Advances in the Treatment of HIV-1 Infections

  • Martin S. Hirsch


As we move into the second decade of the global AIDS epidemic, the search for safe and effective therapies intensifies. Understanding of the human immunodeficiency virus type 1 (HIV-1) replicative cycle and pathogenetic mechanisms has increased at a rapid pace, and with this increased understanding have come dozens of new therapeutic agents for evaluation. New and promising drugs and combinations of drugs have outstripped our ability to study them in a deliberate and thorough fashion, raising the possibility of new and radical approaches to the conduct of clinical trials.


Human Immunodeficiency Virus Simian Immunodeficiency Virus Drug Product Regulation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Agrawal S, Goodchild J, Civeira MP, Thornton AH, Sarin PS, Zamecnik P (1988) Oligodeoxynucleoside phosphoramidates and phosphorothioates as inhibitors of human immunodeficiency virus. Proc Natl Acad Sci USA 85:7079–7083.PubMedCrossRefGoogle Scholar
  2. Berman E, Duigou-Osterndorf R, Krown SE, Fanucchi MP, Chou J, Hirsch MS, Clarkson BD, Chou TC (1989) Synergistic cytotoxic effect of azidothymidine and recombinant interferon alpha on normal human bone marrow progenitor cells. Blood 74:1281–1286.PubMedGoogle Scholar
  3. Boston Interhospital Hospital Virus Study Group and the NIAID Sponsored Cooperative Antiviral Clinical Study (1975) Failure of high does 5-iodo-2′-deoxyuridine in the therapy of herpes simplex virus encephalitis. N Engl J Med 292:599–603.CrossRefGoogle Scholar
  4. Brown PO, Bowerman B, Varmus HE, Bishop JM (1989) Retroviral integration: structure of the initial covalent product and its precursor, and a role for the viral IN protein. Proc Natl Acad Sci USA 86:2525–2529.PubMedCrossRefGoogle Scholar
  5. Capon DJ, Chamow SM, Mordenti J, Marsters SA, Gregory T, Mitsuya H, Byrn RA, Lucas C, Wurm FM, Groopman JE, Broder S, Smith DH (1989) Designing CD4 immunoadhesins for AIDS therapy. Nature 337:525–531.PubMedCrossRefGoogle Scholar
  6. Chaudhary VK, Mizukami T, Ruerst TR, Fitzgerald DJ, Moss B, Pastan I, Berger EA (1989) Selective killing of HIV-infected cells by recombinant human CD4-pseudomonas exotoxin hybrid protein. Nature 335:369–372.CrossRefGoogle Scholar
  7. Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55.PubMedCrossRefGoogle Scholar
  8. Clapham PR, Weber JN, Whitby D, Mclntosh K, Dalgleish AG, Maddon PJ, Deen KC, Sweet RW, Weiss RA (1989) Soluble CD4 blocks the infectivity of diverse strains of HIV and SIV for T cells and monocytes but not for brain and muscle cells. Nature 337:368–370.PubMedCrossRefGoogle Scholar
  9. Creagh-Kirk T, Doi P, Andrews E, Nusinoff-Lehrman S, Tilson H, Hoth D, Barry DW (1988) Survival experience among patients with AIDS receiving zidovudine. Follow-up of patients in a compassionate plea program. JAMA 260:3009–3015.PubMedCrossRefGoogle Scholar
  10. Department of Health and Human Services (1987) New drug, antibodies and biologic drug product regulations. Fed Regist 52:8796–8847.Google Scholar
  11. Department of Health and Human Services (1988) Investigational new drug, antibiotic, and biological drug products regulations: procedures for drugs intended to treat life-threatening and severely debilitating illnesses. Fed Regist 53:41516–41524.Google Scholar
  12. Deray G, Diquet B, Martinez F, Vidal AM, Petitclerc T, Ben Hmida M, Land G, Jacobs C (1988) Pharmacokinetics of zidovudine in a patient on maintenance hemodialysis. N Engl J Med 319:1606–1607.PubMedCrossRefGoogle Scholar
  13. deWit R, Schattenkerk JK, Boucher CA, Bakker PJ, Veenhof KH, Danner SA (1988) Clinical and virological effects of high-dose recombinant interferon-a in disseminated AIDS-related Kaposi’s sarcoma. Lancet 2:1214–1217.CrossRefGoogle Scholar
  14. Dournon E, Matheron S, Rozenbaum W, Gharakhanian S, Michan C, Girard PM, Perronne C, Salmon D, de Truchis P, Leporti C, Bouvet E, Dazza MC, Levacher M, Regnier B (1988) Effects of zidovudine in 365 consecutive patients with AIDS or AIDS-related complex. Lancet 2:1297–1302.PubMedCrossRefGoogle Scholar
  15. Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Schooley RT, Jackson GG, Durack DT, King D, the AZT Collaborative Working Group (1987) 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 317:185–191.PubMedCrossRefGoogle Scholar
  16. Fischl MA, Richman DD, Causey DM, Grieco MH, Bryson Y, Mildvan D, Laskin OL, Groopman JE, Volberding PA, Schooley RT, Jackson GG, Durack D, Andrews JC, Nusinoff-Lehrman S, Barry DW, and the AZT Collaborative Working Group (1989) Prolonged zidovudine therapy in patients with AIDS and advanced AIDS-related complex. JAMA 262:2405–2410.PubMedCrossRefGoogle Scholar
  17. Fisher RA, Bertonis JM, Meier W, Johnson VA, Costopoulos DS, Liu T, Tizard R, Walker BD, Hirsch MS, Schooley RT, Flavell RT (1988) HIV infection is blocked in vitro by recombinant soluble CD4. Nature 331:76–78.PubMedCrossRefGoogle Scholar
  18. Grinde B, Hungnes O, Tjotta E (1989) The proteinase inhibitor pepstatin A inhibits formation of reverse transcriptase in H9 cells infected with human immunodeficiency virus-l. AIDS Res Human Retrov 5:269–274.CrossRefGoogle Scholar
  19. Gruters RA, Neefjes JJ, Tersmette M, de Goede RE, Tulp A, Huisman HG, Miedema F, Ploegh HL (1987) Interference with HIV-induced syncytium formation and viral infectivity by inhibitors of trimming glucosidase. Nature 330:74–77.PubMedCrossRefGoogle Scholar
  20. Hartshorn KL, Neumeyer D, Vogt MW, Schooley RT, Hirsch MS (1987a) Activity of interferons alpha, beta, and gamma against human immunodeficiency virus replication in vitro. AIDS Res Human Retrovirus 3:125–133.CrossRefGoogle Scholar
  21. Hartshorn KL, Vogt MW, Chou TC, Blumberg RS, Byington RE, Schooley RT, Hirsch MS (1987b) Synergistic inhibition of human immunodeficiency virus in vitro by azidothymidine and recombinant alpha A interferon. Antimicrob Ag Chemother 31:168–172.CrossRefGoogle Scholar
  22. Haseltine WA (1989) Development of antiviral drugs for the treatment of AIDS: strategies and prospects. J AIDS 2:311–334.Google Scholar
  23. Helbert M, Robinson D, Peddle B, Forster S, Kocsis A, Jeffries D, Pinching AJ (1988) Acute meningoencephalitis on dose reduction of zidovudine. Lancet 1:1249–1252.PubMedCrossRefGoogle Scholar
  24. Ho DD, Hartshorn KL, Rota TR, Andrews CA, Kaplan JC, Schooley RT, Hirsch MS (1985) Recombinant human interferon alpha-A suppresses HTLV-III replication in vitro. Lancet 1:602–604.PubMedCrossRefGoogle Scholar
  25. Horwitz JP, Chua J, Noel M (1969) The monomesylates of l-(2′-deoxy-b-D-lyxo-furanosyl)thymine. J Organ Chem 29:2076–8.CrossRefGoogle Scholar
  26. Hussey RE, Richardson NE, Kowalski N, Brown NR, Chang HC, Siliciano RF, Dorfman T, Walker B, Sodroski J, Reinherz EL (1988) A soluble CD4 protein selectively inhibits HIV replication and syncytium formation. Nature 331:78–81.PubMedCrossRefGoogle Scholar
  27. Interferon Alpha Study Group (1988) A randomized placebo-controlled trial of recombinant human interferon alpha 2a in patients with AIDS. J AIDS 1:111–118.Google Scholar
  28. Jacks T, Power MD, Masiarz FR, Luciw PA, Barr PJ, Varmus HE (1988) Characterization of ribosomal frameshifting in HIV gag-pol expression. Nature 331:280–283.PubMedCrossRefGoogle Scholar
  29. Jackson GG, Paul DA, Falk LA, Rubenis M, Despotes JC, Mack D, Knigge M, Emeson EE (1988) Human immunodeficiency virus (HIV) antigenemia (p24) in the acquired immunodeficiency syndrome (AIDS) and the effects of treatment with zidovudine (AZT). Ann Intern Med 108:175–180.PubMedCrossRefGoogle Scholar
  30. Johnson VA, Hirsch MS (1989) Combination therapy for HIV infection. In: Mills J, Corey L, (eds) Antiviral Chemotherapy: New Directions for Clinical Application and Research. Vol 2 pp 275–302. New York: Elsevier.Google Scholar
  31. Johnson VA, Barlow MA, Chou T-C, Fisher RA, Walker BD, Hirsch MS, Schooley RT (1989a) Synergistic inhibition of human immunodeficiency virus type 1 (HIV-l) replication in vitro by recombinant soluble CD4 and 3′-azido-3′-deoxythymidine. J Infect Dis 159:837–844.PubMedCrossRefGoogle Scholar
  32. Johnson VA, Merrill DP, Chou TC, Hirsch MS (1989b) Synergistic inhibition of HIV-1 replication by N-butyl deoxynojirimycin (N-butyl-DNJ) and zidovudine (AZT) (abstr. #504). Proceedings of the Twenty-Ninth Interscience Conference on Antimicrobial Agents and Chemotherapy. Houston, Texas, September 17–20, 1989; 185.Google Scholar
  33. Johnson VA, Walker BD, Barlow MA, Paradis TJ, Chou T-C, Hirsch MS (1989c) Synergistic inhibition of human immunodeficiency virus type 1 and 2 replication in vitro by castanospermine and 3′-azido-3′-deoxythymidine. Antimicrob Ag Chemother 33:53–57.CrossRefGoogle Scholar
  34. Johnson VA, Barlow MA, Merrill DP, Chou TC, Hirsch MS (1990) Three drug synergistic inhibition of HIV-l replication in vitro by zidovudine, recombinant soluble CD4, and recombinant interferon alpha-A. J Infect Dis (In press).Google Scholar
  35. Kahn J, Davis AJ, Groopman JE, Kaplan L, Sherwin S (1989) Pharmacokinetics studies of recombinant soluble CD4 in patients with AIDS and AIDS related complex. In: “Program and Abstracts of the Fifth International Conference on AIDS”. Montreal, Canada June 4–9. Abstract ThB05.Google Scholar
  36. Karpas A, Fleet GWJ, Dwek RA, Peturson S, Namgoong SK, Ramsden NG, Jacob GS, Rademacher TW (1988) Aminosugar derivatives as potential anti-human immunodeficiency virus agents. Proc Natl Acad Sci USA 85:9229–9233.PubMedCrossRefGoogle Scholar
  37. Kessler DA (1989) The regulation of investigational drugs. N Engl J Med 320:281–288.PubMedCrossRefGoogle Scholar
  38. Kornhauser DM, Petty BG, Hendrix CW, Woods AS, Nerhood LJ, Bartlett JG, Lietman PS (1989) Probenicid and zidovudine metabolism. Lancet 2:473–475.PubMedCrossRefGoogle Scholar
  39. Kovacs JA, Deyton L, Davey R, Falloon J, Zunich K, Lee D, Metcalf JA, Bigley JW, Sawyer LA, Zoon KC, Masur H, Fauci AS, Lane HC (1989) Combined zidovudine and interferon-a therapy in patients with Kaposi’s sarcoma and the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 111:280–287.PubMedCrossRefGoogle Scholar
  40. Krown S (1988) AIDS-associated Kaposi’s sarcoma: pathogenesis, clinical course and treatment. AIDS 2:71–80.PubMedCrossRefGoogle Scholar
  41. Lamarre D, Ashkenazi A, Fleury S, Smith DH, Sekaly RP, Capon DJ (1989) The MHC-binding and gp120 binding functions of CD4 are separable. Science 245:743–746.PubMedCrossRefGoogle Scholar
  42. Lane HC, Kovacs JA, Feinberg J, Herpin B, Davey V, Walker R, Deyton L, Metcalf JFA, Baseler M, Salzman N, Manischewitz J, Quinnan G, Masur H, Fauci AC (1988) Anti-retroviral effects of interferon-a in AIDS-associated Kaposi’s sarcoma. Lancet 2:1218–1222.PubMedCrossRefGoogle Scholar
  43. Lane HC, Falloon J, Walker RE, Deyton L, Kovacs JA, Masur H, Banks S, Kirk LE, Baseler MW, Salzman NP, Fauci AS (1989) Zidovudine in patients with human immunodeficiency virus (HIV) infection and Kaposi’s sarcoma. A Phase II randomized, placebo-controlled trial. Ann Intern Med 111:41–50.PubMedCrossRefGoogle Scholar
  44. Larder BA, Darby G, Richman DD (1989) HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 243:1731–1734.PubMedCrossRefGoogle Scholar
  45. Lifson JD, Hwang KM, Nara PL, Fraser B, Padgett M, Dunlop NM, Eiden LE (1988) Synthetic CD4 peptide derivatives that inhibit HIV infection and cytopathicity. Science 241:712–716.PubMedCrossRefGoogle Scholar
  46. McBride WG (1977) Thalidomide embryopathy. Teratology 16:79–82.PubMedCrossRefGoogle Scholar
  47. Merigan TC, Skowron G, Bozzette SA, Richman D, Uttamchandani R, Fischl M, Schooley R, Hirsch M, Soo W, Pettinelli C, Schaumburg H, and the ddC Study Group of the AIDS Clinical Trials Group (1989) Circulating p24 antigen levels and responses to dideoxycytidine in human immunodeficiency virus (HIV) infections. Ann Intern Med 110:189–194.PubMedCrossRefGoogle Scholar
  48. Mitsuya H, Broder S (1986) Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2′, 3′-dideoxynucleosides. Proc Natl Acad Sci USA 83:1911–1915.PubMedCrossRefGoogle Scholar
  49. Mitsuya H, Weinhold KJ, Furman PA, St. Clair MH, Lehrman SN, Gallo RC, Bolognesi D, Barry DW, Broder S (1985) 3′-azido-3′-deoxythymidine (BWA509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci USA 82:7096–7100.PubMedCrossRefGoogle Scholar
  50. Mosier DE, Gulizia RJ, Baird SM, Wilson DB (1988) Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature 335:256–259.PubMedCrossRefGoogle Scholar
  51. Myers MG, Oxman MN, Clark JE, Arndt KA (1975) Failure of neutral-red photodynamic inactivation in recurrent herpes simplex infections. N Engl J Med 293:945–949.PubMedCrossRefGoogle Scholar
  52. Navia MA, Fitzgerald PM, McKeever BM, Leu CT, Heimbach JC, Herber WK, Sigal IS, Darke PL, Springer JP (1989) Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-l. Nature 337:615–620.PubMedCrossRefGoogle Scholar
  53. Ostertag W, Roesler G, Kreig CJ, Kind J, Cole T, Crozier T, Gaedicke G, Steinheider G, Kluge N, Dube S (1974) Induction of endogenous virus and of thymidine kinase by bromodeoxyuridine in cell cultures transformed by Friend virus. Proc Natl Acad Sci USA 71:4980–5.PubMedCrossRefGoogle Scholar
  54. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J, Smith PG (1976) Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Brit J Cancer 34:585–612.PubMedCrossRefGoogle Scholar
  55. Pizzo PA, Eddy J, Falloon J, Balis FM, Murphy RF, Moss H, Wolters P, Brouwers P, Jarosinski P, Rubin M, Broder S, Yarchoan R, Brunetti A, Maha M, Nusinoff-Lehrman S, Poplack DG (1988) Effect of continuous intravenous infusion of zidovudine (AZT) in children with symptomatic HIV infection. N Engl J Med 319:889–96.PubMedCrossRefGoogle Scholar
  56. Poli G, Orenstein JM, Kinter A, Folks TM, Fauci AS (1989) Interferon-a but not AZT suppresses HIV expression in chronically infected cell lines. Science 244:575–577.PubMedCrossRefGoogle Scholar
  57. Richman DD, Fischl MA, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Hirsch MS, Jackson GG, Durack DT, Nusinoff-Lehrman S, the AZT Collaborative Working Group (1987) The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS a AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med 317:192–7.PubMedCrossRefGoogle Scholar
  58. Ruprecht RM (1989) Murine models for antiretroviral therapy. Intervirol 305:2–11.Google Scholar
  59. Ruprecht RM, Mullaney S, Anderson J, Bronson R (1989) In vivo analysis of castanospermine, a candidate antiretroviral agent. J AIDS 2:149–157.Google Scholar
  60. Sarin PS, Agrawal S, Civeira MP, Goodchild J, Ikeuchi T, Zamecnik PC (1988) Inhibition of acquired immunodeficiency syndrome virus by oligode-oxynucleoside methylphosphonates. Proc Natl Acad Sci USA 85:7448–7451.PubMedCrossRefGoogle Scholar
  61. Schmitt FA, Bigley JW, McKinnis R, Logue PE, Evans RW, Drucker JL, and the AZT Collaborative Working Group (1988) Neuropsychological outcome of zidovudine (AZT) treatment of patients with AIDS and AIDS-related complex. N Engl J Med 319:1573–8.PubMedCrossRefGoogle Scholar
  62. Schooley RT, Merrigan TC Jr, Gaut P, Hirsch MS, Holodniy M, Flynn T, Liu S, Byington RE, Henochowicz S, Gubish E, Spriggs D, Kute D, Schindler J, Dawson A, Thomas D, Hanson DG, Letwin B, Liu T, Gulinello J, Kennedy S, Fisher R, Ho DD (1990) A phase I (II escalating dose trial of recombinant soluble CD4 therapy in patients with AIDS or AIDS related complex. Ann Intern Med (in press).Google Scholar
  63. Smith DH, Byon RA, Marsters SA, Gregory T, Groopman JE, Capon DJ (1987) Blocking of HIV-l infectivity by a soluble, secreted form of the CD4 antigen. Science 238:1704–1707.PubMedCrossRefGoogle Scholar
  64. Stevens DA, Jordan GW, Waddell TF, Merigan TC (1973) Adverse effect of cytosine arabinoside on disseminated zoster in a controlled trial. N Engl J Med 189:873–878.CrossRefGoogle Scholar
  65. Swiss Group for Clinical Studies on the Acquired Immunodeficiency Syndrome (AIDS) (1988) Zidovudine for the treatment of thrombocytopenia associated with human immunodeficiency virus (HIV). Ann Intern Med 109:718–721.CrossRefGoogle Scholar
  66. Till MA, Ghetie V, Gregory T, Patzer EJ, Porter JP, Uhr JW, Capon DJ, Vitetta ES (1988) HIV-infected cells are killed by rCD4-ricin A chain. Science 242:1166–1168.PubMedCrossRefGoogle Scholar
  67. Traunecker A, Luke W, Karjalainen K (1988) Soluble CD4 molecules neutralize human immunodeficiency virus type 1. Nature 331:84–86.PubMedCrossRefGoogle Scholar
  68. Varmus H, Brown P (1989) Retroviruses In: Howe M, and Berg P (eds) Mobile DNA. ASM, Metals Park, Ohio, pp. 53–107.Google Scholar
  69. Vogt MW, Hartshorn KL, Furman PA, Chou TC, Fyfe JA, Coleman LA, Crumpacker C, Schooley RT, Hirsch MS (1987) Ribavirin antagonizes the effects of azidothymidine on HIV replication. Science 235:1376–1379.PubMedCrossRefGoogle Scholar
  70. Vogt MW, Durno AG, Chou T-C, Coleman LA, Paradis TJ, Schooley RT, Kaplan JC, Hirsch MS (1988) Synergistic interaction of 2′-,3′-dideoxycytidine (ddCyd) and recombinant interferon alpha-A (r-IFN-alpha-A) on HIV-1 replication. J Infect Dis 158:378–385.PubMedCrossRefGoogle Scholar
  71. Walker BD, Kowalski M, Goh WC, Kozarsky K, Krieger M, Rosen C, Rohrschneider L, Haseltine WA, Sodroski J (1987) Inhibition of human immunodeficiency virus syncytium formation and virus replication by castanospermine. Proc Natl Acad Sci USA 84:8120–8124.PubMedCrossRefGoogle Scholar
  72. Watanabe M, Reimann KA, DeLong PA, Liu T, Fisher RA, Letvin NL (1989) Effect of recombinant soluble CD4 in rhesus monkeys infected with simian immunodeficiency virus of macaques. Nature 337:267–270.PubMedCrossRefGoogle Scholar
  73. Wlodawer A, Miller M, Jaskolski M, Sathyanarayana BK, Baldwin E, Weber IT, Selk LM, Clawson L, Schneider J, Kent SB (1989) Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-l protease. Science 245:616–622.PubMedCrossRefGoogle Scholar
  74. Yarchoan R, Perno CF, Thomas RV, Klecker RW, Allain J-P, Wills RJ, McAtee N, Fischl MA, Dubinsky R, McNeeley MC, Mitsuya H, Pluda JM, Lawley TJ, Leuther M, Safai B, Collins JM, Myers CE, Broder S (1988) Phase I studies of 2′-,3′-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT). Lancet 1:76–81.PubMedCrossRefGoogle Scholar
  75. Yarchoan R, Thomas RV, Pluda JM, Perno CF, Mitsuya H, Marczyk KS, Sherwin SA, Broder S (1989a) Phase I study of the administration of recombinant soluble CD4 (rCD4) by continuous infusion to patients with AIDS or ARC. In Program and abstracts of the Fifth International Conference on AIDS. Montreal, Canada June 4′9. Abstract MCP 137.Google Scholar
  76. Yarchoan R, Mitsuya H, Thomas RV, Pluda JM, Hartman NR, Perno CF, Marczyk KS, Allain JP, Johns DG, Broder S (1989b) In vitro activity against HIV and favorable toxicity profile of 2′-3′-dideoxyinosine. Science 245:412–415.PubMedCrossRefGoogle Scholar
  77. Yarchoan R, Mitsuya H, Myers CE, Broder S (1989c) Clinical pharmacology of 3′-azido-2′, 3′-dideoxythymidine (zidovudine) and related dideoxynucleosides. N Engl J Med 321:726–738.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1991

Authors and Affiliations

  • Martin S. Hirsch
    • 1
  1. 1.Department of MedicineMassachusetts General Hospital, Harvard Medical SchoolBostonUSA

Personalised recommendations