Antiretroviral drug summary: Indinavir/r (IDV/r; Crixivan)
Last updated on Sep 07, 2007
Many different protease mutations have been reported in patients receiving IDV (Belec et al. 2000; Condra et al. 1996; Descamps et al. 2005; Gallego et al. 2001). This may be due in part to the nature of the drug or to the fact that IDV was initially frequently used in suboptimal treatment regimens.
V82A/T/F/S and less commonly L90M and I84V occur in patients developing virological failure while receiving an IDV-containing regimen. Alone these mutations reduce susceptibility about 2-fold. In combination with a mutation at positions 46 or 54, these mutations are associated with bout 10-fold IDV-reduced susceptibility (Rhee et al. 2006). V82M has been reported commonly in subtype G isolates from persons receiving IDV(Camacho et al. 2005)
V32I, I47V, G48V, L76V, and N88S each occur in a small proportion of patients receiving IDV failure and cause low-level IDV resistance (Belec et al. 2000; Condra et al. 1996; Descamps et al. 2005; Gallego et al. 2001; Rhee et al. 2006).
L24I, F53L, and G73S/C/T/A are selected by IDV and contribute to reduced IDV susceptibility (Belec et al. 2000; Condra et al. 1996; Descamps et al. 2005; Gallego et al. 2001). (Rhee et al. 2005; Rhee et al. 2006).
IDV/r is not listed by the US DHHS or IAS-USA Guidelines as an option for initial HAART. Although it is highly active virologically, it has bas been associated with higher rate of toxicity than most other boosted PIs (Bongiovanni et al. 2004; Boyd et al. 2006; Burger et al. 2003; Canestri et al. 2007; Duvivier et al. 2003; Rockstroh et al. 2000; Voigt et al. 2002; Young et al. 2002).
IDV/r should not ordinarily be used for salvage therapy because it has generally not performed as well in clinical trials as have LPV/r, TPV/r, and DRV/r (Cahn et al. 2006; Clotet et al. 2007; Dragsted et al. 2003; Gathe et al. 2006; Haubrich et al. 2007; Hicks et al. 2006; Katlama et al. 2007).
Fold-reductions of 2-fold in the PhenoSense assay have been associated with reduced virologic response and fold reductions of 10-fold have been associate with near complete loss of virologic response . The activity of IDV as a salvage PI often depends on pharmacokinetic factors rather than presence of specific PI-resistance mutations (Campo et al. 2003; Casado et al. 2000; Shulman et al. 2002).
- Belec, L., C. Piketty, A. Si-Mohamed, C. Goujon, M.C. Hallouin, S. Cotigny, L. Weiss, and M.D. Kazatchkine. 2000. High levels of drug-resistant human immunodeficiency virus variants in patients exhibiting increasing CD4+ T cell counts despite virologic failure of protease inhibitor-containing antiretroviral combination therapy. J Infect Dis 181: 1808-1812.
- Bongiovanni, M., T. Bini, E. Chiesa, P. Cicconi, F. Adorni, and A. Monforte d'Arminio. 2004. Lopinavir/ritonavir vs. indinavir/ritonavir in antiretroviral naive HIV-infected patients: immunovirological outcome and side effects. Antiviral Res 62: 53-56.
- Boyd, M.A., P. Srasuebkul, M. Khongphattanayothin, K. Ruxrungtham, E.A. Hassink, C.J. Duncombe, S. Ubolyam, D.M. Burger, P. Reiss, M. Stek, Jr., J. Lange, D.A. Cooper, and P. Phanuphak. 2006. Boosted versus unboosted indinavir with zidovudine and lamivudine in nucleoside pre-treated patients: a randomized, open-label trial with 112 weeks of follow-up (HIV-NAT 005). Antivir Ther 11: 223-232.
- Burger, D.M., R.E. Aarnoutse, J.P. Dieleman, I.C. Gyssens, J. Nouwen, S. de Marie, P.P. Koopmans, M. Stek, Jr., and M.E. van der Ende. 2003. A once-daily HAART regimen containing indinavir + ritonavir plus one or two nucleoside reverse transcriptase inhibitors (PIPO study). Antivir Ther 8: 455-461.
- Cahn, P., J. Villacian, A. Lazzarin, C. Katlama, B. Grinsztejn, K. Arasteh, P. Lopez, N. Clumeck, J. Gerstoft, N. Stavrianeas, S. Moreno, F. Antunes, D. Neubacher, and D. Mayers. 2006. Ritonavir-Boosted Tipranavir Demonstrates Superior Efficacy to Ritonavir-Boosted Protease Inhibitors in Treatment-Experienced HIV-Infected Patients: 24-Week Results of the RESIST-2 Trial. Clin Infect Dis 43: 1347-1356.
- Camacho, R., A. Godinho, P. Gomes, A. Abecasis, A.-M. Vandamme, C. Palma, A.P. Carvalho, J. Cabanas, and J. Goncalves. 2005. Different substitutions under drug pressure at protease codon 82 in HIV-1 subtype G compared to subtype B infected individuals including a novel I82M resistance mutations. Antiviral Therapy 10: S151.
- Campo, R.E., J.N. Moreno, G. Suarez, N. Miller, M.A. Kolber, D.J. Holder, M. Shivaprakash, D.M. DeAngelis, J.L. Wright, W.A. Schleif, E.A. Emini, and J.H. Condra. 2003. Efficacy of indinavir-ritonavir-based regimens in HIV-1-infected patients with prior protease inhibitor failures. Aids 17: 1933-1939.
- Canestri, A., M. Cisse, A.G. Marcelin, G. Peytavin, E. Traore, L. Assoumou, O. Traore, V. Koita, F. Diallo, A.T. Sangare, M.K. Sidibe, V. Calvez, A. Sylla, C. Katlama, and R. Tubiana. 2007. Experience of indinavir/ritonavir 400/100 mg twice-daily highly active antiretroviral therapy-containing regimen in HIV-1-infected patients in Bamako, Mali: the NOGOMA Study. J Acquir Immune Defic Syndr 45: 477-479.
- Casado, J.L., A. Moreno, R. Sabido, P. Marti-Belda, A. Antela, F. Dronda, M.J. Perez-Elias, and S. Moreno. 2000. A clinical study of the combination of 100 mg ritonavir plus 800 mg indinavir as salvage therapy: influence of increased plasma drug levels in the rate of response. HIV Clin Trials 1: 13-19.
- 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.
- Condra, J.H., D.J. Holder, W.A. Schleif, O.M. Blahy, R.M. Danovich, L.J. Gabryelski, D.J. Graham, D. Laird, J.C. Quintero, A. Rhodes, H.L. Robbins, E. Roth, M. Shivaprakash, T. Yang, J.A. Chodakewitz, P.J. Deutsch, R.Y. Leavitt, F.E. Massari, J.W. Mellors, K.E. Squires, R.T. Steigbigel, H. Teppler, and E.A. Emini. 1996. Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor. J.Virol. 70: 8270-8276.
- Descamps, D., V. Joly, P. Flandre, G. Peytavin, V. Meiffredy, S. Delarue, S. Lastere, J.P. Aboulker, P. Yeni, and F. Brun-Vezinet. 2005. Genotypic resistance analyses in nucleoside-pretreated patients failing an indinavir containing regimen: results from a randomized comparative trial: (Novavir ANRS 073). J Clin Virol 33: 99-103.
- Dragsted, U.B., J. Gerstoft, C. Pedersen, B. Peters, A. Duran, N. Obel, A. Castagna, P. Cahn, N. Clumeck, J.N. Bruun, J. Benetucci, A. Hill, I. Cassetti, P. Vernazza, M. Youle, Z. Fox, and J.D. Lundgren. 2003. Randomized trial to evaluate indinavir/ritonavir versus saquinavir/ritonavir in human immunodeficiency virus type 1-infected patients: the MaxCmin1 Trial. J Infect Dis 188: 635-642.
- Duvivier, C., A. Myrto, A.G. Marcelin, J. Ghosn, H. Ait-Mohand, L. Schneider, R. Agher, F. Bricaire, D. Costagliola, V. Calvez, G. Peytavin, and C. Katlama. 2003. Efficacy and safety of ritonavir/indinavir 100/400 mg twice daily in combination with two nucleoside analogues in antiretroviral treatment-naive HIV-infected individuals. Antivir Ther 8: 603-609.
- Gallego, O., C. de Mendoza, M.J. Perez-Elias, J.M. Guardiola, J. Pedreira, D. Dalmau, J. Gonzalez, A. Moreno, J.R. Arribas, A. Rubio, I. Garcia-Arata, M. Leal, P. Domingo, and V. Soriano. 2001. Drug resistance in patients experiencing early virological failure under a triple combination including indinavir. Aids 15: 1701-1706.
- Gathe, J., D.A. Cooper, C. Farthing, D. Jayaweera, D. Norris, G. Pierone, Jr., C.R. Steinhart, B. Trottier, S.L. Walmsley, C. Workman, G. Mukwaya, V. Kohlbrenner, C. Dohnanyi, S. McCallister, and D. Mayers. 2006. Efficacy of the protease inhibitors tipranavir plus ritonavir in treatment-experienced patients: 24-week analysis from the RESIST-1 trial. Clin Infect Dis 43: 1337-1346.
- Haubrich, R., D. Berger, P. Chiliade, A. Colson, M. Conant, J. Gallant, T. Wilkin, J. Nadler, G. Pierone, M. Saag, B. van Baelen, and E. Lefebvre. 2007. Week 24 efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients. Aids 21: F11-18.
- Hicks, C.B., P. Cahn, D.A. Cooper, S.L. Walmsley, C. Katlama, B. Clotet, A. Lazzarin, M.A. Johnson, D. Neubacher, D. Mayers, and H. Valdez. 2006. 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: 466-475.
- 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.
- Rhee, S.Y., W.J. Fessel, A.R. Zolopa, L. Hurley, T. Liu, J. Taylor, D.P. Nguyen, S. Slome, D. Klein, M. Horberg, J. Flamm, S. Follansbee, J.M. Schapiro, and R.W. Shafer. 2005. HIV-1 protease and reverse-transcriptase mutations: correlations with antiretroviral therapy in subtype B isolates and implications for drug-resistance surveillance. J Infect Dis 192: 456-465.
- Rhee, S.Y., J. Taylor, G. Wadhera, A. Ben-Hur, D.L. Brutlag, and R.W. Shafer. 2006. Genotypic predictors of human immunodeficiency virus type 1 drug resistance. Proc Natl Acad Sci U S A 103: 17355-17360.
- Rockstroh, J.K., F. Bergmann, W. Wiesel, A. Rieke, A. Thiesen, G. Fatkenheuer, M. Oette, H. Carls, S. Fenske, M. Nadler, and H. Knechten. 2000. Efficacy and safety of twice daily first-line ritonavir/indinavir plus double nucleoside combination therapy in HIV-infected individuals. German Ritonavir/Indinavir Study Group. Aids 14: 1181-1185.
- Shulman, N., A. Zolopa, D. Havlir, A. Hsu, C. Renz, S. Boller, P. Jiang, R. Rode, J. Gallant, E. Race, D.J. Kempf, and E. Sun. 2002. Virtual inhibitory quotient predicts response to ritonavir boosting of indinavir-based therapy in human immunodeficiency virus-infected patients with ongoing viremia. Antimicrob Agents Chemother 46: 3907-3916.
- Voigt, E., A. Wickesberg, J.C. Wasmuth, P. Gute, L. Locher, B. Salzberger, A. Wohrmann, A. Adam, L. Weitner, and J.K. Rockstroh. 2002. First-line ritonavir/indinavir 100/800 mg twice daily plus nucleoside reverse transcriptase inhibitors in a German multicentre study: 48-week results. HIV Med 3: 277-282.
- Young, B., M.A. Fischl, H.M. Wilson, T.S. Finn, E.H. Jensen, M.J. DiNubile, and R.K. Zeldin. 2002. Open-label study of a twice-daily indinavir 800-mg/ritonavir 100-mg regimen in protease inhibitor-naive HIV-infected adults. J Acquir Immune Defic Syndr 31: 478-482.