Drugs

, Volume 55, Issue 3, pp 383–404 | Cite as

Antiretroviral Therapy for HIV Infection

A Knowledge-Based Approach to Drug Selection and Use
  • Graeme J. Moyle
  • Brian G. Gazzard
  • David A. Cooper
  • José Gatell
Disease Management

Summary

In the absence of evidence that eradication of HIV from an infected individual is feasible, the established goal of antiretroviral therapy is to reduce viral load to as low as possible for as long as possible. Achieving this with the currently available antiretroviral agents involves appropriate selection of components of combination regimens to obtain an optimal antiviral response. In addition, consideration of a plan for a salvage or second-line regimen is required if initial therapy fails to achieve an optimal response or should loss of virological control occur despite effective initial therapy. Such a planned approach, based on consideration of the likely modes of therapeutic failure (viral resistance, cellular resistance, toxicity) could be called rational sequencing.

Choice of therapy should never involve compromise in terms of activity. However, the choice of drug should also be guided by tolerability profiles and considerations of coverage of the widest range of infected cells, compartmental penetration, pharmacokinetic interactions and, importantly, the ability of an agent or combination to limit future therapeutic options through selection of cross-resistant virus. Available clinical end-point data clearly indicate that combination therapy is superior to monotherapy, with clinical and surrogate marker data supporting the use of triple drug (or double protease inhibitor) combinations over double nucleoside analogue combinations. Thus, 3-drug therapy should represent current standard practice in a nontrials setting.

Treatment should be considered as early as practical, and may be best guided by measurement of viral load, with a range of other markers having potential utility in individualising treatment decisions. Therapeutic failure may be defined clinically, immunologically or, ideally, virologically, and should prompt substitution of at least 2, and preferably all, components of the treatment regimen. Drug intolerance may also be best managed by rational substitution.

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References

  1. 1.
    Wei X, Ghosh SK, Taylor ME, et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 1995; 373: 117–22PubMedCrossRefGoogle Scholar
  2. 2.
    Ho DD, Neumann AU, Perelson AS, et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995; 373: 123–6PubMedCrossRefGoogle Scholar
  3. 3.
    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: 1295–300PubMedCrossRefGoogle Scholar
  4. 4.
    Emini EA, Holder DJ, Shivaprakash M, et al. The sustained suppression of circulating HIV-1 in indinavir-treated patients is a consequence of the complete prevention of new viral infection cycles. 6th European Conference on Clinical Aspects and Treatment of HIV-infection; 1997 Oct 11–15: HamburgGoogle Scholar
  5. 5.
    Kempf D, Rode R, Xu Y, et al. The durability of response to protease inhibitor therapy is predicted by viral load [abstract no. 62]. International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication; 1997 Jun 25–28: St Petersburg (FL)Google Scholar
  6. 6.
    Luizzi G, Chirianni A, Clementi M, et al. Analysis of HIV-1 load in blood, semen and saliva: evidence for different viral compartments in a cross-sectional and longitudinal study. AIDS 1996; 10: F51–6CrossRefGoogle Scholar
  7. 7.
    Sei S, Stewart SK, Farley M, et al. Evaluation of human immunodeficiency virus (HIV) type 1 RNA levels in cerebrospinal fluid and viral resistance to zidovudine in children with HIV encephalopathy. J Infect Dis 1996; 174: 1200–6PubMedCrossRefGoogle Scholar
  8. 8.
    Deeks S, Grant R, Horton C, et al. Virologic effect of ritonavir (RTV) plus saquinavir (SQV) in subjects who have failed indinavir (IDV). 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1: TorontoGoogle Scholar
  9. 9.
    Mohri H, Singh MK, Ching WTW, et al. Quantitation of zidovudine-resistant human immunodeficiency virus type 1 in the blood of treated and untreated patients. Proc Natl Acad Sci USA 1993; 90: 25–9PubMedCrossRefGoogle Scholar
  10. 10.
    Nàjera 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 Retroviruses 1994; 10: 1479–88PubMedCrossRefGoogle Scholar
  11. 11.
    Nàjera I, Holguin A, Quinones-Mateu E, et al. Pol gene quasispecies of human immunodeficiency virus: mutations associated with drug resistance in virus from patients undergoing no drug therapy. J Virol 1995; 69: 23–31PubMedGoogle Scholar
  12. 12.
    Frost SDW, McLean AR. Quasispecies dynamics and the emergence of drug resistance during zidovudine therapy of HIV infection. AIDS 1994; 8: 323–32PubMedCrossRefGoogle Scholar
  13. 13.
    Kellam P, Boucher CAB, Tijnagal 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: 341–51PubMedCrossRefGoogle Scholar
  14. 14.
    Deeks S, Loftus R, Cohen P, et al. Incidence and predictors of virologic failure to indinavir (IDV) or/and ritonavir (RTV) in an urban health clinic. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1: TorontoGoogle Scholar
  15. 15.
    Conway B. The activity and safety of two formulations of saquinavir combined with two nucleosides in treatment-naive patients. 6th European Conference on Clinical Aspects and Treatment of HIV-infection; 1997 Oct 11–15: HamburgGoogle Scholar
  16. 16.
    BHIVA Guidelines co-ordinating committee. British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals. Lancet 1997; 349: 1086–92CrossRefGoogle Scholar
  17. 17.
    Carpenter CJ, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1997. JAMA 1997; 277: 1962–9PubMedCrossRefGoogle Scholar
  18. 18.
    DeMasi R, Staszewski S, Dawson D, et al. Control of HIV-1 RNA prevents clinical disease progression to AIDS [abstract no. 105]. International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication: 1997 Jun 25–28: St Petersburg (FL)Google Scholar
  19. 19.
    Fischl MA, Richman DD, Greico MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: a double-blind, placebo controlled trial. N Engl J Med 1987; 317: 185–91PubMedCrossRefGoogle Scholar
  20. 20.
    Fischl MA, Richman DD, Hansen N, et al. The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus type 1 (HIV) infection: a double-blind, placebo-controlled trial. Ann Intern Med 1990; 112: 727–37PubMedGoogle Scholar
  21. 21.
    Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic human immunodeficiency virus infection — a controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl J Med 1990; 322: 941–9PubMedCrossRefGoogle Scholar
  22. 22.
    Hamilton JD, Hartigan PM, Simberkoff MS, et al. Acontrolled trial of early versus late treatment with zidovudine in symptomatic human immunodeficiency virus infection. N Engl J Med 1992; 326: 437–43PubMedCrossRefGoogle Scholar
  23. 23.
    Cooper DA, Gatell JM, Kroon S, et al. Zidovudine in persons with asymptomatic HIV infection and CD4+ cell counts greater than 400 per cubic millimeter. N Engl J Med 1993; 329: 297–303PubMedCrossRefGoogle Scholar
  24. 24.
    Concorde Coordinating Committee. Concorde: MRC/ANRS randomized double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Lancet 1994; 343: 871–81CrossRefGoogle Scholar
  25. 25.
    Lenderking WR, Gelber RD, Cotton DJ, et al. Evaluation of the quality of life associated with zidovudine treatment in asymptomatic human immunodeficiency virus infection. N Engl J Med 1994; 330: 738–43PubMedCrossRefGoogle Scholar
  26. 26.
    Volberding PA, Lagakos SW, Grimes JM, et al. The duration of zidovudine benefit in persons with asymptomatic HIV infection. JAMA 1994; 272: 437–42PubMedCrossRefGoogle Scholar
  27. 27.
    Noticeboard: didanosine and ACTG 116A [editorial]. Lancet 1993; 341: 109Google Scholar
  28. 28.
    Follansbee S, Drew L, Olsen R, et al. The efficacy of zalcitabine (ddC, HIVID) versus zidovudine (ZDV) as monotherapy in ZDV naïve patients with advanced HIV disease: a randomized, double-blind comparative trial (ACTG 114; N3300) [abstract no. PO-B26-2113]. IXth International Conference on AIDS and 4th World Congress on STD; 1993 Jun 7–11: BerlinGoogle Scholar
  29. 29.
    Hammer S, Katzenstein D, Hughes, M. et al. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. N Engl J Med 1996; 335: 1081–90Google Scholar
  30. 30.
    Katzenstein DA, Hammer SM, Hughes MD, et al. The relation of virologie and immunologie 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: 1091–8PubMedCrossRefGoogle Scholar
  31. 31.
    Massari F, Staszewski S, Berry P, et al. A double-blind, randomized trial of indinavir (MK-639) alone or with zidovudine vs zidovudine alone in zidovudine naïve patients [abstract no. LB-6]. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1995 Sep 17–20: San FranciscoGoogle Scholar
  32. 32.
    Massari F, ConantM, Mellors J. Aphase II open-label, randomized study of the triple combination of indinavir, zidovudine, and didanosine versus indinavir alone and zidovudine/didanosine in antiretroviral naïve patients [abstract no. 90]. 3rd Conference on Retroviruses and Opportunistic Infections: 1996 Jan 28: Washington, D.C.Google Scholar
  33. 33.
    Danner SA, Carr A, Leonard JM, et al. Safety, pharmacokinetics and antiviral activity of ritonavir, an inhibitor of HIV-1 protease [abstract no. 75]. 4th International Workshop on HIV Drug Resistance; 1995 Jul 6–9: Sardinia, ItalyGoogle Scholar
  34. 34.
    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: 1528–33PubMedCrossRefGoogle Scholar
  35. 35.
    Markowitz M, Saag M, Powderly WG, et al. A preliminary study of ritonavir, an inhibitor of HIV-1 infection. N Engl J Med 1995; 333: 1534–9PubMedGoogle Scholar
  36. 36.
    Molla A, Korneyeva M, Gao Q. Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. Nature Med 1996; 2: 760–6PubMedCrossRefGoogle Scholar
  37. 37.
    Norbeck D, Hsu A, Granneman R, et al. Virologie and immunologie response to ritonavir (ABT-538), an inhibitor of HIV protease [abstract no. 70]. 4th International Workshop on HIV Drug Resistance; 1995 Jul 6–9; Sardinia, ItalyGoogle Scholar
  38. 38.
    Markowitz M, Conant M, Hurley A, et al. Phase I/II dose range-finding study of the HIV protease inhibitor Ag 1343 [abstract no. LB-4]. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1995 Sep 17–29: San FranciscoGoogle Scholar
  39. 39.
    Moyle G, Youle M, Chapman S, et al. A Phase II dose-escalation study of the Agouron protease inhibitor Ag 1343 [abstract no. LB-3]. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1995 Sep 17–20: San FranciscoGoogle Scholar
  40. 40.
    Schapiro JM, Winters MA, Stewart F, et al. The effect of high-dose saquinavir on viral load and CD4: pl T-cell counts in HIV-infected patients. Ann Intern Med 1996; 124: 1039–50PubMedGoogle Scholar
  41. 41.
    Delta Coordinating Committee. Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet 1996; 348: 283–91CrossRefGoogle Scholar
  42. 42.
    CAESAR Coordinating Committee. Randomised trial of addition of lamivudine or lamivudine plus loviride to zidovudine-containing regimens for patients with HIV-1 infection: the CAESAR trial. Lancet 1997; 349: 1413–21CrossRefGoogle Scholar
  43. 43.
    Hammer SM, Hughes MD, Squires K, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 1997; 337: 725–33PubMedCrossRefGoogle Scholar
  44. 44.
    Loveday C, Devereux H, Burke A, et al. Acomparison of HIV-1 RNA load assays for baseline values prior to commencing therapy in a clinic population with epidemiological evidence of non-clade B virus [abstract no. 45]. International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication; 1997 Jun 25–28: St Petersburg (FL)Google Scholar
  45. 45.
    Opravil M, DeMasi R, Hill A. Prediction of long-term HIV RNA suppression during zidovudine/lamivudine treatment [abstract no. 60]. International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication; 1997 Jun 25–28: St Petersburg (FL)Google Scholar
  46. 46.
    Borleffs JCC, Boucher CAB, Schuurman R, et al. Saquinavir-soft gelatin capsules versus indinavir as part of AZT and 3TC containing triple therapy. 6th European Conference on Clinical Aspects and Treatment of HIV-infection; 1997 Oct 11–15: HamburgGoogle Scholar
  47. 47.
    Posniak A. Study of protease inhibitors in combination in Europe (SPICE). 6th European Conference on Clinical Aspects and Treatment of HIV-infection; 1997 Oct 11–15: HamburgGoogle Scholar
  48. 48.
    Murphy R, Pottage J, Peterson D, et al. A 15-site, open-label, randomized, comparative study of stavudine + didanosine + indinavir versus zidovudine + lamivudine + indinavir in treatment naïve HlV-infected patients. 6th European Conference on Clinical Aspects and Treatment of HIV-infection; 1997 Oct 11–15: HamburgGoogle Scholar
  49. 49.
    Gulick R, Santana J, Squires K, et al. A 15-site, open-label, randomized, comparative study of stavudine + lamivudine + indinavir versus zidovudine + lamivudine + indinavir in treatment naïve HlV-infected patients. 6th European Conference on Clinical Aspects and Treatment of HIV-infection; 1997 Oct 11–15: HamburgGoogle Scholar
  50. 50.
    Moyle GJ, Gazzard BG. The role of stavudine in the management of adults with HIV infection. Antiviral Ther 1997; 2: 207–18Google Scholar
  51. 51.
    Conway B, Montaner JSG, Cooper D, et al. Randomised double blind one year study of the immunological and virological effects of nevirapine, didanosine and zidovudine combinations among antiretroviral naïve, AIDS-free patients with CD4 200-600 [abstract no. OP7.2]. AIDS 1996; 10 Suppl. 2: S15Google Scholar
  52. 52.
    Murphy RL, Montaner J. Nevirapine: a review of its development, pharmacological profile and potential for clinical use. Exp Opin Invest Drugs 1996; 5: 1183–99CrossRefGoogle Scholar
  53. 53.
    Hicks C, Hass D, Seekins D, et al. A phase II, double-blind, placebo-controlled, dose-ranging study to assess the antiretroviral activity and safety of DMP 266 (Efavirenz, Sustiva) in combination with open label zidovudine (ZDV) with lamivudine [abstract no. 920]. 6th European Conference on Clinical Aspects and Treatment of HIV-infection; 1997 Oct 11–15: HamburgGoogle Scholar
  54. 54.
    Mathez D, Bagnarelli P, Gorin I, et al. Reductions in viral load and increases in T lymphocyte numbers in treatment-naïve patients with advanced HIV-1 infection treated with ritonavir, zidovudine, and zalcitabine triple therapy. Antiviral Ther 1997; 2: 175–83Google Scholar
  55. 55.
    Saag M, Knowles M, Chang Y, et al. Durable effect of VIRACEPT (nelfinavir mesylate) in triple combination therapy. Infectious Diseases Society of America Annual Meeting; 1997 Sep 13–16: San FranciscoGoogle Scholar
  56. 56.
    Cameron DW, Heath-Chiozzi M, Kravcik S. Prolongation of life and prevention of AIDS complications in advanced HIV immunodeficiency with ritonavir: update [abstract no. Mo.B.411]. Xlth International Conference on AIDS; 1996 Jul 7–12: VancouverGoogle Scholar
  57. 57.
    Heath-Chiozzi M, Leonard J, Sun E, et al. Ritonavir clinical benefit correlates with HIV RNA and CD4 cell levels in advanced HIV illness [abstract no. We.B.3127]. Xlth International Conference on AIDS; 1996 Jul 7–12: VancouverGoogle Scholar
  58. 58.
    Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 1997; 337: 725–33PubMedCrossRefGoogle Scholar
  59. 59.
    Gulick RM, 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: 734–9PubMedCrossRefGoogle Scholar
  60. 60.
    Mayers D, Riddler S, Bach M, et al. Durable clinical activity and tolerability for DMP 266 in combination with indinavir (IDV) at 24 weeks [abstract no. 1-175]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); 1997 Sep 28–Oct 1: TorontoGoogle Scholar
  61. 61.
    PedneaultL, Elion R, Adler M, et al. Stavudine, didanosine, and nelfinavir combination therapy in HIV-infected subjects: antiviral effect and safety in an ongoing pilot study. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26: Washington, DCGoogle Scholar
  62. 62.
    Hirsch M, Meilbohm A, Rawlins A, et al. Indinavir in combination with zidovudine and lamivudine in ZDV-experienced patients with CD4 counts <50 cells/mm3. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26: Washington, DCGoogle Scholar
  63. 63.
    Harris M, Rachlis A, Shillington A, et al. Long-term suppression of HIV in plasma with a combination of two nucleosides and nevirapine (NVP). 6th European Conference on Clinical Aspects and Treatment of HIV-infection; 1997 Oct 11–15: HamburgGoogle Scholar
  64. 64.
    Pakker N, Kroon E, Hall D, et al. Functional capacity of T cells and immunological response in naïve HIV-1 patients treated with combinations of reverse transcriptase inhibitors [abstract no. OP2.1]. AIDS 1996; 10 Suppl. 2: S10Google Scholar
  65. 65.
    Ruiz NM, Manion DJ, Labriola DF, et al. HIV-1 suppression to ‘<1 copy/mL’ by Amplicor assay in patients receiving indinavir +/- DMP 266 (efavirenz): results of DMP 266-003, cohort IV [abstract no. 921]. 6th European Conference on Clinical Aspects and Treatment of HIV-infection; 1997 Oct 11–15: HamburgGoogle Scholar
  66. 66.
    Gao WY, Johns DG, Mitsuya H. Anti-HIV-1 activity of hydroxyurea in combination with 2′,3′-dideoxynucleosides. Mol Pharmacol 1994; 46: 767–72PubMedGoogle Scholar
  67. 67.
    Biron F, Lucht F, Peyramond D, et al. Anti-HIV activity of the combination of didanosine and hydroxyurea in HIV-1-infected individuals. J Acquir Immune Defic Syndr 1995; 10: 36–40Google Scholar
  68. 68.
    Montaner JSG, Zala C, Raboud JM, et al. A pilot study of hydroxyurea (HO-urea) as adjuvant therapy among patients with advanced HIV disease receiving didanosine (ddl) therapy [abstract no. 406]. 3rd Conference on Retroviruses and Opportunistic Infections; 1996 Jan 28; Washington, DCGoogle Scholar
  69. 69.
    Molla A, Korneyeva M, Chernyavskiy T, et al. Characterization of HIV-1 protease mutations, compliance and drug concentrations in patients who have HIV RNA rebound on ritonavir/saquinavir. International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication; 1997 Jun 25–28: St Petersburg (FL)Google Scholar
  70. 70.
    Bodsworth NJ, Heaps M, Gosling D, et al. Efficacy of indinavir (IDV) and ritonavir (RTV) in patients pretreated with saquinavir [abstract]. 7th International Antiviral Symposium; 1997 Feb 17–19: SydneyGoogle Scholar
  71. 71.
    Novak RM, Colombo J, Linares-Diaz M, et al. Comparison of AZT/3TC VS. D4T/3TC for the treatment of HIV in persons with CD4 counts <300 and prior AZT experience [abstract no. Tu.B. 2132]. Xlth International Conference on AIDS; 1996 Jul 7–12: VancouverGoogle Scholar
  72. 72.
    Kahn JO, Lagakos SW, Richman DD, et al. A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. N Engl J Med 1992; 327: 581–7PubMedCrossRefGoogle Scholar
  73. 73.
    Holodniy M, Katzentein D, Mole L, et al. Human immunodeficiency virus reverse transcriptase Codon 215 mutations diminish virologic response to didanosine-zidovudine therapy in subjects with non-syncytium-inducing viral phenotype. J Infect Dis 1996; 174: 854–7PubMedCrossRefGoogle Scholar
  74. 74.
    Fischl MA, Stanley K, Collier AC, et al. Combination and monotherapy with zidovudine and zalcitabine in patients with advanced HIV disease. Ann Intern Med 1995; 122: 24–32PubMedGoogle Scholar
  75. 75.
    Abrams DI, Goldman A, Launer C, et al. A comparative trial of didanosine or zidovudine after treatment with zidovudine in patients with human immunodeficiency virus infection. N Engl J Med 1994; 330: 657–62PubMedCrossRefGoogle Scholar
  76. 76.
    Spruance SL, Pavia AT, Mellors JW, et al. Clinical efficacy of monotherapy with stavudine compared with zidovudine in HIV-infected, zidovudine-experienced patients: a randomized, double-blind, controlled trial. Bristol-Myers Squibb Stavudine/019 Study Group. Ann Intern Med 1997; 126: 355–63Google Scholar
  77. 77.
    Japour AJ, Welles S, D’Aquila 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: 1172–9PubMedCrossRefGoogle Scholar
  78. 78.
    Lalezari J, Haubrich R, Burger HU, et al. Improved survival and decreased progression of HIV in patients treated with saquinavir and zalcitabine [abstract no. LB.B. 6033]. Xlth International Conference on AIDS; 1996 Jul 7–12: VancouverGoogle Scholar
  79. 79.
    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
  80. 80.
    Sylvester S, Caliendo A, An D, et al. HIV-1 resistance mutations and plasma RNA during ZDV+ddC combination therapy [abstract]. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 10 Suppl. 3: 23Google Scholar
  81. 81.
    Schooley RT, Ramirez-Ronda C, Lange JMA. Virologic and immunologie benefits of initial combination therapy with zidovudine and zalcitabine or didanosine compared with zidovudine monotherapy. J Infect Dis 1996; 173: 1354–66PubMedCrossRefGoogle Scholar
  82. 82.
    Quinones-Mateu ME. A unique mechanism for zidovudine-resistance and evidence for a zidovudine-mediated cross-resistance to other nucleoside analogues by zidovudine-resistant viruses [abstract no. 10]. International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication; 1997 Jun 25–28: St Petersburg (FL)Google Scholar
  83. 83.
    Kleim JP, Pauosner M, Winkler I, et al. Nucleoside reverse transcriptase inhibitor-specific mutations within the HIV-1 pol gene selected with a non-nucleoside type RT inhibitor [abstract]. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 10 Suppl. 3: 2Google Scholar
  84. 84.
    Shirasaka T, Kavlick MF, Veno 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 USA 1995; 92: 2398–402PubMedCrossRefGoogle Scholar
  85. 85.
    Para MF, Collier A, Coombs R, et al. ACTG 333: antiviral effects of switching from saquinavir hard capsules (SQVhc) to saquinavir soft gelatin capsule (SQVsgc) vs switching to indinavir (IDV) after prior saquinavir [abstract no. 299]. Infectious Diseases Society of America Annual Meeting; 13–16 Sep 1997: San FranciscoGoogle Scholar
  86. 86.
    Schapiro J, Winters M, Lawrence J, et al. Clinical and genotypic cross-resistance between the protease inhibitors saquinavir and indinavir. International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication; 1997 Jun 25–28; St Petersburg (FL)Google Scholar
  87. 87.
    Dulioust A, Paulous S, Guillemot L, et al. Selection of saquinavir-resistant mutants by indinavir following a switch from saquinavir [abstract no. 16]. International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication; 1997 Jun 25–28: St Petersburg (FL)Google Scholar
  88. 88.
    Lawrence J, Schapiro J, Pesano R, et al. Clinical response and genotypic resistance patterns of sequential therapy with nelfinavir followed by indinavir plus nevirapine in saquinavir/reverse transcriptase inhibitor-experienced patients [abstract no. 64]. International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication; 1997 Jun 25–28: St PetersburgGoogle Scholar
  89. 89.
    Pym AS, Churchill DR, Galpin S, et al. Presence of mutation at codon 90 may predict response to ritonavir/saquinavir combination in HIV seropositive patients pretreated with saquinavir monotherapy [abstract no. 84]. International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication; 1997 Jun 25–28: St Petersburg (FL)Google Scholar
  90. 90.
    Walmsley S, Clark J, Salti I, et al. Can protease inhibitors be used sequentially in patients with advanced HIV infection [abstract no. 1-189]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 28 Sep–1 Oct 1997: TorontoGoogle Scholar
  91. 91.
    Miller V, Hertogs K, de Bethune M-P, et al. Incidence of HIV-1 resistance and cross-resistance to protease inhibitors after indinavir failure: impact on subsequent ritonavir/saquinavir combination therapy [abstract no. 81]. International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication; 1997 Jun 25–28: St Petersburg (FL)Google Scholar
  92. 92.
    Alpha International Coordinating Committee. The Alpha trial: European/Australian randomized double-blind trial of two doses of didanosine in zidovudine intolerant patients with symptomatic HIV disease. AIDS 1996; 10(8): 867–80CrossRefGoogle Scholar
  93. 93.
    Allan JD, De Gruttola V, Cross A, et al. An efficacy study of 23-dideoxyinosine (ddl) (BMY-40900) administered orally twice daily to zidovudine intolerant patients with HIV infections (ACTG 118) [abstract no. WS-B24-2]. IXth International Conference on AIDS and 4th World Congress on STD; 7–11 June 1993: BerlinGoogle Scholar
  94. 94.
    Moyle GJ, Nelson MR, Hawkins D, et al. The use and toxicity of didanosine (ddl) in HIV antibody positive individuals intolerant to zidovudine (AZT). Q J Med 1993; 86: 155–63PubMedGoogle Scholar
  95. 95.
    Abrams DI, Goldman AI, Launer C, et al. A comparative trial of didanosine or zalcitabine after treatment with zidovudine in patients with human immunodeficiency virus infection. N Engl J Med 1994; 330: 657–62PubMedCrossRefGoogle Scholar
  96. 96.
    Moyle G, Goll A, Snape S, et al. Safety and tolerability of zalcitabine (ddC) in patients with AIDS or advanced AIDS-related complex in the European Expanded Access Programme. Int J Antimicrob Agents 1996; 7: 41–8PubMedCrossRefGoogle Scholar
  97. 97.
    Farthing C, Japour A, Cohen C, et al. Cerebrospinal fluid (CSF) and plasma HIV RNA suppression with ritonavir (RIT)-saquinavir (SQV) in protease inhibitor naïve patients [abstract no. LB3]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); 28 Sep–1 Oct 1997: TorontoGoogle Scholar
  98. 98.
    Cohen C, Sun E, Cameron D, et al. Ritonavir-saquinavir combination treatment in HIV-infected patients [abstract no. LB7b]. 36th Interscience Conference on Antimicrobial Agents and Chemotherapy; 15–18 Sep 1996: New OrleansGoogle Scholar
  99. 99.
    Gazzard BG, Moyle GJ. Individualisation of HIV therapy: the clinician’s perspective. Br J Clin Prac 1995; 49: 145–7Google Scholar
  100. 100.
    O’Brien WA, Hartigan PM, Martin D, et al. Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. N Engl J Med 1996; 334: 426–31PubMedCrossRefGoogle Scholar
  101. 101.
    Keilbaugh SA, Prusoff WH, Simpson MV. The PC12 cell as a model for studies of the mechanism of induction of peripheral neuropathy by anti-HIV 1-dideoxynucleoside analogs. Biochem Pharmacol 1991; 42: R5–8PubMedCrossRefGoogle Scholar
  102. 102.
    LeLacher SF, Simon GI. Exacerbation of dideoxycytidine-induced neuropathy with dideoxyinosine. J Acquir Immune Defic Syndr 1991; 4: 538–9Google Scholar
  103. 103.
    Cupler EJ, Dalakas MC. Exacerbation of peripheral neuropathy by lamivudine. Lancet 1995; 345: 460–1PubMedCrossRefGoogle Scholar
  104. 104.
    Gazzard BG, Moyle GJ. The role of didanosine in the management of HIV-1 infection. Antiviral Therapy 1997; 2(3): 135–47PubMedGoogle Scholar
  105. 105.
    Sahai J. Risks and synergies from drug interactions. AIDS 1996; 10 Suppl. 1: S21–5PubMedGoogle Scholar
  106. 106.
    Adkins JC, Peters DH, Faulds D. Zalcitabine: an update of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in the management of HIV infection. Drugs 1997 Jun; 53(6): 1054–80PubMedCrossRefGoogle Scholar
  107. 107.
    Ferry JJ, Herman BD, Cox SR, et al. Delavirdine (DLV) and indinavir (IDV): a pharmacokinetic drug-drug interaction study in healthy adult volunteers [abstract]. 4th Conference on Retroviruses and Opportunistic Infections: 1997 Jan 22–26; Washington, DCGoogle Scholar
  108. 108.
    Cox SR, Batts DH, Stewart F, et al. Evaluation of the pharmacokinetic interaction between saquinavir and delavirdine in healthy volunteers [abstract]. 4th Conference on Retroviruses and Opportunistic Infections: 1997 Jan 22–26; Washington, DCGoogle Scholar
  109. 109.
    Kravcik S, Sahai J, Kerr B, et al. Nelfinavir mesylate increases saquinavir soft gel capsule exposure in HIV patients [abstract]. 4th Conference on Retroviruses and Opportunistic Infections: 1997 Jan 22–26; Washington, DCGoogle Scholar
  110. 110.
    Lea AP, Faulds D. Ritonavir. Drugs 1996 Oct; 52(4): 541–6PubMedCrossRefGoogle Scholar
  111. 111.
    Cato A, Cavanaugh J, Shi H, et al. Assessment of multiple doses of ritonavir on the pharmacokinetics of rifabutin [abstract no. Mo.B.1199]. Xlth International Conference on AIDS; 1996 Jul 7–12: VancouverGoogle Scholar
  112. 112.
    Bertz R, Cao G, Cavanaugh J, et al. Effect of ritonavir on the pharmacokinetics of desipramine [abstract no. Mo.B.1201]. Xlth International Conference on AIDS; 1996 Jul 7–12: VancouverGoogle Scholar
  113. 113.
    Ouellet D, Hsu A, Qian J, et al. Effect of ritonavir on the pharmacokinetics of ethinylestradiol in healthy female volunteers [abstract no. Mo.B.1198]. Xlth International Conference on AIDS; 1996 Jul 7–12: VancouverGoogle Scholar
  114. 114.
    Hsu A, Granneman GR, Witt G, et al. Assessment of multiple doses of ritonavir on the pharmacokinetics of theophylline [abstract no. Mo.B.1200]. Xlth International Conference on AIDS; 1996 Jul 7–12: VancouverGoogle Scholar
  115. 115.
    Yven G, Anderson R, Daniels R, et al. Investigation of nelfinavir mesylate pharmacokinetic interactions with indinavir and ritonavir [abstract]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26: Washington, DCGoogle Scholar
  116. 116.
    McCrea J, Buss N, Stone J, et al. Indinavir-saquinavir single dose pharmacokinetic study [abstract]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26: Washington, DCGoogle Scholar
  117. 117.
    Kerr B, Yven G, Daniels R, et al. Strategic approach to nelfinavir mesylate drug interactions involving CYP3A metabolism [abstract]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26: Washington, DCGoogle Scholar
  118. 118.
    Back DJ, Haggard PG, Veal GJ, et al. Intracellular phosphorylation interactions between nucleoside analogues [abstract no. 41]. 5th European Conference on Clinical Aspects and Treatment of HIV Infection; 1995: CopenhagenGoogle Scholar
  119. 119.
    Ruiz L, Romeu J, Martainez-Picado J, et al. Efficacy of triple combination therapy with zidovudine (ZDV) plus zalcitabine (ddC) plus lamivudine (3TC) versus double (ZDV/3TC) combination therapy in patients previously treated with ZDV/ddC. AIDS 1996; 10: F61–6PubMedCrossRefGoogle Scholar
  120. 120.
    Stretcher BN, Pesce AJ, Frame PT, et al. Correlates of zidovudine phosphorylation with markers of HIV disease: progression and drug-toxicity. AIDS 1994; 8: 763–9PubMedCrossRefGoogle Scholar
  121. 121.
    Johnson VA. Combination therapy: more effective control of HIV type 1? AIDS Res Hum Retrovirol 1994; 8: 907–12CrossRefGoogle Scholar
  122. 122.
    Merrill DP, Moonis M, Chou T-C, et al. Lamivudine or stavudine in two- and three-drug combinations against human immunodeficiency virus type 1 replication in vitro. J Infect Dis 1996; 173: 355–64PubMedCrossRefGoogle Scholar
  123. 123.
    Merrill DP, Manion DJ, Chou T-C, et al. Protease inhibitor combination regimens against HIV-1 in vitro. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26: Washington, DCGoogle Scholar
  124. 124.
    Gao WY, Agbaria R, Driscoll JS, et al. Divergent anti-human immunodeficiency virus activity and anabolic phosphorylation of 23-dideoxynucleoside analogs in resting and activated human cells. J Biol Chem 1994; 269: 12633–8PubMedGoogle Scholar
  125. 125.
    Koot M, Keet IPM, Vos AHV, et al. Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell depletion and progression to AIDS. Ann Intern Med 1993; 118: 681–8PubMedGoogle Scholar
  126. 126.
    Richman DD, Bozette SA. The impact of syncytium-inducing phenotype of human immunodeficiency virus on disease progression. J Infect Dis 1994; 169: 968–74PubMedCrossRefGoogle Scholar
  127. 127.
    Schellekens PTA, Koot M, Roos MTL, et al. Immunologic and virologic markers determining progression to AIDS. J Acquir Immune Defic Syndr 1995; 10 Suppl. 2: S62–6Google Scholar
  128. 128.
    Delforge M-L, Liesnard C, Debaisieux L, et al. In vivo inhibition of syncytium-inducing variants of HIV in patients treated with didanosine. AIDS 1995; 9: 89–90PubMedCrossRefGoogle Scholar
  129. 129.
    Moyle G. Saquinavir: a review of its development, pharmacological properties and clinical use. Exp Opin Invest Drugs 1996; 5: 155–67CrossRefGoogle Scholar
  130. 130.
    Epstein LG, Kuiken C, Blumberg BM, et al. HIV-1 V3 domain variation in brain and spleen of children with AIDS: tissue-specific evolution within host-determined quasispecies. Virology 1991; 180: 583–90PubMedCrossRefGoogle Scholar
  131. 131.
    Ball JK, Holmes EC, Whitwell H, et al. Genomic variation of human immunodeficiency virus type-1 (HIV-1): molecular analysis of HIV-1 in sequential blood samples and various organs obtained at autopsy. J Gen Virol 1994; 75: 867–79CrossRefGoogle Scholar
  132. 132.
    Haggerty S, Stevenson M. Predominance of distinct viral genotypes in brain and lymph node compartments of HIV-1-infected individuals. Viral Immunol 1991; 4: 123–31PubMedCrossRefGoogle Scholar
  133. 133.
    Wildemann B, Haas J, Ehrhart K, et al. In vivo comparison of zidovudine resistance mutations in blood and CSF of HIV-1 infected patients both simultaneously in plasma but also between different body compartments such as blood and CSF. Neurology 1993; 43: 2659–63PubMedCrossRefGoogle Scholar
  134. 134.
    Portegies P. AIDS dementia complex: a review. J Acquir Immune Defic Syndr 1994; 7 Suppl. 2; S38–49PubMedGoogle Scholar
  135. 135.
    Di Stephano M, Norkrans G, Chiodi F, et al. Zidovudine-resistant variants of HIV-1 in brain [letter]. Lancet 1993; 342: 865CrossRefGoogle Scholar
  136. 136.
    Foudraine N, de Wolf F, Hoetelmans R, et al. CSF and serum HIV-RNA during AZT/3TC and d4T/3TC treatment. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26: Washington, DCGoogle Scholar
  137. 137.
    Collier AC, Marra C, Coombs RW, et al. Cerebrospinal fluid (CSF) indinavir (IDV) and HIV RNA levels in patients on chronic indinavir therapy [abstract no. 286]. Infectious Diseases Society of America Annual Meeting: 13–16 Sep 1997: San FranciscoGoogle Scholar
  138. 138.
    Moyle GJ, Sadler M, Buss N, et al. Correlation between plasma and CSF viral load in patients on saquinavir containing regimens: pharmacokinetics (PK) of saquinavir at steady state in CSF and plasma [abstract no. 249]. 6th European Conference on Clinical Aspects and Treatment of HIV-infection; 1997 Oct 11–15: HamburgGoogle Scholar
  139. 139.
    Moyle GJ. Use of viral resistance patterns to antiretroviral drugs in optimising selection of drug combinations and sequences. Drugs 1996 Aug; 52(2): 168–85PubMedCrossRefGoogle Scholar
  140. 140.
    Moyle G. Influence of emergence of viral resistance on HIV treatment choice. Int J STD AIDS 1995; 6: 225–6PubMedGoogle Scholar
  141. 141.
    Moyle GJ. Current knowledge of HIV-1 reverse transcriptase (RT) mutations selected during nucleoside analogue therapy: the potential to use resistance data to guide clinical decisions. J Antimicrob Chemother 1997; 40: 765–77PubMedCrossRefGoogle Scholar
  142. 142.
    D’Aquila RT, Johnson VA, Welles SL, et al. Zidovudine resistance and HIV-1 disease progression during antiretroviral therapy. Ann Intern Med 1995; 122: 401–8PubMedGoogle Scholar
  143. 143.
    Tremblay M, Rooke R, Wainberg MA. Zidovudine-resistant and -sensitive HIV-1 isolates from patients on drug therapy: in vitro studies evaluating level of replication-competent viruses and cytopathogenicity. AIDS 1992; 6: 1445–9PubMedCrossRefGoogle Scholar
  144. 144.
    Caliendo A, Savara A, An D. Zidovudine-resistance mutations increase replication in drug-free PBMC stimulated after infection [abstract]. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 10 Suppl. 3: 2–3Google Scholar
  145. 145.
    Mayers DL, Japour AJ, Arduino J-M, et al. Dideoxynucleoside resistance emerges with prolonged zidovudine therapy. Antimicrob Agents Chemother 1994; 38: 307–14PubMedCrossRefGoogle Scholar
  146. 146.
    Rooke R, Parniak MA, Tremblay M, et al. Biological comparisons of wild-type and zidovudine-resistant isolates of human immunodeficiency virus type 1 from the same subjects: susceptibility and resistance to other drugs. Antimicrob Agents Chemother 1991; 35: 988–91PubMedCrossRefGoogle Scholar
  147. 147.
    Dianzani F, Antonelli G, Turriziani O, et al. Zidovudine induces the expression of cellular resistance affecting its antiviral activity. AIDS Res Hum Retroviruses 1994; 10: 1471–8PubMedCrossRefGoogle Scholar
  148. 148.
    Kozal MJ, Kroodsma K, Winters MA, et al. Didanosine resistance in HIV-infected patients switched from zidovudine to didanosine monotherapy. Ann Intern Med 1994; 121: 263–8PubMedGoogle Scholar
  149. 149.
    Gu Z, Gao Q, Parniak MA, et al. Novel mutation in the human immunodeficiency virus type 1 reverse transcriptase gene encodes cross resistance to 2′,3′-dideoxyinosine and 2′,3′-dide-oxycytidine. J Virol 1992; 66: 7128–35PubMedGoogle Scholar
  150. 150.
    Gao Q, Gu ZX, Parniak MA, et al. The same mutation that encodes low-level human immunodeficiency virus type 1 resistance to 2′,3′-dideoxyinosine and 2′,3′-dideoxycytidine confers high-level resistance to the (-) enantiomer of 2′,3′-dideoxy-3′-thiacytidine. Antimicrob Agents Chemother 1993; 37: 1390–2PubMedCrossRefGoogle Scholar
  151. 151.
    Lin HJ, Myers LE, et al. Multicenter evaluation of quantification methods for plasma human immunodeficiency virus type 1 RNA. J Infect Dis 1994; 170: 553–62PubMedCrossRefGoogle Scholar
  152. 152.
    Fitzgibbon JE, Howell RM, Haberzettl C al. Human immunodeficiency virus type 1 pol gene mutations which caused decreased susceptibility to 2′,3′-dideoxycytidine. Antimicrob Agents Chemother 1992; 36: 153–7PubMedCrossRefGoogle Scholar
  153. 153.
    Craig C, Moyle G. The development of resistance of HIV-1 to zalcitabine. AIDS 1997; 11: 271–9PubMedCrossRefGoogle Scholar
  154. 154.
    Condra JH, Schleif WA, Blahy OM, et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature 1995; 374: 569–71PubMedCrossRefGoogle Scholar
  155. 155.
    Jacobsen H, Hanggi M, Ott M, et al. In vivo resistance to a human immunodeficiency virus type 1 protease inhibitor: mutations, kinetics and frequencies. J Infect Dis 1996; 173: 1379–87PubMedCrossRefGoogle Scholar
  156. 156.
    Patick AK, Duran M, Cao Y, et al. Genotypic and phenotypic characterisation of HIV-1 variants isolated from in vitro selection studies and from patients treated with the protease inhibitor, nelfinavir [abstract no. 29]. 5th International Workshop on HIV Drug Resistance; 1996 Jul 3–6: Whistler, British Columbia, CanadaGoogle Scholar
  157. 157.
    Tisdale M, Myers R, Najera I, et al. Analysis of resistant interactions with 141W94 (VX-478) and other protease inhibitors. 5th International Workshop on HIV Drug Resistance; 1996 Jul 3–6: Whistler, British Columbia, CanadaGoogle Scholar
  158. 158.
    Kinloch-de Loës S, Hirschel BJ, Hoen B, et al. A controlled trial of zidovudine in primary human immunodeficiency virus infection. N Engl J Med 1995; 333: 408–13PubMedCrossRefGoogle Scholar
  159. 159.
    Wolinsky SM, Wike CM, Korber BT, et al. Selective transmission of human immunodeficiency virus type-1 variants from mother to infants. Science 1992; 255: 1134–7PubMedCrossRefGoogle Scholar
  160. 160.
    Zhang L, MacKenzie P, Cleland A, et al. Selection for specific sequences in the external envelope protein of human immunodeficiency virus type 1 upon primary infection. J Virol 1993; 67: 3345–56PubMedGoogle Scholar
  161. 161.
    Zhu T, Mo H, Wang N, et al. Genotypic and phenotypic characterization of HIV-1 in patients with primary infection. Science 1993; 261: 1179–81PubMedCrossRefGoogle Scholar
  162. 162.
    Ho DD. Time to hit HIV, early and hard. N Engl J Med 1995; 333: 450–1PubMedCrossRefGoogle Scholar
  163. 163.
    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: 355–8PubMedCrossRefGoogle Scholar
  164. 164.
    Pantaleo G, Menzo S, Vaccarezza M, et al. Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N Engl J Med 1995; 332: 209–16PubMedCrossRefGoogle Scholar
  165. 165.
    Cao Y, Qin L, Zhang L, et al. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med 1995; 332: 201–8PubMedCrossRefGoogle Scholar
  166. 166.
    Hogervorst E, Jurriaans S, deWolf F, et al. Predictors for non- and slow progression in human immunodeficiency virus (HIV) type 1 infection: low viral RNA copy numbers in serum and maintenance of high HIV-1 p24-specific but not V3-specific antibody levels. J Infect Dis 1995; 171: 811–21PubMedCrossRefGoogle Scholar
  167. 167.
    Mellors JW, Kingsley LA, Rinaldo CR, et al. Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion. Ann Intern Med 1995; 122: 573–9PubMedGoogle Scholar
  168. 168.
    Luque F, Caruz A, Pineda JA, et al. Provirus load changes in untreated and zidovudine-treated human immunodeficiency virus type 1-infected patients. J Infect Dis 1994; 169: 267–73PubMedCrossRefGoogle Scholar
  169. 169.
    Yerly S, Kaiser L, Baumberger C, et al. Early and prolonged decrease of viraemia in HTV-1-infected patients treated with didanosine. J Acquir Immune Defic Syndr 1995; 8: 358–64Google Scholar
  170. 170.
    Yerly S, Kaiser L, Mermillod B, et al. Response of HIV RNA to didanosine as a predictive marker of survival. AIDS 1995; 9: 159–63PubMedGoogle Scholar

Copyright information

© Adis International Limited 1998

Authors and Affiliations

  • Graeme J. Moyle
    • 1
  • Brian G. Gazzard
    • 1
  • David A. Cooper
    • 2
  • José Gatell
    • 3
  1. 1.Kobler CentreChelsea and Westminster HospitalLondonEngland
  2. 2.National Health and Medical Research Council and St Vincent’s HospitalSydneyAustralia
  3. 3.Hospital Clinic ProvencalBarcelonaSpain

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