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La resistencia a los inhibidores de la proteasa (IP) generalmente es consecuencia de una mutación en el gen de la proteasa. Se han descrito distintos cambios para cada uno de los IP. La mutación I50L es la característica de resistencia al atazanavir (ATV). No produce resistencia cruzada con otros IP; por el contrario, aumenta la susceptibilidad a todos ellos (hipersusceptibilidad). Cuando los IP se administran conjuntamente con dosis bajas de ritonavir (r), la exposición a concentraciones más elevadas de IP hace necesaria la selección de múltiples mutaciones de resistencia en la proteasa para que haya una pérdida significativa de susceptibilidad. Para la mayoría de IP/r, incluido el ATV/r, se requieren ≥ 5 mutaciones en la proteasa para ocasionar un compromiso en la respuesta virológica. A pesar de tener una moderada barrera genética cuando no se potencia con ritonavir, la prolongada semivida del ATV minimiza el riesgo de resistencias en la práctica clínica.
Palabras clave:
Atazanavir
Resistencias
Inhibidores de la proteasa
VIH
Resistance to protease inhibitors (PI) is generally due to a mutation in the protease gene. Different changes have been described for each PI. The I 50L mutation is characteristic of resistance to atazanavir (ATV). It does not produce cross resistance to other PI; but it does increase susceptibility to all of them (hypersusceptibility). When PI are given concomitantly with low doses of ritonavir, the exposure to higher levels of PI requires that multiple resistance mutations have to be selected in the protease so that there is a significant loss of susceptibility. For the majority of PI/r, including ATV/r, ≥5 mutations in the protease are required to produce a compromise in the virological response. Despite having a moderate genetic barrier when not boosted with ritonavir, the prolonged half life of ATV minimises the risk of resistance in clinical practice.
Key words:
Atazanavir
Resistances
Protease inhibitors
HIV
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Bibliografía
[1.]
C. De Mendoza, V. Soriano.
Resistance to HIV protease inhibitors: mechanisms and clinical consequences.
Curr Drug Metab, 5 (2004), pp. 321-328
[2.]
P. Barreiro, A. Rendón, S. Rodríguez-Nóvoa, V. Soriano.
Atazanavir: the advent of a new generation of more convenient protease inhibitors.
HIV Clin Trials, 6 (2005), pp. 50-61
[3.]
Jiménez-Nácher I, García B, Barreiro P, Rodriguez-Novoa S, Morello J, González-Lahoz J, et al. Trends in the prescription of antiretroviral drugs and impact on plasma HIV-RNA measurements. J Antimicrob Chemother. En prensa.
[4.]
R. Shafer, J. Schapiro.
HIV-1 drug resistance mutations: an updated framework for the second decade of HAART.
AIDS Rev, 10 (2008), pp. 67-84
[5.]
M. Hirsch, H. Günthard, J. Schapiro, F. Brun-Vézinet, B. Clotet, S. 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
[6.]
R. Colonno, R. Rose, C. McLaren.
Identification of I50L as the signature atazanavir (ATV)-resistance mutation in treatment-naive patients receiving ATV-containing regimens.
J Infect Dis, 189 (2004), pp. 1802-1810
[7.]
P. Sista, B. Wasikowski, P. Lecocq, T. Pattery, L. Bacheler.
The HIV-1 protease resistance mutation I50L is associated with resistance to atazanavir and susceptibility to other protease inhibitors in multiple mutational contexts.
J Clin Virol, 42 (2008), pp. 405-408
[8.]
K. Squires, A. Lazzarin, J. Gatell.
Comparison of once daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV.
J Acquir Immune Defic Syndr, 36 (2004), pp. 1011-1019
[9.]
D. Malan, E. Krantz, N. David, V. Wirtz, J. Hammond, D. McGrath, et al.
Efficacy and safety of atazanavir, with or without ritonavir, as part of once-daily highly active antiretroviral therapy regimens in antiretroviral-naive patients.
J Acquir Immune Defic Syndr, 47 (2008), pp. 161-167
[10.]
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
[11.]
J. Gatell, D. Salmon-Ceron, A. Lazzarin, E. Van Wijngaerden, F. Antunes, C. Leen, et al.
Efficacy and safety of atazanavir-based highly active antiretroviral therapy in patients with virologic suppression switched from a stable, boosted or unboosted protease inhibitor treatment regimen: the SWAN Study (AI424-097) 48-week results.
Clin Infect Dis, 44 (2007), pp. 1484-1492
[12.]
V. Soriano, P. García-Gasco, E. Vispo, A. Ruiz-Sancho, F. Blanco, L. Martín-Carbonero, et al.
Efficacy and safety of replacing lopinavir with atazanavir in HIV-infected patients with undetectable plasma viraemia: final results of the SLOAT trial.
J Antimicrob Chemother, 61 (2008), pp. 200-205
[13.]
S. Rodríguez-Nóvoa, J. Morello, P. Barreiro, I. Maida, P. García-Gascó, E. Vispo, et al.
Switch from ritonavir-boosted to unboosted atazanavir guided by therapeutic drug monitoring.
AIDS Res Hum Retrovirus, 24 (2008), pp. 821-825
[14.]
R. Cleijsen, M. Van de Ende, F. Kroon, F. Lunel, P. Koopmans, L. Gras, et al.
Therapeutic drug monitoring of the HIV protease inhibitor atazanavir in clinical practice.
J Antimicrob Chemother, 60 (2007), pp. 897-900
[15.]
S. Rodríguez-Nóvoa, L. Martín-Carbonero, P. Barreiro, G. González-Pardo, I. Jiménez- Nácher, J. González-Lahoz, et al.
Genetic factors influencing atazanavir plasma concentrations and the risk of severe hyperbilirubinemia.
AIDS, 21 (2007), pp. 41-46
[16.]
S. Rodríguez Nóvoa, P. Barreiro, A. Rendón, A. Barrios, A. Corral, I. Jiménez-Nacher, et al.
Plasma levels of atazanavir and the risk of hyperbilirubinemia are predicted by the 3435C ->T polymorphism at the multidrug resistance gene 1.
Clin Infect Dis, 42 (2006), pp. 291-295
[17.]
P. Barreiro, S. Rodríguez-Novoa, P. Labarga, A. Ruiz, I. Jiménez-Nácher, L. Martín-Carbonero, et al.
Influence of liver fibrosis stage on plasma levels of antiretroviral drugs in HIV-infected patients with chronic hepatitis C.
J Infect Dis, 195 (2007), pp. 973-979
[18.]
A. Barrios, A.L. Rendón, O. Gallego, L. Martín-Carbonero, L. Valer, P. Ríos, et al.
Predictors of virological response to atazanavir in protease inhibitor-experienced patients.
HIV Clin Trials, 5 (2004), pp. 201-205
[19.]
C. Solas, P. Colson, I. Ravaux, I. Poizot-Martin, J. Moreau, B. Lacarelle, et al.
The genotypic inhibitory quotient: a predictive factor of atazanavir response in HIV-1-infected treatment-experienced patients.
J Acquir Immune Defic Syndr, 48 (2008), pp. 177-180
[20.]
K. Smith, W. Weinberg, E. De Jesus, M. Fischl, Q. Liao, L. Ross, et al.
Fosamprenavir or atazanavir once daily boosted with ritonavir 100 mg, plus tenofovir/ emtricitabine, for the initial treatment of HIV infection: 48-week results of ALERT.
AIDS Res Ther, 5 (2008), pp. 5-14
[21.]
Molina JM, Andrade-Villanueva J, Echevarria J. Efficacy and safety of once daily atazanavir/ritonavir compared to twice daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine in ARV-naïve HIV-1-infected subjects. CROI 2008, Boston. Abstract 37.
[22.]
J. Stebbing, B. Nathan, R. Jones, A. McKenna, T. Powles, M. Bower, et al.
Virological failure and subsequent resistance profiles in individuals exposed to atazanavir.
AIDS, 21 (2007), pp. 1826-1828
[23.]
M. Johnson, B. Grinsztejn, C. Rodriguez, J. Coco, E. De Jesus, A. Lazzarin, et al.
Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures.
AIDS, 19 (2005), pp. 685-694
[24.]
C. De Mendoza, L. Valer, E. Ribera, P. Barreiro, L. Martín-Carbonero, G. Ramirez, et al.
Performance of six different ritonavir-boosted protease inhibitor-ba- sed regimens in heavily antiretroviral-experienced HIV-infected patients.
HIV Clin Trials, 7 (2006), pp. 163-171
[25.]
L. Cuzin, P. Flandre, P. Pugliese, C. Duvivier, Y. Yazdanpanah, E. Billaud, et al.
Atazanavir in patients with persistent viral replication despite HAART: results from the French prospective NADIS cohort.
HIV Clin Trials, 9 (2008), pp. 147-151
[26.]
S. Sahali, M.L. Chaix, J.F. Delfraissy, J. Ghosn.
Ritonavir-boosted protease inhibitor monotherapy for the treatment of HIV-1 infection.
AIDS Rev, 10 (2008), pp. 4-14
[27.]
P. Vernazza, S. Daneel, V. Schiffer, L. Decosterd, W. Fierz, T. Klimkait, et al.
The role of compartment penetration in PI-monotherapy: the Atazanavir- Ritonavir Monomaintenance (ATARITMO) Trial.
AIDS, 21 (2007), pp. 1309-1315
[28.]
J. McKinnon, R. Delgado, J.R. Arribas, F. Pulido, J. Mellors.
More frequent detection of lopinavir resistance by single genome sequencing at virological failure of lopinavir/ritonavir maintenance therapy in the OK04 study.
Antivir Ther, 13 (2008), pp. A87
[29.]
O. Karlström, F. Josephson, A. Sönnerborg.
Early virologic rebound in a pilot trial of ritonavir-boosted atazanavir as maintenance monotherapy.
J Acquir Immune Defic Syndr, 44 (2007), pp. 417-422
[30.]
J. Yanchunas, D. Langley, L. Tao, R. Rose, J. Friborg, R. Colonno, et al.
Molecular basis for increased susceptibility of isolates with atazanavir resistance- conferring substitution I50L to other protease inhibitors.
Antimicrob Agents Chemother, 49 (2005), pp. 3825-3832
[31.]
A. Holguín, E. Ramirez de Arellano, P. Rivas, V. Soriano.
Efficacy of antiretroviral therapy in individuals infected with HIV-1 non-B subtypes.
AIDS Rev, 8 (2006), pp. 98-107
[32.]
M. Lataillade, J.M. Molina, A. Thiry, M. Mancini, D. McGrath, For the BMSAI424138 Study Group.
The CASTLE study 48 weeks results: the impact of HIV subtypes and baseline resistance on treatment outcomes and the emergence of resistance.
Antivir Ther, 13 (2008), pp. A135
[33.]
B. Rodés, J. Sheldon, C. Toro, V. Jiménez, M.A. Alvarez, V. Soriano.
Susceptibility to protease inhibitors in HIV-2 primary isolates from patients failing antiretroviral therapy.
J Antimicrob Chemother, 57 (2006), pp. 709-713
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