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Case 7: Discussion

Efavirenz (Sustiva) is a potent nonnucleoside reverse transcriptase inhibitor (NNRTI) frequently used in antiretroviral therapy regimens. With the availability of the triple-drug co-formulated product tenofovir-emtricitabine-efavirenz (Atripla), the use of efavirenz in clinical practice has further increased. The major adverse effects associated with efavirenz use include neuropsychiatric manifestations, skin rash, and teratogenicity. The case study presented here highlights some of the neuropsychiatric issues that may arise in patients taking efavirenz. In clinical practice, the concern for neuropsychiatric adverse effects often plays a role in the decision of whether to include efavirenz as part of an antiretroviral regimen. Unfortunately, conflicting data have confounded clinicians' understanding of the incidence and severity of these neuropsychiatric manifestations. The following discussion will review existing data related to efavirenz-related neuropsychiatric manifestations, with an emphasis on the incidence, spectrum of manifestations, genetic component, and general recommendations for use in patients with known psychiatric disorders. For the other drugs in the in the NNRTI class--delavirdine (Rescriptor), etravirine (Intelence), and nevirapine (Viramune)--neuropsychiatric manifestations are not a major problem.

Spectrum and Incidence of Neuropsychiatric Adverse Effects

The range of reported neuropsychiatric adverse effects associated with efavirenz use is broad and includes dizziness, confusion, impaired concentration, insomnia, abnormal dreams, irritability, restlessness, anxiety, emotional instability, euphoria, post-traumatic stress disorder, obsessive-compulsive behavior, depression, and hallucinations[1,2,3,4,5,6,7,8,9]. The overall incidence of efavirenz-related central nervous system (CNS) toxicity varies widely among studies and depends on the definition of neuropsychiatric manifestations used by the investigators. In one cross-sectional comparative study, investigators reported that 54% of patients chronically taking efavirenz had at least one neuropsychiatric adverse effect in the 4-week period prior to the visit, compared to 27% of patients taking a protease inhibitor[5]. Other studies, however, have not shown significant rates of CNS adverse effect in persons taking efavirenz on a long-term basis[10,11]. Nevertheless, most studies have suggested that efavirenz can cause prominent CNS adverse effects during the first month after starting this medication; these early symptoms frequently include dizziness, headache, mild cognitive difficulty, fatigue, and sleep disturbances (characterized by intense and sometimes disturbing dreams[2]. Fortunately, these early-onset CNS symptoms abate in most patients within one month[10]. In a substudy of the large randomized AIDS Clinical Trials Group (ACTG) 5095 study, patients on an efavirenz-based regimen experienced significantly more neuropsychiatric symptoms than those on a non-efavirenz-containing regimen at week 1, but not at weeks 4, 12, or 24[10]. Results have been conflicting as to whether either short- or long-term CNS adverse effects result in high discontinuation rates[4,5,11].

Efavirenz-Related Psychiatric Manifestations

Although there is a general consensus that efavirenz can cause some CNS adverse effects, the relationship of efavirenz and psychiatric disturbances remains controversial. Studies vary widely on definitions of depression, methods used to detect depression, patient populations, duration of follow-up, and primary study endpoints. In addition, detecting differences in frequency of psychiatric conditions in a high-risk population with high background rates of complex life stressors, substance use, and depression is problematic. Further, several studies have shown high baseline rates of anxiety and depression among HIV-infected individuals[2,12]. Sorting out the contribution of efavirenz can be difficult given that other antiretroviral medications may cause lipodystrophy, sexual dysfunction, and fatigue--all of which may indirectly lead to depression[13]. Nonetheless, post-marketing data and case reports have highlighted the potential for serious psychiatric complications with efavirenz, including depression, psychosis, amnesia, extreme excitability, aggressive behavior, post-traumatic stress disorder symptoms, and suicidal ideation[1,3,14]. In an uncontrolled report involving 174 patients taking efavirenz, a substantial number of these patients reported new psychiatric symptoms, including irritability, agitation, emotional instability, sadness, and suicidal ideation (Figure 1) [2]. Hawkins explored this further by self-report questionnaire and psychological evaluation test of individuals on efavirenz compared to protease inhibitor-based therapy: patients who received efavirenz had higher scores for somatization, anxiety, and obsessive-compulsive disorder during the first six months of therapy[7]. During the second six months of therapy, however, these differences were not statistically different. In a trial that examined protease inhibitor-based therapy versus efavirenz-based therapy (ALIZE-NS 099), French investigators performed a 48-week subset analysis and found the incidence of depressive disorder was comparable between the two arms (8% versus 7% in efavirenz versus protease inhibitor-based therapy, respectively; P =0.56)[12]. In the ACTG A5095 substudy, the only randomized, double-blind, controlled trial that has addressed this issue, investigators examined neuropsychological performance and found no evidence that efavirenz caused an excess of anxiety or depression[10].

Central Nervous System Adverse Effects Related to Efavirenz Levels

Some studies have suggested a strong correlation of CNS adverse effects and levels of efavirenz[6,15], whereas others have shown a relationship only early in the course of efavirenz therapy[10,16] or did not show a correlation at all [5,17]. In a study from Switzerland involving 130 patients, CNS toxicity occurred approximately three times more frequently in patients with high plasma levels of efavirenz (greater than 4.0 ug/mL) compared with those who had lower levels (1.0 to 4.0 ug/ml range) (Figure 2); these authors proposed an optimal range of dosing based on viral suppression and adverse effects (Figure 3)[15]. Similarly, investigators from Spain reported that patients with efavirenz levels greater than 2.74 ug/ml were 5.68 times more likely to experience CNS toxicity than patients with lower levels; in this study, patients took their efavirenz at night, and mid-interval levels were drawn at 9 a.m.[6]. In ACTG 5097, efavirenz levels were analyzed in 154 patients, and higher levels of efavirenz correlated with CNS adverse effects at week 1, but not at week 24[16]. Similarly, in ACTG 5095 the correlation between efavirenz levels and neurologic symptoms occurred at week 1, but not at weeks 4, 12, or 24[10] In a subset of the 2NN study, plasma efavirenz levels did not correlate with CNS side effects[17]. Fumaz and colleagues also found no correlation between efavirenz levels and CNS effects[5].

Genetic Differences and Efavirenz Levels

Higher efavirenz levels may result from genetic differences in metabolism of this drug[16]. Efavirenz is metabolized primarily by the hepatic cytochrome P450 2B6 (CYP2B6) enzyme[18]. Polymorphisms in CYP2B6 resulting from an amino acid substitution at position 516 (G to T substitution) are associated with variable rates of efavirenz metabolism[16] In ACTG 5097 the CYP2B6 T/T genotype, which was more common among African-Americans than European-Americans (Figure 4), was associated with higher efavirenz levels during the first 24 weeks of antiretroviral therapy (Figure 5) and with greater CNS adverse effects during the first week of therapy[16]. In contrast, the EuroSIDA study investigators reported a significantly greater proportion of non-Caucasians than Caucasians who had high efavirenz levels, but these higher levels did not correspond with CNS adverse effects or a risk of stopping efavirenz[19]. Further, a study in the United Kingdom performed genotyping for CYP2B6 516T allele, but found no correlation with this polymorphism and efavirenz discontinuation[20]. In summarizing the available data, non-Caucasians appear to have higher efavirenz levels, but it is not clear that these higher levels result in a higher rate CNS adverse effects or greater efavirenz discontinuation rates.

Risk Factors for Developing Neuropsychiatric Adverse Effects

In a retrospective chart review involving 110 patients, those patients with any history of depression had a significantly greater risk of developing depression while taking efavirenz than those without a history of depression[21]. In this study, 18% of patients with a history of depression discontinued efavirenz (because of treatment-related symptoms of depression) compared with only 2% in those patients without a history of depression. Similarly, in a French study involving self-reports from 327 patients, a history of multiple episodes of depression was associated with a higher rate of discontinuation of therapy[4]. In this same French study, women had a higher rate of developing adverse effects and discontinuing therapy; the authors suggested that gender-specific toxicity might occur because efavirenz dosing is not based on body weight[4]. In one study, patients with opiate injection drug use had an increased incidence of efavirenz-related CNS adverse effects, but this may have resulted from efavirenz-induced reduction of methadone levels and resultant precipitation of opiate withdrawal[22]. Two retrospective studies did not show a correlation between current or past substance abuse and efavirenz-related neuropsychiatric adverse effects[23,24]. In addition, a retrospective analysis of 134 patients found no significant differences in efavirenz discontinuation rates or CNS side effects in subjects who regularly used one or more recreational drugs (cocaine, ecstasy, or marijuana) and those subjects who did not use recreational drugs[24].

Prevention and Management

From a practical clinical standpoint, using prevention strategies to minimize efavirenz-related CNS symptoms can play an important role in the patient's tolerance of an efavirenz-based regimen. Although clear guidelines do not exist regarding prevention and management of efavirenz-related CNS symptoms, we offer the following recommendations:

  • To diminish early CNS adverse effects, such as dizziness, take efavirenz at nighttime. Even with nighttime dosing, some patients will have persistent symptoms, particularly in the morning.
  • Take efavirenz on an empty stomach. Taking efavirenz with food will substantially increase plasma efavirenz levels.
  • Therapeutic drug level monitoring is not routinely recommended.
  • Although no formal recommendations exist regarding use of efavirenz with coexisting psychiatric illness, providers should address any past or current psychiatric issues prior to the patient initiating therapy. In particular, the provider should address any history of depression with suicidal ideation, psychosis, and post-traumatic stress disorder (PTSD), as these disorders may worsen on efavirenz therapy.
  • For individuals with a past or current psychiatric disorder, we recommend obtaining psychiatric consultation prior to initiating therapy with efavirenz.
  • In general, patients with active, uncontrolled psychiatric disorders are not good candidates to receive efavirenz.
  • For individuals taking efavirenz who develop a new psychiatric disorder or a worsening of an underlying psychiatric disorder while on efavirenz therapy, psychiatric consultation is warranted. In this setting, medical providers should consider organic causes of neuropsychiatric symptoms, but in the absence of a clear organic cause, strong consideration should be made to replace efavirenz with an alternative antiretroviral regimen, especially given the number of effective alternatives now available.
  • Individuals with significant neuropsychiatric symptoms that persist after 4 weeks on efavirenz, the clinician should consider switching to a different antiretroviral regimen that does not contain efavirenz. The clinician should base this decision on the severity of efavirenz-related symptoms, the patient's input, and the options available for other antiretroviral regimens. A recently published study described 32 men who switched from efavirenz to etravirine and the switch resulted in significant improvement in grade 2 to 4 central nervous system adverse effects, with no adverse impact on control of HIV RNA levels[25].

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    Figure 1. Neuropsychiatric Adverse Effects Associated with the Use of Efavirenz

    This graph shows results from 174 self-administered questionnaires given to HIV-infected patients in an out-patient setting.  This graph shows a comparison of various neuropsychiatric adverse effects among patients prior to starting efavirenz, during the first month of efavirenz therapy, and at the time of the study.

    Data from: Lochet P, Peyrière H, Lotthé A, Mauboussin JM, Delmas B, Reynes J. Long-term assessment of neuropsychiatric adverse reactions associated with efavirenz. HIV Med. 2003;4:62-6.

    Figure 1
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    Figure 2. Central Nervous System Toxicity Related to Efavirenz Level

    This study involved an analysis of 130 patients on an-efavirenz based antiretroviral regimen.  Blood samples for efavirenz levels were drawn at an average of 14 hours after efavirenz intake.  The bar graph shows the percentage of patients with central nervous system toxicity based on efavirenz levels.  Patients with levels greater than 4.0 ug/ml had an approximately three-fold greater incidence of with central nervous system toxicity than patients with levels in the 1.0-4.0 ug/ml range.

    Data from: Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T.  Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS. 2001;15:71-5.

    Figure 2
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    Figure 3. Central Nervous System Toxicity Related to Efavirenz Levels

    This graph shows a correlation of plasma efavirenz levels and probability of CNS adverse effects.  The probability of viral suppression is shown by the purple line and the central nervous system adverse effects are shown by the blue line.  The data shown as stepped lines represent the observed frequency in predefined concentration ranges and the curved lines represent the fitted regression model. The grey box in the middle represents the optimal efavirenz concentration range of 1000-4,000 ug/l (equivalent to 1-4 ug/ml).

    This figure is reproduced and adapted from: Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T.  Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS. 2001;15:71-5.  Reproduced with permission from Lippincott Williams & Wilkins.

    Figure 3
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    Figure 4. <em>CYP2B6</em> 516 Genetic Polymorphisms by Race

    The genetic polymorphisms were analyzed for 157 patients in ACTG 5097 based on race. The study population included 89 (57%) European-Americans, 50 (32%) African Americans, and 15 (10%) Hispanics. Overall, the G/G (wild type) was the most common genotype. The T/T genotype was more commonly found in African Americans than in European Americans.

    Data from: Haas DW, Ribaudo HJ, Kim RB, et al. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS. 2004;18:2391-400.

    Figure 4
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    Figure 5. Efavirenz Levels According to Polymorphisms in the <em>CYP2B6</em> 516T Genotype

    In ACTG study 5097, efavirenz levels were measure in 154 patients and analyzed based on the patient's CYP2B6 genotype.  The numbers shown in the graph represent median efavirenz area under the curve levels. Overall, patients with the CYP2B6 T/T genotype had significantly higher efavirenz levels than patients with the G/T or G/G genotype (P < 0.0001) for all comparisons.  The correlation of efavirenz levels with CYP2B6 genotype was found with both European Americans (P < 0.0001) and African Americans (P = 0.001).

    Date from: Haas DW, Ribaudo HJ, Kim RB, et al. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS. 2004;18:2391-400.

    Figure 5