Antiretroviral drug summary: Etravirine (ETR; Intelence)
Last updated on Nov 10, 2008
Associated with decreased ETR susceptibility in >= 2 studies
Other Tibotec GSS mutations
In vitro passage experiments: E138K, Y181C/I, V179F, G190E, and M230L are among the most common mutations emerging during ETR selection pressure in vitro (Brillant et al. 2004; Su et al. 2007; Vingerhoets et al. 2005). L100I emerged in isolates with K103N (Vingerhoets et al. 2005).
Mutations emerging in individuals receiving ETR: L100I, E138G, V179F/I, Y181C/I, and H221Y have been the mutations most commonly been reported to emerge in vivo (Tibotec 2008).
Phenotypic susceptibility: site-directed mutants: The greatest decreases in susceptibility (Antivirogram) were observed with Y181V (17-fold), Y181I (13-fold), K101P (6-fold), E138Q (5-fold), K101Q (3-fold), V179D (3-fold), M230L (3-fold), A98G (2-fold), L100I (2-fold), H221Y (2-fold), and K238T (2-fold) (Vingerhoets et al. 2008). In earlier studies, Y181C/I/V, F227C, and M230L were found to cause the greatest reductions (>10 to >20-fold) in ETR susceptibility(Andries et al. 2004; Vingerhoets et al. 2005; Vingerhoets et al. 2004). By itself, V179F does not reduce ETR susceptibility but in combination with mutations at position 181 (the only context in which it has so far been observed, 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. 2004).
Phenotypic susceptibility: clinical isolates: In a phenotypic analysis of 2,700 samples with NNRTI-resistance mutations L100I, K101P, Y181C/I, and M230L were the best predictors of having a 3-fold decrease ETR susceptibility (PhenoSense) (Benhamida et al. 2008). E138A/G, V179E, G190Q, M230L, and K238N > K101E, V106A, E138K, V179L, and Y188L > E138Q, V179D/F/M, Y181F, G190E/T, H221Y, P225H, and K238T were also predictors (Benhamida et al. 2008).
Genotype-clinical outcome correlations: V90I, A98G, L100I, K101E/H/P, V106I, E138A, V179D/T/F, Y181C/I/V, and G190A/S were the mutations most strongly associated with a decreased virological response in clinical trials (Vingerhoets et al. 2007; Vingerhoets et al. 2006; Vingerhoets et al. 2008). The current Tibotec GSS includes these 16 mutations + M230L.
However, V90I and V106I are highly polymorphic; A98G and G190A/S do not appear to decrease ETR susceptibility (Benhamida et al. 2008) (Vingerhoets et al. 2008). V179T is extremely rare but also appears to be polymorphic
ETR has been licensed by the FDA and is recommended for use in salvage therapy in combination with other active ARVs (Hammer et al. 2008; Lazzarin et al. 2007; Madruga et al. 2007; Ruxrungtham et al. 2008).
- Andries, K., H. Azijn, T. Thielemans, D. Ludovici, M. Kukla, J. Heeres, P. Janssen, B. De Corte, J. Vingerhoets, R. Pauwels, and M.P. de Bethune. 2004. TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother 48: 4680-4686.
- Benhamida, J., C. Chappey, and N. Parkin. 2008. HIV-1 genotypic algorithms for prediction of etravirine susceptibility: novel mutations and weighting factors identified through correlations to phenotype [abstract 130]. Antivir Ther 13: Suppl 3:A142.
- Brillant, J., K. Klumpp, S. Swallow, N. Cammack, and G. Heilek-Snyder. 2004. In vitro resistance development for a second-generation NNRTI: TMC125 Antivir Ther Volume 9: S20.
- Hammer, S.M., J.J. Eron, Jr., P. Reiss, R.T. Schooley, M.A. Thompson, S. Walmsley, P. Cahn, M.A. Fischl, J.M. Gatell, M.S. Hirsch, D.M. Jacobsen, J.S. Montaner, D.D. Richman, P.G. Yeni, and P.A. Volberding. 2008. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. Jama 300: 555-570.
- Lazzarin, A., T. Campbell, B. Clotet, M. Johnson, C. Katlama, A. Moll, W. Towner, B. Trottier, M. Peeters, J. Vingerhoets, G. de Smedt, B. Baeten, G. Beets, R. Sinha, and B. Woodfall. 2007. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 370: 39-48.
- Madruga, J.V., P. Cahn, B. Grinsztejn, R. Haubrich, J. Lalezari, A. Mills, G. Pialoux, T. Wilkin, M. Peeters, J. Vingerhoets, G. de Smedt, L. Leopold, R. Trefiglio, and B. Woodfall. 2007. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 370: 29-38.
- Ruxrungtham, K., R. Pedro, G. Latiff, F. Conradie, P. Domingo, S. Lupo, W. Pumpradit, J. Vingerhoets, M. Peeters, I. Peeters, T. Kakuda, G. De Smedt, and B. Woodfall. 2008. Impact of reverse transcriptase resistance on the efficacy of TMC125 (etravirine) with two nucleoside reverse transcriptase inhibitors in protease inhibitor-naive, nonnucleoside reverse transcriptase inhibitor-experienced patients: study TMC125-C227. HIV Med 9: 883-896.
- Su, G., J. Yan, Y. Li, A. Paul, J. Hang, S. Harris, H. Hogg, J. Dunn, C. N, K. Klumpp, and G. Heilek. 2007. In vitro selection and characterization of viruses resistant to R1206 a novel non-nucleoside reverse transcriptase inhibitor [abstract 33]. Antivir Ther 12: S35.
- Tibotec. 2008. Intellence. Package Insert.
- Vingerhoets, J., H. Azijn, E. Fransen, I. De Baere, L. Smeulders, D. Jochmans, K. Andries, R. Pauwels, and M.P. de Bethune. 2005. TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. J Virol 79: 12773-12782.
- Vingerhoets, J., M. Buelens, M. Peeters, G. Picchio, L. Pambuyzer, H. Van Barck, G. de Smedt, B. Woodfall, and M.P. de Bethune. 2007. Impact of baseline mutations on the virological response to TMC125 in the phase III clinical trials DUET-1 and DUET-2 [abstract 32]. Antivir Ther 12: S34.
- Vingerhoets, J., I. De Baere, H. Azijin, T. Van den Bulcke, P. McKenna, T. Patterry, R. Pauwels, and M.P. de Bethune. 2004. Antiviral activity of TMC125 against a panel of site-directed mutants encompassing mutations observed in vitro and in vivo [abstract 621]. 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, February 8 - 11.
- Vingerhoets, J., K. Janssen, J. Welkenhuysen-Gybels, M. Peeters, K. Cao-Van, L. Tambuyzer, W. B., and M.P. de Béthune. 2006. Impact of baseline K103N or Y181C on the virological response to the NNRTI TMC125: analysis of study TMC125-C223 Antivir Ther 11: S22.
- Vingerhoets, J., M. Peeters, H. Azjin, L. Tambuyzer, A. Hoogstoel, S. Nijs, M. de Bethune, and G. Picchio. 2008. An update of the list of NNRTI mutations associated with decreased virological response to etravirine: multivariate analysis on the pooled DUET-1 and DUET-2 clinical trial data [abstract 24]. Antivir Ther 13: Suppl 3:A26.