Intern Med. 2014 Jul 1;161(1):1-10.