Background:  We wanted to evaluate the prevalence of mutations (RAM) associated with diminished virological response to etravirine (TMC125) in the DUET trials in routine clinical samples with resistance to first generation NNRTI.

Methods:  We identified 1586 of 4981 (31.8%) samples submitted for routine clinical resistance testing from 1998 to 2006 with resistance to first-generation NNRTI (1 RAM in the reverse transcriptase gene associated with resistance to NNRTI in the International AIDS Society [IAS] -USA list).

Results: Most of the samples (68.9%) harbored >1 IAS-USA RAM to first generation NNRTI: 670 (42.2%) harbored 2 RAM, 333 (21%) 3 RAM, and 90 (5.7%) ≥4 RAM. The prevalence of specific TMC125 RAM associated with decreased virological response (ranked in decreasing order by their effect on virologic response) was:  V179F 0.12%, G190S 1.0%, Y181V 0.1%, V106I 0.75%, V179D 0.75%, K101P 1.38%, K101E 1.89%, Y181C 4%, A98G 5.9%, V90I 6.9%, Y181I 3.6%, G190A 3.65%, L100I 9.1%. The top 5 mutations with higher effect on the virologic response (V179F, G190S, Y181V, V106I, V179D) showed the lower occurrence rates. The overall prevalence of samples with >2 TMC125-associated RAM was 8.2%, whereas only 1.14% of samples had >3 TMC125-associated RAM. Patterns of mutations previously associated with intermediate TMC125 resistance in vitro or during TMC125 development (Y181C + 2 RAM, V179D + 2 RAM, K101E + 2 RAM, Y188L + 2 RAM, L100I + K103N) were detected in 219 (13.8%) samples, while 150 (9.46%) further samples (23.26% in total) displayed patterns associated with high-degree resistance in vitro (F227C, Y181I/V + 2 RAM, M230L + 2 RAM, G190S + 2 RAM, Y181I/V + 2 RAM, V179E/D/F + 4 RAM, G190S + 3 RAM, K101P + 2 RAM).

Conclusions: Resistance to TMC125 in routinely collected clinical specimens considering only RAM associated with decreased virologic response is lower than previously reported. High-degree resistance to TMC125 is rare, even in patients with resistance to first generation NNRTI. However, low-to-intermediate TMC125 resistance is rather more common. These results further support the recommendation of early withdrawal of first generation NNRTI from non-suppressive antiretroviral regimens in order to avoid the accumulation of further mutations that would endanger TMC125 activity.