Article information
Resumen
La necesidad de conocer previamente el tropismo constituye un requisito imprescindible para el uso de los fármacos antagonistas de los correceptores CCR5. Un fármaco de esta clase, maraviroc, está ya aprobado para el tratamiento de la infección por el virus de la inmunodeficiencia humana (VIH). Aunque en los ensayos de desarrollo de maraviroc, el tropismo se determinó mediante pruebas fenotípicas (Trofile®), la realización de éstas es compleja, tiene un coste elevado y su accesibilidad es limitada, lo que dificulta su utilización en la práctica clínica. Los métodos genotípicos basados en el análisis de la tercera región variable (V3) de la envuelta del VIH utilizando algoritmos de interpretación como geno2pheno y PSSM representan una alternativa rápida, barata y accesible en laboratorios diagnósticos para predecir el tropismo viral. En los análisis retrospectivos de los ensayos clínicos de maraviroc, las pruebas genotípicas realizadas mediante técnicas de genotipo convencional (o poblacional) o mediante las nuevas plataformas de secuenciación masiva (pirosecuenciación por 454) fueron capaces de predecir la respuesta virológica al fármaco con una exactitud similar a las pruebas fenotípicas y, actualmente, las recomendaciones españolas y europeas las incluyen como una alternativa aceptable para la determinación del tropismo viral en la práctica clínica.
Palabras clave:
Tropismo VIH
Región V3
Maraviroc
Antagonistas del CCR5
Abstract
Determination of HIV-1 tropism is mandatory before using CCR5 antagonists in clinical practice. One drug of this class, maraviroc, has been approved for the treatment of HIV infection. The phenotypic assay, TrofileTM, was clinically validated in the clinical development program of maraviroc and has been widely used to select candidates for maraviroc therapy. Phenotypic tests, however, have the disadvantage of being complex, are costly and time-consuming, and their accessibility is limited, which hampers their routine use in clinical diagnosis. Genotypic assays, based on sequencing the third hypervariable (V3 loop) of the viral gene env, interpreted according to various genotypic bioinformatic tools, such as geno2pheno and PSSM, are faster and cheaper than phenotypic assays, and are also more accessible. In retrospective analyses of the maraviroc pivotal trials, genotypic methods using either conventional (“bulk”) or deep-sequencing technology predicted virologic response to maraviroc similarly to phenotypic assays and are now included within several European recommendations to guide the clinical use of CCR5 antagonists.
Keywords:
HIV tropism
V3 genotyping
Maraviroc
CCR5 antagonists
Full text is only aviable in PDF
Bibliografía
[1.]
J. Esté, A. Telenti.
HIV entry inhibitors.
Lancet, 370 (2007), pp. 81-88
[2.]
E. Comier, T. Dragic.
The crown and stem of the V3 loop play distinct roles in HIV type 1 envelope glycoprotein interactions with the CCR5 coreceptor.
J Virol, 76 (2002), pp. 8953-8957
[3.]
A. Thielen, T. Lengauer, L.C. Swenson, W.W. Dong, R.A. McGovern, M. Lewis, et al.
Mutations in gp41 are correlated with coreceptor tropism but do not improve prediction methods substantially.
Antivir Ther, 16 (2011), pp. 319-328
[4.]
E. Poveda, V. Briz, M. Quinones-Mateu, V. Soriano.
HIV tropism: diagnostic tools and implications for disease progression and treatment with entry inhibitors.
AIDS, 20 (2006), pp. 1359-1367
[5.]
M. Pérez-Olmeda, E. Poveda.
Methods for determining viral tropism: genotype and phenotype tests.
Enferm Infecc Microbiol Clin, Suppl 11 (2008), pp. 40-48
[6.]
J.M. Whitcomb, W. Huang, S. Fransen, K. Limoli, J. Toma, T. Wrin, et al.
Development and characterization of a novel single-cycle recombinant-virus assay to determine human immunodeficiency virus type 1 coreceptor tropism.
Antimicrob Agents Chemother, 51 (2007), pp. 566-575
[7.]
L. Trinh, D. Han, W. Huang, T. Wrin, J. Larson, L. Kiss, et al.
Technical validation of an enhanced sensitivity Trofile HIV coreceptor tropism assay for selecting patients for therapy with entry inhibitors targeting CCR5.
Antiviral Therapy, 13 (2008), pp. A128
[8.]
K. Van Baelen, I. Vandenbrouke, E. Rondelez, V. Van Eygen, H. Vermeiren, L. Stuyver.
HIV-1 coreceptor usage determination in clinical isolates using clonal and population-based genotypic and phenotypic assays.
J Virol Methods, 146 (2007), pp. 61-73
[9.]
A. González-Serna, M. Leal, M. Genebat, M.A. Abad, A. García-Perganeda, S. Ferrando Martínez, et al.
TROCAI (tropism coreceptor assay information): a new phenotypic tropism test and its correlation with Trofile enhanced sensitivity and genotypic approaches.
J Clin Microbiol, 48 (2010), pp. 4453-4458
[10.]
Alcami J, Sánchez-Palomino S, García J, González N. Utilización de virus recombinantes en tests de sensibilidad a fármacos, detección de anticuerpos neutralizantes y cribado y caracterización de compuestos con actividad antiviral nuevos clones virales recombinantes basados en VIH-1 y su utilización en métodos analiticos. N.° PATENTE: 200401116. N.° BOPI: 16022007.
[11.]
N. González, M. Pérez-Olmeda, E. Mateos, A. Cascajero, A. Álvarez, S. Spijkers, et al.
A sensitive phenotypic assay for the determination of human immunodeficiency virus type 1 tropism.
J Antimicrob Chemother, 65 (2010), pp. 2493-2501
[12.]
R. Gulick, J. Lalezari, J. Goodrich, N. Clumeck, E. DeJesus, A. Horban, et al.
Maraviroc for previously treated patients with R5 HIV-1 infection.
N Engl J Med, 359 (2008), pp. 1429-1441
[13.]
D. Cooper, J. Heera, J. Goodrich, M. Tawadrous, M. Saag, E. Dejesus, et al.
Maraviroc versus efavirenz, both in combination with zidovudine-lamivudine for the treatment of antiretroviral-naive subjects with CCR5- tropic HIV-1 infection.
J Infect Dis, 201 (2010), pp. 803-813
[14.]
G. Fätkenheuer, M. Nelson, A. Lazzarin, I. Konourina, A. Howpelman, H. Lampiris, et al.
Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection.
N Engl J Med, 359 (2008), pp. 1442-1455
[15.]
E. Poveda, J. Alcamí, R. Paredes, J. Córdoba, F. Gutiérrez, J.M. Llibre, et al.
Genotypic determination of HIV tropism - clinical and methodological recommendations to guide the therapeutic use of CCR5 antagonists.
AIDS Rev, 12 (2010), pp. 135-148
[16.]
L.P. Vandekerckhove, A.M. Wensing, R. Kaiser, F. Brun-Vézinet, B. Clotet, A. De Luca, et al.
European guidelines on the clinical management of HIV-1 tropism testing.
Lancet Infect Dis, 11 (2011), pp. 394-407
[17.]
A.J. Low, W. Dong, D. Chan, T. Sing, R. Swanstrom, M. Jensen, et al.
Current V3 genotyping algorithms are inadequate for predicting X4 co-receptor usage in clinical isolates.
AIDS, 21 (2007), pp. F17-F24
[18.]
E. Poveda, V. Briz, V. Roulet, M.M. González, J.L. Faudon, K. Skrabal, et al.
Correlation between a phenotypic assay and three bioinformatic tools for determining HIV co-receptor use.
AIDS, 21 (2007), pp. 1487-1490
[19.]
C. De Mendoza, K. Van Baelen, E. Poveda, E. Rondelez, N. Zahonero, L. Stuyver, et al.
Performance of a population-based HIV-1 tropism phenotypic assay and correlation with V3 genotypic prediction tools in recent HIV-1 seroconverters.
J Acquir Immune Defic Syndr, 48 (2008), pp. 241-244
[20.]
C. Garrido, V. Roulet, N. Chueca, E. Poveda, A. Aguilera, K. Skrabal, et al.
Evaluation of eight different bioinformatics tools to predict viral tropism in different human immunodeficiency virus type 1 subtypes.
J Clin Microbiol, 46 (2008), pp. 887-891
[21.]
E. Poveda, E. Seclén, M. González, F. García, N. Chueca, A. Aguilera, et al.
Design and validation of new genotypic tools for easy and reliable estimation of HIV tropism before using CCR5 antagonists.
J Antimicrob Chemother, 63 (2009), pp. 1006-1010
[22.]
N. Chueca, C. Garrido, M. Álvarez, E. Poveda, L. De Dios Luna, N. Zahonero, et al.
Improvement in the determination of HIV-1 tropism using the V3 gene sequence and a combination of bioinformatic tools.
J Med Virol, 81 (2009), pp. 763-767
[23.]
V. Sánchez, M. Masiá, C. Robledano, S. Padilla, J. Ramos, F. Gutiérrez.
Performance of genotypic algorithms for predicting HIV-1 tropism measured against the enhancedsensitivity Trofile coreceptor tropism assay.
J Clin Microbiol, 48 (2010), pp. 4135-4139
[24.]
E. Seclén, C. Garrido, M.M. González, J. González-Lahoz, C. De Mendoza, V. Soriano, et al.
High sensitivity to detect X4 variants using specific genotypic tools in antiretroviral-experienced HIV patients suitable to CCR5 antagonists therapy.
J Antimicrob Chemother., 65 (2010), pp. 1486-1492
[25.]
V. Sánchez, C. Robledano, B. Lumbreras, S. Padilla, B. Lumbreras, E. Poveda, et al.
A highly sensitive and specific model for predicting HIV-1 tropism in treatmentexperienced patients combining V3 loop sequences interpretation and clinical parameters.
J Acquir Immune Defic Syndr, 56 (2011), pp. 51-58
[26.]
T. Sing, A.J. Low, N. Beerenwinkel, O. Sander, P.K. Cheung, F.S. Domingues, et al.
Predicting HIV coreceptor usage on the basis of genetic and clinical covariates.
Antivir Ther, 12 (2007), pp. 1097-1106
[27.]
M.A. Jensen, F.S. Li, A.B. Van’t Wout, D.C. Nickle, D. Shriner, H.X. He, et al.
Improved coreceptor usage prediction and genotypic monitoring of R5-to-X4 transition by motif analysis of human immunodeficiency virus type 1 env V3 loop sequences.
J Virol, 77 (2003), pp. 13376-13388
[28.]
R. McGovern, A. Thielen, T. Mo, W. Dong, C.K. Woods, D. Chapman, et al.
Populationbased V3 genotypic tropism assay: a retrospective analysis using screening samples from the A4001029 and MOTIVATE studies.
AIDS., 24 (2010), pp. 2517-2525
[29.]
McGovern R, Dong W, Zhong X, Knapp D, Thielen A, Chapman D, et al. Populationbased sequencing of the V3-loop is comparable to the enhanced sensitivity trofile assay in predicting virologic response to maraviroc of treatment-naive patients in the MERIT trial. 17th Conference on Retroviruses and Opportunistic Infections. San Francisco; 2010.[Abstract 92].
[30.]
Sierra S, Thielen A, Reuter S, Jensen B, Esser S, Faetkenheuer G, et al. Tropism determination and clinical outcome of 61 patients under maraviroc treatment. 8th European HIV Drug Resistance Workshop. Sorrento, Italy; 2010.[Abstract 20].
[31.]
Obermeier M, Carganico A, Bieniek B, Schleehauf D, Dupke S, Fischer K, et al. Tropism testing from proviral DNA- analysis of a subgroup from the Berlin maraviroc cohort. 8th European HIV Drug Resistance Workshop. Sorrento, Italy; 2010.[Abstract 23].
[32.]
Van Lelyveld S, Symons J, Hoepelman A, Stam A, Van Ham P, Nijhuis M, et al. Correlation of clinical outcome of maraviroc treatment with different methods to determine HIV tropism: genotypic assay, MT-2 assay and Trofile. 8th European HIV Drug Resistance Workshop. Sorrento, Italy; 2010.[Abstract 41].
[33.]
García F, Chueca N, Álvarez M, Codoñer F, Paredes R, Téllez MJ, et al. Low detection of non-CCR5 using strains by ultra deep sequencing does not compromise response to a maraviroc containing regimen. 8th European HIV Drug Resistance Workshop. Sorrento, Italy; 2010.[Abstract 22].
[34.]
J.J. Rodríguez, E. Seclén, E. Poveda, E. Varela, B. Regueiro, A. Aguilera.
Variability in HIV viral tropism determination using different genotypic algorithms in patients infected with B versus non-B HIV-1 subtypes.
Enferm Infecc Microbiol Clin, 29 (2011), pp. 4-8
[35.]
S. Raymond, P. Delobel, M. Mavigner, M. Cazabat, C. Souyris, S. Encinas, et al.
Genotypic prediction of human immunodeficiency virus type 1 CRF02-AG tropism.
J Clin Microbiol, 47 (2009), pp. 2292-2294
[36.]
S. Raymond, P. Delobel, M. Mavigner, L. Ferradini, M. Cazabat, C. Souyris, et al.
Prediction of HIV type 1 subtype C tropism by genotypic algorithms built from subtype B viruses.
J Acquir Immune Defic Syndr, 53 (2010), pp. 167-175
[37.]
Chueca N, Álvarez M, Guillot V, López Bueno MJ, Mérida MD, Peña A, et al. Genotypic estimation of coreceptor usage in HIV-infected patients from the South of Spain carrying non-B subtypes. 9th European Workshop on HIV & Hepatitis Treatment Strategies & HIV Antiviral Drug Resistance. Paphos, Cyprus; 2011.[Abstract P 45].
[38.]
Harrigan R, Zhong X, Lewis M, Dong W, Knapp D, Swenson L, et al. The influence of PCR amplification variation on the ability of population based-PCR to detect non-R5 HIV. 8th European HIV Drug Resistance Workshop. Sorrento, Italy; 2010.[Abstract 38].
[39.]
S. Raymond, P. Recordon-Pinson, A. Saliou, P. Delobel, F. Nicot, D. Descamps, et al.
Improved V3 genotyping with duplicate PCR amplification for determining HIV-1 tropism.
J Antimicrob Chemother.\, (2011),
[40.]
E. Seclén, M. Del Mar González, C. De Mendoza, V. Soriano, E. Poveda.
Dynamics of HIV tropism under suppressive antiretroviral therapy: implications for tropism testing in subjects with undetectable viraemia.
J Antimicrob Chemother, 65 (2010), pp. 1493-1496
[41.]
Obermeier M, Carganico A, Cordes C, Fisher K, Schuler C, Mayr C, et al. Week 48 update on the Berlin Maraviroc Cohort. 9th European Workshop on HIV & Hepatitis Treatment Strategies & HIV Antiviral Drug Resistance. Paphos, Cyprus; 2011.[Abstract P 19].
[42.]
Seclén E, Soriano V, González MM, Sarriá C, Prosper L, Sepúlveda MJ, et al. Clinical validation of a genotypic HIV tropism assay to guide the therapeutic use of CCR5 antagonists. 9th European Workshop on HIV & Hepatitis Treatment Strategies & HIV Antiviral Drug Resistance. Paphos, Cyprus; 2011.[Abstract O 23].
[43.]
J. Leamon, W. Lee, K. Tartaro, J. Lanza, G. Sarkis, A. DeWinter, et al.
A massively parallel PicoTiterPlate based platform for discrete picoliter-scale polymerase chain reactions.
Electrophoresis, 24 (2003), pp. 3769-3777
[44.]
M. Margulies, M. Egholm, W. Altman, S. Attiya, J. Bader, L. Bemben.
Genome sequencing in microfabricated high-density picolitre reactors.
Nature, 437 (2005), pp. 376-380
[45.]
J. Archer, M. Braverman, B. Taillon, B. Desany, I. James, P. Harrigan, et al.
Detection of low-frequency pretherapy chemokine (CXC motif) receptor 4 (CXCR4)-using HIV-1 with ultra-deep pyrosequencing.
AIDS, 23 (2009), pp. 1209-1218
[46.]
Pou C, Codoñer F, Thielen A, Bellido R, Cabrera C, Dalmau J, et al. High resolution tropism kinetics by quantitative deep sequencing in HIV-1-infected subjects initiating suppressive first-line ART. 17th Conference on Retroviruses and Opportunistic Infections. San Francisco, USA; 2010.[Abstract 544].
[47.]
A. Saliou, P. Delobel, M. Dubois, F. Nicot, S. Raymond, V. Calvez, et al.
Concordance between two phenotypic assays and ultradeep pyrosequencing for determining HIV-1 tropism.
Antimicrob Agents Chemother, 55 (2011), pp. 2831-2836
[48.]
L.C. Swenson, T. Mo, W.W. Dong, X. Zhong, C.K. Woods, M.A. Jensen, et al.
Deep sequencing to infer HIV-1 co-receptor usage: application to three clinical trials of maraviroc in treatment-experienced patients.
J Infect Dis, 203 (2011), pp. 237-245
[49.]
V. Soriano, C. Perno, R. Kaiser, V. Calvez, J.M. Gatell, G. Di Perri, et al.
When and how to use maraviroc in HIV-infected patients.
AIDS, 23 (2009), pp. 2377-2385
[50.]
Panel de expertos de Gesida y Plan Nacional sobre el Sida. National consensus document by GESIDA/National AIDS Plan on antiretroviral treatment in adults infected by the human immunodeficiency virus (January 2011 update)]. Enferm Infecc Microbiol Clin. 2011; 29:209.e1-103.
Copyright © 2011. Elsevier España S.L.. Todos los derechos reservados
