Current Infectious Disease Reports

, Volume 5, Issue 3, pp 257–265

Cytomegalovirus disease in the highly active antiretroviral therapy era

  • William Lawrence Drew
Article

Abstract

Cytomegalovirus (CMV) is a major cause of morbidity and mortality in AIDS patients. Epidemiologic studies indicate that until 10 years ago, nearly one half of HIV-infected patients eventually developed CMV end-organ disease, including chorioretinitis, esophagitis, colitis, pneumonia, and central nervous system disease. Since the introduction of highly active antiretroviral therapy (HAART) this incidence has declined dramatically. Nonetheless, patients still present with CMV disease and resistance or intolerance to HAART does develop, which may give rise to a resurgence of CMV syndromes in AIDS patients. Until recently, only intravenous ganciclovir and foscarnet were available for management of CMV infection. With the advent of additional agents, clinicians now face the challenge of optimizing therapy for individual patients. This paper reviews the most common clinical syndromes caused by CMV, the treatment options, as well as an approach to diagnosing and treating antiviral resistance.

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References and Recommended Reading

  1. 1.
    Drew WL, Mintz L, Miner RC, et al.: Prevalence of cytomegalovirus infection in homosexual men. J Infect Dis 1981, 143:188–192.PubMedGoogle Scholar
  2. 2.
    Mintz L, Drew Wl, Miner RC, Braff EH: Cytomegalovirus infections in homosexual men: an epidemiological study. Ann Intern Med 1983, 99:326–329.PubMedGoogle Scholar
  3. 3.
    Shinkai M, Bozette SA, Powderly W, et al.: Utility of urine and leukocyte cultures and plasma DNA polymerase chain reaction for identification of AIDS patients at risk for developing human cytomegalovirus infection. J Infect Dis 1997, 175:302–308.PubMedGoogle Scholar
  4. 4.
    O’Sullivan CE, Drew WL, McMullen DJ, et al.: Decrease of cytomegalvovirus replication in human immunodeficiency virus-infected patients after treatment with highly active antiretroviral therapy. J Infect Dis 1999, 180:847–849. This paper documents the fact that HAART alone decreases CMV titers in blood, and accounts for the marked decline of CMV retinitis since the beginning of the HAART era.PubMedCrossRefGoogle Scholar
  5. 5.
    Deayton J, Mocroft A, Wilson P, et al.: Loss of cytomegalovirus (CMV) viraemia following highly active antiretroviral therapy in the absence of specific anti-CMV therapy. AIDS 1999, 13:1203–1206. This paper also documents the fact that HAART alone decreases CMV titers in blood.PubMedCrossRefGoogle Scholar
  6. 6.
    Stone SF, Price P, Tay-Kearney M-L, French MA: Cytomegalovirus (CMV) retinitis immune restoration disease occurs during highly active antiretroviral therapy - induced restoration of CMV-specific immune responses within a predominant Th2 cytokine environment. J Infect Dis 2002, 185:1813–1817. Reports a proposed immunologic mechanism for the development of immune recovery vitritis and uveitis in AIDS patients treated with HAART.PubMedCrossRefGoogle Scholar
  7. 7.
    Jacobson MA, Stanley H, Holtzer C, et al.: Natural history and outcome of new AIDS-related cytomegalovirus retinitis diagnosed in the era of highly active antiretroviral therapy. Clin Infect Dis 2000, 30:231–233. Describes the different scenarios in which patients may present with CMV retinitis in the HAART era.PubMedGoogle Scholar
  8. 8.
    Spector SA, Weingeist T, Pollard RE, et al.: Randomized, controlled study of intravenous ganciclovir therapy for cytomegalovirus peripheral retinitis in patients with AIDS. AIDS Clinical Trials Group and Cytomegalovirus Cooperative Study Group. J Infect Dis 1993, 168:557–563.PubMedGoogle Scholar
  9. 9.
    Martin DF, Sierra-Madero J, Walmsley S, et al.: A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med 2002, 346:1119–1126.PubMedCrossRefGoogle Scholar
  10. 10.
    Lalezari JP, Stagg RJ, Kupperman BD, et al.: Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. A randomized, controlled trial. Ann Intern Med 1997, 126:257–263.PubMedGoogle Scholar
  11. 11.
    Vitravene Study Group: A randomized controlled trial of intravenous fomivirsen for treatment of newly diagnosed peripheral cytomegalovirus retinitis in patients with AIDS. Am J Ophthalmol 2002, 133:467–474.CrossRefGoogle Scholar
  12. 12.
    The Studies of Ocular Complications of AIDS Research Group. The AIDS Clinical Trials Group: The ganciclovir implant plus oral ganciclovir versus parenteral cidofovir for the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome: The Ganciclovir Cidofovir Cytomegalovirus Retinitis Trial. Am J Ophthalmol 2001, 131:457–467.CrossRefGoogle Scholar
  13. 13.
    Drew WL, Ives D, Lalezari JP, et al., for the Syntex Cooperative Oral Ganciclovir Study Group: Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis in patients with AIDS. N Engl J Med 1995, 333:615–620.PubMedCrossRefGoogle Scholar
  14. 14.
    Combination foscarnet and ganciclovir therapy vs. monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with AIDS. Cytomegalovirus Retreatment Trials. Studies of Ocular Complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group. Arch Ophthalmol 1996, 114:23–33.Google Scholar
  15. 15.
    Lalezari JP, Holland GN, Kramer F, et al.: Randomized, controlled study of the safety and efficacy of intravenous cidofovir for the treatment of relapsing cytomegalovirus retinitis in patients with AIDS. J Acquir Immune Defic Syndr Hum Retrovirol 1998, 17:339–344.PubMedGoogle Scholar
  16. 16.
    Martin DF, Kupperman BD, Wolitz RA, et al.: Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. Roche Ganciclovir Study Group. N Engl J Med 1999, 340:1063–1070.PubMedCrossRefGoogle Scholar
  17. 17.
    Tural C, Romeu J, Sirera G, et al.: Long-lasting remission of cytomegalovirus retinitis without maintenance therapy in human immunodeficiency virus-infected patients. J Infect Dis 1998, 177:1080–1083.PubMedGoogle Scholar
  18. 18.
    Vrabec TR, Baldassano VF, Whitcup SM: Discontinuation of maintenance therapy in patients with quiescent cytomegalovirus retinitis and elevated CD4+ counts. Ophthalmology 1998, 105:1259–1264.PubMedCrossRefGoogle Scholar
  19. 19.
    MacDonald JC, Torriani FJ, Morse T, et al.: Lack of reactivation of cytomegalovirus (CMV) retinitis after stopping CMV maintenance therapy in AIDS patients with sustained elevations in CD4 T cells in response to highly active antiretroviral therapy. J Infect Dis 1998, 177:1182–1187.PubMedGoogle Scholar
  20. 20.
    Jouan M, Saves H, Tubiana R, et al.: Discontinuation of maintenance therapy for cytomegalovirus retinitis in HIVinfected patients receiving highly active antiretroviral therapy: RESTIMOP Study Team. AIDS 2001, 15:23–31.PubMedCrossRefGoogle Scholar
  21. 21.
    Song MK, Schrier RD, Smith IL, et al.: Paradoxical activity of CMV retinitis in patients receiving highly active antiretroviral therapy. Retina 2002, 22:262–267.PubMedCrossRefGoogle Scholar
  22. 22.
    Karavellas MP, Lowder CY, MacDonald JC, et al.: Immune recovery vitritis associated with inactive CMV retinitis: a new syndrome. Arch Ophthalmol 1998, 116:169–175.PubMedGoogle Scholar
  23. 23.
    Zegans ME, Walton RC, Holland GN, et al.: Transient vitreous inflammatory reactions associated with combination antiretroviral therapy in patients with AIDS and cytomegalovirus retinitis. Am J Ophthalmol 1998, 125:292–300.PubMedCrossRefGoogle Scholar
  24. 24.
    Karavellas MP, Azen SP, MacDonald JC, et al.: Immune recovery vitritis and uveitis in AIDS: clinical predctors, sequelae, and treatment outcomes: Retina 2001, 21:1–9. The best description of the entire spectrum of ophthalmologic consequences of immune recovery in AIDS patients treated with HAART.PubMedCrossRefGoogle Scholar
  25. 25.
    Drew WL, Miner RC, Busch DF, et al.: Prevalence of resistance of in-patients receiving ganciclovir for serious CMV infections. J Infect Dis 1991, 163:716–719.PubMedGoogle Scholar
  26. 26.
    Jabs DA, Enger C, Dunn JP, et al.: Cytomegalovirus retinitis and viral resistance: ganciclovir resistance. J Infect Dis 1998, 177:770–773.PubMedCrossRefGoogle Scholar
  27. 27.
    Jabs DA, Enger C, Forman M, Dunn JP, for The Cytomegalovirus Retinitis and Viral Resistance Study Group: Incidence of foscarnet resistance and cidofovir resistance in patients treated for cytomegalovirus retinitis. Antimicrob Agents and Chemother 1998, 42:2240–2244.Google Scholar
  28. 28.
    Chou S, Waldemer RH, Senters AE, et al.: Cytomegalovirus UL 97 phosphotransferase mutations that affect susceptibility to ganciclovir: J Infect Dis 2002, 185:162–169.PubMedCrossRefGoogle Scholar
  29. 29.
    Chou S, Guentzel S, Michels KR, et al.: Frequency of UL 97 phosphotransferase mutations related to ganciclovir resistance in clincal cytomegalovirus isolates. J Infect Dis 1995, 172:239–242.PubMedGoogle Scholar
  30. 30.
    Smith IL, Cherrington JM, Jiles RE, et al.: High-level resistance of cytomegalovirus to ganciclovir is associated with alterations in both the UL 97 and DNA polymerase genes. J Infect Dis 1997, 176:69–77. This paper advances the thought that CMV strains with both UL 97 and UL 54 (polymerase) mutations are more resistant than strains with only UL 97 mutations, ie, that resistance is cumulative.PubMedGoogle Scholar
  31. 31.
    Chou S, Marousek G, Parenti DM et al.: Mutation in Region III of the DNA polymerase gene conferring foscarnet resistance in cytomegalovirus isolates from 3 subjects receiving prolonged antiviral therapy. J Infect Dis 1998, 178:526–530.PubMedGoogle Scholar
  32. 32.
    Chou S, Miner RC, Drew WL: A deletion mutation in region V of the cytomegalovirus DNA polymerase sequence confers multidrug resistance. J Infect Dis 2000, 182:1765–1768.PubMedCrossRefGoogle Scholar
  33. 33.
    Mousavi-Jazi M, Schloss, Drew WL, et al.: Variations in the cytomegalovirus DNA polymerase and phosphotransferase genes in relation to foscarnet and ganciclovir sensitivity. J Clin Virol 2001, 23:1–15.PubMedCrossRefGoogle Scholar
  34. 34.
    Dieterich DT, Kotler DP, Busch DF: Ganciclovir treatment of cytomegalovirus colitis is AIDS. A randomized, doubleblind, placebo-controlled multicenter study. J Infect Dis 1993, 167:278–282.PubMedGoogle Scholar
  35. 35.
    Wilcox CM, Diehl DL, Cello JP, et al.: Cytomegalovirus esophagitis in patients with AIDS. A clinical, endoscopic, and pathologic correlation. Ann Intern Med 1990, 113:589–593.PubMedGoogle Scholar
  36. 36.
    Blanshard C, Benamou Y, Dohin E, et al.: Treatment of AIDSassociated gastrointestinal cytomegalovirus infection with foscarnet and ganciclovir: a randomized comparison. J Infect Dis 1995, 172:622–628.PubMedGoogle Scholar
  37. 37.
    Miller RG, Storey JR, Greco CM: Ganciclovir in the treatment of progressive AIDS-related polyradiculopathy. Neurology 1990, 40:569–574.PubMedGoogle Scholar
  38. 38.
    Kim YS, Hollander H: Polyradiculopathy due to cytomegalovirus: report of two cases in which improvement occurred after prolonged therapy and review of the literature. Clin Infect Dis 1993, 17:32–37.PubMedGoogle Scholar
  39. 39.
    Flood J, Drew WL, Miner RC, et al.: Diagnosis of cytomegalovirus (CMV) polyradiculopathy and documentation of in-vivo anti-CMV activity in cerebrospinal fluid using branched DNA signal amplification and antigen assays. J Infect Dis 1997, 176:50–58.Google Scholar
  40. 40.
    Morgello S, Cho E, Nielsen S, et al.: Cytomegalovirus encephalitis in patients with acquired immunodeficiency syndrome: An autopsy study of 30 cases and review of literature. Hum Pathol 1987, 18:289–297.PubMedCrossRefGoogle Scholar
  41. 41.
    Holland NR, Power C, Matthews VP, et al.: Cytomegalovirus encephalitis in AIDS. Neurology 1994, 44:507–514.PubMedGoogle Scholar
  42. 42.
    Cohen BA: Prognosis and response to therapy of cytomegalovirus encephalitis and meningomyelitis in AIDS. Neurology 1996, 46:444–450.PubMedGoogle Scholar

Copyright information

© Current Science Inc 2003

Authors and Affiliations

  • William Lawrence Drew
    • 1
  1. 1.Division of Infectious DiseasesUCSF-Mount Zion Medical CenterSan FranciscoUSA

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