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: Nelfinavir (NFV; Viracept)

Last updated on Sep 07, 2007
Key Mutations
Major NFV-selected
D30N ± N88D
M46I/L
L90M
N88S
In patients developing NFV resistance while receiving NFV, there are three distinct non-overlapping patterns of PI resistance mutations: D30N±N88D, L90M, and N88S (Atkinson et al. 2000; Patick et al. 1998; Patick et al. 1996; Walmsley et al. 2001); (Deforche et al. 2006; Kempf et al. 2004; Mitsuya et al. 2006; Shafer et al. 2003). M46I/L may occur alone or with any of the 3 mutation patterns.

D30N occurs more commonly than L90M and N88S in subtype B but not in all other subtypes. L90M occurs more commonly in subtype C (Abecasis et al. 2005; Cane et al. 2001; Grossman et al. 2004). N88S has been reported more commonly in subtype AE (Ariyoshi et al. 2003).
 
Cross-resistance
G48V/M
I54V/M/L/T/A/S
V82A/T/F/S
I84V/A/C
Mutations at positions 48, 54, 82, and 84 rarely occur in patients receiving NFV as their initial PI. By themselves, they cause low-level phenotypic resistance. But in combination with other mutations, they are associated with high-level resistance and lack of virological response (Rhee et al. 2006).
 
Accessory
L10I/V/F
K20R/M//I
L23I
L33F
M36I
A71V/T/I/L
G73S/T/C/A
T74S
L89I/V
L23I is a rare NFV-selected mutation which occurs in <1% of NFV treated patients (Johnston et al. 2004). L23I is in the protease substrate cleft and by itself reduces NFV susceptibility by several fold.

L33F and G73S/T/C/A are selected by NFV and decrease NFV susceptibility (Rhee et al. 2005; Rhee et al. 2006).

In contrast to ritonavir-boosted PIs, many polymorphic mutations including those at positions 10, 20, 36, 71, and 77 may be associated with decreased NFV susceptibility and virological responsiveness even in the absence of major PI-resistance mutations (Perno et al. 2001).

Several additional mutations including T74S and L89IV may be more commonly associated with NFV resistance in several non-B subtypes (Abecasis et al. 2005; Deforche et al. 2006)
 
Clinical Uses
Initial therapy
The US DHHS and IAS-USA Guidelines list NFV as an alternative, rather than preferred option for PI-based initial ARV therapy because the combination of two NRTIs + NFV has a significantly higher failure rate than two NRTIs + NVP, EFV, LPV/r or other RTV-boosted PIs (Kempf et al. 2004; Podzamczer et al. 2002; Shafer et al. 2003; Walmsley et al. 2002).
 
Salvage therapy
Because most PI-resistance mutations reduce NFV susceptibility and because NFV has a low genetic barrier to resistance, NFV is not a recommended PI for salvage therapy (Dronda et al. 2001; Lawrence et al. 1999; Walmsley et al. 2001).
 
References
  • Abecasis, A.B., K. Deforche, J. Snoeck, L.T. Bacheler, P. McKenna, A.P. Carvalho, P. Gomes, R.J. Camacho, and A.M. Vandamme. 2005. Protease mutation M89I/V is linked to therapy failure in patients infected with the HIV-1 non-B subtypes C, F or G. Aids 19: 1799-1806.
  • Ariyoshi, K., M. Matsuda, H. Miura, S. Tateishi, K. Yamada, and W. Sugiura. 2003. Patterns of point mutations associated with antiretroviral drug treatment failure in CRF01_AE (subtype E) infection differ from subtype B infection. J Acquir Immune Defic Syndr 33: 336-342.
  • Atkinson, B., J. Isaacson, M. Knowles, E. Mazabel, and A.K. Patick. 2000. Correlation between human immunodeficiency virus genotypic resistance and virologic response in patients receiving nelfinavir monotherapy or nelfinavir with lamivudine and zidovudine. J Infect Dis 182: 420-427.
  • Cane, P.A., A. de Ruiter, P. Rice, M. Wiselka, R. Fox, and D. Pillay. 2001. Resistance-associated mutations in the human immunodeficiency virus type 1 subtype c protease gene from treated and untreated patients in the United Kingdom. J Clin Microbiol 39: 2652-2654.
  • Deforche, K., T. Silander, R. Camacho, Z. Grossman, M. Soares, K. Van Laethem, R. Kantor, Y. Moreau, and A.M. Vandamme. 2006. Analysis of HIV-1 pol sequences using Bayesian networks: implications for drug resistance. Bioinformatics.
  • Dronda, F., J.L. Casado, S. Moreno, K. Hertogs, I. Garcia-Arata, A. Antela, M.J. Perez-Elias, L. Ruiz, and B. Larder. 2001. Phenotypic cross-resistance to nelfinavir: the role of prior antiretroviral therapy and the number of mutations in the protease gene. AIDS Res Hum Retroviruses 17: 211-215.
  • Grossman, Z., E.E. Paxinos, D. Averbuch, S. Maayan, N.T. Parkin, D. Engelhard, M. Lorber, V. Istomin, Y. Shaked, E. Mendelson, D. Ram, C.J. Petropoulos, and J.M. Schapiro. 2004. Mutation D30N is not preferentially selected by human immunodeficiency virus type 1 subtype C in the development of resistance to nelfinavir. Antimicrob Agents Chemother 48: 2159-2165.
  • Johnston, E., M.A. Winters, S.Y. Rhee, T.C. Merigan, C.A. Schiffer, and R.W. Shafer. 2004. Association of a novel human immunodeficiency virus type 1 protease substrate cleft mutation, L23I, with protease inhibitor therapy and in vitro drug resistance. Antimicrob Agents Chemother 48: 4864-4868.
  • Kempf, D.J., M.S. King, B. Bernstein, P. Cernohous, E. Bauer, J. Moseley, K. Gu, A. Hsu, S. Brun, and E. Sun. 2004. Incidence of resistance in a double-blind study comparing lopinavir/ritonavir plus stavudine and lamivudine to nelfinavir plus stavudine and lamivudine. J Infect Dis 189: 51-60.
  • Lawrence, J., J. Schapiro, M. Winters, J. Montoya, A. Zolopa, R. Pesano, B. Efron, D. Winslow, and T.C. Merigan. 1999. Clinical resistance patterns and responses to two sequential protease inhibitor regimens in saquinavir and reverse transcriptase inhibitor- experienced persons. J.Infect.Dis. 179: 1356-1364.
  • Mitsuya, Y., M.A. Winters, W.J. Fessel, S.Y. Rhee, L. Hurley, M. Horberg, C.A. Schiffer, A.R. Zolopa, and R.W. Shafer. 2006. N88D facilitates the co-occurrence of D30N and L90M and the development of multidrug resistance in HIV type 1 protease following nelfinavir treatment failure. AIDS Res Hum Retroviruses 22: 1300-1305.
  • Patick, A.K., M. Duran, Y. Cao, D. Shugarts, M.R. Keller, E. Mazabel, M. Knowles, S. Chapman, D.R. Kuritzkes, and M. Markowitz. 1998. Genotypic and phenotypic characterization of human immunodeficiency virus type 1 variants isolated from patients treated with the protease inhibitor nelfinavir. Antimicrob.Agents Chemother. 42: 2637-2644.
  • Patick, A.K., H. Mo, M. Markowitz, K. Appelt, B. Wu, L. Musick, V. Kalish, S. Kaldor, S. Reich, D. Ho, and S. Webber. 1996. Antiviral and resistance studies of AG1343, an orally bioavailable inhibitor of human immunodeficiency virus protease. Antimicrob.Agents Chemother. 40: 292-297.
  • Perno, C.F., A. Cozzi-Lepri, C. Balotta, F. Forbici, M. Violin, A. Bertoli, G. Facchi, P. Pezzotti, G. Cadeo, G. Tositti, S. Pasquinucci, S. Pauluzzi, A. Scalzini, B. Salassa, A. Vincenti, A.N. Phillips, F. Dianzani, A. Appice, G. Angarano, L. Monno, G. Ippolito, M. Moroni, and A. Monforte. 2001. Secondary mutations in the protease region of human immunodeficiency virus and virologic failure in drug-naive patients treated with protease inhibitor-based therapy. J Infect Dis 184: 983-991.
  • Podzamczer, D., E. Ferrer, E. Consiglio, J.M. Gatell, P. Perez, J.L. Perez, E. Luna, A. Gonzalez, E. Pedrol, L. Lozano, I. Ocana, J.M. Llibre, A. Casiro, M. Aranda, P. Barrufet, J. Martinez-Lacasa, J.M. Miro, X. Badia, A. Casado, S. Lupo, P. Cahn, M. Manos, and J. Estela. 2002. A randomized clinical trial comparing nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients (the Combine Study). Antivir Ther 7: 81-90.
  • 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.
  • Shafer, R.W., L.M. Smeaton, G.K. Robbins, V. De Gruttola, S.W. Snyder, R.T. D'Aquila, V.A. Johnson, G.D. Morse, M.A. Nokta, A.I. Martinez, B.M. Gripshover, P. Kaul, R. Haubrich, M. Swingle, S.D. McCarty, S. Vella, M.S. Hirsch, and T.C. Merigan. 2003. Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 349: 2304-2315.
  • Walmsley, S., B. Bernstein, M. King, J. Arribas, G. Beall, P. Ruane, M. Johnson, D. Johnson, R. Lalonde, A. Japour, S. Brun, and E. Sun. 2002. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med 346: 2039-2046.
  • Walmsley, S.L., M.I. Becker, M. Zhang, A. Humar, and P.R. Harrigan. 2001. Predictors of virological response in HIV-infected patients to salvage antiretroviral therapy that includes nelfinavir. Antivir Ther 6: 47-54.