A curated public database designed to represent, store, and analyze the divergent forms of data underlying HIV drug resistance.

Data on ETR resistance have been derived from three sources: (i) in vitro passage experiments, (ii) genotype-phenotype data on isolates emerging during in vitro passage and on isolates containing NNRTI-resistance mutations observed with other NNRTIs, and (iii) clinical trials in which ETR was used as part of a salvage therapy regimen in NNRTI-experienced patients. Data are not yet available on which mutations emerge during ETR virological failure.

In vitro passage experiments: During ETR in vitro passage experiments reported by Tibotec, Y181C was the most consistently observed initial drug-resistance mutation (Vingerhoets et al. 2005). V179F, M230L, and G190E were also observed. L100I occurred in isolates that had K103N prior to in vitro passage (Vingerhoets et al. 2005). In independent experiments reported by researchers at Hoffman-LaRoche, E138K, V179F, and M230L were the most common mutations to emerge following Y181C (Brillant et al. 2004; Su et al. 2007). With continued passage Y181I became more common than Y181C (Su et al. 2007).

Genotype-phenotype studies: Y181C/I/V, F227C, and M230L have consistently been found to produce the greatest (>10 to >20-fold) reductions in ETR susceptibility (Andries et al. 2004; Vingerhoets et al. 2005; Vingerhoets et al. 2004). V179F has little effect alone, but in combination with mutations at position 181 (the only context in which it has so far been observed (Rhee et al. 2003)), V179F is associated with >100-fold decreased susceptibility (Vingerhoets et al. 2005). L100I alone reduces susceptibility 3-fold but in combination with K103N (a mutation which has no effect alone), it reduces ETR susceptibility 15-fold (Andries et al. 2004; Vingerhoets et al. 2005). Insufficient published data are available for many of the other common drug resistance mutations such as those at positions 188 and 190.

Genotype-clinical studies: Correlations between baseline mutations and the virological response to an ETR-containing salvage therapy regimen have been studied in TMC125-C223 and in the DUET studies. In TMC125-C223, Y181C but not K103N was associated with a decreased response to ETR salvage (Vingerhoets et al. 2006). In the DUET studies (Lazzarin et al. 2007; Madruga et al. 2007), a genotypic sensitivity score of 13 mutations was found by multivariate analysis to predict response to ETR salvage therapy: V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, and G190A/S (Vingerhoets et al. 2007). Y181V, V179F, and G190S had the most pronounced effect on virological response (Vingerhoets et al. 2007). Of note, V90I and V106I are two highly polymorphic mutations that may represent epiphenomena (or over-fitting to the DUET dataset). V90I occurs in 1.4% of untreated persons, in 3.3% of NNRTI-naive NRTI treated persons, and in 4.7% of NNRTI treated persons. V106I occurs in about 2% of untreated and NNRTI-treated persons.

ETR has been submitted to the FDA for use in the treatment of HIV infection. It is currently available through an expanded access protocol in triple-class experienced patients. There are currently no formal expert panel recommendations on its use.