Drugs

, Volume 57, Issue 3, pp 337–361

Managing Resistance to Anti-HIV Drugs

An Important Consideration for Effective Disease Management
  • Anne-Mieke Vandamme
  • Kristel Van Laethem
  • Erik De Clercq
Disease Management

Abstract

Current recommendations for the treatment of HIV-infected patients advise highly active antiretroviral therapy (HAART) consisting of combinations of 3 or more drugs to provide long-term clinical benefit. This is because only a complete suppression of virus replication will be able to prevent virus drug resistance, the main cause of drug failure. Virus drug resistance may remain a cause of concern in patients who have already received suboptimal mono- or bitherapy, or for patients who do not experience complete shut-down of virus replication under HAART For these patients, replacement of one combination therapy regimen by another at drug failure, taking into account the existing resistance profile, will be needed. The development of new drugs will remain necessary for those patients who have failed to respond to all currently available drugs, as will be the institution of more effective and less toxic HAART regimens.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    DeNoon DJ. AIDS therapies. Atlanta (GA): Charles W. Henderson, 1998Google Scholar
  2. 2.
    Markowitz M, Saag M, Powderly WG, et al. A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection. N Engl J Med 1995; 333: 1534–9PubMedGoogle Scholar
  3. 3.
    Danner SA, Carr A, Leonard JM, et al. A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. N Engl J Med 1995; 333: 1528–33PubMedGoogle Scholar
  4. 4.
    Havlir D, Cheeseman SH, McLaughlin MM, et al. High-dose nevirapine: safety, pharmacokinetics, and antiviral effect in patients with human immunodeficiency virus infection. J Infect Dis 1995; 171: 537–45PubMedGoogle Scholar
  5. 5.
    Schinazi RF, Larder BA, Mellors JW. Mutations in retroviral genes associated with drug resistance. Int Antiviral News 1997; 5: 129–42Google Scholar
  6. 6.
    Lea AP, Faulds D. Stavudine: a review of its pharmacodynamic and pharmacokinetic properties and clinical potential in HIV infection. Drugs 1996; 51: 846–64PubMedGoogle Scholar
  7. 7.
    Havlir DV, Richman DD. Viral dynamics of HIV: implications for drug development and therapeutic strategies. Ann Intern Med 1996; 124: 984–94PubMedGoogle Scholar
  8. 8.
    Katzenstein DA, Hammer SM, Hughes MD, et al. The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. N Engl J Med 1996; 335: 1091–8PubMedGoogle Scholar
  9. 9.
    Gulick R, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997; 337: 734–9PubMedGoogle Scholar
  10. 10.
    Davey RT, Chaitt DG, Reed GF, et al. Randomized, controlled phase I/II, trial of combination therapy with delavirdine (U-90152S) and conventional nucleosides in human immunodeficiency virus type 1-infected patients. Antimicrob Agents Chemother 1996; 40: 1657–64PubMedGoogle Scholar
  11. 11.
    Lanier ER, Stone C, Griffin P, et al. Phenotypic sensitivity to 1592 (abacavir) in the presence of multiple genotypic mutations: correlation with viral load response [abstract no. 686]. Fifth Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1-5: ChicagoGoogle Scholar
  12. 12.
    Schuurman R, Nijhuis M, van Leeuwen R, et al. Rapid changes in human immunodeficiency virus type 1 RNA load and appearance of drug-resistant virus populations in persons treated with lamivudine (3TC). J Infect Dis 1995; 171: 1411–9PubMedGoogle Scholar
  13. 13.
    Schmit J-C, Ruiz L, Clotet B, et al. Resistance-related mutations in the HIV-1 protease gene of patients treated for 1 year with the protease inhibitor ritonavir (ABT-538). AIDS 1996; 10: 995–9PubMedGoogle Scholar
  14. 14.
    Larder B, Richman D, Vella S. HIV resistance and implications for therapy. Atlanta (GA): Medicom Inc., 1998Google Scholar
  15. 15.
    Tisdale M, Myers RE, Ait-Khaled, et al. HIV drug resistance analysis during clinical studies with the protease inhibitor amprenavir [abstract 118]. Sixth Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4; ChicagoGoogle Scholar
  16. 16.
    Staszewski S, Harrigan PR, Stone S, et al. Efficacy and resistance profile of abacavir at 24 and 48 weeks therapy including monotherapy and following switch to combination therapy (abacavir/zidovudine/lamivudine) [abstract 99]. 2nd International Workshop on HIV Drug Resistance and Treatment Strategies; 1998 Jun 24–27; Lake Maggiore, ItalyGoogle Scholar
  17. 17.
    Bacheler LT, Anton B, Baker D, et al. Genotypic correlates of in vivo resistance to efavirenz [abstract 109]. Sixth Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4; ChicagoGoogle Scholar
  18. 18.
    De Clercq E. Virus replication: target functions and events for virus-specific inhibitors. In: Galasso GJ, Whitley RJ, Merigan TC, editors. Antiviral agents and human viral diseases. Philadelphia (PA): Lippincott-Raven, 1997: 1–44Google Scholar
  19. 19.
    Debouck C. The HIV-1 protease as a therapeutic target for AIDS. AIDS Res Hum Retrovir 1992; 8: 153–64PubMedGoogle Scholar
  20. 20.
    Kavlick MF, Shirasaka T, Kojima E, et al. Genotypic and phenotypic characterization of HIV-1 isolated from patients receiving (−)-2,3,-dideoxy-3-thiacytidine. Antiviral Res 1995; 28: 133–46PubMedGoogle Scholar
  21. 21.
    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. N Engl J Med 1993; 329: 1065–72PubMedGoogle Scholar
  22. 22.
    Richman DD, Havlir D, Corbeil J, et al. Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol 1994; 68: 1660–6PubMedGoogle Scholar
  23. 23.
    Vandamme A-M, Debyser Z, Pauwels R, et al. Characterization of HIV-1 strains isolated from patients treated with TIBO R 82913. AIDS Res Hum Retroviruses 1994; 10: 39–45PubMedGoogle Scholar
  24. 24.
    Cheeseman SH, Havlir D, McLaughlin MM, et al. Phase I/II evaluation of nevirapine alone and in combination with zidovudine for infection with human immunodeficiency virus. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 8: 141–51PubMedGoogle Scholar
  25. 25.
    Boucher CAB, O’Sullivan E, Mulder JW, et al. Ordered appearance of zidovudine resistance mutations during treatment of 18 human immunodeficiency virus-positive subjects. J Infect Dis 1992; 165: 105–10PubMedGoogle Scholar
  26. 26.
    Fitzgibbon JE, Farnham AE, Sperber SJ, et al. Human immunodeficiency virus type 1 pol gene mutations in an AIDS patient treated with multiple antiretroviral drugs. J Virol 1993; 67: 7271–5PubMedGoogle Scholar
  27. 27.
    Larder B A, Darby G, Richman DD. HIV with reduced sensitivity to zidovudine (AZT) related during prolonged therapy. Science 1989; 243: 1731–4PubMedGoogle Scholar
  28. 28.
    Craig C, Moyle G. The development of resistance of HIV-1 to zalcitabine. AIDS 1997; 11: 271–9PubMedGoogle Scholar
  29. 29.
    Jacobsen H, Hänggi M, Ott M, et al. In vivo resistance to a human immunodeficiency virus type 1 proteinase inhibitor: mutations, kinetics, and frequencies. J Infect Dis 1996; 173: 1379–87PubMedGoogle Scholar
  30. 30.
    Condra JH, Holder DJ, Schleif WA, et al. Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor. J Virol 1996; 70: 8270–6PubMedGoogle Scholar
  31. 31.
    Molla A, Korneyeva M, Gao Q, et al. Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. Nature Med 1996; 2: 760–6PubMedGoogle Scholar
  32. 32.
    Cherrington JM, Mulato AS, Fuller MD, et al. Novel mutation (K70E) in human immunodeficiency virus type 1 reverse transcriptase confers decreased susceptibility to 9-[2-(phosphonomethoxy)ethyl]adenine in vitro. Antimicrob Agents Chemother 1996; 40: 2212–6PubMedGoogle Scholar
  33. 33.
    Pantaleo G, Graziosi C, Demarest JF, et al. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 1993; 362: 355–8PubMedGoogle Scholar
  34. 34.
    Ho DD, Neumann AU, Perelson AS, et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995; 373: 123–6PubMedGoogle Scholar
  35. 35.
    Wei X, Ghosh SK, Taylor ME, et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 1995; 373: 117–21PubMedGoogle Scholar
  36. 36.
    Wolthers KL, Schuitemaker H, Miedema F. Rapid CD4+ T-cell turnover in HIV-1 infection: a paradigm revisited. Immunol Today 1998; 19: 44–8PubMedGoogle Scholar
  37. 37.
    Domingo E, Menendezarias L, Holland JJ. RNA virus fitness. Rev Med Virol 1997; 7: 87–96PubMedGoogle Scholar
  38. 38.
    Nakano T, Morozumi H, Inuzuka S, et al. Clonal selection of HIV type 1 variants associated with resistance to foscarnet in vitro: confirmation by molecular evolutionary analysis. AIDS Res Hum Retrovir 1997; 13: 563–73PubMedGoogle Scholar
  39. 39.
    de Jong MD, Veenstra J, Stilianakis NI, et al. Host-parasite dynamics and outgrowth of virus containing a single K70R amino acid change in reverse transcriptase are responsible for the loss of human immunodeficiency virus type 1 RNA load suppression by zidovudine. Proc Natl Acad Sci U S A 1996; 93: 5501–6PubMedGoogle Scholar
  40. 40.
    Ren J, Esnouf RM, Garman E, et al. High resolution structures of HIV-1 RT from four RT-inhibitor complexes. Nature Struct Biol 1995; 2: 293–302PubMedGoogle Scholar
  41. 41.
    Kervinen J, Thanki A, Zdanov A, et al. Structural analysis of the native and drug-resistant HIV-1 proteinases complexed with an aminodiol inhibitor. Protein Pept Lett 1996; 3: 399–406Google Scholar
  42. 42.
    Esnouf RM. An extensively modified version of MolScript that includes greatly enhanced coloring capabilities. J Mol Graph 1997; 15: 132–4Google Scholar
  43. 43.
    Arnold E, Ding J, Hughes SH, et al. Structures of DNA and RNA polymerases and their interactions with nucleic acid substrates. Curr Opin Struct Biol 1995; 5: 27–38PubMedGoogle Scholar
  44. 44.
    Tantillo C, Ding J, Jacobo-Molina A, et al. Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. J Mol Biol 1994; 243: 369–87PubMedGoogle Scholar
  45. 45.
    Arts EJ, Wainberg MA. Mechanisms of nucleoside analog antiviral activity and resistance during human immunodeficiency virus reverse transcription. Antimicrob Agents Chemother 1996; 40: 527–40PubMedGoogle Scholar
  46. 46.
    Boyer PL, Tantillo C, Jacobo-Molina A, et al. Sensitivity of wild-type human immunodeficiency virus type 1 reverse transcriptase to dideoxynucleotides depends on template length. Proc Natl Acad Sci U S A 1994; 91: 4882–6PubMedGoogle Scholar
  47. 47.
    Wilson JE, Aulabaugh A, Caligan B, et al. Human immunodeficiency viras type-1 reverse transcriptase: contribution of Met-184 to binding of nucleoside 5-triphosphate. J Biol Chem 1996; 271: 13656–62PubMedGoogle Scholar
  48. 48.
    Gu ZX, Fletcher RS, Arts EJ, et al. The K65R mutant reverse transcriptase of HIV-1 cross-resistant to 2,3-dideoxycytidine, 2,3-dideoxy-3-thiacytidine, and 2,3-dideoxyinosine shows reduced sensitivity to specific dideoxynucleoside triphosphate inhibitors in vitro. J Biol Chem 1994; 269: 28118–22PubMedGoogle Scholar
  49. 49.
    Mayers DL, Japour AJ, Arduino J-M, et al. Dideoxynucleoside resistance emerges with prolonged zidovudine monotherapy. Antimicrob Agents Chemother 1994; 38: 307–14PubMedGoogle Scholar
  50. 50.
    Arion D, Borkow G, Kaushik N, et al. Phenotypic mechanism of HIV-1 resistance to 3-azido-3-deoxythymidine (AZT) [abstract no. 32]. Fifth Conference on Retroviruses and Opportunistic Infections: 1998 Feb 1–5: ChicagoGoogle Scholar
  51. 51.
    Arion D, Kaushik N, McCormick S, et al. Phenotypic mechanism of HIV-1 resistance to 3-azido-3-deoxythymidine (zidovudine) [abstract no. 14]. 2nd International Workshop on Drug Resistance and Treatment Strategies; 1998 Jun 24–27: Lake Maggiore, ItalyGoogle Scholar
  52. 52.
    Esnouf R, Ren JS, Ross C, et al. Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors. Nat Struct Biol 1995; 2: 303–8PubMedGoogle Scholar
  53. 53.
    Balzarini J, Karlsson A, Vandamme A-M, et al. Human immunodeficiency virus type 1 (HIV-1) strains selected for resistance against the HIV-1-specific [2,5-bis-O-(tertbutyldimethylsilyl)-3-spiro-5-(4-amino-1,2-oxathiole-2,2-d ioxide)]-D-pentofuranosyl (TSAO) nucleoside analogues retain sensitivity to HIV-1-specific nonnucleoside inhibitors. Proc Natl Acad Sci U S A 1993; 90: 6952–6PubMedGoogle Scholar
  54. 54.
    Jonckheere H, Taymans J-M, Balzarini J, et al. Resistance of HIV-1 reverse transcriptase against [2,5-Bis-O-(tert-butyldimethylsilyl)-3-spiro-5-(4-amino-1,2-oxathiole-2,2-dioxid e)] (TSAO) derivatives is determined by the mutation Glu138 Lys on the p51 subunit. J Biol Chem 1994; 269: 25255–8PubMedGoogle Scholar
  55. 55.
    Boyer PL, Currens MJ, McMahon JB, et al. Analysis of non-nucleoside drug-resistant variants of human immunodeficiency virus type 1 reverse transcriptase. J Virol 1993; 67: 2412–20PubMedGoogle Scholar
  56. 56.
    Baldwin ET, Bhat TN, Liu B, et al. Structural basis of drug resistance for the V82A mutant of HIV-1 proteinase. Nature Struct Biol 1995; 2: 244–9PubMedGoogle Scholar
  57. 57.
    Ala PJ, Huston EE, Klabe RM, et al. Molecular basis of HIV-1 protease drug resistance: structural analysis of mutant proteases complexed with cyclic urea inhibitors. Biochemistry 1997; 36: 1573–80PubMedGoogle Scholar
  58. 58.
    Shao W, Everitt L, Manchester M, et al. Sequence requirements of the HIV-1 protease flap region determined by saturation mutagenesis and kinetic analysis of flap mutants. Proc Natl Acad Sci U S A 1997; 94: 2243–8PubMedGoogle Scholar
  59. 59.
    Shao X, Ekstrand DHL, Bhikhabhai R, et al. A non-radioactive microtitre plate reverse transcriptase (RT) assay, based on immobilized template, for screening of RT activity inhibitors and evaluation of theirmode of action. Antiviral Chem Chemother 1997; 8: 149–59Google Scholar
  60. 60.
    Vandamme A–M, Witvrouw M, Pannecouque C, et al. Evaluating clinical isolates for their phenotypic and genotypic resistance against anti-HIV drugs. In: Kinchington D, Schinazi RF, editors. Antiviral methods and protocols. Totowa (NJ): Humana Press Inc. In pressGoogle Scholar
  61. 61.
    von der Helm K, Seelmeier S, Kisselev A, et al. Identification, purification and cell culture assays of retroviral proteases. Methods Enzymol 1994; 241: 89–104PubMedGoogle Scholar
  62. 62.
    Gu ZX, Gao Q, Li X, et al. Novel mutation in the human immunodeficiency virus type 1 reverse transcriptase gene that encodes cross-resistance to 2,3-dideoxyinosine and 2,3-dideoxycytidine. J Virol 1992; 66: 7128–35PubMedGoogle Scholar
  63. 63.
    Gu ZX, Salomon H, Cherrington JM, et al. K65R mutation of human immunodeficiency viras type 1 reverse transcriptase encodes cross-resistance to 9-(2-phosphonylmethoxyethyl)adenine. Antimicrob Agents Chemother 1995; 39: 1888–91PubMedGoogle Scholar
  64. 64.
    St.Clair MH, Martin JL, Tudor-Williams G, et al. Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science 1991; 253: 1557–9PubMedGoogle Scholar
  65. 65.
    Wainberg MA, Lewis L, Salomon H, et al. Resistance to (−)-2,3-dideoxy-3-thiacytidine (3TC) in HIV-1 isolated from paediatric patients. Antiviral Ther 1996; 1: 98–104Google Scholar
  66. 66.
    Winters MA, Shafer RW, Jellinger RA, et al. Human immunodeficiency viras type 1 reverse transcriptase genotype and drug susceptibility changes in infected individuals receiving dideoxyinosine monotherapy for 1 to 2 years. Antimicrob Agents Chemother 1997; 41: 757–62PubMedGoogle Scholar
  67. 67.
    Gong Y-F, Marshall DR, Srinivas RV, et al. Susceptibilities of zidovudine-resistant variants of human immunodeficiency viras type 1 to inhibition by acyclic nucleoside phosphonates. Antimicrob Agents Chemother 1994; 38: 1683–7PubMedGoogle Scholar
  68. 68.
    Condra JH, Schleif WA, Blahy OM, et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature 1995; 374: 569–71PubMedGoogle Scholar
  69. 69.
    Mulato AS, Lamy PL, Li W, et al. Genotypic characterization of HIV-1 variants isolated from AIDS patients treated with adefovir dipivoxil (bis-POM PMEA) [abstract no. 24]. International Workshop on HIV Drag Resistance, Treatment Strategies and Eradication; 1997 Jun 25–28: St Petersburg (FL)Google Scholar
  70. 70.
    Schmit J-C, Cogniaux J, Hermans P, et al. Multiple drag resistance to nucleoside analogues and nonnucleoside reverse transcriptase inhibitors in an efficiently replicating human immunodeficiency virus type 1 patient strain. J Infect Dis 1996; 174: 962–8PubMedGoogle Scholar
  71. 71.
    Schmit J-C, Van Laethem K, Ruiz L, et al. Multiple dideoxynucleoside analogue resistant (MddNR) HIV-1 strains isolated from patients from different European countries. AIDS 1998; 12: 2007–15PubMedGoogle Scholar
  72. 72.
    Palmer S, Alaeus A, Albert J, et al. Drag susceptibility of subtypes A, B, C, D, and E human immunodeficiency virus type 1 primary isolates. AIDS Res Hum Retrovir 1998; 14: 157–62PubMedGoogle Scholar
  73. 73.
    Mellors JW, Hertogs K, Peeters F, et al. Susceptibility of clinical HIV-1 isolates to 1592U89 [abstract no. 687]. Fifth Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5: ChicagoGoogle Scholar
  74. 74.
    Miller MD, Anton KE, Mulato AS, et al. Antiviral susceptibilities of HIV-1 RT recombinant viruses derived from AIDS patients after prolonged adefovir dipivoxil therapy [abstract no. 677]. Fifth Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5: ChicagoGoogle Scholar
  75. 75.
    Hertogs K, Mellors JW, Schel P, et al. Patterns of cross-resistance among protease inhibitors in 483 clinical HIV-1 isolates [abstract no. 395]. Fifth Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5: ChicagoGoogle Scholar
  76. 76.
    Hertogs K, de Béthune M-P, Miller V, et al. A rapid method for simultaneous detection of phenotypic resistance to inhibitors of protease and reverse transcriptase in recombinant human immunodeficiency viras type 1 isolates from patients treated with antiretroviral drugs. Antimicrob Agents Chemother 1998; 42: 269–76PubMedGoogle Scholar
  77. 77.
    Lin P-F, Samanta H, Rose RE, et al. Genotypic and phenotypic analysis of human immunodeficiency virus type 1 isolates from patients on prolonged stavudine therapy. J Infect Dis 1994; 170: 1157–64PubMedGoogle Scholar
  78. 78.
    Demeter LM, Meehan PM, Morse G, et al. HIV-1 drug susceptibilities and reverse transcriptase mutations in patients receiving combination therapy with didanosine and delavirdine. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 14: 136–44PubMedGoogle Scholar
  79. 79.
    Larder B A, Kohli A, Bloor S, et al. Human immunodeficiency virus type 1 drug susceptibility during zidovudine (AZT) monotherapy compared with AZT plus 2,3-dideoxyinosine or AZT plus 2,3-dideoxycytidine combination therapy. J Virol 1996; 70: 5922–9PubMedGoogle Scholar
  80. 80.
    Deminie CA, Bechtold CM, Riccardi K, et al. Clinical HIV-1 isolates remain sensitive to stavudine following prolonged therapy. AIDS 1998; 12: 110–2PubMedGoogle Scholar
  81. 81.
    Van Laethem K, Witvrouw M, Schmit J-C, et al. The multiple nucleoside analogue resistance mutations confer cross-resistance to abacavir. Sixth Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4; ChicagoGoogle Scholar
  82. 82.
    Palmer S, Shafer R, Alaeus A, et al. Drug susceptibility and sequence analysis of non-subtype B HIV-1 isolates [abstract no. 36]. International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication; 1997 Jun 25–28: St Petersburg (FL)Google Scholar
  83. 83.
    Cox SW, Apéria K, Albert J, et al. Comparison of the sensitivities of primary isolates of HIV type 2 and HIV type 1 to antiviral drugs and drug combinations. AIDS Res Hum Retroviruses 1994; 10: 1725–9PubMedGoogle Scholar
  84. 84.
    Miller V, Staszewski S, Boucher CAB, et al. Clinical experience with non-nucleoside reverse transcriptase inhibitors. AIDS 1997; 11 Suppl. A: S157–64PubMedGoogle Scholar
  85. 85.
    Hertogs K, de Béthune M–P, Miller V, et al. Performance characteristics of phenotypic drug resistance testing (Antivirogram™) in monitoring of anti-HIV therapy [abstract no. 43]. International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication; 1997 Jun 25–28: St Petersburg (FL)Google Scholar
  86. 86.
    Schuurman R. State of the art of genotypic HIV-1 drug resistance. Curr Opin Infect Dis 1997; 10: 480–4Google Scholar
  87. 87.
    Van Laethem K, Van Vaerenbergh K, Schmit J-C, et al. Selective PCR for the detection of HIV-1 drug resistance mutations in the follow-up of HIV-1-infected patients [abstract no. 154-P4]. Third European Conference on Experimental AIDS Research; 1998 Feb 28–Mar 3: MunichGoogle Scholar
  88. 88.
    Van Laethem K, Van Vaerenbergh K, Schmit J-C, et al. Phenotypic assays and sequencing are less sensitive for the detection of resistance in mixed genotype compared to point mutation assays. Fourth International Congress on Drug Therapy in HIV Infection; 1998 Nov 8–12; GlasgowGoogle Scholar
  89. 89.
    Larder BA. Interactions between drug resistance mutations in human immunodeficiency virus type 1 reverse transcriptase. J Gen Virol 1994; 75: 951–7PubMedGoogle Scholar
  90. 90.
    Nijhuis M, Schuurman R, de Jong D, et al. Lamivudine-resistant human immunodeficiency virus type 1 variants (184V) require multiple amino acid changes to become co-resistant to zidovudine in vivo. J Infect Dis 1997; 176: 398–405PubMedGoogle Scholar
  91. 91.
    Schmit J-C, Martinez-Picado J, Ruiz L, et al. Evolution of HIV drug resistance in zidovudine/zalcitabine- and zidovudine/ didanosine-experienced patients receiving lamivudine-containing combination therapy. Antiviral Ther 1998; 3: 81–8Google Scholar
  92. 92.
    Larder BA. 3-Azido-3-deoxythymidine resistance suppressed by a mutation conferring human immunodeficiency virus type 1 resistance to nonnucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 1992; 36: 2664–9PubMedGoogle Scholar
  93. 93.
    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 U S A 1993; 90: 4713–7PubMedGoogle Scholar
  94. 94.
    Tachedjian G, Mellors J, Bazmi H, et al. Zidovudine resistance is suppressed by mutations conferring resistance of human immunodeficiency virus type 1 to foscarnet. J Virol 1996; 70: 7171–81PubMedGoogle Scholar
  95. 95.
    Larder BA, Kemp SD, Harrigan PR. Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science 1995; 269: 696–9PubMedGoogle Scholar
  96. 96.
    Balzarini J, Karlsson A, Pérez-Pérez M-J, et al. Treatment of human immunodeficiency virus type 1 (HTV-l)-infected cells with combinations of HIV-1-specific inhibitors results in a different resistance pattern than does treatment with single-drug therapy. J Virol 1993; 67: 5353–9PubMedGoogle Scholar
  97. 97.
    Shirasaka T, Kavlick MF, Ueno T, et al. Emergence of human immunodeficiency virus type 1 variants with resistance to multiple dideoxynucleosides in patients receiving therapy with dideoxynucleosides. Proc Natl Acad Sci U S A 1995; 92: 2398–402PubMedGoogle Scholar
  98. 98.
    Shafer RW, Kozal MJ, Winters MA, et al. Combination therapy with zidovudine and didanosine selects for drug-resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene mutations. J Infect Dis 1994; 169: 722–9PubMedGoogle Scholar
  99. 99.
    Iversen AKN, Shafer RW, Wehrly K, et al. Multidrug-resistant human immunodeficiency virus type 1 strains resulting from combination antiretroviral therapy. J Virol 1996; 70: 1086–90PubMedGoogle Scholar
  100. 100.
    Kemp SD, Shi C, Bloor S, et al. A novel polymorphism at codon 333 of human immunodeficiency virus type 1 reverse transcriptase can facilitate dual resistance to zidovudine and 1-2,3-dideoxy-3-thiacytidine. J Virol 1998; 72: 5093–8PubMedGoogle Scholar
  101. 101.
    Winters MA, Coolley KL, Girard YA, et al. Phenotypic and molecular analysis of HIV-1 isolates possessing 6 bp inserts in the reverse transcriptase gene that confer resistance to nucleoside analogues [abstract no. 16]. 2nd International Workshop on Drug Resistance and Treatment Strategies; 1998 Jun 24–27: Lake Maggiore, ItalyGoogle Scholar
  102. 102.
    De Jong JJ, Jurriaans S, Goudsmit J, et al. Insertion of two amino acids in reverse transcriptase (RT) during antiretroviral combination therapy: implications for resistance against nucleoside RT inhibitors [abstract no. 18]. 2nd International Workshop on Drug Resistance and Treatment Strategies; 1998 Jun 24–27: Lake Maggiore, ItalyGoogle Scholar
  103. 103.
    Molla A, Japour A. HIV protease inhibitors. Curr Opin Infect Dis 1997; 10: 491–5Google Scholar
  104. 104.
    Tisdale M. HIV protease inhibitors — resistance issues. Intern Antiviral News 1996; 4: 41–3Google Scholar
  105. 105.
    Swanstrom R, Smith T. In vitro selection for resistance to protease inhibitors used singly and in pairs. AIDS Pathogenesis; 1997 Apr 8–13: Keystone (CO)Google Scholar
  106. 106.
    Lorenzi P, Yerly S, Abderrakim K, et al. Toxicity, efficacy, plasma drug concentrations and protease mutations in patients with advanced HIV infection treated with ritonavir plus saquinavir. AIDS 1997; 11: F95–9PubMedGoogle Scholar
  107. 107.
    Sharma PL, Crumpacker CS. Attenuated replication of human immunodeficiency virus type 1 with a didanosine-selected reverse transcriptase mutation. J Virol 1997; 71: 8846–51PubMedGoogle Scholar
  108. 108.
    Boyer PL, Hughes SH. Analysis of mutations at position 184 in reverse transcriptase of human immunodeficiency virus type 1. Antimicrob Agents Chemother 1995; 39: 1624–8PubMedGoogle Scholar
  109. 109.
    Back NKT, Nijhuis M, Keulen W, et al. Reduced replication of 3TC-resistant HIV-1 variants in primary cells due to a processivity defect of the reverse transcriptase enzyme. EMBO J 1996; 15: 4040–9PubMedGoogle Scholar
  110. 110.
    Ueno T, Shirasaka T, Mitsuya H. Enzymatic characterization of human immunodeficiency virus type 1 reverse transcriptase resistant to multiple 2,3-dideoxynucleoside 5-triphosphates. J Biol Chem 1995; 270: 23605–11PubMedGoogle Scholar
  111. 111.
    Wainberg MA, Drosopoulos WC, Salomon H, et al. Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase. Science 1996; 271: 1282–5PubMedGoogle Scholar
  112. 112.
    Drosopoulos WC, Prasad VR. Polymerase fidelity of E86G, a nucleoside analog-resistant variant of human immunodeficiency virus type 1 reverse transcriptase. J Virol 1996; 70: 4834–8PubMedGoogle Scholar
  113. 113.
    Rubinek T, Bakhanashvili M, Taube R, et al. The fidelity of 3 misinsertion and mispair extension during DNA synthesis exhibited by two drug resistant mutants of the reverse transcriptase of human immunodeficiency virus type 1 with leu74-val and glu89-gly. Eur J Biochem 1997; 247: 238–47PubMedGoogle Scholar
  114. 114.
    Rezende LF, Curr K, Ueno T, et al. The impact of multi-dideoxynucleoside resistance-conferring mutations in human immunodeficiency virus type 1 reverse transcriptase on polymerase fidelity and error specificity. J Virol 1998; 72: 2890–5PubMedGoogle Scholar
  115. 115.
    Balzarini J, Pelemans H, Karlsson A, et al. Concomitant combination therapy for HIV infection preferable over sequential therapy with 3TC and non-nucleoside reverse transcriptase inhibitors. Proc Natl Acad Sci U S A 1996; 93: 13152–7PubMedGoogle Scholar
  116. 116.
    Jonckheere H, Witvrouw M, De Clercq E, et al. Lamivudine resistance of HIV type 1 does not delay development of resistance to nonnucleoside HIV type 1-specific reverse transcriptase inhibitors as compared with wild-type HIV type 1. AIDS Res Hum Retrovir 1998; 14: 249–53PubMedGoogle Scholar
  117. 117.
    Schmit J-C, Cogniaux J, Hermans P, et al. An efficiently replicating HIV strain with multiple resistance to nucleoside analogues including 3TC is able to additionally acquire resistance to non-nucleoside analogues [abstract no. 62]. Fifth International Workshop on HIV Drug Resistance; 1996 Jul 3–6; Whistler (BC)Google Scholar
  118. 118.
    Preston BD, Garvey N. Retroviral mutation and reverse transcriptase fidelity. Pharm Tech 1992; 16: 34–52Google Scholar
  119. 119.
    Kleim J-P, Bender R, Billhardt U-M, et al. Activity of a novel quinoxaline derivative against human immunodeficiency virus type 1 reverse transcriptase and viral replication. Antimicrob Agents Chemother 1993; 37: 1659–64PubMedGoogle Scholar
  120. 120.
    Olmsted RA, Slade DE, Kopta LA, et al. (Alkylamino)piperidine bis(heteroaryl)piperizine analogs are potent, broadspectrum nonnucleoside reverse transcriptase inhibitors of drug-resistant isolates of human immunodeficiency virus type 1 (HIV-1) and select for drug-resistant variants of HIV-1IIIB with reduced replication phenotypes. J Virol 1996; 70: 3698–705PubMedGoogle Scholar
  121. 121.
    Rayner MM, Cordova B, Jackson DA. Population dynamics studies of wild-type and drug-resistant mutant HIV in mixed infections. Virology 1997; 236: 85–94PubMedGoogle Scholar
  122. 122.
    Ermolieff J, Lin XL, Tang J. Kinetic properties of saquinavir resistant mutants of human immunodeficiency virus type 1 protease and their implications in drug resistance in vivo. Biochemistry 1997; 36: 12364–70PubMedGoogle Scholar
  123. 123.
    Wilson SI, Phylip LH, Mills JS, et al. Escape mutants of HIV-1 proteinase: enzymic efficiency and susceptibility to inhibition. Biochim Biophys Acta 1997; 1339: 113–25PubMedGoogle Scholar
  124. 124.
    Nijhuis M, Schuurman R, de Jong D, et al. Selection of HIV-1 variants with increased fitness during ritonavir therapy [abstract no. 92]. International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication; 1997 Jun 25–28: St Petersburg (FL)Google Scholar
  125. 125.
    Kaplan AH, Michael SF, Wehbie RS, et al. Selection of multiple human immunodeficiency virus type 1 variants that encode viral proteases with decreased sensitivity to an inhibitor of the viral protease. Proc Natl Acad Sci U S A 1994; 91: 5597–601PubMedGoogle Scholar
  126. 126.
    Ho DD, Toyoshima T, Mo H, et al. Characterization of human immunodeficiency virus type 1 variants with increased resistance to a C2-symmetric protease inhibitor. J Virol 1994; 68: 2016–20PubMedGoogle Scholar
  127. 127.
    Zhang Y-M, Imamichi H, Imamichi T, et al. Drug resistance during indinavir therapy is caused by mutations in the protease gene and in its Gag substrate cleavage sites. J Virol 1997; 71: 6662–70PubMedGoogle Scholar
  128. 128.
    Borman AM, Paulous S, Clavel F Resistance of human immunodeficiency virus type 1 to protease inhibitors: selection of resistance mutations in the presence and absence of the drug. J Gen Virol 1996; 77: 419–26PubMedGoogle Scholar
  129. 129.
    Wlodawer A, Miller M, Jaskolski M, et al. Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease. Science 1989; 245: 616–21PubMedGoogle Scholar
  130. 130.
    Navia MA, Fitzgerald PM, McKeever BM, et al. Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature 1989; 337: 615–20PubMedGoogle Scholar
  131. 131.
    Croteau G, Doyon L, Thibeault D, et al. Impaired fitness of human immunodeficiency virus type 1 variants with high-level resistance to protease inhibitors. J Virol 1997; 71: 1089–96PubMedGoogle Scholar
  132. 132.
    Tozser J, Yin FH, Cheng YSE, et al. Activity of tethered human immunodeficiency virus 1 protease containing mutations in the flap region of one subunit. Eur J Biochem 1997; 244: 235–41PubMedGoogle Scholar
  133. 133.
    Schock HB, Garsky VM, Kuo LC. Mutational anatomy of an HIV-1 protease variant conferring cross-resistance to protease inhibitors in clinical trials: compensatory modulations of binding and activity. J Biol Chem 1996; 271: 31957–63PubMedGoogle Scholar
  134. 134.
    Doyon L, Croteau G, Thibeault D, et al. Second locus involved in human immunodeficiency virus type I resistance to protease inhibitors. J Virol 1996; 70: 3763–9PubMedGoogle Scholar
  135. 135.
    Smith MS, Koerber KL, Pagano JS. Long-term persistence of AZT-resistance mutations in the plasma HIV-1 of patients removed from AZT therapy. Leukemia 1994; 8 Suppl. 1: S179–82PubMedGoogle Scholar
  136. 136.
    Masquelier B, Pellegrin I, Ruffault A, et al. Genotypic evolution of HIV-1 isolates from patients after a switch of therapy from zidovudine to didanosine. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 8: 330–4PubMedGoogle Scholar
  137. 137.
    Kellam P, Boucher CAB, Tijnagel JMGH, et al. Zidovudine treatment results in the selection of human immunodeficiency virus type 1 variants whose genotypes confer increasing levels of drug resistance. J Gen Virol 1994; 75: 341–51PubMedGoogle Scholar
  138. 138.
    Caliendo AM, Savara A, An D, et al. Effects of zidovudine-selected human immunodeficiency virus type 1 reverse transcriptase amino acid substitutions on processive DNA synthesis and viral replication. J Virol 1996; 70: 2146–53PubMedGoogle Scholar
  139. 139.
    Richman DD, Guatelli JC, Grimes J, et al. Detection of mutations associated with zidovudine resistance in human immunodeficiency virus by use of the polymerase chain reaction. J Infect Dis 1991; 164: 1075–81PubMedGoogle Scholar
  140. 140.
    Hooker DJ, Tachedjian G, Solomon AE, et al. An in vivo mutation from leucine to trypthophan at position 210 in human immunodeficiency virus type 1 reverse transcriptase contributes to high-level resistance to 3-azido-3-deoxythymidine. J Virol 1996; 70: 8010–8PubMedGoogle Scholar
  141. 141.
    Cleland A, Watson H, Robertson P, et al. Evolution of zidovudine resistance-associated genotypes in human immunodeficiency virus type 1-infected patients. J Acquir Immune Defic Syndr 1996; 12: 6–18Google Scholar
  142. 142.
    Gallant JE, Hall C, Barnett S, et al. Ritonavir/saquinavir (RTV/SQV) as salvage therapy after failure of initial protease inhibitor (PI) regimen [abstract no. 427]. Fifth Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5: ChicagoGoogle Scholar
  143. 143.
    Mellors JW, Munoz A, Giorgi JV, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997; 126: 946–54PubMedGoogle Scholar
  144. 144.
    O’Brien WA, Hartigan PM, Daar ES, et al. Changes in plasma HIV RNA levels and CD4 lymphocyte counts predict both response to antiretroviral therapy and therapeutic failure. Ann Intern Med 1997; 126: 939–45PubMedGoogle Scholar
  145. 145.
    Saag MS, Holodny M, Kuritzkes DR, et al. HIV viral load markers in clinical practice. Nature Med 1996; 2: 625–9PubMedGoogle Scholar
  146. 146.
    Fessel WJ. Human immunodeficiency virus (HIV) RNA in plasma as the preferred target for therapy in patients with HIV infection: a critique. Clin Infect Dis 1997; 24: 116–22PubMedGoogle Scholar
  147. 147.
    Tudor-Williams G, St Clair MH, McKenney RE, et al. HIV-1 sensitivity to zidovudine and clinical outcome in children. Lancet 1992; 339: 15–9PubMedGoogle Scholar
  148. 148.
    St Clair MH, Hartigan PM, Andrews JC, et al. Zidovudine resistance, syncytium-inducing phenotype and HIV disease progression in a case-control study. J Acquir Immune Defic Syndr 1993; 6: 891–7PubMedGoogle Scholar
  149. 149.
    Montaner JSG, Singer J, Schlechter MT, et al. Clinical correlates of in vitro HIV-1 resistance to zidovudine: results of the Multicentre Canadian AZT Trial. AIDS 1993; 7: 189–96PubMedGoogle Scholar
  150. 150.
    Principi N, Marchisio P, De Pasquale MP, et al. HIV-1 reverse transcriptase codon 215 mutation and clinical outcome in children treated with zidovudine. AIDS Res Hum Retrovir 1994; 10: 721–6PubMedGoogle Scholar
  151. 151.
    Kozal MJ, Shafer RW, Winters MA, et al. HIV-1 syncytium-inducing phenotype, virus burden, codon 215 reverse transcriptase mutation and CD4 cell decline in zidovudine-treated patients. J Acquir Immune Defic Syndr Hum Retrovirol 1994; 7: 832–8Google Scholar
  152. 152.
    Loveday C, Kaye S, Tenant-Flowers M, et al. HIV RNA serumload and resistant viral genotypes during early zidovudine therapy. Lancet 1996; 345: 820–4Google Scholar
  153. 153.
    Günthard HF, Wong JK, Ignacio CC, et al. Human immunodeficiency virus replication and genotypic resistance in blood and lymph nodes after a year of potent antiretroviral therapy. J Virol 1998; 72: 2422–8PubMedGoogle Scholar
  154. 154.
    Lopez-Galindez C, Rojas JM, Najera R, et al. Characterization of genetic variation and 3-azido-3-deoxythymidine-resistance mutations of human immunodeficiency virus by the RNase: a mismatch cleavage method. Proc Natl Acad Sci USA 1991; 88: 4280–4PubMedGoogle Scholar
  155. 155.
    Stuyver L, Wyseur A, Rombout A, et al. Line probe assay for rapid detection of drug-selected mutations in the human immunodeficiency virus type 1 reverse transcriptase gene. Antimicrob Agents Chemother 1997; 41: 284–91PubMedGoogle Scholar
  156. 156.
    Nowak MA. AIDS pathogenesis: from models to viral dynamics in patients. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 10 Suppl. 1: Sl–5Google Scholar
  157. 157.
    Leigh Brown AJ, D’Aquila RT, Johnson VA, et al. Baseline sequence clusters predict response to combination therapy in ACTG 241 [abstract no. 50]. 2nd International Workshop on Drug Resistance and Treatment Strategies; 1998 Jun 24–27: Lake Maggiore, ItalyGoogle Scholar
  158. 158.
    Lanier R, Danehower S, Daluge S, et al. Genotypic and phenotypic correlates of response to abacavir (ABC, 1592) [abstract no. 52]. 2nd International Workshop on Drug Resistance and Treatment Strategies; 1998 Jun 24-27: Lake Maggiore, ItalyGoogle Scholar
  159. 159.
    Deeks SG, Parkin N, Petropoulos CJ, et al. Correlation of baseline phenotypic drug susceptibility with 16 week virologic response in a pilot combination therapy study in HIV-infected patients who failed indinavir therapy [abstract no. 53]. 2nd International Workshop on Drug Resistance and Treatment Strategies; 1998 Jun 24–27: Lake Maggiore, ItalyGoogle Scholar
  160. 160.
    Zolopa AR, Shafer RW, Warford A, et al. Predictors of antiviral response to saquinavir/ritonavir therapy in a clinical cohort who have failed prior protease inhibitors: a comparison of clinical characteristics, antiretroviral drug history and HIV genotype [abstract no. 54]. 2nd International Workshop on Drug Resistance and Treatment Strategies; 1998 Jun 24–27: Lake Maggiore, ItalyGoogle Scholar
  161. 161.
    Harrigan PR, Montaner JS, Hogg RS, et al. Baseline resistance profile predicts response to ritonavir/saquinavir therapy in a community setting [abstract no. 55]. 2nd International Workshop on Drug Resistance and Treatment Strategies; 1998 Jun 24–27: Lake Maggiore, ItalyGoogle Scholar
  162. 162.
    Van Vaerenbergh K, Van Laethem K, Van Wijngaerden E, et al. Predictive value on viral load and CD4 counts of HIV-1 genotypic resistance at the moment of changing therapy [abstract no. 105]. 2nd International Workshop on Drug Resistance and Treatment Strategies; 1998 Jun 24–27: Lake Maggiore, ItalyGoogle Scholar
  163. 163.
    Holodniy M, Mole L, Margolis D, et al. Determination of human immunodeficiency virus RNA in plasma and cellular viral DNA genotypic zidovudine resistance and viral load during zidovudine-didanosine combination therapy. J Virol 1995; 69: 3510–6PubMedGoogle Scholar
  164. 164.
    Calderon EJ, Torres Y, Medrano FJ, et al. Emergence and clinical relevance of mutations associated with zidovudine resistance in asymptomatic HIV-1 infected patients. Eur J Clin Microbiol Infect Dis 1995; 14: 512–9PubMedGoogle Scholar
  165. 165.
    Merigan TC, Hirsch RL, Fisher AC, et al. The prognostic significance of serum viral load, codon 215 reverse transcriptase mutation and CD4+ T cells on progression of HIV disease in a double-blind study of thymopentin. AIDS 1996; 10: 159–65PubMedGoogle Scholar
  166. 166.
    Japour AJ, Welles S, Daquila RT, et al. Prevalence and clinical significance of zidovudine resistance mutations in human immunodeficiency virus isolated from patients after long-term zidovudine treatment. J Infect Dis 1995; 171: 1172–9PubMedGoogle Scholar
  167. 167.
    Rey D, Hughes M, Pi J-T, et al. HIV-1 reverse transcriptase codon 215 mutation in plasma RNA: immunologic and virologic responses to zidovudine. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 17: 203–8PubMedGoogle Scholar
  168. 168.
    Balzarini J, De Clercq E. Biochemical pharmacology of nucleoside analogs active against HIV. In: Textbook of AIDS medicine. Philadelphia (PA): Williams & Wilkins, 1994: 751–72Google Scholar
  169. 169.
    Dianzani F, Antonelli G, Turriziani O, et al. Zidovudine induces the expression of cellular resistance affecting its antiviral activity. AIDS Res Hum Retrovir 1994; 10: 1471–8PubMedGoogle Scholar
  170. 170.
    Salomon H, Gu Z, Gao Q, et al. Host cell dependence of human immunodeficiency viras type-1 drag reistance profiles and tissue culture selection patterns. Antiviral Chem Chemother 1995; 6: 222–9Google Scholar
  171. 171.
    Magnani M, Gazzanelli G, Brandi G, et al. 2,3-dideoxycytidine induced drag resistance in human cells. Life Sci 1995; 57: 881–7PubMedGoogle Scholar
  172. 172.
    Peter K, Gambertoglio JG. Zidovudine phosphorylation after short-term and long-term therapy with zidovudine in patients infected with the human immunodeficiency virus. Clin Pharmacol Ther 1996; 60: 168–76PubMedGoogle Scholar
  173. 173.
    Stilianakis NI, Boucher CAB, de Jong MD, et al. Clinical data sets of human immunodeficiency virus type 1 reverse transcriptase-resistant mutants explained by a mathematical model. J Virol 1997; 71: 161–8PubMedGoogle Scholar
  174. 174.
    Bran-Vézinet F, Boucher C, Loveday C, et al. HIV-1 viral load, phenotype, and resistance in a subset of drug naive participants from the Delta trial. Lancet 1997; 350: 983–90Google Scholar
  175. 175.
    Deantoni A, Foli A, Lisziewicz J, et al. Mutations in the pol gene of human immunodeficiency virus type 1 in infected patients receiving didanosine and hydroxyurea combination therapy. J Infect Dis 1997; 176: 899–903Google Scholar
  176. 176.
    Lori F, Malykh AG, Foli A, et al. Combination of a drug targeting the cell with a drug targeting the virus controls human immunodeficiency viras type 1 resistance. AIDS Res Hum Retrovir 1997; 13: 1403–9PubMedGoogle Scholar
  177. 177.
    Montaner JSG, Reiss P, Cooper D, et al. A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients. JAMA 1998; 279: 930–7PubMedGoogle Scholar
  178. 178.
    Demeter L, Griffith B, Bosch R, et al. HIV-1 drag susceptibilities during therapy with delavirdine (DLV)+ZDV, DLV+DDI, or DLV+ZDV+DDI [abstract no. 706]. Fifth Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5: ChicagoGoogle Scholar
  179. 179.
    Coffin J. HIV dynamics and genetic variation. Plenary lecture at the Eleventh International Conference on Antiviral Research; 1998 Apr 5–10; an Diego (CA). Antiviral Res 1998; 37: A12Google Scholar
  180. 180.
    Van Vaerenbergh K, Harrer T, Schmit JC, et al. Breakthrough of resistant virus 1 year after the initiation of triple or quadruple drug therapy in naive HIV-1 seropositives [abstract no. 83]. 2nd International Workshop on Drug Resistance and Treatment Strategies; 1998 Jun 24–27: Lake Maggiore, ItalyGoogle Scholar
  181. 181.
    Wong JK, Giinthard HF, Havlir DV, et al. Reduction of HIV-1 in blood and lymph nodes following potent antiretroviral therapy and the virologic correlates of treatment failure. Proc Natl Acad Sci U S A 1997; 94: 12574–9PubMedGoogle Scholar
  182. 182.
    Autran B, Carcelain G, Li TS, et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997; 277: 112–6PubMedGoogle Scholar
  183. 183.
    Cavert W, Notermans DW, Staskus K, et al. Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science 1997; 276: 960–2PubMedGoogle Scholar
  184. 184.
    Tseng AL, Foisy MM. Management of drug interactions in patients with HIV. Ann Pharmacother 1997; 31: 1040–58PubMedGoogle Scholar
  185. 185.
    Vandamme A-M, Van Vaerenbergh K, De Clercq E. Anti-human immunodeficiency virus drug combination strategies. Antiviral Chem Chemother 1998; 9: 187–203Google Scholar
  186. 186.
    Kellam P, Larder BA. Recombinant virus assay: a rapid, phenotypic assay for assessment of drag susceptibility of human immunodeficiency viras type 1 isolates. Antimicrob Agents Chemother 1994; 38: 23–30PubMedGoogle Scholar
  187. 187.
    Maschera B, Furfine E, Blair ED. Analysis of resistance to human immunodeficiency viras type 1 protease inhibitors by using matched bacterial expression and proviral infection vectors. J Virol 1995; 69: 5431–6PubMedGoogle Scholar
  188. 188.
    Larder BA, Kellam P, Kemp SD. Zidovudine resistance predicted by direct detection of mutations in DNA from HIV-infected lymphocytes. AIDS 1991; 5: 137–44PubMedGoogle Scholar
  189. 189.
    Kaye S, Loveday C, Tedder RS. A microtitre format point mutation assay: application to the detection of drag resistance in human immunodeficiency virus type-1 infected patients treated with zidovudine. J Med Virol 1992; 37: 241–6PubMedGoogle Scholar
  190. 190.
    Schmit J-C, Ruiz L, Stuyver L, et al. Comparison of the LiPA HIV-1 RT test, selective PCR and direct solid phase sequencing for the detection of HIV-1 drug resistance mutations. J Virol Methods 1998; 73: 77–82PubMedGoogle Scholar
  191. 191.
    Kaye S, Comber E, Tenant-Flowers M, et al. The appearance of drug resistance-associated point mutations in HIV type 1 plasma RNA precedes their appearance in proviral DNA. AIDS Res Hum Retrovir 1995; 11: 1221–5PubMedGoogle Scholar
  192. 192.
    Hirsch MS, Conway B, D’Aquila RT, et al. Antiretroviral drag resistance testing in adults with HIV infection. JAMA 1998; 279: 1984–91PubMedGoogle Scholar
  193. 193.
    Fauci AS, Bartlett JG, Goosby EP, et al. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Ann Intern Med 1998; 128: 1079–100Google Scholar
  194. 194.
    Rubio R, Leal M, Pineda JA, et al. Increase in the frequency of mutation at codon 215 associated with zidovudine resistance in HIV-1 infected antiviral naive patients from 1989 to 1996. AIDS 1997; 11: 1184–6PubMedGoogle Scholar
  195. 195.
    Cunningham P, Hurren L, Cooper DA. HIV-1 reverse transcriptase inhibitor resistance patterns in blood of patients during primary HIV-1 infection by a novel line probe assay [abstract no. 332]. Fifth Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; ChicagoGoogle Scholar
  196. 196.
    Berlusconi A, Violin M, Colombo MC, et al. Genotypic prevalence of ZDV-resistant HIV-1 strains and preexistent mutations in protease coding region of recently infected subjects [abstract no. 675]. Fifth Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; ChicagoGoogle Scholar
  197. 197.
    Lech WJ, Wang G, Yang YL, et al. In vivo sequence diversity of the protease of human immunodeficiency viras type 1: presence of protease inhibitor-resistant variants in untreated subjects. J Virol 1996; 70: 2038–43PubMedGoogle Scholar
  198. 198.
    Najera I, Richman DD, Olivares I, et al. Natural occurrence of drug resistance mutations in the reverse transcriptase of human immunodeficiency virus type 1 isolates. AIDS Res Hum Retrovir 1994; 10: 1479–88PubMedGoogle Scholar
  199. 199.
    Rowe PM. Breaking the mother-to-child transmission of HIV-1. Lancet 1997; 350: 788PubMedGoogle Scholar
  200. 200.
    Perdue BE, Weidle PJ, Everson Mays RE, et al. Evaluating the cost of medications for ambulatory HIV-infected persons in association with landmark changes in antiretroviral therapy. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 17: 354–60Google Scholar
  201. 201.
    Perelson AS, Essunger P, Cao Y, et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 1997; 387: 188–91PubMedGoogle Scholar
  202. 202.
    Schooley RT. Changing treatment strategies and goal. Antiviral Ther 1997; 2 Suppl. 4: 59–70Google Scholar
  203. 203.
    Finzi D, Hermankova M, Pierson T, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 1997; 278: 1295–300PubMedGoogle Scholar
  204. 204.
    Chun T-W, Fauci AS, Stuyver L, et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A 1997; 94: 13193–7PubMedGoogle Scholar
  205. 205.
    Wong JK, Hezareh M, Günthard HF, et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 1997; 278: 1291–5PubMedGoogle Scholar
  206. 206.
    Buckheit RW, Snow MJ, Fliakasboltz V, et al. Highly potent oxathiin carboxanilide derivatives with efficacy against non-nucleoside reverse transcriptase inhibitor resistant human immunodeficiency virus isolates. Antimicrob Agents Chemother 1997; 41: 831–7PubMedGoogle Scholar
  207. 207.
    Romero DL, Olmsted RA, Poel TJ, et al. Targeting delavirdine/atevirdine resistant HIV-1: identification of (alkylamino)piperidine-containing bis(heteroaryl)piperazines as broad spectrum HIV-1 reverse transcriptase inhibitors. J Med Chem 1996; 39: 3769–89PubMedGoogle Scholar
  208. 208.
    Balzarini J, Baba M, De Clercq E. Differential activities of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives against different human immunodeficiency virus type 1 mutant strains. Antimicrob Agents Chemother 1995; 39: 998–1002PubMedGoogle Scholar
  209. 209.
    Balzarini J, Brouwer WG, Dao DC, et al. Identification of novel thiocarboxanilide derivatives that suppress a variety of drugresistant mutant human immunodeficiency virus type 1 strains at a potency similar to that for wild-type virus. Antimicrob Agents Chemother 1996; 40: 1454–66PubMedGoogle Scholar
  210. 210.
    Kleim J-P, Bender R, Kirsch R, et al. Preclinical evaluation of HBU 097, a new nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 replication. Antimicrob Agents Chemother 1995; 39: 2253–7PubMedGoogle Scholar
  211. 211.
    Schols D, Struyf S, Van Damme J, et al. Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR 4. J Exp Med 1997; 186: 1383–8PubMedGoogle Scholar
  212. 212.
    Daelemans D, Vandamme A–M, De Clercq E. Human immunodeficiency virus (HIV) gene regulation as target for anti-HIV chemotherapy. Antiviral Chem Chemother. In pressGoogle Scholar
  213. 213.
    Pommier Y, Pilon AA, Bajaj K, et al. HIV-1 integrase as a target for antiviral drugs. Antiviral Chem Chemother 1997; 8: 463–83Google Scholar
  214. 214.
    Endres MJ, Jaffer S, Haggarty B, et al. Targeting of HIV- and SIV-infected cells by CD4-chemokine receptor pseudotypes. Science 1997; 278: 1462–4PubMedGoogle Scholar

Copyright information

© Adis International Limited 1999

Authors and Affiliations

  • Anne-Mieke Vandamme
    • 1
  • Kristel Van Laethem
    • 1
  • Erik De Clercq
    • 1
  1. 1.Rega Institute for Medical Research and University HospitalsKatholieke Universiteit LeuvenLeuvenBelgium

Personalised recommendations