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Treatment Options for Cytomegalovirus Retinitis: A Time for Reassessment

Treatment Options for Cytomegalovirus Retinitis: A Time for Reassessment Abstract THE NEW ENGLAND JOURNAL OF MEDICINE Oral Ganciclovir for Patients With Cytomegalovirus Retinitis Treated With a Ganciclovir Implant Daniel F. Martin, MD; Baruch D. Kuppermann, MD, PhD; Richard A. Wolitz, MD; Alan G. Palestine, MD; Hong Li, MS; Charles A. Robinson, MD; and the Roche Ganciclovir Study Group Background The intraocular ganciclovir implant is effective for local treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS), but it does not treat or prevent other systemic manifestations of cytomegalovirus infection. Methods Three hundred seventy-seven patients with AIDS and unilateral cytomegalovirus retinitis were randomly assigned to 1 of 3 treatments: a ganciclovir implant plus oral ganciclovir (4.5 g daily), a ganciclovir implant plus oral placebo, or intravenous ganciclovir alone. The primary outcome measure was the development of new cytomegalovirus disease, either contralateral retinitis or biopsy-proved extraocular disease. Results The incidence of new cytomegalovirus disease at 6 months was 44.3% in the group assigned to the ganciclovir implant plus placebo, as compared with 24.3% in the group assigned to the ganciclovir implant plus oral ganciclovir (P = .002) and 19.6% in the group assigned to intravenous ganciclovir alone (P<.001). As compared with placebo, oral ganciclovir reduced the overall risk of new cytomegalovirus disease by 37.6% over the 1-year period of the study (P = .02). However, in the subgroup of 103 patients who took protease inhibitors, the rates of new cytomegalovirus disease were low and of similar magnitude, regardless of treatment assignment. Progression of retinitis in the eye that initially received an implant was delayed by the addition of oral ganciclovir, as compared with placebo (P = .03). Treatment with oral or intravenous ganciclovir reduced the risk of Kaposi sarcoma by 75% (P = .008) and 93% (P<.001), respectively, as compared with placebo. Conclusions In patients with AIDS and cytomegalovirus retinitis, oral ganciclovir in conjunction with a ganciclovir implant reduces the incidence of new cytomegalovirus disease and delays progression of the retinitis. Treatment with oral or intravenous ganciclovir also reduces the risk of Kaposi sarcoma. 1999;340:1063-1070. Commentary THE STUDY BY Martin et al1 provides important information on several issues. It confirms the value of using oral ganciclovir in conjunction with ganciclovir implants for preventing cytomegalovirus (CMV) infection in the opposite eye and extraocular sites of patients with unilateral CMV retinitis. More surprising, the progression of preexisting lesions was also significantly delayed by the addition of oral ganciclovir. Another important observation, unrelated to CMV retinitis, was a decreased rate of Kaposi sarcoma in patients receiving systemic ganciclovir, presumably because of the drug's effect on human herpesvirus 8, the putative cause of Kaposi sarcoma. These results must, however, be viewed in the context of a new era in the treatment of CMV retinitis. Many patients may no longer need specific anti-CMV therapy because of improved immunity associated with potent antiretroviral therapy against human immunodeficiency virus.2,3 The current study showed that new CMV disease was markedly reduced in those patients receiving potent antiretroviral therapy, and there was no evidence that oral ganciclovir reduced the rate further. New strategies must therefore be developed for treating CMV retinitis. It may not be appropriate to place ganciclovir implants in people with CMV retinitis who are beginning potent antiretroviral therapy, because eventually there may be no need for specific anti-CMV therapy.4 Implantation may place them at unnecessary risk of surgical complications. What then is the role for ganciclovir implants and oral ganciclovir in the treatment of CMV disease? With the continued use of antiretroviral drugs, we are seeing the development of human immunodeficiency virus resistance, drug failure, and the return of immune dysfunction. Furthermore, there may be patients who do not tolerate these drugs or who do not have access to them. For these groups, the combined approach of a ganciclovir implant and oral ganciclovir is an effective, convenient, and relatively safe treatment option. This combination is not a perfect therapy, however. In the current study,1 some individuals did develop new CMV disease despite combined therapy, and the group receiving oral ganciclovir was shown to have a substantial rate of neutropenia. It should be noted that the dose of oral ganciclovir used in this study (4.5 g daily) was higher than the dose approved by the Food and Drug Administration and used in previous studies (3.0 g daily).5 Also, there are new issues that must be considered in patients whose survival has increased because of potent antiretroviral therapy, including the uncertain long-term effects of having a ganciclovir implant in the eye. Despite the encouraging results of the study by Martin et al,1 we must continue to develop additional new strategies for the treatment of CMV retinitis in the era of potent antiretroviral therapy. This commentary was supported in part by Research to Prevent Blindness, Inc, New York, NY, and the David May II Endowed Professorship. Dr Holland is the recipient of a Research to Prevent Blindness, Inc, Lew R. Wassermann Merit Award. Corresponding author: Gary N. Holland, MD, Jules Stein Eye Institute, 100 Stein Plaza, UCLA, Los Angeles, CA 90095-7003. Reprints: Daniel F. Martin, MD, Department of Ophthalmology, Emory University School of Medicine, 1365B Clifton Rd NE, Atlanta, GA 30322 (e-mail: dmart04@emory.edu). References 1. Martin DFKuppermann BDWolitz RA et al. Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. N Engl J Med. 1999;3401063- 1070Google ScholarCrossref 2. MacDonald JCTorriani FJMorse LS 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;1771182- 1187Google ScholarCrossref 3. Jabs DABolton SFDunn JPPalestine AG Discontinuing anti-CMV therapy in patients with immune reconstitution after combination antiretroviral therapy. Am J Ophthalmol. 1998;126817- 822Google ScholarCrossref 4. Martin DFDunn JPDavis JL et al. Use of the ganciclovir implant for the treatment of cytomegalovirus retinitis in the era of potent antiretroviral therapy: recommendations of an International AIDS Society–USA panel. Am J Ophthalmol. 1999;127329- 339Google ScholarCrossref 5. Drew WLIves DLalezari JP et al. Oral ganciclovir as maintenance treatment of cytomegalovirus retinitis inatients with AIDS. N Engl J Med. 1999;333615- 620Google ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Ophthalmology American Medical Association

Treatment Options for Cytomegalovirus Retinitis: A Time for Reassessment

Archives of Ophthalmology , Volume 117 (11) – Nov 1, 1999

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Publisher
American Medical Association
Copyright
Copyright © 1999 American Medical Association. All Rights Reserved.
ISSN
0003-9950
eISSN
1538-3687
DOI
10.1001/archopht.117.11.1549
Publisher site
See Article on Publisher Site

Abstract

Abstract THE NEW ENGLAND JOURNAL OF MEDICINE Oral Ganciclovir for Patients With Cytomegalovirus Retinitis Treated With a Ganciclovir Implant Daniel F. Martin, MD; Baruch D. Kuppermann, MD, PhD; Richard A. Wolitz, MD; Alan G. Palestine, MD; Hong Li, MS; Charles A. Robinson, MD; and the Roche Ganciclovir Study Group Background The intraocular ganciclovir implant is effective for local treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS), but it does not treat or prevent other systemic manifestations of cytomegalovirus infection. Methods Three hundred seventy-seven patients with AIDS and unilateral cytomegalovirus retinitis were randomly assigned to 1 of 3 treatments: a ganciclovir implant plus oral ganciclovir (4.5 g daily), a ganciclovir implant plus oral placebo, or intravenous ganciclovir alone. The primary outcome measure was the development of new cytomegalovirus disease, either contralateral retinitis or biopsy-proved extraocular disease. Results The incidence of new cytomegalovirus disease at 6 months was 44.3% in the group assigned to the ganciclovir implant plus placebo, as compared with 24.3% in the group assigned to the ganciclovir implant plus oral ganciclovir (P = .002) and 19.6% in the group assigned to intravenous ganciclovir alone (P<.001). As compared with placebo, oral ganciclovir reduced the overall risk of new cytomegalovirus disease by 37.6% over the 1-year period of the study (P = .02). However, in the subgroup of 103 patients who took protease inhibitors, the rates of new cytomegalovirus disease were low and of similar magnitude, regardless of treatment assignment. Progression of retinitis in the eye that initially received an implant was delayed by the addition of oral ganciclovir, as compared with placebo (P = .03). Treatment with oral or intravenous ganciclovir reduced the risk of Kaposi sarcoma by 75% (P = .008) and 93% (P<.001), respectively, as compared with placebo. Conclusions In patients with AIDS and cytomegalovirus retinitis, oral ganciclovir in conjunction with a ganciclovir implant reduces the incidence of new cytomegalovirus disease and delays progression of the retinitis. Treatment with oral or intravenous ganciclovir also reduces the risk of Kaposi sarcoma. 1999;340:1063-1070. Commentary THE STUDY BY Martin et al1 provides important information on several issues. It confirms the value of using oral ganciclovir in conjunction with ganciclovir implants for preventing cytomegalovirus (CMV) infection in the opposite eye and extraocular sites of patients with unilateral CMV retinitis. More surprising, the progression of preexisting lesions was also significantly delayed by the addition of oral ganciclovir. Another important observation, unrelated to CMV retinitis, was a decreased rate of Kaposi sarcoma in patients receiving systemic ganciclovir, presumably because of the drug's effect on human herpesvirus 8, the putative cause of Kaposi sarcoma. These results must, however, be viewed in the context of a new era in the treatment of CMV retinitis. Many patients may no longer need specific anti-CMV therapy because of improved immunity associated with potent antiretroviral therapy against human immunodeficiency virus.2,3 The current study showed that new CMV disease was markedly reduced in those patients receiving potent antiretroviral therapy, and there was no evidence that oral ganciclovir reduced the rate further. New strategies must therefore be developed for treating CMV retinitis. It may not be appropriate to place ganciclovir implants in people with CMV retinitis who are beginning potent antiretroviral therapy, because eventually there may be no need for specific anti-CMV therapy.4 Implantation may place them at unnecessary risk of surgical complications. What then is the role for ganciclovir implants and oral ganciclovir in the treatment of CMV disease? With the continued use of antiretroviral drugs, we are seeing the development of human immunodeficiency virus resistance, drug failure, and the return of immune dysfunction. Furthermore, there may be patients who do not tolerate these drugs or who do not have access to them. For these groups, the combined approach of a ganciclovir implant and oral ganciclovir is an effective, convenient, and relatively safe treatment option. This combination is not a perfect therapy, however. In the current study,1 some individuals did develop new CMV disease despite combined therapy, and the group receiving oral ganciclovir was shown to have a substantial rate of neutropenia. It should be noted that the dose of oral ganciclovir used in this study (4.5 g daily) was higher than the dose approved by the Food and Drug Administration and used in previous studies (3.0 g daily).5 Also, there are new issues that must be considered in patients whose survival has increased because of potent antiretroviral therapy, including the uncertain long-term effects of having a ganciclovir implant in the eye. Despite the encouraging results of the study by Martin et al,1 we must continue to develop additional new strategies for the treatment of CMV retinitis in the era of potent antiretroviral therapy. This commentary was supported in part by Research to Prevent Blindness, Inc, New York, NY, and the David May II Endowed Professorship. Dr Holland is the recipient of a Research to Prevent Blindness, Inc, Lew R. Wassermann Merit Award. Corresponding author: Gary N. Holland, MD, Jules Stein Eye Institute, 100 Stein Plaza, UCLA, Los Angeles, CA 90095-7003. Reprints: Daniel F. Martin, MD, Department of Ophthalmology, Emory University School of Medicine, 1365B Clifton Rd NE, Atlanta, GA 30322 (e-mail: dmart04@emory.edu). References 1. Martin DFKuppermann BDWolitz RA et al. Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. N Engl J Med. 1999;3401063- 1070Google ScholarCrossref 2. MacDonald JCTorriani FJMorse LS 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;1771182- 1187Google ScholarCrossref 3. Jabs DABolton SFDunn JPPalestine AG Discontinuing anti-CMV therapy in patients with immune reconstitution after combination antiretroviral therapy. Am J Ophthalmol. 1998;126817- 822Google ScholarCrossref 4. Martin DFDunn JPDavis JL et al. Use of the ganciclovir implant for the treatment of cytomegalovirus retinitis in the era of potent antiretroviral therapy: recommendations of an International AIDS Society–USA panel. Am J Ophthalmol. 1999;127329- 339Google ScholarCrossref 5. Drew WLIves DLalezari JP et al. Oral ganciclovir as maintenance treatment of cytomegalovirus retinitis inatients with AIDS. N Engl J Med. 1999;333615- 620Google ScholarCrossref

Journal

Archives of OphthalmologyAmerican Medical Association

Published: Nov 1, 1999

Keywords: cytomegalovirus retinitis,ganciclovir,kaposi sarcoma,infections,cytomegalovirus,acquired immunodeficiency syndrome,retinitis,biopsy,protease inhibitor,eye

References

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