Table 3. Summary of Phase I/II trials.

Phase I/II study	Sample size	Study design	Treatment arms (n)	Primary outcome	HIV RNA reduction from baseline or viral decay rate	Categorical HIV RNA change	Change in CD4 cell count (cells/μl)	Ref.
Gazzard Phase IIa	n = 16	OL SA	ETR substituted for EFV or NVP with continued BR (16) Phenotypic NNRTI resistance	HIV-1 RNA decay rate per day	Median decrease of 0.89 log10 in HIV-1 RNA after 7 days Viral decay rate = 0.13 log10 HIV-1 RNA c/ml/day	7 (44%) had a greater than 1 log10 decline in HIV-1 RNA	No significant change in 7-day study period	[18]
Gruzdev TMC125-C208 Phase IIa	n = 19	DB PC DA 2:1 R	ETR monotherapy (12) Placebo (7) Treatment-naive patients 7-day study period	7-day decline in HIV-1 RNA from baseline and fold change ITT	Mean HIV-1 RNA decline: ETR: 1.99 log10 c/ml PLB: 0.06 log10 c/ml (p <0.001)	ETR: 8/12 (67%) had HIV-1 RNA <400 copies/ml PLB: 0/7 (0%)	ETR: +104 PLB: -150 (p = 0.016)	[23]
					Viral decay rate: ETR: 0.33 log10 c/ml/day PLB: 0.02 log10 c/ml/day (p <0.001)	ETR: 2/12 (16%) had HIV-1 RNA <50 copies/ml PLB: 0/7 (0%)
Sankatsing	n = 23	Retrospective DA	ETR monotherapy (12) Triple-class, 5-drug regimen (ERA;11)	Median plasma HIV RNA elimination rate	Median HIV-1 RNA decline: ETR: 1.92 log10 c/ml ERA: 1.76 log10 c/ml (p = 0.77)	Not reported	ETR: +119 ERA: +60 (p = 0.29)	[24]
					Viral decay rate: ETR: 0.68 log10 c/ml/day ERA: 0.56 log10 c/ml/day (p = 0.24)
Nadler TMC125-C223 Phase IIb	n = 199	OL Partially-blinded 2:2:1 R	ETR 400 mg twice daily with BR of ≥2 NRTIs and/or LPV/r and/or enfuvirtide (80) ETR 800 mg twice daily with BR of ≥2 NRTIs and/or LPV/r and/or enfuvirtide (79) Controls received ≥3 approved agents selected from NRTIs and/or PIs and/or enfuvirtide (40) All subjects had genotypic NNRTI resistance and ≥3 primary PI mutations	Change in HIV-1 RNA from baseline values at week 24 ITT	Mean decline in HIV-1 RNA at week 24: ETR 400: 1.04 log10 c/ml (p = 0.005 vs control) ETR 800: 1.18 log10 c/ml (p <0.001 vs control) Control: 0.19 log10 c/ml	Proportion with HIV-1 RNA <400 c/ml: ETR 400: 30% (p = 0.018 vs control) ETR 800: 39% (p = 0.002 vs control) Control: 7.5%	ETR 400: +47 (p = NS vs control) ETR 800: +48	[27]
					Proportion with decrease in HIV-1 RNA by ≥1 log10 c/ml: ETR 400: 36.3% (p = 0.005 vs control) ETR 800: 41.8% (p <0.001 vs control) Controls: 7.5%	Proportion with HIV-1 RNA <50 c/ml: ETR 400: 21.3% (p = 0.133 vs control) ETR 800: 17.7% (p = 0.218 vs control) Control: 7.5%	(p = NS vs control) Control: +10

ARV: Antiretroviral; B: Blinded; BR: Background regimen; c/ml/day = HIV-1 RNA copies/milliliter of blood/day; c/ml: HIV-1 RNA copies/milliliter of blood; DA: Double arm; DB: Double blinded; DRV/r: Darunavir/ritonavir; EFV: Efavirenz; ERA: ERA study historical control arm; ETR: Etravirine; ITT: Intent-to-treat analysis; LPV/r: Lopinavir/ritonavir; NRTI: Nucleoside reverse transcriptase inhibitor; NS: Not significant; NVP: Nevirapine; OL: Open label; PC: Placebo controlled; PI: Protease inhibitor; PLB: Placebo; R: Randomized; SA: Single Arm.