Antiretroviral drug summary: Atazanavir/r (ATV/r; Reyataz)
Last updated on Nov 10, 2008
I50L is the most common protease mutation to develop in PI-naive patients with virologic failure while receiving unboosted ATV. I50L reduces ATV susceptibility by ~8-fold (Weinheimer et al. 2005). I50L occurs less frequently in patients receiving ATV/r or in previously PI-treated patients receiving ATV (Colonno et al. 2004; Malan et al. 2008; McGrath et al. 2006; Zolopa et al. 2007).
N88S is one of the mutations to emerge in vitro when HIV-1 is cultured in the presence of increasing ATV concentrations and has been reported in patients developing virologic failure with ATV/r (Coakley et al. 2005; Gong et al. 2000) It reduces ATV susceptibility ~10-fold (Coakley et al. 2005; McGrath et al. 2006; Rhee et al. 2006; Zolopa et al. 2007).
These mutations have generally not been reported in patients receiving ATV or ATV/r. However, they have been associated with reduced ATV susceptibility and reduced virological responses to an ATV/r containing salvage therapy regimen (Bertoli et al. 2006; Marcelin et al. 2006; Naeger and Struble 2006; Pellegrin et al. 2006; Rhee et al. 2006; Vermeiren et al. 2007; Vora et al. 2006).
G73S/T/C/A occurs frequently in patients developing virologic failure while receiving unboosted ATV and have been associated with decreased ATV susceptibility and decreased virologic response to an ATV or ATV/r containing regimen (Colonno et al. 2004; Malan et al. 2008; Rhee et al. 2006; Vermeiren et al. 2007).
G48M and I84A/C are rare mutations associated with high-levels of resistance to multiple PIs including LPV (Mo et al. 2007; Vermeiren et al. 2007).
D30N+N88D have been associated with a 2-fold to 4-fold decrease in ATV susceptibility (Di Giambenedetto et al. 2008; Rhee et al. 2006; Vermeiren et al. 2007). L33F has been selected by ATV in vitro and is associated with reduced ATV susceptibility (Gong et al. 2000; Rhee et al. 2006; Zolopa et al. 2007).
L76V increases ATV susceptibility.
The U.S. DHHS and IAS-USA guidelines recommend ATV/r as a preferred PI for initial HAART based on its tolerability and apparent equivalency to LPV/r and FPV/r in previously untreated persons (Hammer et al. 2008; Molina et al. 2008; Smith et al. 2008; US Department of Health and Human Services Panel on Clinical Practices for Treatment of HIV Infection 2008). Like other boosted PIs, virological failure has generally not been associated with the selection of PI resistance mutations suggesting that failure has generally resulted from nonadherence (Malan et al. 2008; Smith et al. 2008).
ATV/r should not ordinarily be used for salvage therapy because it has not performed as well in clinical trials as have LPV/r, TPV/r, DRV/r (Clotet et al. 2007; Cohen et al. 2005; Johnson et al. 2005; Katlama et al. 2007; Naeger and Struble 2006) and because the genetic barrier to resistance is low with decreased virological responses occurring in viruses with 2-fold decreased susceptibility and nearly complete loss of response in viruses with 5-fold or higher decreased susceptibility (Coakley et al. 2006; Winters et al. 2008). ATV/r may be useful in patients who failed previous PI-containing regimens because of non-adherence.
- Bertoli, A., M. Santoro, P. Lorenzini, F. Ceccherini-Silberstein, A. Lazzarin, G. Di Perri, D. Esposito, P. Caramello, A. Cargme, A. Cargnel, P. Narciso, G. Rizzrdini, G. Filice, L. Minoli, G. Carosi, A. Antinori, and C.F. Perno. 2006. Different patterns of mutations involved in the genotypic resistance score for atazanavir boosted versus atazanavir unboosted in multiplying failing patients. HIVDRW2006.
- 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. Maa, S. Wang, M. Bates, R. Pesano, A. Thirty, and D. Seekins. 2006. Evaluation of phenotypic clinical cutoff for atazanavir/ritonavir in patients who changed only the protease inhibitor component of HAART: A confirmatory week 2 analysis of AI424-045 [abstract 634]. 13th Conference on Retroviruses and Opportunistic Infections, Denver, CO, February 5 - 8.
- Coakley, E., M. Mass, and N. Parkin. 2005. Atazanavir resistance in a protease inhibitor-naïve patient treated with atazanavir/ritonavir associated with development of high-level atazanavir resistance and the N88S mutation in protease [Abstract 716]. 12th Conference on Retroviruses and Opportunistic Infections, Boston, MA, February 22 - 25.
- Cohen, C., L. Nieto-Cisneros, C. Zala, W.J. Fessel, J. Gonzalez-Garcia, A. Gladysz, R. McGovern, E. Adler, and C. McLaren. 2005. Comparison of atazanavir with lopinavir/ritonavir in patients with prior protease inhibitor failure: a randomized multinational trial. Curr Med Res Opin 21: 1683-1692.
- Colonno, R., R. Rose, C. McLaren, A. Thiry, N. Parkin, and J. Friborg. 2004. Identification of I50L as the signature atazanavir (ATV)-resistance mutation in treatment-naive HIV-1-infected patients receiving ATV-containing regimens. J Infect Dis 189: 1802-1810.
- Di Giambenedetto, S., M. Prosperi, L. Bracciale, A. Callegaro, F. Maggiolo, A. Di Garbo, B. Bruzzone, S. Bonora, F. Baldanti, D. Francisci, S. Menzo, G. Colao, M. Zazzi, L. Monno, and A. De Luca. 2008. A rigorous statistical learning method for the estimation and validation of weighted drug susceptibility scores applied to in vivo virological outcome prediction in atazanavir/ritonavir-containing HAART. Antivir Ther 13: Suppl 3:A105.
- Gong, Y.F., B.S. Robinson, R.E. Rose, C. Deminie, T.P. Spicer, D. Stock, R.J. Colonno, and P.F. Lin. 2000. In vitro resistance profile of the human immunodeficiency virus type 1 protease inhibitor BMS-232632. Antimicrob Agents Chemother 44: 2319-2326.
- 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.
- Johnson, M., B. Grinsztejn, C. Rodriguez, J. Coco, E. Dejesus, A. Lazzarin, K. Lichtenstein, A. Rightmire, S. Sankoh, and R. Wilber. 2005. Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS 19: 153-162.
- 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.
- Malan, D.R., E. Krantz, N. David, V. Wirtz, J. Hammond, and D. McGrath. 2008. 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: 161-167.
- Marcelin, A.G., C. Chazallon, L. Gerard, Y. Saidi, J.P. Aboulker, P.M. Girard, V. Calvez, and C. Piketty. 2006. External validation of atazanavir/ritonavir genotypic score in HIV-1 protease inhibitor-experienced patients. J Acquir Immune Defic Syndr 42: 127-128.
- McGrath, D., J. Hammond, D. Frederick, N. Mathew, K. Kastango, and C. McLaren. 2006. Evaluation of resistance patterns in treatment-naive subjects with virological failure on atazanavir- or atazanavir/ritonavir-containing regimens. HIVDRW2006.
- Mo, H., N. Parkin, K.D. Stewart, L. Lu, T. Dekhtyar, D.J. Kempf, and A. Molla. 2007. Identification and structural characterization of I84C and I84A mutations that are associated with high-level resistance to human immunodeficiency virus protease inhibitors and impair viral replication. Antimicrob Agents Chemother 51: 732-735.
- Molina, J.M., J. Andrade-Villanueva, J. Echevarria, P. Chetchotisakd, J. Corral, N. David, G. Moyle, M. Mancini, L. Percival, R. Yang, A. Thiry, and D. McGrath. 2008. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet 372: 646-655.
- Naeger, L.K. and K.A. Struble. 2006. Effect of baseline protease genotype and phenotype on HIV response to atazanavir/ritonavir in treatment-experienced patients. AIDS 20: 847-853.
- Pellegrin, I., D. Breilh, J.M. Ragnaud, S. Boucher, D. Neau, H. Fleury, M.H. Schrive, M.C. Saux, J.L. Pellegrin, E. Lazaro, and M. Vray. 2006. Virological responses to atazanavir-ritonavir-based regimens: resistance-substitutions score and pharmacokinetic parameters (Reyaphar study). Antivir Ther 11: 421-429.
- 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.
- Smith, K.Y., W.G. Weinberg, E. Dejesus, M.A. Fischl, Q. Liao, L.L. Ross, G.E. Pakes, K.A. Pappa, and C.T. Lancaster. 2008. 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: 5.
- US Department of Health and Human Services Panel on Clinical Practices for Treatment of HIV Infection, A. 2008. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (The living document, November, 2008), http://aidsinfo.nih.gov/.
- 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.
- Vora, S., A.G. Marcelin, H.F. Gunthard, P. Flandre, H.H. Hirsch, B. Masquelier, A. Zinkernagel, G. Peytavin, V. Calvez, L. Perrin, and S. Yerly. 2006. Clinical validation of atazanavir/ritonavir genotypic resistance score in protease inhibitor-experienced patients. AIDS 20: 35-40.
- Weinheimer, S., L. Discotto, J. Friborg, H. Yang, and R. Colonno. 2005. Atazanavir signature I50L resistance substitution accounts for unique phenotype of increased susceptibility to other protease inhibitors in a variety of human immunodeficiency virus type 1 genetic backbones. Antimicrob Agents Chemother 49: 3816-3824.
- Winters, B., J. Montaner, P.R. Harrigan, B. Gazzard, A. Pozniak, M.D. Miller, S. Emery, F. van Leth, P. Robinson, J.D. Baxter, M. Perez-Elias, D. Castor, S. Hammer, A. Rinehart, H. Vermeiren, E. Van Craenenbroeck, and L. Bacheler. 2008. Determination of clinically relevant cutoffs for HIV-1 phenotypic resistance estimates through a combined analysis of clinical trial and cohort data. J Acquir Immune Defic Syndr 48: 26-34.
- Zolopa, A., W. Towner, D. Butcher, S. Wang, J. Maa, and D. Seekins. 2007. Resistance profile after viral rebound on atazanavir-containing therapy: focus on protease inhibitor-naive subjects in the IMPACT study (BMS AI424-128) [abstract 77]. Antivir Ther 12: S86.