Comparison of NNRTI vs. NNRTI in SENSE Study

The comparison between Etravirine (ETR) and Efavirenz (EFV) in the SENSE Study showed differences in neuropsychiatric adverse events, treatment response, and patient characteristics. ETR with 2 NRTIs resulted in fewer drug-related adverse events than EFV with 2 NRTIs. ETR also showed better response to treatment at week 48 in patients with HIV RNA levels above 100,000 c/mL. However, EFV had higher rates of nervous system and psychiatric adverse events.

• NNRTI
• SENSE Study
• Etravirine
• Efavirenz
• HIV treatment

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1. Comparison of NNRTI vs NNRTI ENCORE EFV vs RPV ECHO-THRIVE STAR EFV vs ETR SENSE DOR vs EFV DRIVE-AHEAD

2. SENSE Study: ETR QD + 2 NRTI vs EFV QD + 2 NRTI Design Randomisation 1 : 1 Open-label W12 W48 N = 79 ETR 400 mg (4 tablets) QD + EFV placebo + 2 NRTI* ARV-na ve HIV RNA > 5,000 c/mL No R to study drugs EFV 600 mg QD + ETR placebo + 2 NRTI* N = 78 Randomisation was stratified by HIV RNA (< or > 100,000 c/mL) at screening * Open-label NRTI combination selected by investigator : ZDV/3TC BID or ABC/3TC QD or TDF/FTC QD Primary endpoint Difference in percentage of patients with at least one grade 1-4 treatment- emergent, drug related neuropsychiatric adverse event by week 12 (adjusted ITT analysis, two-sided test, 90% power) Gazzard B. AIDS 2011;25:2249-58 SENSE

3. SENSE Study: ETR QD + 2 NRTI vs EFV QD + 2 NRTI Baseline characteristics and patient disposition ETR + 2 NRTI, N = 79 EFV + 2 NRTI, N = 78 Mean age, years Female HIV RNA (log10c/mL), median CD4 cell count (/mm3), median > 1 IAS-USA NNRTI mutation > 1 IAS-USA NRTI mutation HCV antibody positive 38 15% 4.8 319 38 23% 4.8 273 4 (5%)* 0 10% 12 (15%)* 6% 11% Selected NRTI TDF/FTC ; ABC/3TC ; ZD/3TC Discontinuation by W12 For adverse event Lost to follow-up Withdrew consent Other reasons 60% ; 26% ; 14% N = 10 N = 4 N = 1 N = 3 N = 2 N = 8 N = 8 0 0 0 * E138A, N = 5, V106I, N = 4, V108I, N = 1, V90I, N = 6 Nelson M. AIDS 2011;25:335-40 SENSE

4. SENSE Study: ETR QD + 2 NRTI vs EFV QD + 2 NRTI Neuropsychiatric adverse events during 12 weeks ETR + 2 NRTI EFV + 2 NRTI P All events grade 1-4 27.8% 55.1% < 0.001 Drug-related (primary endpoint) 16.5% 46.2 % < 0.001 All events grade 2-4 10.1% 19.2% 0.103 Drug-related 5.1% 16.7% 0.019 Nervous system adverse events, all grade 20.2% 33.4% Dizziness 4% 19% Psychiatric adverse events, all grade 11 % 39 % Sleep disorders 9% 32% Depression N = 1 N = 4 Serious adverse events : ETR, N = 5, EFV, N = 3 Grade 2-4 skin or subcutaneous AE : ETR, N = 8, EFV, N = 9 ; discontinuation for rash : 4/8 and 4/9 Grade 2-4 elevations in total cholesterol and LDL cholesterol : ETR = 3 and 6 ; EFV = 18 and 13 Nelson M. AIDS 2011;25:335-40 SENSE

5. SENSE Study: ETR QD + 2 NRTI vs EFV QD + 2 NRTI Response to treatment at week 48 ETR + 2 NRTI EFV + 2 NRTI HIV RNA < 40 c/mL ITT, TLOVR Non-VF censored analysis 97.6 % 100 93.0 92.3 89.2 83.3 81.8 78.4 75.9 76.8 74.4 74.1 75 66.7 50 25 0 All patients All patients Difference (95% CI) = 2.9% (-5.8 ; 11.7) Baseline HIV RNA > 100,000 c/ml Baseline HIV RNA > 100,000 c/ml Baseline HIV RNA < 100,000 c/ml Baseline HIV RNA < 100,000 c/ml Difference (95% CI) = 1.6% (-12.0 ; 15.2) Gazzard B. AIDS 2011;25:2249-58 SENSE

6. SENSE Study: ETR QD + 2 NRTI vs EFV QD + 2 NRTI Protocol-defined criteria for genotype testing - Discontinuation with detectable HIV RNA - HIV RNA decrease < 1 log10c/mL or > 400 c/mL at week 12 - HIV RNA > 50 c/mL at week 48 - Virologic failure (2 consecutive HIV RNA > 50 c/mL) by TLOVR algorithm Resistance data ETR + 2 NRTI EFV + 2 NRTI Virologic failure, n Baseline HIV RNA > 100,000 c/mL Presence of resistance mutations, n K103N 4 7 3/4 0 4/7 3 1 V106I + M184I 1 K103N + M184V + P225H Additional patients genotyped at time of discontinuation (HIV RNA > 50 c/mL), n NNRTI mutation (V90I) 1 7 2 1 0 Among patients with baseline IAS-USA NNRTI mutations, 10/10 in the ETR arm and 4/4 in the EFV arm had HIV RNA < 50 c/mL at week 48 Gazzard B. AIDS 2011;25:2249-58 SENSE

7. SENSE Study: ETR QD + 2 NRTI vs EFV QD + 2 NRTI Summary First-line treatment with etravirine 400 mg once daily and two nucleoside reverse transcriptase inhibitors (NRTI) led to similar rates of HIV RNA suppression, compared with efavirenz and two NRTI None of the patients with virological failure in the etravirine arm developed resistance to NNRTI Etravirine was associated with significantly fewer neuropsychiatric adverse events than EFV. The difference was still statistically significant at the week 48 visit There were greater rises in lipids in the EFV arm The risk of grade 2-4 skin or subcutaneous adverse events was similar in the two arms Gazzard B. AIDS 2011;25:2249-58 SENSE