Stanford University HIV Drug Resistance Database - A curated public database designed to represent, store, and analyze the divergent forms of data underlying HIV drug resistance.

Antiretroviral drug summary:
Amprenavir/r (APV/r; Agenerase), Fosamprenavir/r (fAPV/r; Lexiva)

Last updated on Nov 10, 2008
Key Mutations
Major FPV-selected
V32I
I47V
I50V
I54M/L
I84V
L76V
V32I, I47V, I50V, I54M/L, and I84V are the most common mutations to develop during in vitro passage with APV and in patients developing virologic failure while receiving APV or FPV containing regimens (Ait-Khaled et al. 2003; MacManus et al. 2003; Maguire et al. 2002; Murphy et al. 1999; Partaledis et al. 1995; Prado et al. 2002). These mutations also cause the greatest decreases in FPV susceptibility (Murphy et al. 2004; Parkin et al. 2003; Rhee et al. 2006; Vermeiren et al. 2007).
 
Potential cross-resistance
M46I/L/V
I54V/A/T/S
V82A/T/F/S
L90M
M46I/L, I54V/A/T/S, V82A/T/F/S, and L90M rarely occur during FPV failure. However, these mutations, which occur commonly with other PIs confer low-to-intermediate cross resistance to FPV (Duval et al. 2002; Lastere et al. 2004; Marcelin et al. 2007; Marcelin et al. 2003; Masquelier et al. 2008; Pellegrin et al. 2007; Schmidt et al. 2000).
 
Accessory
V11I
L33F
L89V
L33F and to a lesser extent V11I and L89V are associated with decreased FPV susceptibility (Kozal et al. 2006; Prado et al. 2002; Rhee et al. 2006).
 
Hypersusceptibility
N88S increases FPV susceptibility in vitro and potentially in vivo (Masquelier et al. 2008; Ziermann et al. 2000).
 
Clinical Uses
Initial therapy
The US DHHS and IAS-USA Guidelines list FPV/r as a preferred PI for initial HAART. In contrast to APV, APV/r, and FPV, virologic failure in patients receiving FPV/r has not been associated with PI resistance (Eron et al. 2006; Gathe et al. 2004; Smith et al. 2008). Moreover, FPV/r has had similar efficacy to LPV/r (Eron et al. 2006) and ATV/r (Smith et al. 2008) in previously untreated patients.
 
Second-line therapy
Salvage therapy
FPV/r does not have the same track record as LPV/r, TPV/r, or DRV/r for salvage therapy (Cahn et al. 2006; Clotet et al. 2007; Gathe et al. 2006; Haubrich et al. 2007; Hicks et al. 2006; Katlama et al. 2007). FPV/r has a relatively low genetic barrier to resistance: loss of clinical activity begins with 2-fold decreases in susceptibility and near complete loss of clinical activity occurs at about 10-fold decreased susceptibility (Coakley et al. 2007 ).
 
References
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  • 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.
  • 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.
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  • 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.
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  • 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.
  • Kozal, M.J., K.H. Hullsiek, R. Leduc, R.M. Novak, R.D. MacArthur, J. Lawrence, and J.D. Baxter. 2006. Prevalence and impact of HIV-1 protease codon 33 mutations and polymorphisms in treatment-naive and treatment-experienced patients. Antivir Ther 11: 457-463.
  • Lastere, S., C. Dalban, G. Collin, D. Descamps, P.M. Girard, F. Clavel, D. Costagliola, and F. Brun-Vezinet. 2004. Impact of insertions in the HIV-1 p6 PTAPP region on the virological response to amprenavir. Antivir Ther 9: 221-227.
  • MacManus, S., P. Yates, S. White, N. Richards, and W. Snowden. 2003. GW433908 in ART-naive subjects: absence of resistance at 48 weeks with boosted regimen and APV-like resistance profile with unboosted regimen [abstract 598]. CROI2003.
  • Maguire, M., D. Shortino, A. Klein, W. Harris, V. Manohitharajah, M. Tisdale, R. Elston, J. Yeo, S. Randall, F. Xu, H. Parker, J. May, and W. Snowden. 2002. Emergence of resistance to protease inhibitor amprenavir in human immunodeficiency virus type 1-infected patients: selection of four alternative viral protease genotypes and influence of viral susceptibility to coadministered reverse transcriptase nucleoside inhibitors. Antimicrob Agents Chemother 46: 731-738.
  • Marcelin, A.G., P. Flandre, J. Molina, C. Katlama, P. Yeni, F. Raffi, M. Wirden, Z. Antoun, M. Ait Khaled, and V. Calvez. 2007. Genotypic analysis of the virological response to fosamprenavir/ritonavir in clinical trials: CONTEXT and TRIAD [abstract 608]. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, February 25-28.
  • Marcelin, A.G., C. Lamotte, C. Delaugerre, N. Ktorza, H. Ait Mohand, R. Cacace, M. Bonmarchand, M. Wirden, A. Simon, P. Bossi, F. Bricaire, D. Costagliola, C. Katlama, G. Peytavin, and V. Calvez. 2003. Genotypic inhibitory quotient as predictor of virological response to ritonavir-amprenavir in human immunodeficiency virus type 1 protease inhibitor-experienced patients. Antimicrob Agents Chemother 47: 594-600.
  • Masquelier, B., K.L. Assoumou, D. Descamps, L. Bocket, J. Cottalorda, A. Ruffault, A.G. Marcelin, L. Morand-Joubert, C. Tamalet, C. Charpentier, G. Peytavin, Z. Antoun, F. Brun-Vezinet, and D. Costagliola. 2008. Clinically validated mutation scores for HIV-1 resistance to fosamprenavir/ritonavir. J Antimicrob Chemother 61: 1362-1368.
  • Murphy, M.D., G.I. Marousek, and S. Chou. 2004. HIV protease mutations associated with amprenavir resistance during salvage therapy: importance of I54M. J Clin Virol 30: 62-67.
  • Murphy, R.L., R.M. Gulick, V. DeGruttola, R.T. D'Aquila, J.J. Eron, J.P. Sommadossi, J.S. Currier, L. Smeaton, I. Frank, A.M. Caliendo, J.G. Gerber, R. Tung, and D.R. Kuritzkes. 1999. Treatment with amprenavir alone or amprenavir with zidovudine and lamivudine in adults with human immunodeficiency virus infection. AIDS Clinical Trials Group 347 Study Team. J Infect Dis 179: 808-816.
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  • Pellegrin, I., D. Breilh, G. Coureau, S. Boucher, D. Neau, P. Merel, D. Lacoste, H. Fleury, M.C. Saux, J.L. Pellegrin, E. Lazaro, F. Dabis, and R. Thiebaut. 2007. Interpretation of genotype and pharmacokinetics for resistance to fosamprenavir-ritonavir-based regimens in antiretroviral-experienced patients. Antimicrob Agents Chemother 51: 1473-1480.
  • Prado, J.G., T. Wrin, J. Beauchaine, L. Ruiz, C.J. Petropoulos, S.D. Frost, B. Clotet, R.T. D'Aquila, and J. Martinez-Picado. 2002. Amprenavir-resistant HIV-1 exhibits lopinavir cross-resistance and reduced replication capacity. AIDS 16: 1009-1017.
  • 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.
  • Schmidt, B., K. Korn, B. Moschik, C. Paatz, K. Uberla, and H. Walter. 2000. Low level of cross-resistance to amprenavir (141W94) in samples from patients pretreated with other protease inhibitors. Antimicrob Agents Chemother 44: 3213-3216.
  • 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.
  • 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.
  • Ziermann, R., K. Limoli, K. Das, E. Arnold, C.J. Petropoulos, and N.T. Parkin. 2000. A mutation in human immunodeficiency virus type 1 protease, N88S, that causes in vitro hypersensitivity to amprenavir. J Virol 74: 4414-4419.