Efavirenz

Observational studies

In 77 HIV-positive subjects randomized to switch from protease inhibitors to nevirapine or efavirenz or to continue taking protease inhibitors, quality of life significantly improved among those who switched [ ]. In those who took efavirenz there was an increase in gamma-glutamyl transferase activity and three patients interrupted treatment because of central nervous system symptoms. Eight patients withdrew because of adverse events: rashes (n = 3), dizziness (n = 2), irritability and depression (n = 1), depression (n = 1), or hepatotoxicity (n = 1).

Comparative studies

In an open comparison of efavirenz and indinavir (plus two nucleoside analogues) in predominantly treatment-naive patients efavirenz-based triple therapy provided at least similar antiviral effects over 48 weeks [ ]. Furthermore, fewer patients discontinued efavirenz-based triple therapy than indinavir-based therapy because of adverse events. Adverse effects associated with efavirenz included a maculopapular rash and central nervous system disturbances (dizziness, vivid dreams, poor concentration, sleep disturbances), which generally occurred (but later resolved) within the first weeks of therapy.

Nervous system

In a randomized comparison of an efavirenz-containing regimen and a protease inhibitor-containing regimen, nervous system adverse effects were specifically sought [ ]. Patients were randomized to two NRTIs plus efavirenz (n = 51) or two NRTIs plus one or more protease inhibitors (n = 49). The patients who took efavirenz reported the following at week 4: dizziness (66%), abnormal dreaming (48%), light-headedness (37%), and difficulty in sleeping (35%). At week 24, dizziness (13%), abnormal dreaming (18%), light-headedness (13%), difficulty in sleeping (7%), and nervousness (13%) were significantly less common. Irritability, abnormal dreaming, and nervousness persisted at week 48 in 13%, 10%, and 8% respectively.

An efavirenz-containing HAART regimen was associated with altered dreams or sleep disorders in 14% of patients [ ]. In another study, efavirenz had a modest but persistent impact on the time spent in several key sleep stages [ ].

In 740 patients who took zidovudine + lamivudine + efavirenz, efavirenz was commonly associated with insomnia, vertigo, or nightmares, and less often with severe neuropsychiatric syndromes such as delirium [ ]. In the same study there was one case of febrile rash, two of intolerable pruritus, and one of cytolytic cellulitis attributed to efavirenz.

Insomnia and abnormal dreams are well described adverse effects of efavirenz. There were grade 3 or 4 sleep disturbances in six of 400 patients in the 2NN trial [ ]. Eleven of 287 patients stopped taking efavirenz within 30 days because of these disturbances [ ]. There were sleep abnormalities in 13 of 18 patients taking efavirenz, evaluated using the Pittsburgh Sleep Quality Index. These abnormalities have been explained by disturbances in sleep architecture, since ambulatory encephalographic monitoring showed marked sleep fragmentation [ ].

Mild and clinically tolerable neuropsychiatric disorders can persist after a mean of 2 years after withdrawal of an efavirenz-based therapy [ ].

In a cross-sectional study, 60 patients taking an efavirenz-based approach were compared with 60 patients taking a protease inhibitor-containing regimen for at least 1 year. The mean times on treatment were 91 weeks and 120 weeks respectively. Mild dizziness (22%), sadness (37%), mood changes (27%), irritability (30%), lightheadedness (28%), nervousness (30%), impaired concentration (27%), abnormal dreams (48%), and somnolence (25%) were reported more often with efavirenz than the protease inhibitor. Of 60 patients 49 had plasma concentrations in the target range (1.0–4.0 mg/l). Efavirenz plasma concentrations were similar in subjects with and without neuropsychiatric disorders.

In a retrospective study in 134 patients taking efavirenz there were no significant differences in nervous system adverse effects or discontinuation rates between recreational substance (cocaine, ecstasy, cannabis) users and non-users [ ].

Psychiatric

Neuropsychiatric symptoms provoked by efavirenz have been reviewed [ ]. Of 103 patients who took didanosine, lamivudine, and efavirenz for 48 weeks 19 had neuropsychiatric adverse effects related to efavirenz [ ].

In an evaluation of the effectiveness and adverse effects of a simplification regimen with tenofovir, lamivudine, and efavirenz in 154 HAART-experienced HIV-1–infected subjects with sustained viral suppression nine had psychiatric adverse effects related to efavirenz, leading to drug withdrawal in most cases; the symptoms included nightmares, insomnia, nervousness, and anxiety [ ].

Efavirenz has been associated with psychiatric problems, such as anxiety, depression, and confusion [ ] or relief of symptoms after withdrawal [ ]. In a retrospective study of 1897 patients, dementia and depression were significantly associated with efavirenz compared with other drugs; the respective odds ratios were 4.0 (95% CI = 1.2, 14) and 1.7 (1.0, 3.0) [ ]. However, those who were given efavirenz were perhaps more ill than those who were not, judging by CD4 counts and opportunistic infections.

Most clinicians tend to avoid efavirenz in patients with a psychiatric history. However, it is important to remember that efavirenz can precipitate sudden and severe psychiatric symptoms in patients with no such history. Three patients developed sudden irritability; excitability with anxiety; and insomnia, confusion, and amnesia [ ].

The psychiatric adverse effects of efavirenz correlate with its plasma concentrations. In 130 HIV-infected patients, toxicity was three times more common in patients who had an efavirenz concentration over 4000 ng/ml [ ].

In a retrospective study the overall incidence of neuropsychiatric symptoms of any kind in patients taking an efavirenz-containing regimen was 30%; a previous history of depression was significantly associated with depressive symptoms [ ]. However, in a randomized trial efavirenz was not associated with depression significantly more often than a protease inhibitor-containing regimen [ ].

In a single-center, cross-sectional comparison of patients who had used efavirenz as part of their combination antiretroviral regimen for at least 6 months with a matched cohort who were stable on non-efavirenz combination therapy, those who took efavirenz reported higher degrees of severe stress and anxiety and a higher rate of unusual dreams than patients who were not taking efavirenz [ ].

• A 40-year-old man had a classic manic episode after taking efavirenz for 2 weeks [ ]. He had no previously personal or family psychiatric history. The symptoms completely disappeared 1 month after withdrawal of efavirenz.

• A 40-year-old patient with pre-existing depressive symptoms developed suicidal thoughts and schizophrenia-like first-rank symptoms in within the first month of efavirenz administration and attempted suicide [ ].

In a questionnaire survey of 152 patients who stopped taking efavirenz 82 did so because of neuropsychiatric symptoms; a history of multiple episodes of depression was associated with efavirenz discontinuation [ ].

Metabolism

ACTG study 5095 was a randomized, placebo-controlled, double-blind study designed to compare three protease inhibitor-sparing antiretroviral drug regimens (zidovudine + lamivudine + abacavir; zidovudine + lamivudine + efavirenz; zidovudine + lamivudine + abacavir + efavirenz) in initial treatment of HIV-1 infection in 1147 subjects [ ]. There were modest rises in serum triglycerides, LDL cholesterol, and HDL cholesterol in the two efavirenz-containing arms compared with the triple-nucleoside arm.

In a randomized, double-blind study of 327 patients, cholesterol and triglycerides were raised in patients taking efavirenz, although this did not reach statistical significance [ ].

In a cross-sectional evaluation of 1018 HIV-infected patients treated with HAART during the previous 12 months in an Italian clinic, isolated hypertriglyceridemia was more common in 183 naive patients taking efavirenz compared with nevirapine, and both hypertriglyceridemia and hypercholesterolemia appeared earlier [ ]. In the 295 antiretroviral-experienced patients, in whom an NNRTI was introduced for the first time, the frequency of raised triglyceride concentrations was higher and occurred earlier with efavirenz. In the 145 subjects taking salvage HAART, including an NNRTI plus a protease inhibitor-containing regimen, the rates of hypertriglyceridemia, hypercholesterolemia, and hyperglycemia were greater among patients taking efavirenz compared with nevirapine, and the time to peak metabolic alterations in hypercholesterolemia and hyperglycemia, but not hypertriglyceridemia, were more rapid in the whole efavirenz group. Comparing all of the 324 patients who took efavirenz with the 299 subjects who took nevirapine, the frequencies of raised triglyceride, cholesterol, and glucose concentrations were much higher in those taking efavirenz. There was some grade of lipodystrophy in 207 pretreated patients, but there was appreciable improvement after an NNRTI was introduced in patients taking efavirenz compared with those taking nevirapine.

Nutrition

A man taking efavirenz developed vitamin D deficiency and the authors speculated that this could have been due to CYP450 enzyme induction by efavirenz [ ].

Hematologic

A woman who had previously reacted to nevirapine in form of a rash with angioedema and systemic features, developed an immune-mediated hemolytic anemia [ ].

In a 48-year-old man who developed neutropenia while taking efavirenz, the neutrophil count recovered after withdrawal [ ].