The Use of Antiviral Drugs in the Prevention and Treatment of Kaposi Sarcoma, Multicentric Castleman Disease and Primary Effusion Lymphoma

  • C. Casper
  • A. Wald
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 312)


Kaposi sarcoma-associated herpesvirus [KSHV, also known as human herpesvirus 8 (HHV-8)] is the most recently identified member of the human herpesvirus family. Kaposi sarcoma (KS), primary effusion lymphoma, and multicentric Castleman disease are all associated with KSHV infection. Although the incidence of KS has declined dramatically in areas with access to highly active antiretroviral therapy, it remains the most common AIDS-associated malignancy in the developed world and is one of the most common cancers in developing nations. Current treatment options for KSHV-associated disease are ineffective, unavailable, or toxic to many affected persons. A growing body of basic science, preclinical, and observational data suggests that antiviral medications may play an important role in the prevention and treatment of KSHV-associated disease.


Primary Effusion Lymphoma Multicenter AIDS Cohort Study Lytic Replication Multicentric Castleman Disease Intravenous Cidofovir 
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. Aaron L, Lidove O, Yousry C, Roudiere L, Dupont B, Viard JP (2002) Human herpesvirus 8-positive Castleman disease in human immunodeficiency virus-infected patients: the impact of highly active antiretroviral therapy. Clin InfectDis 35:880–882CrossRefGoogle Scholar
  2. Bani-Sadr F, Fournier S, Molina JM (2003) Relapse of Kaposi’s sarcomain HIV-infected patients switching from a protease inhibitor toanon-nucleoside reverse transcrip-tase inhibitor-based highly active antiretroviral therapy regimen. AIDS 17:1580–1581PubMedCrossRefGoogle Scholar
  3. Berezne A, Agbalika F, Oksenhendler E, Casper C, Nichols WG, Huang M-L, Corey L, Wald A (2004) Failure of cidofovir in HIV-associated multicentric Castleman disease. Blood 103:4368–4369PubMedCrossRefGoogle Scholar
  4. Boivin G, Cote S, Cloutier N, Abed Y, Maguigad M, Routy JP (2002) Quantification of human herpesvirus 8 by real-time PCR in blood fractions of AIDS patients with Kaposi’s sarcoma and multicentric Castleman’s disease. J Med Virol 68:399–403PubMedCrossRefGoogle Scholar
  5. Bottieau E, Colebunders R, Schroyens W, Van Droogenbroeck J, De Droogh E, Depraetere K, De Raeve H, Van Marck E (2000) Multicentric Castleman’s disease in 2 patients with HIV infection, unresponsive to antiviral therapy. Acta Clin Belg 55:97–101PubMedGoogle Scholar
  6. Bower M, Fox P, Fife K, Gill J, Nelson M, Gazzard B (1999) Highly active anti-retroviral therapy (HAART) prolongs time to treatment failure in Kaposi’s sarcoma. Aids 13:2105–2111PubMedCrossRefGoogle Scholar
  7. Broccolo F, Bossolasco S, Careddu AM, Tambussi G, Lazzarin A, Cinque P (2002) Detection of DNA of lymphotropic herpesviruses in plasma of human immunodeficiency virus-infected patients: frequency and clinical significance. Clin Diagn Lab Immunol 9:1222–1228PubMedCrossRefGoogle Scholar
  8. Campbell TB, Borok M, Gwanzura L, MaWhinney S, White IE, Ndemera B, Gudza I, Fitzpatrick L, Schooley RT (2000)Relationship of human herpesvirus 8 peripheral blood virus load and Kaposi’s sarcoma clinical stage. AIDS 14:2109–2116PubMedCrossRefGoogle Scholar
  9. Cannon JS, Hamzeh F, Moore S, Nicholas J, Ambinder RF (1999) Human herpesvirus 8-encoded thymidine kinase and phosphotransferase homologues confer sensitivity to ganciclovir. J Virol 73:4786–4793PubMedGoogle Scholar
  10. Cannon MJ, Dollard SC, Black JB, Edlin BR, Hannah C, Hogan SE, Patel MM, Jaffe HW, Offermann MK, Spira TJ, Pellett PE, Gunthel CJ (2003) Risk factors for Kaposi’s sarcoma in men seropositive for both human herpesvirus 8 and human immunodeficiency virus. AIDS 17:215–222PubMedCrossRefGoogle Scholar
  11. Carroll PA, Brazeau E, Lagunoff M (2004) Kaposi’s sarcoma-associated herpesvirus infection of blood endothelial cells induces lymphatic differentiation. Virology 328:7–18PubMedCrossRefGoogle Scholar
  12. Casper C, Nichols WG, Huang ML, Corey L, Wald A (2004) Remission of HHV-8 and HIV-associated multicentric Castleman disease with ganciclovir treatment. Blood 103:1632–1634PubMedCrossRefGoogle Scholar
  13. Cattelan A, Calabro M, Gasperini P, Aversa S, Zanchetta M, Meneghetti F, De Rossi AA, Chieco-Bianchi L (2001) Acquired immunodeficiency syndrome-related Kaposi’s sarcoma regression after highly active antiretroviral therapy: biologic correlates of clinical outcome. J Natl Cancer Inst Monogr 28:44–49PubMedGoogle Scholar
  14. Center for Disease Control (1981) Kaposi’s sarcoma and Pneumocystis pneumonia among homosexual men-New York City and California. MMWR Morb Mortal Wkly Rep 30:305–308Google Scholar
  15. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science 266:1865–1869PubMedCrossRefGoogle Scholar
  16. Clifford GM, Polesel J, Rickenbach M, on behalf of the Swiss HIV Cohort Study, Dal Maso L, Keiser O, Kofler A, Rapiti E, Levi F, Jundt G, Fisch T, Bordoni A, De Weck D, Franceschi S (2005) Cancer Risk in the Swiss HIV Cohort Study: associations with immunodeficiency, smoking, and highly active antiretroviral therapy 10.1093/jnci/dji072. J Natl Cancer Inst 97:425–432PubMedGoogle Scholar
  17. Conant MA, Opp KM, Poretz D, Mills RG (1997) Reduction of Kaposi’s sarcoma lesions following treatment of AIDS with ritonovir. AIDS 11:1300–1301PubMedGoogle Scholar
  18. Corbellino M, Bestetti G, Scalamogna C, Calattini S, Galazzi M, Meroni L, Manganaro D, Fasan M, Moroni M, Galli M, Parravicini C (2001) Long-term remission of Kaposi sarcoma-associated herpesvirus-related multicentric Castleman disease with anti-CD20 monoclonal antibody therapy. Blood 98:3473–3475PubMedCrossRefGoogle Scholar
  19. Dittmer D, Stoddart C, Renne R, Linquist-Stepps V, Moreno ME, Bare C, McCune JM, Ganem D (1999) Experimental transmission of Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8) to SCID-hu Thy/Liv mice. J Exp Med 190:1857–1868PubMedCrossRefGoogle Scholar
  20. Diz Dios P, Ocampo Hermida A, Miralles Alvarez C, Vazquez Garcia E, Martinez Vazquez C (1998) Regression of AIDS-related Kaposi’s sarcoma following ritonavir therapy. Oral Oncol 34:236–238PubMedCrossRefGoogle Scholar
  21. Dupin N, Fisher C, Kellam P, Ariad S, Tulliez M, Franck N, van Marck E, Salmon D, Gorin I, Escande JP, Weiss RA, Alitalo K, Boshoff C (1999) Distribution of human herpesvirus-8 latently infected cells in Kaposi’s sarcoma, multicentric Castleman’s disease, and primary effusion lymphoma. Proc Natl Acad Sci USA 96:4546–4551PubMedCrossRefGoogle Scholar
  22. Eltom MA, Jemal A, Mbulaiteye SM, Devesa SS, Biggar RJ (2002) Trends in Kaposi’s sarcoma and non-Hodgkin’s lymphoma incidence in the United States from 1973 through 1998. J Natl Cancer Inst 94:1204–1210PubMedGoogle Scholar
  23. Friedrichs C, Neyts J, Gaspar G, Clercq ED, Wutzler P (2004) Evaluation of antiviral activity against human herpesvirus 8 (HHV-8) and Epstein-Barr virus (EBV) by a quantitative real-time PCR assay. Antiviral Res 62:121–123PubMedCrossRefGoogle Scholar
  24. Gill J, Bourboulia D, Wilkinson J, Hayes P, Cope A, Marcelin AG, Calvez V, Gotch F, Boshoff C, Gazzard B (2002) Prospective study of the effects of antiretroviral therapy on kaposi sarcoma-associated herpesvirus infection in patients with and without kaposi sarcoma. J Acquir Immune Defic Syndr 31:384–390PubMedGoogle Scholar
  25. Glesby MJ, Hoover DR, Weng S, Graham NM, Phair JP, Detels R, Ho M, Saah AJ (1996) Use of antiherpes drugs and the risk of Kaposi’s sarcoma: data from the Multicenter AIDS Cohort Study. J Infect Dis 173:1477–1480PubMedGoogle Scholar
  26. Grandadam M, Dupin N, Calvez V, Gorin I, Blum L, Kernbaum S, Sicard D, Buisson Y, Agut H, Escande JP, Huraux JM (1997) Exacerbations of clinical symptoms in human immunodeficiency virus type 1-infected patients with multicentric Castleman’s disease are associated with a high increase in Kaposi’s sarcoma herpesvirus DNA load in peripheral blood mononuclear cells. J Infect Dis 175:1198–1201PubMedCrossRefGoogle Scholar
  27. Gustafson EA, Schinazi RF, Fingeroth JD (2000) Human herpesvirus 8 open reading frame 21 is a thymidine and thymidylate kinase of narrow substrate specificity that efficiently phosphorylates zidovudine but not ganciclovir. J Virol 74:684–692PubMedCrossRefGoogle Scholar
  28. Hocqueloux L, Agbalika F, Oksenhendler E, Molina JM (2001) Long-term remission of an AIDS-related primary effusion lymphoma with antiviral therapy. AIDS 15:280–282PubMedCrossRefGoogle Scholar
  29. Huang LM, Chao MF, Chen MY, Shih H, Chiang YP, Chuang CY, Lee CY (2001) Reciprocal regulatory interaction between human herpesvirus 8 and human immunodeficiency virus type 1. J Biol Chem 276:13427–13432PubMedCrossRefGoogle Scholar
  30. Hymes KB, Cheung T, Greene JB, Prose NS, Marcus A, Ballard H, William DC, Laubenstein LJ (1981) Kaposi’s sarcoma in homosexual men-a report of eight cases. Lancet 2:598–600PubMedCrossRefGoogle Scholar
  31. Ioannidis JP, Collier AC, Cooper DA, Corey L, Fiddian AP, Gazzard BG, Griffiths PD, Contopoulos-Ioannidis DG, Lau J, Pavia AT, Saag MS, Spruance SL, Youle MS (1998) Clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: a meta-analysis of randomized individual patient data. J Infect Dis 178:349–359PubMedGoogle Scholar
  32. Joffe MM, Hoover DR, Jacobson LP, Kingsley L, Chmiel JS, Visscher BR (1997) Effect of treatment with zidovudine on subsequent incidence of Kaposi’s sarcoma. Clin Infect Dis 25:1125–1133PubMedGoogle Scholar
  33. Jung C, Bogner JR, Goebel F (1998) Resolution of severe Kaposi’s sarcoma after initiation of antiretroviral triple therapy. Eur J Med Res 3:439–442PubMedGoogle Scholar
  34. Katano H, Sato Y, Itoh H, Sata T (2001) Expression of human herpesvirus 8 (HHV-8)-encoded immediate early protein, open reading frame 50, in HHV-8-associated diseases. J Hum Virol 4:96–102PubMedGoogle Scholar
  35. Katano H, Sato Y, Kurata T, Mori S, Sata T (2000) Expression and localization of human herpesvirus 8-encoded proteins in primary effusion lymphoma, Kaposi’s sarcoma, and multicentric Castleman’s disease. Virology 269:335–344PubMedCrossRefGoogle Scholar
  36. Kedes DH, Ganem D (1997) Sensitivity of Kaposi’s sarcoma-associated herpesvirus replication to antiviral drugs. Implications for potential therapy. J Clin Invest 99:2082–2086PubMedCrossRefGoogle Scholar
  37. Klass CM, Krug LT, Pozharskaya VP, Offermann MK (2005) The targeting of primary effusion lymphoma cells for apoptosis by inducing lytic replication of human herpesvirus 8 while blocking virus production. Blood: 2004-2009-3569Google Scholar
  38. Krischer J, Rutschmann O, Hirschel B, Vollenweider-Roten S, Saurat JH, Pechere M (1998) Regression of Kaposi’s sarcoma during therapy with HIV-1 protease inhibitors: a prospective pilot study. J Am Acad Dermatol 38:594–598PubMedCrossRefGoogle Scholar
  39. Krown SE (2004) Highly active antiretroviral therapy in AIDS-associated Kaposi’s sarcoma: implications for the design of therapeutic trials in patients with advanced, symptomatic Kaposi’s sarcoma. J Clin Oncol 22:399–402PubMedCrossRefGoogle Scholar
  40. Krug LT, Pozharskaya VP, Yu Y, Inoue N, Offermann MK (2004) Inhibition of infection and replication of human herpesvirus 8 in microvascular endothelial cells by α interferon and phosphonoformic acid. J Virol 78:8359–8371PubMedCrossRefGoogle Scholar
  41. Leao JC, Kumar N, McLean KA, Porter SR, Scully CM, Swan AV, Teo CG (2000) Effect of human immunodeficiency virus-1 protease inhibitors on the clearance of human herpesvirus 8 from blood of human immunodeficiency virus-1-infected patients. J Med Virol 62:416–420PubMedCrossRefGoogle Scholar
  42. Lebbe C, Blum L, Pellet C, Blanchard G, Verola O, Morel P, Danne O, Calvo F (1998) Clinical and biological impact of antiretroviral therapy with protease inhibitors on HIV-related Kaposi’s sarcoma. AIDS 12: F45–F49PubMedCrossRefGoogle Scholar
  43. Little RF, Merced-Galindez F, Staskus K, Whitby D, Aoki Y, Humphrey R, Pluda JM, Marshall V, Walters M, Welles L, Rodriguez-Chavez IR, Pittaluga S, Tosato G, Yarchoan R (2003) A pilot study of cidofovir in patients with Kaposi sarcoma. J Infect Dis 187:149–153PubMedCrossRefGoogle Scholar
  44. Lock MJ, Thorley N, Teo J, Emery VC (2002) Azidodeoxythymidine and didehydrodeoxythymidine as inhibitors and substrates of the human herpesvirus 8 thymidine kinase. J Antimicrob Chemother 49:359–366PubMedCrossRefGoogle Scholar
  45. Lorenzen T, Albrecht D, Paech V, Meyer T, Hoffmann C, Stoehr A, Degen O, Stellbrink HJ, Meigel WN, Arndt R, Plettenberg A (2002) HHV-8 DNA in blood and the development of HIV-associated Kaposi’s sarcoma in the era of HAART—a prospective evaluation. Eur J Med Res 7:283–286PubMedGoogle Scholar
  46. Lu M, Suen J, Frias C, Pfeiffer R, Tsai M-H, Chuang E, Zeichner SL (2004) Dissection of the Kaposi’s sarcoma-associated herpesvirus gene expression program by using the viral DNA replication inhibitor cidofovir. J Virol 78:13637–13652PubMedCrossRefGoogle Scholar
  47. Luppi M, Trovato R, Barozzi P, Vallisa D, Rossi G, Re A, Ravazzini L, Potenza L, Riva G, Morselli M, Longo G, Cavanna L, Roncaglia R, Torelli G (2005) Treatment of herpesvirus associated primary effusion lymphoma with intracavity cidofovir. Leukemia 19:473–476PubMedCrossRefGoogle Scholar
  48. Martin DF, Kuppermann BD, Wolitz RA, Palestine AG, Li H, Robinson CA (1999) Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. Roche Ganciclovir Study Group. N Engl J Med 340:1063–1070PubMedCrossRefGoogle Scholar
  49. Martinelli C, Zazzi M, Ambu S, Bartolozzi D, Corsi P, Leoncini F (1998) Complete regression of AIDS-related Kaposi’s sarcoma-associated human herpesvirus-8 during therapy with indinavir. AIDS 12:1717–1719PubMedGoogle Scholar
  50. McCune JM, Namikawa R, Kaneshima H, Shultz LD, Lieberman M, Weissman IL (1988) The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science 241:1632–1639PubMedCrossRefGoogle Scholar
  51. Medveczky MM, Horvath E, Lund T, Medveczky PG (1997) In vitro antiviral drug sensitivity of the Kaposi’s sarcoma-associated herpesvirus. AIDS 11:1327–1332PubMedCrossRefGoogle Scholar
  52. Mocroft A, Youle M, Gazzard B, Morcinek J, Halai R, Phillips AN (1996) Antiherpesvirus treatment and risk of Kaposi’s sarcoma in HIV infection. Royal Free/Chelsea and Westminster Hospitals Collaborative Group. AIDS 10:1101–1105PubMedCrossRefGoogle Scholar
  53. Murphy M, Armstrong D, Sepkowitz KA, Ahkami RN, Myskowski PL (1997) Regression of AIDS-related Kaposi’s sarcoma following treatment with an HIV-1 protease inhibitor. AIDS 11:261–262PubMedGoogle Scholar
  54. Neyts J, De Clercq E (1997) Antiviral drug susceptibility of human herpesvirus 8. Antimicrob Agents Chemother 41:2754–2756PubMedGoogle Scholar
  55. Oksenhendler E, Carcelain G, Aoki Y, Boulanger E, Maillard A, Clauvel JP, Agbalika F (2000) High levels of human herpesvirus 8 viral load, human interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric castleman disease in HIV-infected patients. Blood 96:2069–2073PubMedGoogle Scholar
  56. Pastore RD, Chadburn A, Kripas C, Schattner EJ (2000) Novel association of haemophagocytic syndrome with Kaposi’s sarcoma-associated herpesvirus-related primary effusion lymphoma. Br J Haematol 111:1112–1115PubMedCrossRefGoogle Scholar
  57. Pati S, Pelser CB, Dufraine J, Bryant JL, Reitz MS, Jr., Weichold FF (2002) Antitumorigenic effects of HIV protease inhibitor ritonavir: inhibition of Kaposi sarcoma. Blood 99:3771–3779PubMedCrossRefGoogle Scholar
  58. Pellet C, Chevret S, Blum L, Gauville C, Hurault M, Blanchard G, Agbalika F, Lascoux C, Ponscarme D, Morel P, Calvo F, Lebbe C (2001) Virologic and immunologic parameters that predict clinical response of AIDS-associated Kaposi’s sarcoma to highly active antiretroviral therapy. J Invest Dermatol 117:858–863PubMedCrossRefGoogle Scholar
  59. Portsmouth S, Stebbing J, Gill J, Mandalia S, Bower M, Nelson M, Gazzard B (2003) A comparison of regimens based on non-nucleoside reverse transcriptase inhibitors or protease inhibitors in preventing Kaposi’s sarcoma. AIDS 17: F17–F22PubMedCrossRefGoogle Scholar
  60. Renne R, Lagunoff M, Zhong W, Ganem D (1996) The size and conformation of Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8) DNA in infected cells and virions. J Virol 70:8151–8154PubMedGoogle Scholar
  61. Rey D, Schmitt MP, Partisani M, Hess-Kempf G, Krantz V, de Mautort E, Bernard-Henry C, Priester M, Cheneau C, Lang JM (2001) Efavirenz as a substitute for protease inhibitors in HIV-1-infected patients with undetectable plasma viral load on HAART: a median follow-up of 64 weeks. J Acquir Immune Defic Syndr 27:459–462PubMedGoogle Scholar
  62. Schaeffer HJ, Beauchamp L, de Miranda P, Elion GB, Bauer DJ, Collins P (1978) 9-(2-Hydroxyethoxymethyl) guanine activity against viruses of the herpes group. Nature 272:583–585PubMedCrossRefGoogle Scholar
  63. Sgadari C, Barillari G, Toschi E, Carlei D, Bacigalupo I, Baccarini S, Palladino C, Leone P, Bugarini R, Malavasi L, Cafaro A, Falchi M, Valdembri D, Rezza G, Bussolino F, Monini P, Ensoli B (2002) HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma. Nat Med 8:225–232PubMedCrossRefGoogle Scholar
  64. Sgadari C, Monini P, Barillari G, Ensoli B (2003) Use of HIV protease inhibitors to block Kaposi’s sarcoma and tumour growth. Lancet Oncol 4:537–547PubMedCrossRefGoogle Scholar
  65. Shimba N, Nomura AM, Marnett AB, Craik CS (2004) Herpesvirus protease inhibition by dimer disruption. J Virol 78:6657–6665PubMedCrossRefGoogle Scholar
  66. Sirianni MC, Vincenzi L, Topino S, Giovannetti A, Mazzetta F, Libi F, Scaramuzzi D, Andreoni M, Pinter E, Baccarini S, Rezza G, Monini P, Ensoli B (2002) NK cell activity controls human herpesvirus 8 latent infection and is restored upon highly active antiretroviral therapy in AIDS patients with regressing Kaposi’s sarcoma. Eur J Immunol 32:2711–2720PubMedCrossRefGoogle Scholar
  67. Stebbing J, Portsmouth S, Nelson M, Mandalia S, Kandil H, Alexander N, Davies L, Brock C, Bower M, Gazzard B (2004) The efficacy of ritonavir in the prevention of AIDS-related Kaposi’s sarcoma. Int J Cancer 108:631–633PubMedCrossRefGoogle Scholar
  68. Tavio M, Nasti G, Spina M, Errante D, Vaccher E, Tirelli U (1998) Highly active antiretroviral therapy in HIV-related Kaposi’s sarcoma. Ann Oncol 9:923PubMedCrossRefGoogle Scholar
  69. Whitby D, Howard MR, Tenant-Flowers M, Brink NS, Copas A, Boshoff C, Hatzioannou T, Suggett FE, Aldam DM, Denton AS, et al. (1995) Detection of Kaposi sarcoma associated herpesvirus in peripheral blood of HIV-infected individuals and progression to Kaposi’s sarcoma Lancet 346:799–802PubMedCrossRefGoogle Scholar
  70. Wilkinson J, Cope A, Gill J, Bourboulia D, Hayes P, Imami N, Kubo T, Marcelin A, Calvez V, Weiss R, Gazzard B, Boshoff C, Gotch F (2002) Identification of Kaposi’s sarcoma-associated herpesvirus (KSHV)-specific cytotoxic T-lymphocyte epitopes and evaluation of reconstitution of KSHV-specific responses in human immunodeficiency virus type 1-infected patients receiving highly active antiretroviral therapy. J Virol 76:2634–2640PubMedCrossRefGoogle Scholar
  71. Zietz C, Bogner JR, Goebel FD, Lohrs U (1999) An unusual cluster of cases of Castle-man’s disease during highly active antiretroviral therapy for AIDS. N Engl J Med 340:1923–1924PubMedCrossRefGoogle Scholar
  72. Zoeteweij JP, Eyes ST, Orenstein JM, Kawamura T, Wu L, Chandran B, Forghani B, Blauvelt A (1999) Identification and rapid quantification of early-and late-lytic human herpesvirus 8 infection in single cells by flow cytometric analysis: characterization of antiherpesvirus agents. J Virol 73:5894–5902PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2007

Authors and Affiliations

  • C. Casper
    • 1
  • A. Wald
    • 1
  1. 1.University of Washington Virology Research ClinicSeattleUSA

Personalised recommendations