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New Issues in the Management of Patients With AIDS-Related Cytomegalovirus Retinitis

New Issues in the Management of Patients With AIDS-Related Cytomegalovirus Retinitis Abstract JAMA Discontinuation of Anticytomegalovirus Therapy in Patients With HIV Infection and Cytomegalovirus Retinitis Scott M. Whitcup, MD; Eric Fortin, MD; Anne S. Lindblad, PhD; Paul Griffiths, MD; Julia A. Metcalf, BA; Michael R. Robinson, MD; Jody Manischewitz, MS; Barbara Baird, RN; Cheryl Perry, RN; I. Michael Kidd, PhD; Tamara Vrabec, MD; Richard T. Davey, Jr, MD; Judith Falloon, MD; Robert E. Walker, MD; Joseph A. Kovacs, MD; H. Clifford Lane, MD; Robert B. Nussenblatt, MD; Janine Smith, MD; Henry Masur, MD; Michael A. Polis, MD Context Persons with cytomegalovirus (CMV) retinitis and acquired immunodeficiency syndrome (AIDS) have required lifelong anti-CMV therapy to prevent the progression of retinal disease and subsequent loss of vision. Objective To determine whether patients who were taking highly active antiretroviral therapy (HAART) and who had stable CMV retinitis could safely discontinue anti-CMV therapy without reactivation of their retinitis or increase in human immunodeficiency virus (HIV) viral load. Design Prospective nonrandomized interventional trial performed from July 1997 to August 1999. Setting Clinical Center of the National Institutes of Health, Bethesda, Md. Patients Fourteen patients with stable CMV retinitis and HIV infection and CD4+ cell counts higher than 0.15 × 109/L and being treated with systemic anti-CMV medications and HAART. Interventions Discontinuation of specific anti-CMV therapy. Main Outcome Measures Reactivation of CMV retinitis, development of extraocular CMV infection, detection of CMV in blood and urine, HIV burden, immunologic function, quality of life, morbidity, and mortality. Results Twelve (89.7%) of 14 patients had evidence of immune recovery uveitis before anti-CMV drugs were discontinued. No patient had reactivation of CMV retinitis or development of extraocular CMV disease during mean follow-up of 16.4 months (range, 8.3-22.0 months) without anti-CMV therapy. Human immunodeficiency viral load remained stable following cessation of anti-CMV medications. Blood and urine assays for CMV were briefly positive in 9 patients but did not predict reactivation of CMV disease. Worsening immune recovery uveitis was associated with a substantial (>3 lines) vision loss in 3 patients. Conclusions Maintenance anti-CMV medications were safely stopped in those patients who had stable CMV retinitis and elevated CD4+ cell counts and who were taking HAART. The study demonstrates that immune recovery following potent antiretroviral therapy is effective in controlling a major opportunistic infection, even in patients with a history of severe immunosuppression. 1999;282:1633-1637. Abstract JAMA Cytomegalovirus Retinitis in the Era of Highly Active Antiretroviral Therapy Scott M. Whitcup, MD A number of striking changes have occurred recently in the presentation and course of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) who are receiving highly active antiretroviral therapy (HAART). Before the use of HAART, CMV retinitis was the most common intraocular infection in patients with AIDS, occurring in up to 40% of patients, typically when CD4+ cell counts have decreased to less than 0.10 × 109/L. By studying CMV retinitis, clinicians can investigate whether the rejuvenated immune system that results from HAART can effectively control opportunistic infections in patients with AIDS. In some patients, retinitis has not progressed when specific anti-CMV therapy was discontinued, but a number of patients have developed substantial intraocular inflammation, which has resulted in decreased visual acuity. Anterior uveitis, cataract, vitreitis, cystoid macular edema, epiretinal membrane, and disc edema may occur in patients with CMV retinitis who have experienced HAART-associated elevation in CD4+ cell counts. Since immune recovery uveitis does not occur in eyes without CMV retinitis, the ocular inflammation appears to be related to the CMV infection. Anti-CMV maintenance therapy likely can be safely discontinued in some patients with CMV retinitis if CD4+ cell counts are stable or increasing and have been higher than 0.10 × 109/L for at least 3 months. Immune recovery in patients receiving HAART has been effective in controlling opportunistic infections, but it may also result in intraocular inflammation, which can have adverse effects on the eye.2000;283():653-657. Commentary THE MANAGEMENT OF cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) continues to be an important issue, despite a reduced number of cases since the introduction of potent antiretroviral therapies. These therapies have also led to changes in how CMV retinitis is treated. The case series presented by Whitcup et al1 and Whitcup's grand rounds discussion of 1 featured case2 illustrate many factors of concern to clinicians. In particular, 2 issues are highlighted: (1) the possibility of withdrawing patients who have undergone immune reconstitution with potent antiretroviral therapy from specific anti-CMV therapy, and (2) the emergence of "immune recovery uveitis" as an important AIDS-related problem. In the case series, specific anti-CMV therapy given to 14 patients was discontinued after each person had evidence of improved immune function attributable to potent antiretroviral therapy. This study adds to a growing list of similar reports showing that CMV retinitis will not reactivate for prolonged periods of time after the withdrawal of anti-CMV therapy in the setting of immune reconstitution.3-8 Whitcup et al1 discuss the benefits of discontinuing specific anti-CMV therapy; in particular, the toxic effects and inconvenience of daily therapy is eliminated. The investigators were not able to demonstrate any changes in patient status using the National Eye Institute's 25-item Visual Function Questionnaire.9 One would expect a positive effect on a patient's overall quality of life. Some patients in the case series had evidence of CMV viremia after discontinuation of anti-CMV medications. The importance of this finding remains unknown, but if prolonged or recurrent, CMV viremia might have implications not only for the overall health of the patient but also for immune recovery uveitis, which is believed to be a reaction against CMV antigens in the eye. This series included many patients with immune recovery uveitis, but it was not possible to determine whether discontinuation of treatment had an effect on inflammation in these individuals. We cannot necessarily expect that all patients will do as well after the withdrawal of anti-CMV therapy as those reported to date. All reported patients have had high CD4+ T-lymphocyte counts and other evidence of markedly improved immune function.1-8 As more patients stop receiving anti-CMV medications (and stop receiving it earlier) and as increased numbers of patients fail antiretroviral therapies, clinicians should be prepared to encounter reactivation of CMV retinitis. We still do not know a great deal about the risk of reactivation after the withdrawal of anti-CMV therapy, but another recent series8 in which patients were followed up for similar lengths of time (median follow-up, 72 weeks) has reported reactivation in 3 patients. In each, CD4+ T-lymphocyte counts had again fallen below 0.05 × 109/L. Thus, it seems that patients are at risk for reactivation if there is deterioration of immune function through the development of HIV resistance to antiretroviral therapy, discontinuation of antiretroviral therapy, or other factors. Because reactivation can occur, patients should be followed up closely. Unfortunately, we do not yet know which factors best predict waning immunity and increased risk of reactivation. As discussed by Whitcup et al,1 CD4+ T-lymphocyte counts serve as a general guideline. Unresolved in other reports is the value of following human immunodeficiency virus (HIV) blood levels.5,7,8 Potentially more useful will be specific tests of CMV immunity that are now in development. In considering management issues related to CMV retinitis, we also need to be aware of changes in the populations at risk for this infection. As mentioned previously, reactivation of preexisting CMV lesions can be expected as HIV resistance to antiretroviral agents develops and immune function again wanes in some patients. In addition, however, new cases of CMV retinitis can be expected. An increasing proportion of new HIV infections involves minorities, and teenagers are at particular risk. Many of these individuals remain poorly informed about the disease and may have limited access to health care information and treatments. There will undoubtedly be new cases of CMV retinitis in these groups, which will need to be controlled before immune reconstitution can be undertaken. Future patients may receive various anti-CMV therapies for long periods, and it will be necessary to adapt established, short-term treatments for CMV retinitis to its long-term management as a chronic disease. Previously, treatments were designed to control the spread of retinal infection during an estimated life expectancy of 1 to 2 years in an attempt to preserve sight until death for patients with AIDS. Now, with prolonged survival, clinicians must deal with new issues, including increased resistance of CMV to antiviral agents, cumulative toxic effects of antiviral drugs, the expense of prolonged treatment, and the emerging problem of inflammation. The questions raised by Whitcup2 demonstrate the current limitations of our knowledge regarding the best management strategies for CMV retinitis in the era of potent antiretroviral therapy. Regarding the withdrawal of anti-CMV therapy, we need better predictors of success with this strategy, which will allow selection of the best candidates, and we need better ways to monitor patients for recurrent immune deficits, which will allow reinitiation of anti-CMV therapy before reactivation occurs. Regarding immune recovery uveitis, we need to identify risk factors for its development, understand associated disease mechanisms, and develop treatments for its complications, such as macular edema. Current concepts regarding these issues are based on anecdotal reports and small case series. With reduced support for research, fewer subjects, and redistribution of care away from a small number of referral centers, creative new ways to study these problems must be found. Corresponding author and reprints: Scott M. Whitcup, MD, National Eye Institute, National Institutes of Health, 10/10S221, 10 Center Dr, MSC 1863, Bethesda, MD 20892-1863 (e-mail:scottw@helix.nih.gov). Corresponding author: Scott M. Whitcup, MD, National Eye Institute, National Institutes of Health, 10/10S221, 10 Center Dr, MSC 1863, Bethesda, MD 20892-1863 (e-mail: scottw@helix.nih.gov). Corresponding author: Gary N. Holland, MD, Jules Stein Eye Institute, 100 Stein Plaza, University of California, Los Angeles, Los Angeles, CA 90095-7003 (e-mail: uveitis@jsei.ucla.edu). References 1. Whitcup SMFortin ELindblad AS et al. Discontinuation of anticytomegalovirus therapy in patients with HIV infection and cytomegalovirus retinitis. JAMA. 1999;2821633- 1637Google ScholarCrossref 2. Whitcup SM Cytomegalovirus retinitis in the era of highly active antiretroviral therapy. JAMA. 2000;283653- 657Google ScholarCrossref 3. Whitcup SMFortin ENussenblatt RB et al. Therapeutic effect of combination antiretroviral therapy on cytomegalovirus retinitis [letter]. JAMA. 1997;2771519- 1520Google ScholarCrossref 4. Tural CRomeu JSirera G et al. Long-lasting remission of cytomegalovirus retinitis without maintenance therapy in human immunodeficiency virus–infected patients. J Infect Dis. 1998;1771080- 1083Google ScholarCrossref 5. 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 6. Vrabec TRBaldassano VFWhitcup SM Discontinuation of maintenance therapy in patients with quiescent cytomegalovirus retinitis and elevated CD4+ counts. Ophthalmology. 1998;1051259- 1264Google ScholarCrossref 7. Jabs DABolton SFDunn JPPalestine AG Discontinuing anti-cytomegalovirus therapy in patients with immune reconstitution after combination antiretroviral therapy. Am J Ophthalmol. 1998;126817- 822Google ScholarCrossref 8. Macdonald JCKaravellas MPTorriani FJ et al. Highly active antiretroviral therapy-related immune recovery in AIDS patients with cytomegalovirus retinitis. Ophthalmology. In press.Google Scholar 9. National Eye Institute, Visual Function Questionnaire-25. Santa Monica, Calif RAND Corp1996; http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Ophthalmology American Medical Association

New Issues in the Management of Patients With AIDS-Related Cytomegalovirus Retinitis

Archives of Ophthalmology , Volume 118 (5) – May 1, 2000

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Publisher
American Medical Association
Copyright
Copyright © 2000 American Medical Association. All Rights Reserved.
ISSN
0003-9950
eISSN
1538-3687
DOI
10.1001/archopht.118.5.704
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Abstract

Abstract JAMA Discontinuation of Anticytomegalovirus Therapy in Patients With HIV Infection and Cytomegalovirus Retinitis Scott M. Whitcup, MD; Eric Fortin, MD; Anne S. Lindblad, PhD; Paul Griffiths, MD; Julia A. Metcalf, BA; Michael R. Robinson, MD; Jody Manischewitz, MS; Barbara Baird, RN; Cheryl Perry, RN; I. Michael Kidd, PhD; Tamara Vrabec, MD; Richard T. Davey, Jr, MD; Judith Falloon, MD; Robert E. Walker, MD; Joseph A. Kovacs, MD; H. Clifford Lane, MD; Robert B. Nussenblatt, MD; Janine Smith, MD; Henry Masur, MD; Michael A. Polis, MD Context Persons with cytomegalovirus (CMV) retinitis and acquired immunodeficiency syndrome (AIDS) have required lifelong anti-CMV therapy to prevent the progression of retinal disease and subsequent loss of vision. Objective To determine whether patients who were taking highly active antiretroviral therapy (HAART) and who had stable CMV retinitis could safely discontinue anti-CMV therapy without reactivation of their retinitis or increase in human immunodeficiency virus (HIV) viral load. Design Prospective nonrandomized interventional trial performed from July 1997 to August 1999. Setting Clinical Center of the National Institutes of Health, Bethesda, Md. Patients Fourteen patients with stable CMV retinitis and HIV infection and CD4+ cell counts higher than 0.15 × 109/L and being treated with systemic anti-CMV medications and HAART. Interventions Discontinuation of specific anti-CMV therapy. Main Outcome Measures Reactivation of CMV retinitis, development of extraocular CMV infection, detection of CMV in blood and urine, HIV burden, immunologic function, quality of life, morbidity, and mortality. Results Twelve (89.7%) of 14 patients had evidence of immune recovery uveitis before anti-CMV drugs were discontinued. No patient had reactivation of CMV retinitis or development of extraocular CMV disease during mean follow-up of 16.4 months (range, 8.3-22.0 months) without anti-CMV therapy. Human immunodeficiency viral load remained stable following cessation of anti-CMV medications. Blood and urine assays for CMV were briefly positive in 9 patients but did not predict reactivation of CMV disease. Worsening immune recovery uveitis was associated with a substantial (>3 lines) vision loss in 3 patients. Conclusions Maintenance anti-CMV medications were safely stopped in those patients who had stable CMV retinitis and elevated CD4+ cell counts and who were taking HAART. The study demonstrates that immune recovery following potent antiretroviral therapy is effective in controlling a major opportunistic infection, even in patients with a history of severe immunosuppression. 1999;282:1633-1637. Abstract JAMA Cytomegalovirus Retinitis in the Era of Highly Active Antiretroviral Therapy Scott M. Whitcup, MD A number of striking changes have occurred recently in the presentation and course of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) who are receiving highly active antiretroviral therapy (HAART). Before the use of HAART, CMV retinitis was the most common intraocular infection in patients with AIDS, occurring in up to 40% of patients, typically when CD4+ cell counts have decreased to less than 0.10 × 109/L. By studying CMV retinitis, clinicians can investigate whether the rejuvenated immune system that results from HAART can effectively control opportunistic infections in patients with AIDS. In some patients, retinitis has not progressed when specific anti-CMV therapy was discontinued, but a number of patients have developed substantial intraocular inflammation, which has resulted in decreased visual acuity. Anterior uveitis, cataract, vitreitis, cystoid macular edema, epiretinal membrane, and disc edema may occur in patients with CMV retinitis who have experienced HAART-associated elevation in CD4+ cell counts. Since immune recovery uveitis does not occur in eyes without CMV retinitis, the ocular inflammation appears to be related to the CMV infection. Anti-CMV maintenance therapy likely can be safely discontinued in some patients with CMV retinitis if CD4+ cell counts are stable or increasing and have been higher than 0.10 × 109/L for at least 3 months. Immune recovery in patients receiving HAART has been effective in controlling opportunistic infections, but it may also result in intraocular inflammation, which can have adverse effects on the eye.2000;283():653-657. Commentary THE MANAGEMENT OF cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) continues to be an important issue, despite a reduced number of cases since the introduction of potent antiretroviral therapies. These therapies have also led to changes in how CMV retinitis is treated. The case series presented by Whitcup et al1 and Whitcup's grand rounds discussion of 1 featured case2 illustrate many factors of concern to clinicians. In particular, 2 issues are highlighted: (1) the possibility of withdrawing patients who have undergone immune reconstitution with potent antiretroviral therapy from specific anti-CMV therapy, and (2) the emergence of "immune recovery uveitis" as an important AIDS-related problem. In the case series, specific anti-CMV therapy given to 14 patients was discontinued after each person had evidence of improved immune function attributable to potent antiretroviral therapy. This study adds to a growing list of similar reports showing that CMV retinitis will not reactivate for prolonged periods of time after the withdrawal of anti-CMV therapy in the setting of immune reconstitution.3-8 Whitcup et al1 discuss the benefits of discontinuing specific anti-CMV therapy; in particular, the toxic effects and inconvenience of daily therapy is eliminated. The investigators were not able to demonstrate any changes in patient status using the National Eye Institute's 25-item Visual Function Questionnaire.9 One would expect a positive effect on a patient's overall quality of life. Some patients in the case series had evidence of CMV viremia after discontinuation of anti-CMV medications. The importance of this finding remains unknown, but if prolonged or recurrent, CMV viremia might have implications not only for the overall health of the patient but also for immune recovery uveitis, which is believed to be a reaction against CMV antigens in the eye. This series included many patients with immune recovery uveitis, but it was not possible to determine whether discontinuation of treatment had an effect on inflammation in these individuals. We cannot necessarily expect that all patients will do as well after the withdrawal of anti-CMV therapy as those reported to date. All reported patients have had high CD4+ T-lymphocyte counts and other evidence of markedly improved immune function.1-8 As more patients stop receiving anti-CMV medications (and stop receiving it earlier) and as increased numbers of patients fail antiretroviral therapies, clinicians should be prepared to encounter reactivation of CMV retinitis. We still do not know a great deal about the risk of reactivation after the withdrawal of anti-CMV therapy, but another recent series8 in which patients were followed up for similar lengths of time (median follow-up, 72 weeks) has reported reactivation in 3 patients. In each, CD4+ T-lymphocyte counts had again fallen below 0.05 × 109/L. Thus, it seems that patients are at risk for reactivation if there is deterioration of immune function through the development of HIV resistance to antiretroviral therapy, discontinuation of antiretroviral therapy, or other factors. Because reactivation can occur, patients should be followed up closely. Unfortunately, we do not yet know which factors best predict waning immunity and increased risk of reactivation. As discussed by Whitcup et al,1 CD4+ T-lymphocyte counts serve as a general guideline. Unresolved in other reports is the value of following human immunodeficiency virus (HIV) blood levels.5,7,8 Potentially more useful will be specific tests of CMV immunity that are now in development. In considering management issues related to CMV retinitis, we also need to be aware of changes in the populations at risk for this infection. As mentioned previously, reactivation of preexisting CMV lesions can be expected as HIV resistance to antiretroviral agents develops and immune function again wanes in some patients. In addition, however, new cases of CMV retinitis can be expected. An increasing proportion of new HIV infections involves minorities, and teenagers are at particular risk. Many of these individuals remain poorly informed about the disease and may have limited access to health care information and treatments. There will undoubtedly be new cases of CMV retinitis in these groups, which will need to be controlled before immune reconstitution can be undertaken. Future patients may receive various anti-CMV therapies for long periods, and it will be necessary to adapt established, short-term treatments for CMV retinitis to its long-term management as a chronic disease. Previously, treatments were designed to control the spread of retinal infection during an estimated life expectancy of 1 to 2 years in an attempt to preserve sight until death for patients with AIDS. Now, with prolonged survival, clinicians must deal with new issues, including increased resistance of CMV to antiviral agents, cumulative toxic effects of antiviral drugs, the expense of prolonged treatment, and the emerging problem of inflammation. The questions raised by Whitcup2 demonstrate the current limitations of our knowledge regarding the best management strategies for CMV retinitis in the era of potent antiretroviral therapy. Regarding the withdrawal of anti-CMV therapy, we need better predictors of success with this strategy, which will allow selection of the best candidates, and we need better ways to monitor patients for recurrent immune deficits, which will allow reinitiation of anti-CMV therapy before reactivation occurs. Regarding immune recovery uveitis, we need to identify risk factors for its development, understand associated disease mechanisms, and develop treatments for its complications, such as macular edema. Current concepts regarding these issues are based on anecdotal reports and small case series. With reduced support for research, fewer subjects, and redistribution of care away from a small number of referral centers, creative new ways to study these problems must be found. Corresponding author and reprints: Scott M. Whitcup, MD, National Eye Institute, National Institutes of Health, 10/10S221, 10 Center Dr, MSC 1863, Bethesda, MD 20892-1863 (e-mail:scottw@helix.nih.gov). Corresponding author: Scott M. Whitcup, MD, National Eye Institute, National Institutes of Health, 10/10S221, 10 Center Dr, MSC 1863, Bethesda, MD 20892-1863 (e-mail: scottw@helix.nih.gov). Corresponding author: Gary N. Holland, MD, Jules Stein Eye Institute, 100 Stein Plaza, University of California, Los Angeles, Los Angeles, CA 90095-7003 (e-mail: uveitis@jsei.ucla.edu). References 1. Whitcup SMFortin ELindblad AS et al. Discontinuation of anticytomegalovirus therapy in patients with HIV infection and cytomegalovirus retinitis. JAMA. 1999;2821633- 1637Google ScholarCrossref 2. Whitcup SM Cytomegalovirus retinitis in the era of highly active antiretroviral therapy. JAMA. 2000;283653- 657Google ScholarCrossref 3. Whitcup SMFortin ENussenblatt RB et al. Therapeutic effect of combination antiretroviral therapy on cytomegalovirus retinitis [letter]. JAMA. 1997;2771519- 1520Google ScholarCrossref 4. Tural CRomeu JSirera G et al. Long-lasting remission of cytomegalovirus retinitis without maintenance therapy in human immunodeficiency virus–infected patients. J Infect Dis. 1998;1771080- 1083Google ScholarCrossref 5. 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 6. Vrabec TRBaldassano VFWhitcup SM Discontinuation of maintenance therapy in patients with quiescent cytomegalovirus retinitis and elevated CD4+ counts. Ophthalmology. 1998;1051259- 1264Google ScholarCrossref 7. Jabs DABolton SFDunn JPPalestine AG Discontinuing anti-cytomegalovirus therapy in patients with immune reconstitution after combination antiretroviral therapy. Am J Ophthalmol. 1998;126817- 822Google ScholarCrossref 8. Macdonald JCKaravellas MPTorriani FJ et al. Highly active antiretroviral therapy-related immune recovery in AIDS patients with cytomegalovirus retinitis. Ophthalmology. In press.Google Scholar 9. National Eye Institute, Visual Function Questionnaire-25. Santa Monica, Calif RAND Corp1996;

Journal

Archives of OphthalmologyAmerican Medical Association

Published: May 1, 2000

Keywords: acquired immunodeficiency syndrome,antiretroviral therapy, highly active,cytomegalovirus retinitis,opportunistic infections,retinitis,uveitis,cytomegalovirus,cell count,anti-retroviral agents,cytomegalovirus infections

References

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