To the Editor:
Efavirenz (EFV), a nonnucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1, is associated with neuropsychiatric central nervous system side effects not always seen with other members of the NNRTI class. Although the mechanism of action responsible for these side effects has not been elucidated, EFV has a 60% homology with antidepressants, with autonomic and cognitive adverse events.1,2 The neuropsychiatric side effects secondary to EFV include dizziness, confusion, stupor, impaired concentration, amnesia, hallucinations, abnormal dreams, and insomnia.3 Most of the EFV-related neuropsychiatric side effects occur within the first several days of treatment and tend to resolve within the first 6 to 10 weeks of therapy; however, they may be serious and can include anxiety, depression, and suicidal ideation.4,5 We were particularly interested in evaluating neuropsychiatric side effects in patients able to tolerate an EFV-containing regimen for more than 4 weeks while still experiencing neuropsychological side effects. By identifying an association between depression history and neuropsychological symptoms, we hoped to better predict the development and progression of long-term EFV-related neuropsychiatric side effects, which could negatively affect treatment adherence.6,7
Of all patients in the clinic over the set period, medical records of 110 eligible patients receiving EFV-based therapy from 6 participating private HIV practices in the San Francisco Bay area were reviewed to examine the number of neuropsychiatric side effects and the number of patients discontinuing EFV because of these effects. Baseline demographics, CD4+ cell counts, and viral loads were recorded along with concurrent medications. Patients with documented or suspected use of cocaine, methamphetamines, ecstasy, ketamine, γ-hydroxybutyrate, or heroin were excluded from this statistical analysis. Patients not receiving EFV-based antiretroviral therapy (ART) for more than 4 weeks were also excluded. A history of depression was defined as one or a combination of the following factors diagnosed and resolved more than 6 months before starting an EFV-containing regimen: (a) patient history of depressive symptoms, (b) patient under the care of a psychiatrist/therapist, and (c) patient under antidepressive treatment. The length of time the patient remained on EFV before discontinuation was noted, as was the viral load and CD4+ count at the time of drug discontinuation. Current depression was defined as documented depression in the patient's chart within 6 months of starting EFV. Charts were further examined to identify the occurrence and magnitude of EFV-related depressive symptoms during EFV treatment. Using a specialized evaluation questionnaire as per the Sustiva (Bristol-Myers Squibb, New York, NY) package insert, developed to standardize data collection, EFV-related neuropsychiatric symptoms were graded on a scale of 1 to 5 by frequency of occurrence: grade 1, never experienced; grade 2, rarely (0-1 day a week); grade 3, sometimes (2-4 days a week); grade 4, very often (4-5 days a week); and grade 5, most of the time (6-7 days a week).
For the primary analysis, the number of discontinuations for each group was tabulated, and a relative risk (RR) and 95% confidence interval for the odds ratio were calculated. The P value for the difference between odds ratio was then determined. For the secondary depression subcategory analysis, median scores for each of the previously defined groups were calculated, with the difference in the median values assessed by a Wilcoxon rank sum test.
The charts of 110 patients were screened. Most of the patients were men having sex with men (99%), with a median age of 43 years. All statistical analyses were performed on 101 remaining patients unless otherwise stated. The median baseline CD4+ count was 336 cells/mm3, and the median viral load was 25,000 copies/mL, both with wide ranges. Fifty patients (50%) had a history of depression; of these, 56% were currently depressed. History of depression was further divided into subcategories: reported by patient (n = 5), depression requiring medication (n = 30), and depression requiring psychotherapy (n = 19). Four patients reported depression requiring both medication and psychotherapy in the past; one discontinued EFV-based ART. Relative risk for current depression was significantly higher for patients with any history of depression than for patients without such a history (RR, 31.2; 95% CI, 6.81-142.6, P < 0.0001). Eighteen percent of patients with a history of depression discontinued EFV because of treatment-related symptoms of depression (RR, 11; 95% CI, 1.3-90.2, P = 0.0079), whereas only 2% of patients who did not have a history of depression at any time discontinued EFV (RR, 10.0, 95% CI, 1.2-82.6, P = 0.016). All patients with a history of depression and/or current depression developed at least one subcategory depressive symptom of grade 2 severity or higher. All depression subcategories associated with EFV, excluding the "unintentional weight loss of more than 5%" subcategory and the "suicidal ideation/attempt" subcategory, were statistically significantly higher (P ≤ 0.0009) in patients with a history of depression than in patients without such a history.
Our study revealed an overall incidence of neuropsychiatric symptoms of any kind while on an EFV-containing regimen of 30%, with a 10% discontinuation rate due to EFV-associated neuropsychiatric side effects at or after 4 weeks of treatment. Disparity exists between registration/investigational studies and clinical studies performed within primary HIV practices. It has been suggested that in "real world" settings, there is a much greater likelihood that these symptoms will occur because of unrecognized additional pressures, patient risk-taking, and comorbidities that could negatively affect a patient's outcome.8
Discontinuation of therapy did not appear to be related to virological failure, as ∼40% of the patients discontinuing EFV therapy after 4 weeks continued to have viral loads more than 50 copies/mL. If these results are confirmed, this component of treatment failure could potentially be anticipated and adjusted for. Our results tend to support the complex nature of "treatment success" and show clearly that one can continue to "succeed" virologically while "failing" in some other necessary requirement of ART. It should be noted that the use of alcohol and marijuana was high in our study, but no association was found between their use and the incidence of depression or treatment discontinuation. The prevalence of other documented recreational drug use was too low to allow analysis of any potential associations.
If depressive symptoms cannot be tolerated by the patient or ameliorated by psychotherapy, alteration of the ART regimen may be warranted. Other NNRTIs such as nevirapine and protease inhibitors such as lopinavir/ritonavir have not been associated with neuropsychiatric effects of the same severity as those seen with EFV and yet have been shown to have comparable efficacy.9,10
Limitations of this study include the fact that this was a retrospective chart review, and diagnosing past depression based on chart documentation may either overestimate or underestimate rates of depression. Moreover, it failed to clarify specific diagnoses, such as major depression versus bipolar depression versus dysthymia, etc, and men having sex with men was the only subpopulation well represented in this sample. Future research that controls for other variables and has a comparison group of patients not taking EFV would help establish whether EFV is the direct cause of new depressive symptoms.
Shared Perspectives on Therapies
San Francisco, CA
The authors gratefully acknowledge the editorial assistance of Michael Craig and Benedetta Granelli.
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