Current Management of Cytomegalovirus Retinitis in Aids Update on Ganciclovir and Foscarnet for CMV Infections

  • Mark A. Jacobson
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 394)

Abstract

Two antiviral agents have been approved by the FDA for the therapy of AIDS-associated cytomegalovirus (CMV) retinitis, ganciclovir (Cytovene) and foscarnet (Foscavir). Ganciclovir is a nucleoside analogue of guanosine that is an antiviral pro-drug, as it must be phosphorylated intracellularly, to the active moiety ganciclovir triphosphate; this occurs selectively within CMV-infected cells. Ganciclovir triphosphate selectively inhibits the DNA polymerase of CMV (Ki of 1.7 μM compared to 17 μM for the cellular DNA polymerase)1. Ganciclovir is metabolized to the monophosphate form by a unique kinase which is the product of the CMV ÚL97 gene, 1a,1b then further transformed by host cellular kinases to the di-phosphate. For this reason, levels of ganciclovir-TP within CMV-infected cells are 10 times those found inside uninfected cells.

Keywords

Nephrogenic Diabetes Insipidus Fractional Inhibitory Concentration Cytomegalovirus Retinitis Chronic Maintenance Foscarnet Therapy 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Matthews T, Boehme R. Antiviral activity and mechanism of action of ganciclovir. Rev Infect Dis 1988; 10: S490–4.PubMedCrossRefGoogle Scholar
  2. 1a.
    Sullivan V, Talarico CL, Stanat SC, Davis M et al. A protein kinase homologue controls phosphorylation of ganciclovir in human cytomegalovirus-infected cells. Nature 1992; 358: 162.PubMedCrossRefGoogle Scholar
  3. 1b.
    Littler E, Stuart AD, Chee MS. Human cytomegalovims ÚL97 open reading frame encodes a protein that phosphorylates the antiviral nucleoside analogue ganciclovir. Nature 1992; 358: 160.PubMedCrossRefGoogle Scholar
  4. 2.
    Oberg B. Antiviral effects of phosphonofonnate. Pharmac Ther 1983; 19: 387–415.CrossRefGoogle Scholar
  5. 3.
    Verheyden JPH. Evolution of therapy for cytomegalovirus infections. Rev Infect Dis 1988; 10: S477–89.PubMedCrossRefGoogle Scholar
  6. 4.
    Plotkin SA, Drew WL, Felsenstein D, Hirsch MS. Sensitivity of clinical isolates of human cytomegalovirus to 9-(1,3-dihydroxy-2-propoxymethyl)guanine. J Infect Dis 1985; 152: 833–4.PubMedCrossRefGoogle Scholar
  7. 5.
    Akesson-Johanson A, Lemestedt JO, Ringden O, Lonnqvist B, Wahren B. Sensitivity of cytomegalovirus to intravenous foscarnet treatment. Bone Marrow Transplant 1986; 1: 215–20.Google Scholar
  8. 6.
    Sandstrom EG, Byington RE, Kaplan JE, Hirsch MS. Inhibition of human T cell lymphotropic virus type III in vitro by phosphonoformate. Lancet 1985; 1: 1480–2.PubMedCrossRefGoogle Scholar
  9. 7.
    Sommadossi JP, Bevan R, Long T, et al. Clinical pharmacokinetics of ganciclovir in patients with normal and impaired renal function. Rev Infect Dis 1988; 10: 5507–14.CrossRefGoogle Scholar
  10. 8.
    Sjovall J, Karlsson A, Ogenstad S, Sandstrom E, Saarimaki M. Pharmacokinetics and absorption of foscarnet after intravenous and oral administration to patients with human immunodeficiency virus. Clin Pharmacol Ther 1988; 44: 65–73.PubMedCrossRefGoogle Scholar
  11. 9.
    Smee DR, Boehme R, Chemow M et al. Intracellular metabolism and enzymatic phosphorylation of 9(1,3-dihydroxy-2-propoxymethyl)guanine and acyclovir in herpes simplex virus-infected and uninfected cells. Biochem Pharmacol 1985; 34: 1049–56.PubMedCrossRefGoogle Scholar
  12. 10.
    Collaborative DHPG Treatment Study Group. Treatment of serious cytomegalovirus infections with 9(1,3-dihydroxy-2-propoxymethyl)guanine in patients with AIDS and other immunodeficiencies. N Engl J Med 1986; 314: 801–805.CrossRefGoogle Scholar
  13. 11.
    Walmsley SL, Chew E, Fanning MM, et al. Treatment of cytomegalovirus retinitis with trisodium phosphonoformate hexahydrate (foscarnet). J Infect Dis 1988 157: 569–72.PubMedCrossRefGoogle Scholar
  14. 12.
    Jacobson MA, O’Donnell JJ, Brodie HR, Wofsy C, Mills J. Randomized prospective trial of ganciclovir maintenance therapy for cytomegalovirus retinitis. J Med Virol 1988; 25: 339–49.PubMedCrossRefGoogle Scholar
  15. 13.
    Spector SA, Weingeist T, Pollard RB, et al. A randomized, controlled study of intravenous ganciclovir therapy for cytomegalovirus peripheral retinitis in patients with AIDS. J Infect Dis 1993; 168: 557–63.PubMedCrossRefGoogle Scholar
  16. 14.
    Palestine AG, Polis MA, De Smet MD, et al. A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS. Ann Intern Med 1991; 115: 665–73.PubMedCrossRefGoogle Scholar
  17. 15.
    DeArmond B. Future directions in the management of cytomegalovirus infections. JAIDS. 1991; 4 (Suppl. 1): S53 - S56.Google Scholar
  18. 16.
    Jacobson MA, Stanley HD, Heard SE. Ganciclovir with recombinant methionyl human granulocyte colony-stimulating factor for treatment of cytomegalovirus disease in AIDS patients [letter]. AIDS 1992; 6: 515–6.PubMedCrossRefGoogle Scholar
  19. 17.
    Studies of Ocular Complications of AIDS Research Group. Mortality in patients with the acquired immunodeficiency syndrome treated with either foscarnet or ganciclovir for cytomegalovirus retinitis. N Engl J Med 1992; 326: 213–20.CrossRefGoogle Scholar
  20. 18.
    Cacoub P, Deray G, Baumelou A, et al. Acute renal failure induced by foscarnet: 4 cases. Clin Nephrology 1988; 29: 315–8.Google Scholar
  21. 19.
    Deray G, Martinez F, Katlama C, et al. Foscarnet nephrotoxicity: mechanism, incidence and prevention. Am J Nephrol 1989; 9: 316–21.PubMedCrossRefGoogle Scholar
  22. 20.
    Jacobson MA, Gambertoglio JG, Aweeka FT, Causey DM, Portale AA. Foscarnet-induced hypocalcemia and foscarnet effects on calcium and phosphorus metabolism. J Clin Endocrin Metabol 1991; 72: 1130–5.CrossRefGoogle Scholar
  23. 21.
    Youle MS, Clarbour J, Gazzard B, Chanas A. Severe hypocalcemia in AIDS patients treated with foscarnet and pentamidine [letter]. Lancet 1988; 1: 1455–6.PubMedCrossRefGoogle Scholar
  24. 22.
    Jacobson MA, Causey D, Polsky B, et al. A dose-ranging study of daily maintenance intravenous foscarnet therapy for cytomegalovirus retinitis in AIDS. J Infect Dis. 1993; 168: 444–8.PubMedCrossRefGoogle Scholar
  25. 23.
    Jacobson MA, Drew WL, Feinberg J, O’Donnell JJ, Whitmore PV, Miner RD, Parenti D. Foscarnet therapy for ganciclovir-resistant cytomegalovims retinitis. J Infect Dis 1991; 163: 1348–50.PubMedCrossRefGoogle Scholar
  26. 24.
    Drew WL, Miner RC, Busch DF, et al. Prevalence of resistance in patients receiving ganciclovir for serious cytomegalovirus infection. J Infect Dis 1991; 163: 716–9.PubMedCrossRefGoogle Scholar
  27. 25.
    Manischewitz JF, Quitman GV, Lane HC, Wittek AE. Synergistic effect of ganciclovir and foscarnet on cytomegalovirus replication in vitro. Antimicrob Agents Chemother 1990; 34: 373–75.PubMedCrossRefGoogle Scholar
  28. 26.
    Freitas VR, Fraser-Smith EB, Matthews TR. Increased efficacy of ganciclovir in combination with foscarnet against cytomegalovirus and herpes simplex virus tyl.; 2 in vitro and in vivo. Antiviral Research 1989; 12: 205–12.PubMedCrossRefGoogle Scholar
  29. 27.
    Jacobson MA, Kramer F, Bassiakos Y, et al. Randomized phase I trial of two combination foscarnet/ganciclovir chronic maintenance therapy regimens for AIDS patients with cytomegalovirus retinitis (AIDS Clinical Trials Group Protocol 151). J Infect Dis 1994; 170: 189–93.PubMedCrossRefGoogle Scholar
  30. 28.
    Dieterich DT, Poles MA, Lew EA. Concurrent use of ganciclovir and foscarnet to treat cytomegalovirus infection in AIDS patients. J Infect Dis 1993; 167: 1184–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Mark A. Jacobson

There are no affiliations available

Personalised recommendations