Antiretroviral drug summary: Darunavir/r (DRV/r; Prezista)
Last updated on Nov 10, 2008
V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, and L89V were associated with decreased susceptibility and virological response to DRV/r in the POWER studies (De Meyer et al. 2008c). In the POWER studies, about 60% with 0, 45% with 1-2, and <=20% with >=3 DRMs had RNA <50 copies/ml at wk 24. In a larger follow-up study which also included the DUET studies, all of the mutations with the exception of G73S were confirmed and T74P was added as a predictor of decreased virological response (De Meyer et al. 2008a). In an independent study, V32I, L33F, and I47VA were found to be associated with decreased virological response to DRV/r salvage therapy (Pellegrin et al. 2008).
In two phenotypic analyses, V32I, I50V, I54ML, L76V, and I84V were the mutations associated with the greatest reductions in DRV susceptibility (Van Marck et al. 2007; Vermeiren et al. 2007). The rare mutations V47A and I84A have also been shown to reduce DRV susceptibility (Vermeiren et al. 2007).
V32I, L33F, I47V/A, I54M/L, G73CS, I84V, and L89VI have been the most common mutations to emerge during DRV/r treatment failure (Prezista prescribing information)(De Meyer et al. 2008b; Delaugerre et al. 2008; Lambert-Niclot et al. 2008).
Potential cross resistance
Although V82F has not been reported to develop in viruses from patients receiving DRV/r, it has had a major effect on DRV/r susceptibility in multivariate analyses of the mutations present in DRV/r resistant virus isolates (Van Marck et al. 2007).
In addition to the seven major PI-resistance mutations, these four mutations were associated with a decreased virological response to DRV/r in the POWER and DUET studies (De Meyer et al. 2008a).
DRV/r has recently been approved for first line use based on the results of the ARTEMIS trial (Ortiz et al. 2008). It is a recommended regimen by both the DHHS and IAS-USA guidelines (Hammer et al. 2008).
DRV/r has outperformed ATV/r, SQV/r, FPV/r, and LPV/r when used for salvage therapy in patients previously treated with multiple PIs (Clotet et al. 2007; Katlama et al. 2007). Although it has not been compared directly to TPV/r, it is likely to be more active in the majority of PI-experienced patients (Hill and Moyle 2007).
Preliminary data suggests that DRV/r is also more efficacious virologically than LPV/r in LPV/r-naive PI-experienced patients (Madruga et al. 2007).
DRV/r has a high genetic barrier to resistance. Decreased clinical efficacy requires at least 10-fold decreased susceptibility. Complete loss of activity requires about 90-fold decreased susceptibility (Coakley et al. 2007 ; Winters et al. 2006).
- Clotet, B., N. Bellos, J.M. Molina, D. Cooper, J.C. Goffard, A. Lazzarin, A. Wohrmann, C. Katlama, T. Wilkin, R. Haubrich, C. Cohen, C. Farthing, D. Jayaweera, M. Markowitz, P. Ruane, S. Spinosa-Guzman, and E. Lefebvre. 2007. 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: 1169-1178.
- Coakley, E., C. Chappey, J. Benhamida, G.R. Picchio, and M.-P. de Bethune. 2007 Defining the upper and lower phenotypic clinical cut-offs for darunavir/ritonavir by the PhenoSense assay [abstract 610]. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, February 25 - 28.
- De Meyer, S., I. Dierynck, E. Lathouwers, B. Van Baelen, T. Vangeneugden, S. Spinosa-Guzman, M. Peeters, G. Picchio, and M. de Bethune. 2008a. Phenotypic and genotypic determinants of resistance to darunavir: analysis of data from treatment experienced patients in POWER 1, 2, 3 and DUET-1 and 2 [abstract 33]. Antivir Ther 13: Suppl 3:A33.
- De Meyer, S., E. Lathouwers, I. Dierynck, E. De Paepe, B. Van Baelen, R. Vangeneugden, S. Spinosa-Guzman, G. Picchio, and M. de Bethune. 2008b. Characterization of virological failures on darunavir/ritonavir in the randomized, controlled, phase III Titan trial in treatment-experienced patients [abstract 874]. CROI 2008.
- De Meyer, S., T. Vangeneugden, B. van Baelen, E. de Paepe, H. van Marck, G. Picchio, E. Lefebvre, and M.P. de Bethune. 2008c. Resistance profile of darunavir: combined 24-week results from the POWER trials. AIDS Res Hum Retroviruses 24: 379-388.
- Delaugerre, C., J. Pavie, P. Palmer, J. Ghosn, S. Blanche, L. Roudiere, S. Dominguez, E. Mortier, J.M. Molina, and P. de Truchis. 2008. Pattern and impact of emerging resistance mutations in treatment experienced patients failing darunavir-containing regimen. Aids 22: 1809-1813.
- Hammer, S.M., J.J. Eron, Jr., P. Reiss, R.T. Schooley, M.A. Thompson, S. Walmsley, P. Cahn, M.A. Fischl, J.M. Gatell, M.S. Hirsch, D.M. Jacobsen, J.S. Montaner, D.D. Richman, P.G. Yeni, and P.A. Volberding. 2008. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. Jama 300: 555-570.
- Hill, A. and G. Moyle. 2007. Relative antiviral efficacy of ritonavir-boosted darunavir and ritonavir-boosted tipranavir vs. control protease inhibitor in the POWER and RESIST trials. HIV Med 8: 259-264.
- Katlama, C., R. Esposito, J.M. Gatell, J.C. Goffard, B. Grinsztejn, A. Pozniak, J. Rockstroh, A. Stoehr, N. Vetter, P. Yeni, W. Parys, and T. Vangeneugden. 2007. Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week results of POWER 1. AIDS 21: 395-402.
- Lambert-Niclot, S., P. Flandre, A. Canestri, G. Peytavin, C. Blanc, R. Agher, C. Soulie, M. Wirden, C. Katlama, V. Calvez, and A.G. Marcelin. 2008. Factors associated with the selection of mutations conferring resistance to protease inhibitors (PIs) in PI-experienced patients displaying treatment failure on darunavir. Antimicrob Agents Chemother 52: 491-496.
- Madruga, J.V., D. Berger, M. McMurchie, F. Suter, D. Banhegyi, K. Ruxrungtham, D. Norris, E. Lefebvre, M.P. de Bethune, F. Tomaka, M. De Pauw, T. Vangeneugden, and S. Spinosa-Guzman. 2007. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet 370: 49-58.
- Ortiz, R., E. Dejesus, H. Khanlou, E. Voronin, J. van Lunzen, J. Andrade-Villanueva, J. Fourie, S. De Meyer, M. De Pauw, E. Lefebvre, T. Vangeneugden, and S. Spinosa-Guzman. 2008. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. Aids 22: 1389-1397.
- Pellegrin, I., L. Wittkop, L.M. Joubert, D. Neau, D. Bollens, M. Bonarek, P.M. Girard, H. Fleury, B. Winters, M.C. Saux, J.L. Pellegrin, R. Thiebaut, and D. Breilh. 2008. Virological response to darunavir/ritonavir-based regimens in antiretroviral-experienced patients (PREDIZISTA study). Antivir Ther 13: 271-279.
- Van Marck, H., I. Dierynck, G. Kraus, S. Hallenberger, T. Pattery, G. Muyldermans, H. Van Vijmen, K. Hertogs, and M. Bethune. 2007. Unraveling the complex resistance pathways of darunavir using the bioinformatics resistance determination (BIRD) [abstract]. HIVDRW2007.
- Vermeiren, H., E. Van Craenenbroeck, P. Alen, L. Bacheler, G. Picchio, and P. Lecocq. 2007. Prediction of HIV-1 drug susceptibility phenotype from the viral genotype using linear regression modeling. J Virol Methods 145: 47-55.
- Winters, B., H. Vermeiren, E. Van Craenenbroeck, P. Lecocq, T. Vangeneuden, M.-P. de Bethune, and L. Bacheler. 2006. Development of Virco®TYPE resistance analysis, including clinical cut-offs, for TMC114 Antivir Ther 11: S180.