Etravirina: barrera genética y desarrollo de resistencias

Llibre, Josep M.; Santos, José Ramón; Clotet, Bonaventura

doi:10.1016/S0213-005X(09)73217-3

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Resumen

A diferencia de los inhibidores de la transcriptasa inversa no análogos de nucleósidos (ITINAN) de primera generación, para desarrollar resistencia completa a etravirina (ETR) se requiere el acúmulo de varias mutaciones. Muestra una barrera intermedia frente a la aparición de resistencia parcial, y alta para el de resistencia completa. Algunas mutaciones seleccionadas por nevirapina o efavirenz impactan la actividad de ETR, siendo las más frecuentes Y181C,G190A/S,K101E,L100I,Y188L y V90I. El grado de resistencia conferida por cada una es distinto. En la actualidad se dispone de al menos 3 listados de mutaciones que otorgan la puntuación exacta a cada mutación. Estos listados se han validado con el grado de resistencia observado en fenotipos pareados, y con respuesta clínica en los estudios DUET. Los 3 scores muestran un elevado grado de concordancia entre ellos. ETR es, en la actualidad, uno de los antirretrovirales en los que se puede calcular de modo sencillo y con mayor precisión su actividad basándose en datos genotípicos. Las mutaciones seleccionadas tras fracasos a inhibidores de la transcriptasa inversa análogos de nucleósidos, especialmente análogos de la timidina, T69D/N y M184I/V, confieren hipersusceptibilidad frente a ETR (foldchange < 0,4) en hasta 1 de cada 3 muestras analizadas. Es crucial la retirada precoz de ITINAN de primera generación en pacientes con fracaso virológico para evitar el acúmulo de mutaciones que puedan comprometer la actividad del fármaco.

Palabras clave:

Etravirina

TMC125

Genotipo

Fenotipo

Resistencia a antivirales

Abstract

Unlike first-generation non-nucleoside reverse transcriptase inhibitors (NNRTI), to develop complete resistance to etravirine (ETR), various mutations must be accumulated. This drug shows an intermediate barrier against partial resistance and a high barrier to complete resistance. Some mutations selected by nevirapine or efavirenz affect the activity of ETR, the most frequent being Y181C,G190A/S,K101E,L100I,Y188L and V90I. The grade of resistance conferred by each mutation differs. Currently, there are at least three lists of mutations that confer an exact score to each mutation. These lists have been validated with the grade of resistance observed in paired phenotypes and with clinical response in the DUET studies. The three scores show a high degree of agreement. ETR is currently one of the antiretroviral drugs whose activity can be calculated simply and accurately on the basis of genotypic data. The mutations selected after failure to nucleoside reverse transcriptase inhibitors, thymidine analogue, T69D/N and M184I/V, confer hypersusceptibility to ETR (fold change < 0.4) in up to 1 out of every 3 samples analyzed. The early withdrawal of first-generation NNRTIs in patients with virological failure is essential to avoid the accumulation of mutations that could compromise the activity of this drug.

Keywords:

Etravirine

TMC125

Genotype

Phenotype

Antiviral resistance

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Bibliografía

[1.]

R.W. Shafer, J.M. Schapiro.

HIV-1 drug resistance mutations: an updated framework for the second decade of HAART.

AIDS Rev, 10 (2008), pp. 67-84

Medline

[2.]

F. Clavel, A.J. Hance.

HIV drug resistance.

N Engl J Med, 350 (2004), pp. 1023-1035

http://dx.doi.org/10.1056/NEJMra025195 | Medline

[3.]

J.A. Johnson, J.F. Li, X. Wei, J. Lipscomb, D. Irlbeck, C. Craig, et al.

Minority HIV-1 drug resistance mutations are present in antiretroviral treatment-naive populations and associate with reduced treatment efficacy.

PLoS Med, 5 (2008), pp. e158

http://dx.doi.org/10.1371/journal.pmed.0050158 | Medline

[4.]

K.J. Metzner, S.G. Giulieri, S.A. Knoepfel, P. Rauch, P. Burgisser, S. Yerly, et al.

Minority quasispecies of drug-resistant HIV-1 that lead to early therapy failure in treatment- naive and -adherent patients.

Clin Infect Dis, 48 (2009), pp. 239-247

http://dx.doi.org/10.1086/595703 | Medline

[5.]

J.P. Nadler, D.S. Berger, G. Blick, P.J. Cimoch, C.J. Cohen, R.N. Greenberg, et al.

Efficacy and safety of etravirine (TMC125) in patients with highly resistant HIV-1: primary 24-week analysis.

AIDS, 21 (2007), pp. F1-10

[6.]

J.V. Madruga, P. Cahn, B. Grinsztejn, R. Haubrich, J. Lalezari, A. Mills, et al.

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 (2007), pp. 29-38

http://dx.doi.org/10.1016/S0140-6736(07)61047-2 | Medline

[7.]

A. Lazzarin, T. Campbell, B. Clotet, M. Johson, C. Katlama, A. Moll, et al.

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 (2007), pp. 39-48

http://dx.doi.org/10.1016/S0140-6736(07)61048-4 | Medline

[8.]

C.J. Cohen, D.S. Berger, G. Blick, H.A. Grossman, D.T. Jayaweera, P. Shalit, et al.

Efficacy and safety of etravirine (TMC125) in treatment-experienced HIV-1-infected patients: 48-week results of a phase IIb trial.

AIDS, 23 (2009), pp. 423-426

http://dx.doi.org/10.1097/QAD.0b013e32831c5040 | Medline

[9.]

J.M. Llibre, J.R. Santos, T. Puig, J. Molto, L. Ruiz, R. Paredes, et al.

Prevalence of etravirine- associated mutations in clinical samples with resistance to nevirapine and efavirenz.

J Antimicrob Chemother, 62 (2008), pp. 909-913

[10.]

K. Andries, H. Azijn, T. Thielemans, D. Ludovici, M. Kukla, J. Heeres, et al.

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 (2004), pp. 4680-4686

http://dx.doi.org/10.1128/AAC.48.12.4680-4686.2004 | Medline

[11.]

M. Udier-Blagovic, J. Tirado-Rives, W.L. Jorgensen.

Validation of a model for the complex of HIV-1 reverse transcriptase with nonnucleoside inhibitor TMC125.

J Am Chem Soc, 125 (2003), pp. 6016-6017

http://dx.doi.org/10.1021/ja034308c | Medline

[12.]

M. Peeters, J. Vingerhoets, L. Tambuyzer, H. Azijn, A. Hill, S. De Meyer, et al.

Etravirine protects the activity of darunavir in the DUET trials.

Proceedings of the 9th International Conference on Drug Therapy in HIV Infection,

[13.]

J. Vingerhoets, A. Buelens, M. Peeters, G. Picchio, L. Tambuyzer, H. Van Marck, et al.

Impact of baseline NNRTI mutations on the virologic response to TMC125 in the phase III clinical trials DUET-1 and DUET-2.

Proceedings of the XVI International HIV Drug Resistance Workshop,

[14.]

J. Vingerhoets, M. Peeters, H. Azijn, A. Hoogstoel, S. Nijs, M.P. De Bethune, et al.

An update of the list of NNRTI mutations associated with decreased virologic response to etravirine (ETV): multivariate analyses on the pooled DUET-1 and DUET-2 clinical trial data.

Proceedings of the XVIIth International Drug Resistance Workshop,

[15.]

J. Benhamida, C. Chappey, E. Coakley, N. Parkin.

HIV-1 genotype algorithms for prediction of etravirine susceptibility: novel mutations and weighting factors identified through correlations with phenotype.

Proceedings of the XVIIth International HIV Drug Resistance Workshop,

[16.]

Stanford University HIV Drug Resistance Database [consultado 8-7-2009]. Disponible en: http://hivdb.stanford.edu/

[17.]

J. Vingerhoets, H. Azijn, E. Fransen, I. De Baere, L. Smeulders, D. Jochmans, et al.

TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments.

J Virol, 79 (2005), pp. 12773-12782

http://dx.doi.org/10.1128/JVI.79.20.12773-12782.2005 | Medline

[18.]

M.S. Hirsch, H.F. Gunthard, J.M. Schapiro, F. Brun-Vezinet, B. Clotet, S.M. Hammer, et al.

Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA panel.

Clin Infect Dis, 47 (2008), pp. 266-285

http://dx.doi.org/10.1086/589297 | Medline

[19.]

R.M. Kagan, P. Sista, T. Pattery, L. Bacheler, D.A. Schwab.

Additional HIV-1 mutation patterns associated with reduced phenotypic susceptibility to etravirine in clinical samples.

AIDS, 23 (2009), pp. 1602-1605

http://dx.doi.org/10.1097/QAD.0b013e32832d8771 | Medline

[20.]

L. Tambuyzer, J. Vingerhoets, H. Azijn, A. Hoogstoel, S. Nijs, G. Picchio.

Comparison of two etravirine weighted genotypic scores with phenotypic susceptibility and virological response data.

Proceedings of the 7th European HIV Drug Resistance Workshop,

[21.]

M. Peeters, S. Nijs, J. Vingerhoets, L. Tambuyzer, B. Woodfall, M.P. De Bethune, et al.

Determination of phenotipic clinical cut-offs for etravirine (ETV): pooled week 24 results of the DUET-1 and DUET-2 trials.

Proceedings of the XVIIth International Drug resistance Workshop,

[22.]

E. Coakley, C. Chappey, J. Benhamida, et al.

Biological and clinical cut-off analysis or etravirine in the PhenoSense HIV assay.

Proceedings of the XVII International HIV Drug Resistance Workshop,

[23.]

L. Bacheler, K. Van del Borght, E. Van Craenenbroeck, B. Winters, P. Lecocq.

Exploring etravirine resistance among recent routine clinical samples submitted for resistance testing.

Proceedings of the XVII International HIV drug resistance Workshop,

[24.]

R.H. Haubrich, C.A. Kemper, N.S. Hellmann, P.H. Keiser, M.D. Witt, D.N. Forthal, et al.

The clinical relevance of non-nucleoside reverse transcriptase inhibitor hypersusceptibility: a prospective cohort analysis.

AIDS, 16 (2002), pp. F33-40

Medline

[25.]

J.M. Whitcomb, W. Huang, K. Limoli, E. Paxinos, T. Wrin, G. Skowron, et al.

Hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in HIV-1: clinical, phenotypic and genotypic correlates.

AIDS, 16 (2002), pp. F41-F47

Medline

[26.]

J. Benhamida, E. Coakley, N. Parkin, C. Chappey.

Increased phenotypic susceptibility to etravirine in HIV-1 with nucleoside reverse transcriptase inhibitor resistance.

Antivir Ther, 13 (2008), pp. A24

[27.]

E. Coakley, C. Chappey, J. Benhamida, L. Tambuyzer, J. Vingerhoets, M.P. De Bethune, et al.

Defining the upper and lower clinical cutoffs for etravirine in the phenosense HIV assay.

Proceedings of the 16th Conference on Retroviruses and Opportunistic Infections,

[28.]

L. Tambuyzer, H. Azijn, L.T. Rimsky, J. Vingerhoetas, P. Lecocq, G. Kraus, et al.

Compilation and prevalence of mutations associated with resistance to non-nucleoside reverse transcriptase inhibitors.

Antivir Ther, 14 (2009), pp. 103-109

Medline

[29.]

K. Deforche, R.J. Camacho, Z. Grossman, M.A. Soares, K. Van Laethem, D.A. Katzenstein, et al.

Bayesian network analyses of resistance pathways against efavirenz and nevirapine.

AIDS, 22 (2008), pp. 2107-2115

[30.]

W.P. Bannister, L. Ruiz, A. Cozzi-Lepri, A. Mocroft, O. Kirk, S. Staszewski, et al.

Comparison of genotypic resistance profiles and virological response between patients starting nevirapine and efavirenz in EuroSIDA.

AIDS, 22 (2008), pp. 367-376

[31.]

A. Cozzi-Lepri, B. Clotet, R. Paredes, J. Kjaer, A.N. Phillips, J.D. Lundgren.

The rate of accumulation of NNRTI resistance in patients kept on a virologically failing regimen containing NNRTI: a EuroSIDA study.

Proceedings of the XVII International HIV Drug Resistance Workshop,

[32.]

A.G. Marcelin, P. Flandre, D. Descamps, L. Morand-Jaubert, C., I.zopet. Charpentier, et al.

Factors associated with early virologic response to etravirine in NNRTI experienced HIV-infected patients.

Proceedings of the 16th Conference on Retroviruses and Opportunistic Infections,

[33.]

C. Scott, D. Grover, M. Nelson.

Is there a role for etravirine in patients with Nonnucleoside reverse transcriptase inhibitor resistance?.

AIDS, 22 (2008), pp. 989-990

http://dx.doi.org/10.1097/QAD.0b013e3282fa75df | Medline

[34.]

P. Cahn, J.M. Molina, W. Towner, M. Peeters, J. Vingerhoets, G. Beets, et al.

48-week pooled analysis of the DUET-1 and DUET-2: the impact of baseline characteristics on virologic response to etravirine.

Proceedings of the XVIIth International AIDS Conference,

[35.]

V. Varguese, R. Shariar, S.Y. Rhee, B.B. Simen, M. Egholm.

Minority drug resistance mutations associated with the NNRTI mutation K103N in ART-naïve and NNRTItreated HIV-1 infected patients.

Proceedings of the XVIIIth International Drug Resistance Workshop,

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