Papel de las nuevas moléculas en el tratamiento antirretroviral. Dónde situar el raltegravir

Arribas, José R.

doi:10.1016/S0213-005X(08)76574-1

Información del artículo

Resumen

Bibliografía

Descargar PDF

Estadísticas

El tratamiento antirretroviral de rescate se ha visto revolucionado por la aparición de nuevos fármacos en los últimos años: enfuvirtida (un inhibidor de la fusión), tipranavir/ritonavir (inhibidor de la proteasa de alta barrera genética), darunavir/ritonavir (inhibidor de la proteasa de alta barrera genética), etravirina (no nucleósido activo contra el virus de la inmunodeficiencia humana [VIH] resistente a nevirapina y efavirenz), maraviroc (un inhibidor de los correceptores CCR5) y raltegravir (un inhibidor de la integrasa). La utilización de estos fármacos en pautas de rescate ha hecho posible que el objetivo de la terapia antirretroviral de rescate sea el mismo que en pacientes naïve: alcanzar una carga viral menor de 50 copias/ml de ARN de VIH. Raltegravir es el primer inhibidor de la integrasa disponible para los clínicos en España. Su vía principal de metabolización es glucuronidación mediada por UGT1A1 por lo que tiene un bajo potencial de interacciones con fármacos que se metabolizan por la vía del citocromo P450. Raltegravir ha demostrado alta eficacia en 2 grandes ensayos clínicos de rescate, especialmente cuando se ha combinado con darunavir/ritonavir y enfuvirtida. Los datos preliminares apuntan a que raltegravir también podrá ser un fármaco eficaz para el tratamiento de pacientes naïve y como terapia de sustitución en pacientes que tengan toxicidad relacionada con inhibidores de la proteasa potenciados. Su mecanismo peculiar de acción ha planteado de nuevo la posibilidad de un impacto positivo de raltegravir en los reservorios de latencia del VIH.

Palabras clave:

Raltegravir

Darunavir/zitomavir

Entravirina

Maraviroc

Enfuvirtida

Tipranavir/zitomavir

VIH

Resistencia

Antiretroviral rescue therapy has been revolutionized by the development of new drugs in the last few years: enfuvirtide (a fusion inhibitor), tipranavir/ritonavir (a high genetic barrier protease inhibitor), darunavir/ritonavir (a high genetic barrier protease inhibitor), etravirine (a non-nucleoside reverse transcriptase inhibitor active against nevirapine- and efavirenz- resistant HIV), maraviroc (a CCR5 coreceptor inhibitor) and raltegravir (an integrase inhibitor). The use of these drugs in rescue regimens has allowed the goal of antiretroviral rescue therapy to be the same as that in treatment naïve-patients: to achieve a viral load lower than 50 copies of RNA of HIV/ml. Raltegravir is the first integrase inhibitor available for clinical use in Spain. This drug is primarily metabolized through UGT1A1-mediated glucuronidation and consequently has a low potential for interactions with drugs metabolized by the cytochrome P450 pathway. Raltegravir has been demonstrated to have high efficacy in two large clinical trials of rescue therapy, especially when combined with darunavir /ritonavir and enfuvirtide. Preliminary data suggest that raltegravir could also be an effective drug in treatment-naïve patients and as substitution therapy in patients with toxicity due to boosted protease inhibitor therapy. The drug's unusual mechanism of action has reopened the possibility of a positive effect on latent HIV reservoirs.

Key words:

Raltegravir

Darunavir/zitomavir

Entravirine

Maraviroc

Enfuvirtide

Tipranavir/zitomavir

HIV

Resistance

El Texto completo está disponible en PDF

Bibliografía

[1.]

Recomendaciones de Gesida/Plan Nacional sobre el Sida respecto al tratamiento antirretroviral en adultos infectados por el virus de la inmunodeficiencia humana [actualizado Ene 2008; citado 20 Abr 2008]. Disponible en: http://www.gesida.seimc.org/pcientifica/fuentes/DcyRc/Gesida_dcyrc200802_TARVGesidayPNS.zip

[2.]

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 29, 2008; 1-128 [citado 20 Abr 2008]. Disponible en: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf

[3.]

Guidelines for the Clinical Management and Treatment of HIV-infected Adults in Europe [citado 20 Abr 2008]. Disponible en: http://www.eacs.eu/guide/1_Treatment_of_HIV_Infected_Adults.pdf

[4.]

J. Lu, S.G. Deeks, R. Hoh, G. Beatty, B.A. Kuritzkes, J.N. Martin, et al.

Rapid emergence of enfuvirtide resistance in HIV-1-infected patients: results of a clonal analysis.

J Acquir Immune Defic Syndr, 43 (2006), pp. 60-64

http://dx.doi.org/10.1097/01.qai.0000234083.34161.55 | Medline

[5.]

M. Nelson, K. Arastéh, B. Clotet, D.A. Cooper, K. Henry, C. Katlama, et al.

Durable efficacy of enfuvirtide over 48 weeks in heavily treatment-experienced HIV-1-infected patients in the T-20 versus optimized background regimen only 1 and 2 clinical trials.

Acquir Immune Defic Syndr, 40 (2005), pp. 404-412

[6.]

C.B. Hicks, P. Cahn, D.A. Cooper, S.L. Walmsley, C. Katlama, B. Clotet, RESIST investigator group, et al.

Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials.

Lancet, 368 (2006), pp. 466-475

http://dx.doi.org/10.1016/S0140-6736(06)69154-X | Medline

[7.]

B. Clotet, N. Bellos, J.M. Molina, D. Cooper, J.C. Goffard, A. Lazzarin, POWER 1 and 2 study groups, et al.

Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials.

Lancet, 369 (2007), pp. 1169-1178

http://dx.doi.org/10.1016/S0140-6736(07)60497-8 | Medline

[8.]

J. Lalezari, J. Goodrich, E. DeJesus, H. Lampiris, R. Gulick, M. Saag, et al.

Efficacy and safety of maraviroc in antiretroviral-experienced patients infected with CCR5-tropic HIV-1: 48-week results of MOTIVATE 1 [Abstract H-718a].

47th Interscience Conference on Antimicrobial Agents and Chemotherapy,

[9.]

R. Haubrich, P. Cahn, B. Grinsztejn, J. Lalezari, J. Madruga, A. Mills, On behalf of the DUET-I Study Group, et al.

DUET-1: Week-48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 612 treatment-experienced HIV-1-infected patients.

Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections,

[10.]

M. Johnson, T. Campbell, B. Clotet, C. Katlama, A. Lazzarin, W. Tower, On behalf of the DUET-2 Study Group, et al.

DUET-2: week-48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 591 treatment-experienced HIV-1-infected patients.

Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections,

[11.]

D. Cooper, J. Gatell, J. Rockstroh, C. Katlama, P. Yeni, A. Lazzarin, And the BENCHMRK-1 Study Group, et al.

48-week results from BENCHMRK-1, a phase III study of raltegravir in patients failing ART with triple-class resistant HIV-1.

Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections,

[12.]

R. Steigbigel, P. Kumar, J. Eron, M. Schechter, M. Markowits, M. Loutfhy, The BENCHMRK-2 Study Group, et al.

48-week results from BENCHMRK-2, a phase III study of raltegravir in patients failing ART with triple-class resistant HIV-1.

Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections,

[13.]

M. Schöller, M. Kraft, R. Hoetelmans, V. Vyncke, K. Vandemeulen, M. Peeters, et al.

Significant decrease in TMC125 exposures when co-administered with tipranavir boosted with ritonavir in healthy subjects.

Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections,

[14.]

D. Cooper, R. Zajdenverg, K. Ruxrungtham, J. Scherer, R.L. Chaves.

Efficacy and safety of two doses of tipranavir/ritonavir versus lopinavir/ritonavir-based therapy in antiretroviral-naïve patients: results of BI 1182.33.

Eighth International Congress on Drug Therapy in HIV Infection,

[15.]

J.M. Molina, C. Cohen, C. Katlama, B. Grinsztejin, A. Timerman, R.D. Pedro, et al.

TMC114/r in treatment-experienced HIV patients in POWER 3: 24-week efficacy and safety analysis.

Program and abstracts of the XVI International AIDS Conference,

[16.]

E. DeJesus, R. Ortiz, H. Khanlou, E. Voronin, J. Van Lunzen, J. Andrade-Villanueva, et al.

Efficacy and safety of darunavir/ritonavir vs lopinavir/ritonavir in ARV treatment-naive HIV-1-infected patients at Week 48: ARTEMIS.

Program and abstracts of the 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC),

[17.]

Darunavir/ritonavir. Ficha técnica. Disponible en: www.europa.eu/humandocs(PDFs/EPAR/prexista/H-707-PI-es.pdf

[18.]

B. Woodfall, J. Vingerhoets, M. Peeters, I. Peeters, G. De Smedt, G.D. Miralles, et al.

Impact of NNRTI and NRTI resistance on the response to the regimen of TMC125 Plus 2 NRTIs in Study TMC125-227.

Eighth International Congress on Drug Therapy in HV Infection,

[19.]

C. Katlama, T. Campbell, B. Clotet, M. Johnson, A. Lazzarin, K. Arasteh, et al.

DUET-2: 24 week results of a phase III randomised double-blind trial to evaluate the efficacy and safety of TMC125 versus placebo in 591 treatmentexperienced HIV-1 infected patients.

4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention,

[20.]

H. Mayer, E. Van der Ryst, M. Saag, B. Clotet, G. Fatkenheuer, N. Clumeck, et al.

Safety and efficacy of maraviroc (MVC), a novel CCR5 antagonist, when used in combination with optimized background therapy (OBT) for the treatment of antiretroviral-experienced subjects infected with dual/mixed-tropic HIV-1: 24-week results of a phase 2b exploratory trial [Abstract THLB0215].

XVI International AIDS Conference,

[21.]

E. Coakley, J. Benhamida, C. Chappey, J. Whitcomb, J. Goodrich.

An evaluation of tropism profiles and other characteristics among 3988 individuals screened from A4001026, A4001027 (MOTIVATE 1) and A4001028 (MOTIVATE 2) studies for maraviroc.

Second International Workshop on Targeting HIV Entry,

[22.]

D. Hardy, J. Reynes, I. Konourina, D. Wheeler, S. Moreno, E. Van der Ryst, et al.

Efficacy and Safety of Maraviroc plus Optimized Background Therapy in Treatment-experienced Patients Infected with CCR5-Tropic HIV-1: 48-Week Combined Analysis of the MOTIVATE Studies.

15th Conference on Retroviruses and Opportunistic Infections (CROI),

[23.]

G. Fätkenheuer, I. Konourina, M. Nelson, N. Cluckmeck, A. Lazzarin, I.M. Hoepelman, et al.

Efficacy and Safety of Maraviroc (MVC) Plus Optimized Background Therapy (OBT) in Varaemic, Antiretroviral Treatment-Experienced Patients Infected with CCR5-Tropic (R5) HIV-1 in Europe, Australia and North America (MOTIVATE 2): 48-Week Results [Abstract PS3/5].

11th European AIDS Conference/EACS,

[24.]

M. Saag, I. Prudence, J. Heera, M. Tawadrous, E. DeJesus, N. Clumeck, et al.

A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc versus efavirenz, both in combination with Combivir (zidovudine [ZDV] / lamivudine [3TC]), for the treatment of antiretroviral naïve patients infected with R5 HIV-1: week 48 results of the MERIT study.

Fourth International AIDS Society Conference on HIV Treatment and Pathogenesis,

[25.]

J. Heera, M. Saag, P. Ive, J. Whitcomb, M. Lewis, L. McFadyen, et al.

Virological Correlates associated with treatment failure at week 48 in the phase 3 study of maraviroc in treatment-naive patients.

Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections,

[26.]

T. Wilkin, H. Ribaudo, R. Gulick.

The Relationship of CCR5 Inhibitors to CD4 Cell Count Changes: A Meta-analysis of Recent Clinical Trials in Treatment- experienced Subjects.

15th Conference on Retroviruses and Opportunistic Infections (CROI 2008),

[27.]

E. DeJesus, S. Walmsley, C. Cohen, et al.

Fasted Lipid Changes after Administration of Maraviroc or Efavirenz in Combination with Zidovudine and Lamivudine for 48 weeks to Treatment-naive HIV-infected Patients.

15th Conference on Retroviruses and Opportunistic Infections (CROI 2008),

[28.]

R.S. Klein.

A moving target: the multiple roles of CCR5 in infectious diseases.

J Infect Dis, 197 (2008), pp. 183-186

http://dx.doi.org/10.1086/524692 | Medline

[29.]

J.D. Reeves, D. Han, Y. Liu, et al.

Enhancements to the Trofile HIV coreceptor tropism assay enable reliable detection of CXCR4-using subpopulations at less than 1%.

Program and abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy,

[30.]

M. Markowitz, B.Y. Nguyen, E. Gotuzzo, et al.

Rapid Onset and Durable Antiretroviral Effect of Raltegravir, a Novel HIV-1 Integrase Inhibitor, as part of Combination ART in Treatment-Naive HIV-1 infected patients: 48-week data.

4th International AIDS Society Conference,

[31.]

J.M. Murray, S. Emery, A.D. Kelleher, et al.

Antiretroviral therapy with the integrase inhibitor raltegravir alters decay kinetics of HIV, significantly reducing the second phase.

AIDS, 21 (2007), pp. 2315-2321

http://dx.doi.org/10.1097/QAD.0b013e3282f12377 | Medline

[32.]

M. Harris, G. Larsen, J. Montaner.

Outcomes of patients switched from enfuvirtide to raltegravir within a virologically suppressive regimen.

Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections,

Indexada en:

Síguenos:

Suscribirse:

Indexada en:

Síguenos:

Suscribirse:

Suscríbase a la newsletter