The impact of switching to etravirine on efavirenz-related CNS toxicity.

Laura Waters1, Martin Fisher2, Alan Winston3, Chris Higgs1, Wendy Hadley2, Lucy Garvey3, Sundhiya Mandalia1, Nicky Perry2, Nicola Mackie3 & Mark Nelson1.

1) Chelsea & Westminster Hospital, London; 2) Royal Sussex County Hospital, Brighton; 3) St Mary’s Hospital, London

• 2 NRTI + • ETR 400mg OD• + EFV-placebo

• 2 NRTI +• EFV 600mg OD• + ETR-placebo

• 2 NRTI + EFV • (at least 12 weeks)

• 2 NRTI + • ETR 400mg OD

• 2 NRTI + • ETR 400mg OD

• Blinded Phase:• Baseline to Week 12

• Open-label Phase:• Week 12 to Week 24

• 1:1 randomisation

•38 males, 37 Caucasian, median age 43 years•Median prior EFV exposure 21.4 months•Baseline NRTI: TDF/FTC 58%, ABC/3TC 29%, other 13%•Median baseline CD4 468; 100% HIV-RNA <50 copies/ml•20 randomised to immediate switch (IS) 18 to delayed switch (DS)•Baseline CNS AE similar:

• 90% IS and 88.9% DS at least 1 G2-4 CNS AE• More insomnia in IS arm 74% vs 39% (p=0.024)

•1 LFU in IS arm, 2 LFU and 1 SAE in DS arm

• 12 CNS AE considered according to ACTG DAIDS Grading• Baseline to week 12 results (Blinded Phase):

– IS: G2-4 overall CNS AE (90% to 60%; p=0.041), abnormal dreams (50% to 20%; p=0.041)

– DS: No significant changes

• Week 12 to week 24 results (open-label phase):– IS: No further changes– DS: G2-4 abnormal dreams (67% to 20%; p=0.023), median G2-4 CNS AE (3 to 1;

p=0.003)

0

1

2

3

4

5

6

IS DS

Baseline12 Weeks

16

Baseline12 Weeks

0

2

4

6

8

10

12

14

IS DS

P=0.001

P=0.192P=0.003

P=0.508

Median Number G2-4 CNS AE CNS Score

• Viral suppression: All subjects maintained HIV-RNA <50 copies/ml • CD4: During blinded phase, +40 and +6 in IS and DS arms, respectively; in

combined analysis after 12 weeks ETR +43 (p=0.027 vs baseline)• Safety: 1 SAE; one G3 flatulence on ETR; no other G3/4 AE; no rash or

hepatotoxicity• Lipid changes after 12 weeks ETR (ie combined baseline to week 12 in IS

arm and week 12 to week 24 DS arm):

• Conclusions:– Switching from EFV to ETR improved overall G2-4 CNS AE, median no. G2-4 CNS AE, CNS

score and, specifically, abnormal dreams and insomnia– Switching from EFV to ETR also yielded significant improvements in fasting TC and LDL-C– There were no cases of rash or hepatotoxicity– Virological and immunological efficacy were maintained.

Lipid parameter Change in mmol/l (SD) P-valueTotal cholesterol -0.64 (1.02) <0.001

HDL-cholesterol -0.04 (0.21) ns

LDL-cholesterol -0.58 (1.09) 0.021

Triglycerides -0.19 (0.62) 0.092