Información del artículo
Los inhibidores de la integrasa son la familia de antirretrovirales más recientemente aprobada para el tratamiento de la infección por el virus de la inmunodeficiencia humana (VIH). Al igual que sucede con el resto de los antirretrovirales, bajo presión farmacológica el virus selecciona mutaciones de resistencia si la supresión viral no es completa. Se seleccionan mutaciones en el gen de la integrasa, concretamente en posiciones próximas al centro catalítico. La experiencia clínica con estos fármacos es escasa, de modo que la información sobre resistencias es limitada. Los fracasos a raltegravir se asocian a selección de mutaciones primarias como N155H (40%) y diferentes cambios en la posición Q148 (28%). Con menor frecuencia se seleccionan Y143R (6,6%) y E92Q. Las mutaciones más frecuentemente observadas en los fracasos a elvitegravir son E92Q, E138K, Q148R/K/H y N155H, y con menor frecuencia S147G y T66A/I/K. El patrón de resistencias más común parece ser E138K + E147G + Q148R. Hay un alto grado de resistencia cruzada entre raltegravir y elvitegravir que imposibilitará la secuenciación entre ellos.
Palabras clave:
Raltegravir
Resistencia
Integrasa
VIH
Integrase inhibitors are the most recently approved family of antiretroviral agents for the treatment of HIV infection. As with other antiretroviral agents, under pharmacological pressure, the virus selects resistance mutations if viral suppression is incomplete. Mutations are selected in the integrase gene, specifically in positions proximal to the catalytic center. Because clinical experience with these drugs is scarce, information on resistance is limited. Virologic failure with raltegravir is associated with selection of primary mutations such as N155H (40%) and distinct changes in position Q148 (28%). Less frequently, Y143R (6.6%) and E92Q are selected. The most frequently observed mutations in failure with elvitegravir are E92Q, E138K, Q148R/K/H and N155H, and less frequently S147G and T66A/I/K. The most common resistance pattern seems to be E138K + E147G + Q148R. There is a high grade of cross resistance between raltegravir and elvitegravir, making sequencing between these two drugs impossible.
Key words:
Raltegravir
Resistance
Integrase
HIV
El Texto completo está disponible en PDF
Bibliografía
[1.]
V. DeGruttola, L. Dix, R. D’Aquila, D. Holder, A. Phillips, M. Ait-Khaled, et al.
The relation between baseline HIV drug resistance and response to antiretroviral therapy: re-analysis of retrospective and prospective studies using a standarized data analysis plan.
Antivir Ther, 5 (2000), pp. 41-48
[2.]
C. De Mendoza, C. Garrido, A. Corral, G. Ramírez-Olivencia, I. Jiménez-Nacher, N. Zahonero, et al.
Changing rates and patterns of drug resistance mutations in antiretroviral-experienced HIV-infected patients.
AIDS Res Hum Retroviruses, 23 (2007), pp. 879-885
[3.]
V. Miller, B. Larder.
Mutational patterns in the HIV genome and cross-resistance following nucleoside and nucleotide analogue drug exposure.
Antivir Ther, 6 (2001), pp. 25-44
[4.]
C.F. Perno, G. Moyle, C. Tsoukas, W. Ratanasuwan, J. Gatell, M. Schechter.
Overcoming resistance to existing therapies in HIV-infected patients: the role of new antiretroviral drugs.
J Med Virol, 80 (2008), pp. 565-576
[5.]
D. Hazuda, M. Miller, B. Nguyen, J. Zhao.
Resistance to the HIV integrase inhibitor raltegravir: analysis of protocol 005, a phase 2 study in patients with triple-class resistant HIV-1 infection [Abstract 8].
16th International HIV Drug Resistance Workshop,
[6.]
M. Markowitz, B. Nguyen, E. Gotuzzo, F. Mendo, W. Ratanasuwan, C. Kovacs, et al.
Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study.
J Acquir Immune Defic Syndr, 46 (2007), pp. 125-133
[7.]
D. Cooper, J. Gatell, J. Rockstroh, C. Katlama, P. Yeni, A. Lazzarin, For the BENCHMRK-1 Study Group, et al.
48-Week Results from BENCHMRK-1, a Phase III Study of Raltegravir in Patients Failing Antiretroviral Therapy (ART) with Triple-Class Resistant HIV-1 [Abstract 788].
15th Conference on Retroviruses and Opportunistic Infections,
[8.]
R. Steigbigel, P. Kumar, J. Eron, M. Schechter, M. Markowitz, M. Loutfy, For the BENCHMRK-2 Study Group, et al.
48-Week Results from BENCHMRK-2, a Phase III Study of Raltegravir in Patients Failing Antiretroviral Therapy (ART) with Triple-Class Resistant HIV-1 [Abstract 789].
15th Conference on Retroviruses and Opportunistic Infections,
[9.]
I. Malet, O. Delelis, M. Valantin, B. Montes, C. Soulie, M. Wirden, et al.
Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro.
Antimicrob Agents Chemother, 52 (2008), pp. 1351-1358
[10.]
C. Charpentier, M. Karmochkine, D. Laureillard, P. Tisserand, L. Bélec, L. Weiss, et al.
Drug resistance profiles of HIV integrase gene in patients failing Raltegravir-salvage therapy [Abstract 48].
6th European HIV Drug Resistance Workshop,
[11.]
C. Garrido, F. Blanco, K. Van Baelen, N. Zahonero, J. González-Lahoz, J. Villacian, et al.
Raltegravir clinical response and resistance in heavily experienced patients [Abstract 52].
6th European HIV Drug Resistance Workshop,
[12.]
D. Mc Coll, S. Fransen, S. Gupta, N. Parkin, N. Margot, R. Ledford, et al.
Resistance and cross-resistance to first generation integrase inhibitors: Insights form a Phase 2 study of Elvitegravir (GS-9137) [Abstract 9].
16th International HIV Drug Resistance Workshop,
[13.]
S. Deeks, S. Kar, S. Gubernick, P. Kirkpatrick.
Raltegravir.
Nature Rev, 7 (2008), pp. 117-118
[14.]
E. Rondelez, K. Van Baelen, F. Ceccherini-Silverstein, V. Van Eygen, P. Van den Zegel, B. Winters, et al.
Preliminary biological cut-offs for GS-9137 and MK-0518 integrase inhibitors derived from clonal phenotypic analysis [Abstract 73].
6th European HIV Drug Resistance Workshop,
[15.]
E. Poveda, V. Briz, D. Paraskevis, P. Barreiro, A. Hatzakis, V. Soriano.
Dynamics of drug-resistant HIV-1 in plasma and peripheral blood cells in patients during and after enfuvirtide therapy.
AIDS Res Hum Retroviruses, 23 (2007), pp. 1078-1082
[16.]
G. Jones, R. Ledford, F. Yu, M. Miller, M. Tsiang, D. McColl.
Resistance profile of HIV-1 mutants in vitro selected by the HIV-1 integrase inhibitor GS- 9137 (JTK-303) [Abstract 627].
14th Conference on Retrovirus and Opportunistic Infections,
[17.]
D. Hazuda, P. Felock, M. Witmer, A. Wolfe, K. Stillmock, J. Grobler, et al.
Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells.
Science, 287 (2000), pp. 646-650
[18.]
E. DeJesus, C. Cohen, R. Elion, R. Ortiz, L. Haroldo, S. Franson, et al.
First report of raltegravir (RAL, MK-0518) use alter virologic rebound on elvitegravir (EVT, GS-9137) [Abstract TUPEB032].
4th IAS Conference on HIV,
[19.]
J. Wai, T. Fisher, M. Embrey, M. Egbertson, J. Vacca, D. Hazuda, et al.
Next generation of inhibitors of HIV-1 integrase strand transfer inhibitor: Structural diversity and resistance profiles [Abstract 87].
14th Conference on Retrovirus and Opportunistic Infections,
[20.]
M. Lataillade, J. Chiarella, M. Kozal.
Natural polymorphism of the HIV-1 integrase gene and mutations associated with integrase inhibitor resistance.
Antivir Ther, 12 (2007), pp. 563-570
[21.]
A. Low, H. Mohri, M. Markowitz.
Frequency of naturally occurring polymorphisms associated with resistance to integrase inhibitors in a recently infected cohort [Abstract 625].
14th Conference on Retrovirus and Opportunistic Infections,
[22.]
R. Zioni, S. Rhee, T. Liu, R. Shafer.
Natural variation of HIV-1 group M Integrase: Implications for integrase inhibitor therapy [Abstract 623].
14th Conference on Retrovirus and Opportunistic Infections,
[23.]
C. Garrido, A.M. Geretti, C. De Mendoza, C. Booth, A. Strang, V. Soriano.
Polymorphisms at the integrase gene in distinct HIV populations may influence the susceptibility to integrase inhibitors [Abstract 12].
6th European HIV Drug Resistance Workshop,
[24.]
J. Hackett, B. Harris, V. Holzmayer, J. Yamaguchi, C. Luk K, C. Brennan, et al.
Naturally occurring polymorphisms in HIV-1 group M, N, and O integrase: implications for integrase inhibitors [Abstract 872].
15th Conference on Retroviruses and Opportunistic Infections,
[25.]
N. Sichtig, M. Däumer, S. Esser, U. Dittmer, E. Schülter, M. Oette, et al.
Analysis of integrase inhibitor (INI) resistance of HIV-1 group M in ARTnaïve and -experienced but INI-naïve patients in Germany [Abstract 67].
6th European HIV Drug Resistance Workshop,
[26.]
B. Roquebert, F. Damond, G. Collin, S. Matheron, A. Taieb, G. Peytavin, The French ANRS HIV-2 Cohort (ANRS CO 05 VIH-2), et al.
Polymorphism of HIV-2 integrase gene and in vitro phenotypic susceptibility of HIV-2 clinical isolates to integrase inhibitors: raltegravir and elvitegravir [Abstract 83].
Antivir Ther, 12 (2007), pp. S92
[27.]
V. Briz, C. Garrido, J. Morello, C. De Mendoza, V. Soriano.
Etravirine and Raltegravir are active against HIV-1 group O [Abstract 71].
6th European HIV Drug Resistance Workshop,
[28.]
Martínez-Picado J, Martínez MA. HIV-1 reverse transcriptase inhibitor resistance mutations and fitness: A view from the clinic and ex vivo. Virus Res. 2008 [en prensa].
[29.]
M. Buzón, S. Marfil, M. Puertas, E. García, B. Clotet, J. Blanco, et al.
Evolution of HIV-1 pol under HAART does not restrict fitness progression of HIV-1 integrase [Abstract 49].
6th European HIV Drug Resistance Workshop,
[30.]
B. Grinsztejn, B. Nguyen, C. Katlama, J.M. Gatell, A. Lazzarin, D. Vittecoq, et al.
Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial.
Lancet, 369 (2007), pp. 1261-1269
[31.]
S. Arponen, J. Benito, S. Lozano, F. Blanco, C. Garrido, C. De Mendoza, et al.
More pronounced effect of integrase inhibitor raltegravir on proviral DNA reduction that other antiretroviral drugs in patients achieving undetectable viremia [Abstract 796].
15th Conference on Retroviruses and Opportunistic Infections,
[32.]
K. Shimura, E. Kodama, Y. Sakagami, Y. Matsuzaki, W. Watanabe, K. Yamataka, et al.
Broad antiretroviral activity and resistance profile of the novel HIV integrase inhibitor elvitegravir (JTK-303/GS-9137).
J Virol, 82 (2008), pp. 764-774
[33.]
K. Van Laethem, Y. Schrooten, K. Covens, N. Dekeersmaeker, P. De Munter, E. Van Wijngaerden, et al.
A genotypic assay for the amplification and sequencing of integrase from diverse HIV type 1 group M subtypes [Abstract 78].
6th European HIV Drug Resistance Workshop,
[34.]
P. Smith, V. Holzmayer, L. Fang, P. Swanson, J. Hackett, N. Marlowe.
Performance of prototype integrase genotyping reagents for analysis of diverse HIV-1 strains [Abstract 881].
15th Conference on Retroviruses and Opportunistic Infections,
[35.]
Guía de Resistencias a los Antirretrovirales. Interpretación de genotipos de resistencia de la Red de Investigación en SIDA (RIS). Barcelona: Permanyer; 2007.
Copyright © 2008. Elsevier España S.L.. Todos los derechos reservados
