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Resistance to Non-Nucleoside Reverse Transcriptase Inhibitors

  • Chapter
Reverse Transcriptase Inhibitors in HIV/AIDS Therapy

Part of the book series: Infectious Disease ((ID))

Abstract

The prevalence of non-nucleoside reverse transcriptase (RT) inhibitor (NNRTI) resistance is increasing, especially as the number of patients who have been treated with this class of agents has grown. The three Food and Drug Administration-approved NNRTIs, efavirenz, nevirapine, and delaviridine, have been shown to be potent additions to the antiretroviral (ARV) armamentarium. In many studies, these compounds have been shown to be effective components of highly active ARV therapeutic (HAART) regimens; results have been similar to or better than the comparator protease inhibitors (PIs). Resistance to the NNRTIs occurs more frequently than resistance to other classes of ARVs and is a serious limitation to their use. The use of these agents in monotherapy and in partially suppressive regimens rapidly selects for resistance, and this resistance precludes the use of the other agents in this class. When considering these agents in newly infected or ARV-naive patients, the rate of transmitted resistance, especially in areas in which NNRTIs have been used extensively, may ultimately limit the usefulness of this class of therapeutics. As the incidence of transmission of NNRTI resistance increases, resistance testing for recently infected patients should be strongly considered. The potency of these agents must be balanced against the rapid development of resistance.

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References

  1. Clevenbergh, P, Cua, E, Dam, E, et al. Prevalence of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated mutations and polymorphisms in NNRTI-naive HIV-infected patients. HIV Clin Trials 2002;3(1):36–44.

    Article  PubMed  CAS  Google Scholar 

  2. Kohlstaedt, LA, Wang, J, Friedman, JM, Rice, PA, Steitz, TA. Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 1992;256(5065):1783–1790.

    Article  PubMed  CAS  Google Scholar 

  3. Paolucci, S, Baldanti, F, Tinelli, M, et al. Q145M, a novel HIV-1 reverse transcriptase mutation conferring resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors. Antiviral Therapy 2002;7(2):S35.

    Google Scholar 

  4. Torti, C, Pozniak, A, Nelson, M, Hertogs, K, Gazzard, BG. Distribution of K103N and/or Y181C HIV-1 mutations by exposure to zidovudine and non-nucleoside reverse transcriptase inhibitors. J Antimicrob Chemother 2001;48(1):113–116.

    Article  PubMed  CAS  Google Scholar 

  5. Whitcomb, JM, Huang, W, Limoli, K, et al. Hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in HIV-1: clinical, phenotypic and genotypic correlates. AIDS 2002;16(15):F41–47.

    Article  PubMed  CAS  Google Scholar 

  6. Harrigan, PR, Salim, M, Stammers, DK, et al. A mutation in the 3′ region of the human immunodeficiency virus type 1 reverse transcriptase (Y318F) associated with nonnucleoside reverse transcriptase inhibitor resistance. J Virol 2002;76(13):6836–6840.

    Article  PubMed  CAS  Google Scholar 

  7. Kemp, S, Salim, M, Stammers, D, Wynhoven, B, Larder, B, Harrigan PR. A mutation in HIV-1 RT at codon 318 (Y to F) confers high level NNRTI resistance in clinical samples [abstract 1762]. 41st ICAAC; Chicago, IL; 2001.

    Google Scholar 

  8. Winslow, DL, Garber, S, Reid, C, et al. Selection conditions affect the evolution of specific mutations in the reverse transcriptase gene associated with resistance to DMP 266. AIDS 1996;10(11):1205–1209.

    Article  PubMed  CAS  Google Scholar 

  9. Young, SD, Britcher, SF, Tran, Lo, et al. L-743, 726 (DMP-266): a novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 1995;39(12):2602–2605.

    PubMed  CAS  Google Scholar 

  10. Saag, MS, Emini, EA, Laskin, oL, et al. A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. L-697,661 Working Group. N Engl J Med 1993;329(15):1065–1072.

    Article  PubMed  CAS  Google Scholar 

  11. Bacheler, LT, Anton, ED, Kudish, P, et al. Human immunodeficiency virus type 1 mutations selected in patients failing efavirenz combination therapy. Antimicrob Agents Chemother 2000;44(9):2475–2484.

    Article  PubMed  CAS  Google Scholar 

  12. Mellors, JW, Dutschman, GE, Im, GJ, Tramontano, E, Winkler, SR, Cheng, YC. In vitro selection and molecular characterization of human immunodeficiency virus-1 resistant to non-nucleoside inhibitors of reverse transcriptase. Mol Pharmacol 1992;41(3):446–451.

    PubMed  CAS  Google Scholar 

  13. Iglesias-Ussel, MD, Casado, C, Yuste, E, olivares, I, Lopez-Galindez, C. In vitro analysis of human immunodeficiency virus type 1 resistance to nevirapine and fitness determination of resistant variants. J Gen Virol 2002;83(Pt 1):93–101.

    PubMed  CAS  Google Scholar 

  14. Ren, J, Nichols C, Bird, L, et al. Structural mechanisms of drug resistance for mutations at codons 181 and 188 in HIV-1 reverse transcriptase and the improved resilience of second generation non-nucleoside inhibitors. J Mol Biol 2001;312(4):795–805.

    Article  PubMed  CAS  Google Scholar 

  15. Havlir, DV, Eastman, S, Gamst, A, Richman, DD. Nevirapine-resistant human immunodeficiency virus: kinetics of replication and estimated prevalence in untreated patients. J Virol 1996;70(11):7894–7899.

    PubMed  CAS  Google Scholar 

  16. Havlir, D, McLaughlin, MM, Richman, DD. A pilot study to evaluate the development of resistance to nevirapine in asymptomatic human immunodeficiency virusinfected patients with CD4 cell counts of >500/mm3: AIDS Clinical Trials Group Protocol 208. J Infect Dis 1995;172(5):1379–1383.

    PubMed  CAS  Google Scholar 

  17. Richman, DD, Havlir, D, Corbeil, J, et al. Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol 1994;68(3): 1660–1666.

    PubMed  CAS  Google Scholar 

  18. Casado, JL, Hertogs, K, Ruiz, L, et al. Non-nucleoside reverse transcriptase inhibitor resistance among patients failing a nevirapine plus protease inhibitor-containing regimen. AIDS 2000;14(2):F1–7.

    Article  PubMed  CAS  Google Scholar 

  19. Dueweke, TJ, Pushkarskaya, T, Poppe, SM, et al. A mutation in reverse transcriptase of bis(heteroaryl)piperazine-resistant human immunodeficiency virus type 1 that confers increased sensitivity to other nonnucleoside inhibitors. Proc Natl Acad Sci USA 1993;90(10):4713–4717.

    Article  PubMed  CAS  Google Scholar 

  20. Gerondelis, P, Archer, RH, Palaniappan, C, et al. The P236L delavirdine-resistant human immunodeficiency virus type 1 mutant is replication defective and demonstrates alterations in both RNA 5′-end-and DNA 3′-end-directed RNase H activities. J Virol 1999;73(7):5803–5813.

    PubMed  CAS  Google Scholar 

  21. Demeter, LM, Shafer, RW, Meehan, PM, et al. Delavirdine susceptibilities and associated reverse transcriptase mutations in human immunodeficiency virus type 1 isolates from patients in a phase I/II trial of delavirdine monotherapy (ACTG 260). Antimicrob Agents Chemother 2000;44(3):794–797.

    Article  PubMed  CAS  Google Scholar 

  22. Para, MF, Meehan, P, Holden-Wiltse, J, et al. ACTG 260: a randomized, phase I-II, dose-ranging trial of the anti-human immunodeficiency virus activity of delavirdine monotherapy. The AIDS Clinical Trials Group Protocol 260 Team. Antimicrob Agents Chemother 1999;43(6):1373–1378.

    PubMed  CAS  Google Scholar 

  23. Hertogs, K, Devroey, V, Vandeneynde, C, et al. Common, rare and new genotypic and/or phenotypic HIV-1 resistance profiles observed in routine clinical practice: a survey of over 5,000 isolates [abstract 425]. 39th ICAAC; San Francisco, CA; 1999.

    Google Scholar 

  24. Zacccarelli, M, Cingolani, A, Gori, C, et al. Cross-resistance among non-nucleoside reverse transcriptase (NNRTI) inhibitors limits recycling efavirenz (EFV) after nevirapine (NVP) failure [abstract 1763]. 41st Annual ICAAC; Chicago, IL; 2001.

    Google Scholar 

  25. Casado, JL, Moreno, A, Hertogs, K, Dronda, F, Moreno, S. Extent and importance of cross-resistance to efavirenz after nevirapine failure. AIDS Res Hum Retroviruses 2002;18(11):771–775.

    Article  PubMed  CAS  Google Scholar 

  26. Hammer, SM, Vaida, F, Bennett, KK, et al. Dual vs single protease inhibitor therapy following antiretroviral treatment failure: a randomized trial. JAMA 2002;288(2): 169–180.

    Article  PubMed  CAS  Google Scholar 

  27. Mellors, J, Palmer, S, Nissley, D, et al. Low-frequency NNRTI-resistant Variants Contribute to Failure of Efavirenz-containing Regimens [abstract 39]. 11th Conference on Retroviruses and opportunistic Infections; 2004 February 8–11; San Francisco, CA; 2004.

    Google Scholar 

  28. Huang, W, Parkin, NT, Lie, YS, et al. A novel HIV-1 RT mutation (M230L) confers NNRTI resistance and dose-dependent stimulation of replication. Antivir Ther 2000;5(S3):s14–25.

    Google Scholar 

  29. Little, SJ, Holte, S, Routy, JP, et al. Antiretroviral-drug resistance among patients recently infected with HIV. N Engl J Med 2002;347(6):385–394.

    Article  PubMed  CAS  Google Scholar 

  30. Little, SJ, Daar, ES, D’Aquila, RT, et al. Reduced antiretroviral drug susceptibility among patients with primary HIV infection. JAMA 1999;282(12):1142–1149.

    Article  PubMed  CAS  Google Scholar 

  31. Brenner, B, Wainberg, MA, Salomon, H, et al. Resistance to antiretroviral drugs in patients with primary HIV-1 infection. Investigators of the Quebec Primary Infection Study. Int J Antimicrob Agents 2000;16(4):429–434.

    Article  PubMed  CAS  Google Scholar 

  32. Duwe, S, Brunn, M, Altmann, D, et al. Frequency of genotypic and phenotypic drugresistant HIV-1 among therapy-naive patients of the German Seroconverter Study. J Acquir Immune Defic Syndr 2001;26(3):266–273.

    Article  PubMed  CAS  Google Scholar 

  33. Pilon, R, Sandstrom, P, Burchell, A, et al. Transmitted HIV-1 reverse transcriptase inhibitor resistance mutation stability in ART-naive recent seroconverters: results of the polaris HIV seroconversion study [abstract TuPeB4611]. XIV International AIDS Conference; Barcelona, Spain; 2002.

    Google Scholar 

  34. Imrie, A, Carr, A, Duncombe, C, et al. Primary infection with zidovudine-resistant human immunodeficiency virus type 1 does not adversely affect outcome at 1 year. Sydney Primary HIV Infection Study Group. J Infect Dis 1996;174(1): 195–198.

    PubMed  CAS  Google Scholar 

  35. Conant, M, Brown, S, Cohen, C, et al. An epidemiological prospective survey assessing the prevalence of HIV-1 drug resistance in 230 HIV-1-positive antiretroviral naive patients from the USA [abstract 443]. 39th ICAAC; San Francisco, CA; 1999.

    Google Scholar 

  36. Becker, MI, Haubrich, R, Wesselman, CW, et al. HIV-1 genotypic resistance in treatmentnaive subjects enrolled in an observational trial (GAIN). Antivir Ther 2002;7(2):S134.

    Google Scholar 

  37. Bacheler, LT, Ploughman, L, Hertogs, K, Larder, B. Impact of baseline NNRTI resistance on the efficacy of efavirenz combination therapy in NNRTI therapy-naive patients (study DMP 266-006). Antivir Ther 2000;5(S3):70.

    Google Scholar 

  38. Harrigan, PR, Hertogs, K, Verbiest, W, et al. Modest decreases in NNRTI susceptibility do not influence virological outcome in patients receiving initial NNRTIcontaining triple therapy. Antivir Ther 2003;8(5):395–402.

    PubMed  CAS  Google Scholar 

  39. Gonzalez, de, Requena, D, Gallego, o, Briones, C, Jimenez-Nacher, I, Soriano, V. Attainment of higher efavirenz plasma levels allow to regain complete virus suppression in patients carrying NNRTI resistance [abstract 454]. 9th Conference on Retroviruses and opportunistic Infections; Seattle, WA; February 24–28, 2002.

    Google Scholar 

  40. Masquelier, B, Neau, D, Chene, G, et al. Mechanism of virologic failure after substitution of a protease inhibitor by nevirapine in patients with suppressed plasma HIV-1 RNA. J Acquir Immune Defic Syndr 2001;28(4):309–312.

    PubMed  CAS  Google Scholar 

  41. Pelemans, H, Esnouf, R, Min, KL, Parniak, M, De Clercq, E, Balzarini, J. Mutations at amino acid positions 63, 189, and 396 of human immunodeficiency virus type 1 reverse transcriptase (RT) partially restore the DNA polymerase activity of a Trp229Tyr mutant RT. Virology 2001;287(1):143–150.

    Article  PubMed  CAS  Google Scholar 

  42. Xu, ZQ, Hertogs, K, van den Eynde, C, Bloor, S, Larder, B, Dutta, B. In vitro phenotypic resistance profile of (+)-calanolide A, a naturally occurring NNRTI, against clinical isolates of HIV-1 with Y181C mutation [abstract 440]. 39th ICAAC; San Francisco, CA; September 26–29, 1999.

    Google Scholar 

  43. Buckheit, RW Jr, White, EL, Fliakas-Boltz, V, et al. Unique anti-human immunodeficiency virus activities of the nonnucleoside reverse transcriptase inhibitors calanolide A, costatolide, and dihydrocostatolide. Antimicrob Agents Chemother 1999;43(8):1827–1834.

    PubMed  CAS  Google Scholar 

  44. Gazzard, B, Pozniak, A, Arasteh, K, et al. TMC 125, a next-generation NNRTI, demonstrates high potency after 7 days therapy in treatment-experienced HIV-1-infected individuals with phenotypic NNRTI resistance [abstract 4]. 9th Conference on Retroviruses and opportunistic Infections; Seattle, WA; 2002.

    Google Scholar 

  45. Hernandez, J, Amador, L, Amantea, M, Chao, H, Hawley, P, Paradiso, L. Short course monotherapy with AG1549, a novel nonnucleoside reverse transcriptase inhibitor, in antiretroviral naive patients [abstract 669]. 7th Conference on Retroviruses and opportunistic Infections; San Francisco, CA; 2000.

    Google Scholar 

  46. Wolfe, P, Hawley, P, Boccia, G, et al. Safety and efficacy of capravirine versus placebo in HIV-infected patients failing a nonnucleoside-reverse-transcriptaseinhibitor-containing regimen: results of a phase II, double-blind, placebo-controlled study [abstract 323]. 8th Conference on Retroviruses and opportunistic Infections; Chicago, IL; 2001.

    Google Scholar 

  47. Huang, W, Wrin, T, Gamarnik, A, Beauchaine, J, Whitcomb, JM, Petropoulos CJ. Reverse transcriptase mutations that confer non-nucleoside reverse transcriptase inhibitor resistance may also impair replication capacity. Antivir Ther 2002;7(2):S60.

    Google Scholar 

  48. Soderberg, K, Thompson, M, Alexander, L. Impaired in vitro fitness of nevirapine resistant HIV-1 mutants [abstract 577]. 9th Conference on Retroviruses and opportunistic Infections; Seattle, WA; 2000.

    Google Scholar 

  49. Archer, RH, Dykes, C, Gerondelis, P, et al. Mutants of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase resistant to nonnucleoside reverse transcriptase inhibitors demonstrate altered rates of RNase H cleavage that correlate with HIV-1 replication fitness in cell culture. J Virol 2000;74(18):8390–8401.

    Article  PubMed  CAS  Google Scholar 

  50. Haubrich, RH, Kemper, CA, Hellmann, NS, et al. The clinical relevance of nonnucleoside reverse transcriptase inhibitor hypersusceptibility: a prospective cohort analysis. AIDS] 2002;16(15):F33–F

    Article  PubMed  CAS  Google Scholar 

  51. Mellors, J, Vaida, F, Bennett, K, Hellmann, NS, DeGruttola, V, Hammer, S. Antiretroviral chemotherapy: combination therapy, drug resistance, and treatment interruption [abstract 45]. 9th Conference on Retroviruses and opportunistic Infections, Seattle, WA, 2002.

    Google Scholar 

  52. Haubrich, R, Jiang, H, Swanstrom, R, et al. Delavirdine hypersusceptibility: virologic response and phenotypic cut-points-results from ACTG 359 [abstract 671]. 11th Conference on Retroviruses and opportunistic Infections; San Francisco, CA; 2004.

    Google Scholar 

  53. Taylor, S, Allen, S, Fidler, S, et al. Stop study: after discontinuation of efavirenz, plasma concentrations may persist for 2 weeks or longer [abstract 131]. 11th Conference on Retroviruses and opportunistic Infections; San Francisco, CA; 2004.

    Google Scholar 

  54. Nolan, M, Fowler, MG, Mofenson, LM. Antiretroviral prophylaxis of perinatal HIV-1 transmission and the potential impact of antiretroviral resistance. J Acquir Immune Defic Syndr 2002;30(2):216–229.

    PubMed  CAS  Google Scholar 

  55. Mrcana, M, Guay, L, Dileanis, JA, Mmiro, F. Selection of nevirapine (NVP) resistance mutations in Ugandan women and infants receiving NVP prophylaxis to prevent HIV-1 vertical transmission (HIVNET 012) [abstract Lbor13]. XIII International AIDS Conference; Durban, South Africa; 2000.

    Google Scholar 

  56. Martinson, N, Morris, L, Gray, G, et al. HIV Resistance and transmission following single-dose nevirapine in a PMTCT cohort [abstract 238]. 11th Conference on Retroviruses and opportunistic Infections; San Francisco, CA; 2004.

    Google Scholar 

  57. Jourdain, G, Ngo-Giang-Huong, N, Le Coer, S, et al.,. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med 2004,351:229–240.

    Article  PubMed  CAS  Google Scholar 

  58. Witvrouw, M, Pannecouque, C, Van Laethem, K, Desmyter, J, De Clercq, E, Vandamme, AM. Activity of non-nucleoside reverse transcriptase inhibitors against HIV-2 and SIV. AIDS 1999;13(12):1477–1483.0

    Article  PubMed  CAS  Google Scholar 

  59. Isaka, Y, Miki, S, Kawauchi, S, et al. A single amino acid change at Leu-188 in the reverse transcriptase of HIV-2 and SIV renders them sensitive to non-nucleoside reverse transcriptase inhibitors. Arch Virol 2001;146(4):743–755.

    Article  PubMed  CAS  Google Scholar 

  60. Adje-Toure, CA, Cheingsong, R, Garcia-Lerma, JG, et al. Antiretroviral resistance among HIV-2 infected patients in Abidjan, Cote d’Ivoire. Antivir Ther 2002;7(2):S133.

    Google Scholar 

  61. Harrigan, PR, Montaner, JS, Wegner, SA, et al. World-wide variation in HIV-1 phenotypic susceptibility in untreated individuals: biologically relevant values for resistance testing. AIDS 2001;15(13):1671–1677.

    Article  PubMed  CAS  Google Scholar 

  62. Frater, AJ, Beardall, A, Ariyoshi, K, et al. Impact of baseline polymorphisms in RT and protease on outcome of highly active antiretroviral therapy in HIV-1-infected African patients. AIDS 2001;15(12):1493–1502.

    Article  PubMed  CAS  Google Scholar 

  63. Ristolal, M, Liitsola, K, Lehtola-Vanhanen, L, et al. Genetic resistance pattern of non-B HIV-1 strains to non-nucleoside reverse transcriptase inhibitors among patients who have failed antiretroviral therapy. XIV International AIDS Conference; Barcelona, Spain; July 7–12, 2002.

    Google Scholar 

  64. Phanuphak P. Potential antiretroviral drug resistance in developing countries: the Thailand experience. 9th Conference on Retroviruses and opportunistic Infections; Seattle, WA; February 24–28, 2002.

    Google Scholar 

  65. Hirsch, MS, Brun-Vezinet, F, Clotet, B, et al. Antiretroviral drug resistance testing in adults infected with human immunodeficiency virus type 1: 2003 recommendations of an International AIDS Society-USA Panel. Clin Infect Dis 2003;37(1): 113–128.

    Article  PubMed  Google Scholar 

  66. Department of Health and Human Services panel and the Henry J. Kaiser Family Foundation. Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents, 2003. Available at http://aidsinfo.nih.gov. Last accessed 2003.

  67. Johnson, VA, Brun-Vezinet, F, Clotet, B, et al. Update of the drug resistance mutations in HIV-1: 2004. Topics HIV Med 2004;12(4):119–124.

    Google Scholar 

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Authors and Affiliations

  1. Department of HIV/AIDS, World Health organization, Geneva, Switzerland

    F. Ramzi Asfour

  2. Division of Infectious Diseases, Department of Medicine, University of California, San Diego

    Richard Haubrich (Professor of Medicine)

  3. Antiviral Research Center, San Diego, CA

    Richard Haubrich (Professor of Medicine)

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  1. F. Ramzi Asfour
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Editors and Affiliations

  1. National Institute of Allergy and Infectious Diseases National Institutes of Health, USA

    Vassil St.Georgiev

  2. Division of Infectious Diseases, Roger Williams Medical Center, Providence, RI

    Gail Skowron MD (Chief) (Chief)

  3. Boston University School of Medicine, Boston, MA

    Gail Skowron MD (Chief) (Chief)

  4. Pfizer Inc., San Diego, CA

    Richard Ogden PhD

  5. Center for Poverty-Related Communicable Diseases Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Joep M. A. Lange MD, PhD (Professor of Medicine) (Professor of Medicine)

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Asfour, F.R., Haubrich, R. (2006). Resistance to Non-Nucleoside Reverse Transcriptase Inhibitors. In: St.Georgiev, V., Skowron, G., Ogden, R., Lange, J.M.A. (eds) Reverse Transcriptase Inhibitors in HIV/AIDS Therapy. Infectious Disease. Humana Press. https://doi.org/10.1007/978-1-59745-085-0_14

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