Resistance to Nucleoside Reverse Transcriptase Inhibitors

Last updated March 22, 2015
Case Authors: 
David H. Spach, MD's picture
David H. Spach, MD
Professor of Medicine
Division of Infectious Diseases
Clinical Director, Frontier AIDS Education and Training Center
University of Washington School of Medicine
Learning Objectives: 
  1. List the most common genotypic mutations associated with resistance to nelfinavir (Viracept)
  2. Discuss the response to new treatment regimens in patients who experience virologic failure with nelfinavir.

Display Group

  1. Singh K, Marchand B, Kirby KA, Michailidis E, Sarafianos SG. Structural Aspects of Drug Resistance and Inhibition of HIV-1 Reverse Transcriptase. Viruses. 2010;2:606-638.
  2. Tang MW, Shafer RW. HIV-1 antiretroviral resistance: scientific principles and clinical applications. Drugs. 2012;72:e1-25.
  3. Deval J, Courcambeck J, Selmi B, Boretto J, Canard B. Structural determinants and molecular mechanisms for the resistance of HIV-1 RT to nucleoside analogues. Curr Drug Metab. 2004;5:305-16.
  4. Shafer RW, Schapiro JM. HIV-1 drug resistance mutations: an updated framework for the second decade of HAART. AIDS Rev. 2008;10:67-84.
  5. Tu X, Das K, Han Q, et al. Structural basis of HIV-1 resistance to AZT by excision. Nat Struct Mol Biol. 2010;17:1202-9.
  6. Meyer PR, Matsuura SE, Mian AM, So AG, Scott WA. A mechanism of AZT resistance: an increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase. Mol Cell. 1999;4:35-43.
  7. Keulen W, Back NK, van Wijk A, Boucher CA, Berkhout B. Initial appearance of the 184Ile variant in lamivudine-treated patients is caused by the mutational bias of human immunodeficiency virus type 1 reverse transcriptase. J Virol. 1997;71:3346-50.
  8. Eron JJ, Benoit SL, Jemsek J, et al. Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. North American HIV Working Party. N Engl J Med. 1995;333:1662-9.
  9. Gupta R, Hill A, Sawyer AW, Pillay D. Emergence of drug resistance in HIV type 1-infected patients after receipt of first-line highly active antiretroviral therapy: a systematic review of clinical trials. Clin Infect Dis. 2008;47:712-22.
  10. Whitcomb JM, Parkin NT, Chappey C, Hellmann NS, Petropoulos CJ. Broad nucleoside reverse-transcriptase inhibitor cross-resistance in human immunodeficiency virus type 1 clinical isolates. J Infect Dis. 2003;188:992-1000.
  11. Petrella M, Wainberg MA. Might the M184V substitution in HIV-1 RT confer clinical benefit? AIDS Rev. 2002;4:224-32.
  12. Castagna A, Danise A, Menzo S, et al. Lamivudine monotherapy in HIV-1-infected patients harbouring a lamivudine-resistant virus: a randomized pilot study (E-184V study). AIDS. 2006;20:795-803.
  13. Trignetti M, Sing T, Svicher V, et al. Dynamics of NRTI resistance mutations during therapy interruption. AIDS Res Hum Retroviruses. 2009;25:57-64.
  14. Kulkarni R, Babaoglu K, Lansdon EB, et al. The HIV-1 reverse transcriptase M184I mutation enhances the E138K-associated resistance to rilpivirine and decreases viral fitness. J Acquir Immune Defic Syndr. 2012;59:47-54.
  15. Hu Z, Kuritzkes DR. Interaction of reverse transcriptase (RT) mutations conferring resistance to lamivudine and etravirine: effects on fitness and RT activity of human immunodeficiency virus type 1. J Virol. 2011;85:11309-14.
  16. Marcelin AG, Delaugerre C, Wirden M, et al. Thymidine analogue reverse transcriptase inhibitors resistance mutations profiles and association to other nucleoside reverse transcriptase inhibitors resistance mutations observed in the context of virological failure. J Med Virol. 2004;72:162-5.
  17. Miller V, Larder BA. Mutational patterns in the HIV genome and cross-resistance following nucleoside and nucleotide analogue drug exposure. Antivir Ther. 2001;6 Suppl 3:25-44.
  18. Wensing AM, Calvez V, Günthard HF, et al. 2014 Update of the drug resistance mutations in HIV-1. Top Antivir Med. 2014;22:642-50.
  19. Miller MD. K65R, TAMs and tenofovir. AIDS Rev. 2004;6:22-33.
  20. Beerenwinkel N, Däumer M, Sing T, et al. Estimating HIV evolutionary pathways and the genetic barrier to drug resistance. J Infect Dis. 2005;191:1953-60.
  21. Hu Z, Giguel F, Hatano H, Reid P, Lu J, Kuritzkes DR. Fitness comparison of thymidine analog resistance pathways in human immunodeficiency virus type 1. J Virol. 2006;80:7020-7.
  22. Lengauer T, Sing T. Bioinformatics-assisted anti-HIV therapy. Nat Rev Microbiol. 2006;4:790-7.
  23. Sluis-Cremer N, Sheen CW, Zelina S, Torres PS, Parikh UM, Mellors JW. Molecular mechanism by which the K70E mutation in human immunodeficiency virus type 1 reverse transcriptase confers resistance to nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother. 2006;51:48-53.
  24. Melikian GL, Rhee SY, Taylor J, et al. Standardized comparison of the relative impacts of HIV-1 reverse transcriptase (RT) mutations on nucleoside RT inhibitor susceptibility. Antimicrob Agents Chemother. 2012;56:2305-13.
  25. Ross L, Parkin N, Chappey C, et al. Phenotypic impact of HIV reverse transcriptase M184I/V mutations in combination with single thymidine analog mutations on nucleoside reverse transcriptase inhibitor resistance. AIDS. 2004;18:1691-6.
  26. Parikh UM, Bacheler L, Koontz D, Mellors JW. The K65R mutation in human immunodeficiency virus type 1 reverse transcriptase exhibits bidirectional phenotypic antagonism with thymidine analog mutations. J Virol. 2006;80:4971-7.
  27. Lanier ER, Givens N, Stone C, et al. Effect of concurrent zidovudine use on the resistance pathway selected by abacavir-containing regimens. HIV Med. 2004;5:394-9.
  28. Gallant JE, Rodriguez AE, Weinberg WG, et al. Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects. J Infect Dis. 2005;192:1921-30.
  29. Parikh UM, Zelina S, Sluis-Cremer N, Mellors JW. Molecular mechanisms of bidirectional antagonism between K65R and thymidine analog mutations in HIV-1 reverse transcriptase. AIDS. 2007;21:1405-14.
  30. Ly JK, Margot NA, MacArthur HL, Hung M, Miller MD, White KL. The balance between NRTI discrimination and excision drives the susceptibility of HIV-1 RT mutants K65R, M184V and K65r+M184V. Antivir Chem Chemother. 2007;18:307-16.
  31. White KL, Margot NA, Wrin T, Petropoulos CJ, Miller MD, Naeger LK. Molecular mechanisms of resistance to human immunodeficiency virus type 1 with reverse transcriptase mutations K65R and K65R+M184V and their effects on enzyme function and viral replication capacity. Antimicrob Agents Chemother. 2002;46:3437-46.
  32. Moyle G. Resistance and cross-resistance to abacavir. HIV Med. 2001;2:154-62.
  33. Wang J, Li D, Bambara RA, Yang H, Dykes C. L74V increases the reverse transcriptase content of HIV-1 virions with non-nucleoside reverse transcriptase drug-resistant mutations L100I+K103N and K101E+G190S, which results in increased fitness. J Gen Virol. 2013;94:1597-607.
  34. White KL, Chen JM, Margot NA, et al. Molecular mechanisms of tenofovir resistance conferred by human immunodeficiency virus type 1 reverse transcriptase containing a diserine insertion after residue 69 and multiple thymidine analog-associated mutations. Antimicrob Agents Chemother. 2004;48:992-1003.
  35. Winters MA, Coolley KL, Girard YA, et al. A 6-basepair insert in the reverse transcriptase gene of human immunodeficiency virus type 1 confers resistance to multiple nucleoside inhibitors. J Clin Invest. 1998;102:1769-75.
  36. Scherrer AU, von Wyl V, Götte M, et al. Polymorphic mutations associated with the emergence of the multinucleoside/tide resistance mutations 69 insertion and Q151M. J Acquir Immune Defic Syndr. 2012;59:105-12.