- Email: [email protected]
Valganciclovir therapy for immune recovery uveitis complicated by macular edema
Valganciclovir Therapy for Immune Recovery Uveitis Complicated by Macular Edema BRIAN R. KOSOBUCKI, MD, DANIEL E. GOLDBERG, MD, KENICHIRO BESSHO, MD, HYOUNG J. KOH, MD, NUTTAWUT RODANANT, MD, LAURIE LABREE, MD, LINGYUN CHENG, MD, RACHEL D. SCHRIER, PHD, STANLEY P. AZEN, PHD, AND WILLIAM R. FREEMAN, MD
● PURPOSE: To determine whether treatment with valganciclovir will improve visual acuity in eyes with immune recovery uveitis complicated by macular edema. ● DESIGN: Prospective open label controlled Phase II drug study. ● METHODS: Five patients with chronic macular edema as a result of immune recovery uveitis were studied. Baseline fluorescein angiograms, best-corrected ETDRS visions, and cytomegalovirus (CMV) lymphoproliferative T-cell function assays were obtained and repeated after three months of valganciclovir therapy (900 mg daily) and again three months after withdrawal of therapy. ● RESULTS: Vision improved by a mean of 11 letters in the treatment phase (P ⴝ .05). Graded angiograms showed three patients had treatment reduction of macular edema. One patient had rebound increase in macular edema after the withdrawal phase. The CMV lymphoproliferative response was not affected by the valganciclovir. ● CONCLUSION: Results suggest valganciclovir treatment may benefit visual acuity in patients with macular edema from immune recovery uveitis. (Am J Ophthalmol 2004;137:636 – 638. © 2004 by Elsevier Inc. All rights reserved.)
Biosketches and/or additional material at www.ajo.com Accepted for publication Nov 3, 2003. From the UCSD Jacobs Retina Center, Department of Ophthalmology, Shiley Eye Center, La Jolla, California (B.R.K., D.E.G., K.B., H.J.K., N.R., L.C., W.R.F.); Department of Preventive Medicine - Division of Biostatistics, Keck School of Medicine of the University of Southern California, Los Angeles, California (L.L., S.P.A.); and UCSD Department of Pathology - Division of Infectious Disease, UCSD Medical Center, San Diego, California (R.D.S.). This work was supported by NIH EYO 7366 granted by the National Institute of Health (W.R.F.) and by a grant from the California Universitywide AIDS Research Program (R.D.S.) Inquiries to William R. Freeman, MD, Shiley Eye Center, UCSD, 9415, Campus Point Drive, San Diego, CA 92093– 0946; fax: (858) 534 –7985; e-mail: [email protected]
636
©
2004 BY
I
N HIV PATIENTS, CYTOMEGALOVIRUS (CMV) RETINITIS IS
associated with minimal inflammation.1 After CMV retinitis heals and the immune system has reconstituted sufficiently from Highly Active Anti-Retroviral Therapy (HAART) to allow withdrawal of anti-CMV medications, certain eyes develop immune recovery uveitis (IRU). Eyes with IRU may develop iritis, vitritis, cataract, macular edema, and epiretinal membranes. Vision loss is usually from macular pathology.2 Speculation on the pathophysiology of IRU includes that the intraocular inflammation is a reaction to antigenically altered retinal or glial cells adjacent to the healed CMV lesion or secondary to chronic subclinical viral replication along the border of healed CMV.3 We investigated whether patients with IRU and vision loss from macular edema would regain vision from a decrease in macular edema after anti-CMV treatment with valganciclovir, the oral prodrug of ganciclovir with potency similar to intravenous ganciclovir.4
PATIENTS AND METHODS CONSENT WAS OBTAINED FROM FIVE HIV-INFECTED PA-
tients and their primary care physicians. Four patients were male. Average age was 42 ⫾ 8. Inclusion criteria included prior healed CMV retinitis not involving the fovea or optic nerve, current HAART therapy, immune recovery with CD4 counts above 50 cells/mm3 for at least three consecutive months, and IRU with vision loss from macular edema in the involved eye. Patients unable to tolerate valganciclovir secondary to pancytopenia or neutropenia were excluded. All patients had vision of 20/40 or better before developing IRU. Patients received valganciclovir 900 mg daily for three months (phase 1) then discontinued the valganciclovir for three months (phase 2). Monthly follow-up included best corrected Early Treatment Diabetic Retinopathy Study
ELSEVIER INC. ALL
RIGHTS RESERVED.
0002-9394/04/$30.00 doi:10.1016/j.ajo.2003.11.008
TABLE 1. Acuity/Serologic/Hematologic Data
Visual Acuity (ETDRS letters) CD4 count (/mm3) Absolute Neutrophil Count (/mm3) Platelet Count (⫻ 103/mm3) Hemoglobin (g/dl) CMV Lymphoproliferative Stimulation Index
Baseline Mean ⫾ SD (range)
End Phase 1 Mean ⫾ SD
Mean Change ⫾ SD
P value
28 ⫾ 4 (21–30) 429 ⫾ 272 (205–864) 2653 ⫾ 892 (1200–3604) 243 ⫾ 93 (118–368) 13.4 ⫾ 0.6 (12.4–14.0) 31.3 ⫾ 20.9
39 ⫾ 10 451 ⫾ 246 2930 ⫾ 1021 228 ⫾ 117 12.8 ⫾ 0.9 22.2 ⫾ 16.9
11 ⫾ 9 22 ⫾ 134 277 ⫾ 263 ⫺15 ⫾ 33 ⫺0.6 ⫾ 0.6 ⫺9.1 ⫾ 20.0
.05 .73 .08 .38 .73 .36
End Phase 2 Mean ⫾ SD
Mean Change ⫾ SD
P value
34 ⫾ 9
⫺5 ⫾ 10
.33
FIGURE 1. (A) Baseline angiogram showing cystoid macular edema plus nasal healed CMV retinitis and barrier laser scars. (B) End phase 1 after three months on valganciclovir showing treatment reduction of cystoid macular edema. (C) End phase 2 after three months off valganciclovir showing post-treatment rebound increase in cystoid macular edema.
(ETDRS) vision, slit lamp and dilated fundus examinations, and complete blood count with differential. CMV lymphoproliferative T-cell function assays5 and fluoresVOL. 137, NO. 4
cein angiograms were obtained at baseline and at the end of each phase. Angiograms were obtained using a Topcon 35 degree film system (three patients) and a
VALGANCICLOVIR THERAPY
637
Heidelberg confocal scanning laser ophthalmoscope (two patients). Changes from baseline in visual acuity and blood tests were compared at three and six months using paired t test. Angiograms were graded for improvement or exacerbation of macular edema at three and six months by a masked observer.
therapy for IRU related macular edema. The analysis of macular edema by fluorescein angiography also supports this benefit. The lack of significant decrease in CMV lymphoproliferative response suggests that if valganciclovir is suppressing residual CMV replication, it is not reducing the cellular immune response to CMV. Weaknesses of this study include small cohort size, though the Phase II design improved statistical power. The study was prospective and controlled, but visual acuity measurement was not masked. Also, objective grading of macular volume or thickness was not employed. To further investigate valganciclovir treatment in IRU, these issues plus CMV resistance should be considered within a larger double masked prospective study.
RESULTS BASELINE MEAN VISUAL ACUITY WAS 20/80⫹3 (28 ETDRS
letters). After three months treatment with valganciclovir, mean visual acuity improved 11 ETDRS letters to 20/50⫹4 (39 ETDRS letters) (P ⫽ .05). After three months off valganciclovir, mean visual acuity dropped 5 ETDRS letters to 20/63⫹4 (34 ETDRS letters) (P ⫽ .33). Mean CMV lymphoproliferative response stimulation index fell from 31.3 at baseline to 22.2 post treatment but was not statistically significant (P ⫽ .36). Hematologic and CD4 count data remained stable after three months of valganciclovir treatment (Table 1) summarizes all data. Angiograms for three of five patients showed treatment reduction of macular edema though one patient’s angiograms could not be reliably assessed secondary to vitritis. One patient with treatment edema reduction had rebound increase in macular edema after the withdrawal phase (Figure 1).
REFERENCES 1. Palestine AG, Rodrigues MM, Macher AM, et al. Ophthalmic involvement in acquired immunodeficiency syndrome. Ophthalmology 1984;91:1092–1099. 2. Karavellas MP, Azen SP, Macdonald JC, et al. Immune recovery vitritis in AIDS: Clinical predictors, sequellae, and treatment outcomes. Retina 2001;21:1–9. 3. Kuppermann BD, Holland GN. Immune recovery uveitis. Am J Ophthalmol 2000;103:103–106. 4. Brown F, Banken L, Saywell K, Arum I. Pharmacokinetics of valganciclovir and ganciclovir following multiple oral dosages of valganciclovir in HIV- and CMV-seropositive volunteers. Clin Pharmacokinet 1999;37:167–176. 5. Schrier RD, Wiley CA, Spina C, McCutchan JA, Grant I. Pathogenic and protective correlates of T cell proliferation in AIDS. HNRC Group. HIV Neurobehavioral Research Center. J Clin Invest 1996;98(3):731–740.
DISCUSSION THE MODEST GAIN IN VISUAL ACUITY AFTER VALGANCI-
clovir treatment suggests a beneficial effect of anti-CMV
638
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
APRIL 2004
Biosketch Dr. Freeman is currently Professor of Ophthalmology and director of the Jacobs Retina Center at the University of California San Diego in La Jolla, CA. Freeman has published some 350 Scientific articles in addition to over 200 published scientific abstracts. One of his areas of research is the therapy of infectious retinitis and complications of CMV retinitis. He also is active in the area of intraocular therapy for retinal diseases, Macular degeneration and new imaging modalities of the retina.
VOL. 137, NO. 4
VALGANCICLOVIR THERAPY
638.e1
● PURPOSE: To determine whether treatment with valganciclovir will improve visual acuity in eyes with immune recovery uveitis complicated by macular edema. ● DESIGN: Prospective open label controlled Phase II drug study. ● METHODS: Five patients with chronic macular edema as a result of immune recovery uveitis were studied. Baseline fluorescein angiograms, best-corrected ETDRS visions, and cytomegalovirus (CMV) lymphoproliferative T-cell function assays were obtained and repeated after three months of valganciclovir therapy (900 mg daily) and again three months after withdrawal of therapy. ● RESULTS: Vision improved by a mean of 11 letters in the treatment phase (P ⴝ .05). Graded angiograms showed three patients had treatment reduction of macular edema. One patient had rebound increase in macular edema after the withdrawal phase. The CMV lymphoproliferative response was not affected by the valganciclovir. ● CONCLUSION: Results suggest valganciclovir treatment may benefit visual acuity in patients with macular edema from immune recovery uveitis. (Am J Ophthalmol 2004;137:636 – 638. © 2004 by Elsevier Inc. All rights reserved.)
Biosketches and/or additional material at www.ajo.com Accepted for publication Nov 3, 2003. From the UCSD Jacobs Retina Center, Department of Ophthalmology, Shiley Eye Center, La Jolla, California (B.R.K., D.E.G., K.B., H.J.K., N.R., L.C., W.R.F.); Department of Preventive Medicine - Division of Biostatistics, Keck School of Medicine of the University of Southern California, Los Angeles, California (L.L., S.P.A.); and UCSD Department of Pathology - Division of Infectious Disease, UCSD Medical Center, San Diego, California (R.D.S.). This work was supported by NIH EYO 7366 granted by the National Institute of Health (W.R.F.) and by a grant from the California Universitywide AIDS Research Program (R.D.S.) Inquiries to William R. Freeman, MD, Shiley Eye Center, UCSD, 9415, Campus Point Drive, San Diego, CA 92093– 0946; fax: (858) 534 –7985; e-mail: [email protected]
636
©
2004 BY
I
N HIV PATIENTS, CYTOMEGALOVIRUS (CMV) RETINITIS IS
associated with minimal inflammation.1 After CMV retinitis heals and the immune system has reconstituted sufficiently from Highly Active Anti-Retroviral Therapy (HAART) to allow withdrawal of anti-CMV medications, certain eyes develop immune recovery uveitis (IRU). Eyes with IRU may develop iritis, vitritis, cataract, macular edema, and epiretinal membranes. Vision loss is usually from macular pathology.2 Speculation on the pathophysiology of IRU includes that the intraocular inflammation is a reaction to antigenically altered retinal or glial cells adjacent to the healed CMV lesion or secondary to chronic subclinical viral replication along the border of healed CMV.3 We investigated whether patients with IRU and vision loss from macular edema would regain vision from a decrease in macular edema after anti-CMV treatment with valganciclovir, the oral prodrug of ganciclovir with potency similar to intravenous ganciclovir.4
PATIENTS AND METHODS CONSENT WAS OBTAINED FROM FIVE HIV-INFECTED PA-
tients and their primary care physicians. Four patients were male. Average age was 42 ⫾ 8. Inclusion criteria included prior healed CMV retinitis not involving the fovea or optic nerve, current HAART therapy, immune recovery with CD4 counts above 50 cells/mm3 for at least three consecutive months, and IRU with vision loss from macular edema in the involved eye. Patients unable to tolerate valganciclovir secondary to pancytopenia or neutropenia were excluded. All patients had vision of 20/40 or better before developing IRU. Patients received valganciclovir 900 mg daily for three months (phase 1) then discontinued the valganciclovir for three months (phase 2). Monthly follow-up included best corrected Early Treatment Diabetic Retinopathy Study
ELSEVIER INC. ALL
RIGHTS RESERVED.
0002-9394/04/$30.00 doi:10.1016/j.ajo.2003.11.008
TABLE 1. Acuity/Serologic/Hematologic Data
Visual Acuity (ETDRS letters) CD4 count (/mm3) Absolute Neutrophil Count (/mm3) Platelet Count (⫻ 103/mm3) Hemoglobin (g/dl) CMV Lymphoproliferative Stimulation Index
Baseline Mean ⫾ SD (range)
End Phase 1 Mean ⫾ SD
Mean Change ⫾ SD
P value
28 ⫾ 4 (21–30) 429 ⫾ 272 (205–864) 2653 ⫾ 892 (1200–3604) 243 ⫾ 93 (118–368) 13.4 ⫾ 0.6 (12.4–14.0) 31.3 ⫾ 20.9
39 ⫾ 10 451 ⫾ 246 2930 ⫾ 1021 228 ⫾ 117 12.8 ⫾ 0.9 22.2 ⫾ 16.9
11 ⫾ 9 22 ⫾ 134 277 ⫾ 263 ⫺15 ⫾ 33 ⫺0.6 ⫾ 0.6 ⫺9.1 ⫾ 20.0
.05 .73 .08 .38 .73 .36
End Phase 2 Mean ⫾ SD
Mean Change ⫾ SD
P value
34 ⫾ 9
⫺5 ⫾ 10
.33
FIGURE 1. (A) Baseline angiogram showing cystoid macular edema plus nasal healed CMV retinitis and barrier laser scars. (B) End phase 1 after three months on valganciclovir showing treatment reduction of cystoid macular edema. (C) End phase 2 after three months off valganciclovir showing post-treatment rebound increase in cystoid macular edema.
(ETDRS) vision, slit lamp and dilated fundus examinations, and complete blood count with differential. CMV lymphoproliferative T-cell function assays5 and fluoresVOL. 137, NO. 4
cein angiograms were obtained at baseline and at the end of each phase. Angiograms were obtained using a Topcon 35 degree film system (three patients) and a
VALGANCICLOVIR THERAPY
637
Heidelberg confocal scanning laser ophthalmoscope (two patients). Changes from baseline in visual acuity and blood tests were compared at three and six months using paired t test. Angiograms were graded for improvement or exacerbation of macular edema at three and six months by a masked observer.
therapy for IRU related macular edema. The analysis of macular edema by fluorescein angiography also supports this benefit. The lack of significant decrease in CMV lymphoproliferative response suggests that if valganciclovir is suppressing residual CMV replication, it is not reducing the cellular immune response to CMV. Weaknesses of this study include small cohort size, though the Phase II design improved statistical power. The study was prospective and controlled, but visual acuity measurement was not masked. Also, objective grading of macular volume or thickness was not employed. To further investigate valganciclovir treatment in IRU, these issues plus CMV resistance should be considered within a larger double masked prospective study.
RESULTS BASELINE MEAN VISUAL ACUITY WAS 20/80⫹3 (28 ETDRS
letters). After three months treatment with valganciclovir, mean visual acuity improved 11 ETDRS letters to 20/50⫹4 (39 ETDRS letters) (P ⫽ .05). After three months off valganciclovir, mean visual acuity dropped 5 ETDRS letters to 20/63⫹4 (34 ETDRS letters) (P ⫽ .33). Mean CMV lymphoproliferative response stimulation index fell from 31.3 at baseline to 22.2 post treatment but was not statistically significant (P ⫽ .36). Hematologic and CD4 count data remained stable after three months of valganciclovir treatment (Table 1) summarizes all data. Angiograms for three of five patients showed treatment reduction of macular edema though one patient’s angiograms could not be reliably assessed secondary to vitritis. One patient with treatment edema reduction had rebound increase in macular edema after the withdrawal phase (Figure 1).
REFERENCES 1. Palestine AG, Rodrigues MM, Macher AM, et al. Ophthalmic involvement in acquired immunodeficiency syndrome. Ophthalmology 1984;91:1092–1099. 2. Karavellas MP, Azen SP, Macdonald JC, et al. Immune recovery vitritis in AIDS: Clinical predictors, sequellae, and treatment outcomes. Retina 2001;21:1–9. 3. Kuppermann BD, Holland GN. Immune recovery uveitis. Am J Ophthalmol 2000;103:103–106. 4. Brown F, Banken L, Saywell K, Arum I. Pharmacokinetics of valganciclovir and ganciclovir following multiple oral dosages of valganciclovir in HIV- and CMV-seropositive volunteers. Clin Pharmacokinet 1999;37:167–176. 5. Schrier RD, Wiley CA, Spina C, McCutchan JA, Grant I. Pathogenic and protective correlates of T cell proliferation in AIDS. HNRC Group. HIV Neurobehavioral Research Center. J Clin Invest 1996;98(3):731–740.
DISCUSSION THE MODEST GAIN IN VISUAL ACUITY AFTER VALGANCI-
clovir treatment suggests a beneficial effect of anti-CMV
638
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
APRIL 2004
Biosketch Dr. Freeman is currently Professor of Ophthalmology and director of the Jacobs Retina Center at the University of California San Diego in La Jolla, CA. Freeman has published some 350 Scientific articles in addition to over 200 published scientific abstracts. One of his areas of research is the therapy of infectious retinitis and complications of CMV retinitis. He also is active in the area of intraocular therapy for retinal diseases, Macular degeneration and new imaging modalities of the retina.
VOL. 137, NO. 4
VALGANCICLOVIR THERAPY
638.e1