Antiretroviral drug summary: Darunavir (DRV; Prezista®; TMC114)
Last updated on Sep 07, 2007
Major DRV-associated
V32I
I47V
I50V
I54M/L
L76V
I84V
V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, and L89V are associated with decreased DRV susceptibility and decreased virological response to DRV/r salvage therapy (De Meyer et al. 2006a; De Meyer et al. 2006b; De Meyer et al. 2006c; Picchio et al. 2006). In the POWER studies, bout 60% with 0, 45% with 1-2, and <=20% with >=3 DRMs had RNA <50 copies/ml at wk 24. 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. 2007).
In phenotypic studies, I50V, I54M, L76V, and I84V reduced susceptibility to the greatest extent (Van Marck et al. 2007).
V32I, L33F, I47V, I54ML, G73CS, and I89V have been the most common mutations to emerge with DRV/r treatment failure (Prezista prescribing information) (Delaugerre et al. 2007).
Potential cross resistance
V82F
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).
Accessory
V11I
L33F
G73S
L89V
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 studies (De Meyer et al. 2006c).
Initial therapy
DRV/r is currently being studied for use in initial PI-containing HAART regimens. It is currently not recommended for use outside of salvage therapy.
Salvage therapy
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]. CROI2007.
- De Meyer, S., H. Azijn, E. Fransen, I. De Baere, M. Van Ginderen, B. Maes, and M.-P. de Béthune. 2006a. The pathway leading to TMC114 resistance is different for TMC114 compared with other protease inhibitors HIVDRW2006.
- De Meyer, S., A. Hill, I. De Baere, L. Rimsky, H. Azijin, B. Van Baelen, E. De Paepe, T. Vangeneugden, E. Lefebvre, and M.-P. de Bethune. 2006b. Effect of Baseline Susceptibility and On-treatment Mutations on TMC114 and Control PI Efficacy: Preliminary Analysis of Data from PI-experienced Patients from POWER 1 and POWER 2 [abstract 157]. CROI2006.
- De Meyer, S., T. Vangeneugden, E. Lefebvre, H. Azijn, I. De Baere, B. Van Baelen, and M.-P. de Bethune. 2006c. Phenotypic and genotypic determination of resistance to TMC114: pooled analysis of POWER 1, 2, and 3 [abstract 73]. HIVDRW2006.
- Delaugerre, C., D. Mathez, G. Peytavin, H. Berthe, K. Long, T. Galperine, and P. de Truchis. 2007. Key amprenavir resistance mutations counteract dramatic efficacy of darunavir in highly experienced patients. Aids 21: 1210-1213.
- 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.
- 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.
- Pellegrin, I., L. Wittkop, D. Breilh, P. Merel, B. Winters, M. Bonarek, D. Neau, D. Bollens, J. Pellegrin, P. Girard, H. Fleury, M. Saux, R. Thiebaut, and L. Morand-Joubert. 2007. Impact of baseline protease mutations on virological response to darunavir/ritonavir-containing therapy in protease inhibitor-experienced patients (PREDIZISTA Study) [abstract 20]. HIVDRW2007.
- Picchio, G.R., M. Staes, E. Van Craenenbroeck, H. Vermeiren, L. Bacheler, M.-P. de Bethune, and S. De Meyer. 2006. HIV-1 susceptibility to TMC114 among routine clinical samples with different levels of protease inhibitor susceptibility using linear regression model-based fold change predictions. ICAAC 2006.
- 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.
- 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.
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