1. Switch NNRTI to NNRTI  Switch EFV to ETR –CNS toxicity study –Patient’s preference study

2. Switch EFV to ETR: CNS toxicity ETR 400 mg QD + 2 NRTI 24 weeks 48 weeks Primary Endpoint Secondary Endpoint N = 20 N = 18 EFV 600 mg QD + 2 NRTI ETR + 2 NRTI  Design Randomisation 1: 1 Double blind 12 weeks Primary Endpoint 24 weeks Secondary Endpoint  Objective –Primary Endpoint: change in proportion of patients experiencing grade 2-4 CNS toxicity at W12 –Secondary endpoints: change in CNS score at W12 and W24; combined change (immediate and delayed switch) 12 weeks after switch; median number of grade 2-4 CNS adverse events; viral suppression ; CD4 change; fasting lipids; safety SWITCH EFV/ETR Open-label phase 38 HIV+ adults Stable EFV+ 2 NRTI ≥ 12 weeks EFV-related CNS symptoms HIV RNA < 50 c/mL CD4 > 50/mm 3 No prior ETR or RPV exposure Waters L, AIDS 2011;25:65-71 W12W24

3. Baseline characteristics and disposition * Frequency of individual events similar in both groups except for insomnia (75% vs 39%, p = 0.024)  Median duration of EFV exposure: 21.4 months Switch EFV to ETR: CNS toxicity SWITCH EFV/ETR Immediate switch N = 20 Delayed switch N = 18 Grade 2-4 CNS AE*18 (90%)16 (89%) CNS score1410 NRTI backbone TDF/FTC60%61% Atripla50% ABC/3TC35%22% ABC/TDF5%11% TDF/3TC06% Completed follow-up1913 Waters L, AIDS 2011;25:65-71

4.  Primary endpoint –Grade 2-4 CNS AE at W12: 60% in immediate switch vs 81.3% in deferred switch (significant decrease in immediate switch; p = 0.041) –Abnormal dreams decrease from 50% to 20% in IS group (p = 0.041) vs no change in DS : 67% to 63% –Median number of grade 2-4 CNS AE IS: 4 at baseline vs 1.5 at W12 (p = 0.003) DS: 3 at baseline vs 3 at W12 –CNS score: IS = change from 14 to 6 (p = 0.001); DS = 10 to 7.5 (NS)  Change from W12 to W24 –No further significant change in immediate switch group –Significant improvement in deferred group  Other results –No virologic failure –Improvement in lipids after switch to ETR –Grade 2 AE deemed related to ETR: fatigue, headache, reduced libido Switch EFV to ETR: CNS toxicity SWITCH EFV/ETR Waters L, AIDS 2011;25:65-71

5.  Conclusion –Switching EFV to ETR led to a significant reduction in overall grade 2-4 CNS adverse events, including insomnia, abnormal dreams and nervousness as individual adverse event –No virological failures occurred in the 19 and 15 patients completing 24 and 12 weeks of once-daily ETR-based HAART –Improvement in lipids with significant reductions in total and LDL-cholesterol after 12 weeks of ETR – Proactive switch away from EFV may yield significant reductions in CNS toxicity Switch EFV to ETR: CNS toxicity SWITCH EFV/ETR Waters L, AIDS 2011;25:65-71