1. Neurologic Effects Associated With Efavirenz Generally Mild, Transient Slideset on: Clifford DB, Evans S, Yang Y, et al. Impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals. Ann Intern Med. 2005;143:714-721.

2. clinicaloptions.com/hiv Neurologic Effects Associated With Efavirenz Generally Mild, Transient Clifford DB, et al. Ann Intern Med. 2005;143:714-721. Background and Rationale  Efavirenz “preferred” NNRTI for first-line treatment of HIV-1 according to US Department of Health and Human Services guidelines  Potent; well-tolerated; once-daily administration  Neurologic toxicity most common adverse event –Open-label studies found > 50% of efavirenz-treated persons reported such symptoms  Current study characterized neurologic symptoms associated with and without efavirenz in antiretroviral- naive patients initiating therapy

3. clinicaloptions.com/hiv Neurologic Effects Associated With Efavirenz Generally Mild, Transient Clifford DB, et al. Ann Intern Med. 2005;143:714-721. Treatment-naive patients with HIV-1 RNA > 400 copies/mL (N = 303) Efavirenz-containing regimen (n = 200) Nonefavirenz-containing regimen (n = 103) Week 1Week 4Week 12 Week 24 Summary of Study Design Neuropsychometric assessments, blood samples taken to determine efavirenz trough concentrations in plasma

4. clinicaloptions.com/hiv Neurologic Effects Associated With Efavirenz Generally Mild, Transient Clifford DB, et al. Ann Intern Med. 2005;143:714-721. Baseline Characteristics Characteristic Efavirenz-Containing Regimen (n = 200) Non-Efavirenz-Containing Regimen (n = 103) Median age, yrs3738 Male, n (%)164 (82)82 (80) Median NPZ3 score, value (IQR) -0.09 (-0.82 to 0.56) (n = 196) -0.03 (-0.91 to 0.42) Median depression score, value (IQR) 12 (5-21) (n = 197) 12 (4-21) Median anxiety score, value (IQR) 54 (42-64) (n = 199) 56 (47-64) (n = 102) Median sleep status score, value (IQR) 6 (4-9)* (n = 189) 5 (3-9) (n = 101) Median efavirenz symptom score, value (IQR) 8 (3-16) (n = 199) 6 (3-12) (n = 102) IQR, interquartile range; NPZ3, summary neuropsychological Z score *P =.048 vs non-efavirenz arm

5. clinicaloptions.com/hiv Neurologic Effects Associated With Efavirenz Generally Mild, Transient Clifford DB, et al. Ann Intern Med. 2005;143:714-721.  Median NPZ3 scores improved in both groups; greatest during first treatment week –Neuropsychological performance changes not significantly different between groups at any time point –Small negative correlation between efavirenz plasma levels, neuropsychological performance at Weeks 4 (  = -.31; P =.002) and 12 (  = -.28; P =.012)  Comparable or mixed results for other neuropsychological assessments Changes in Neuropsychological Performance

6. clinicaloptions.com/hiv Neurologic Effects Associated With Efavirenz Generally Mild, Transient Clifford DB, et al. Ann Intern Med. 2005;143:714-721. Other Outcomes  Efavirenz symptom questionnaire changes greater for patients receiving efavirenz only at Week 1 (P <.001)  Minor changes in sleep quality scores for both groups  Greater changes in bad dream score with efavirenz only at Week 1 (P =.038)  > 80% of patients in both groups experienced clinically significant anxiety at baseline, during study  Depressive symptoms comparable between groups  More CNS/mood-related treatment modifications with efavirenz (6% vs 0%; P =.01)

7. clinicaloptions.com/hiv Neurologic Effects Associated With Efavirenz Generally Mild, Transient Clifford DB, et al. Ann Intern Med. 2005;143:714-721. Key Conclusions  Efavirenz-containing regimens associated with transient neurologic symptoms early in treatment, typically resolved within first 4 weeks –Correlation between efavirenz-associated symptoms and efavirenz trough plasma concentration significant only at Week 1 –Significant report of bad dreams at Week 1; effect did not persist  Neuropsychological performance improved similarly for patients on regimens with and without efavirenz  No observed efavirenz effect on anxiety or depression