Pathogenesis, clinical manifestations, and diagnosis of AIDS-related cytomegalovirus retinitis
- Mark A Jacobson, MD
Mark A Jacobson, MD
- Clinical Health Sciences Professor of Medicine
- University of California San Francisco
Cytomegalovirus (CMV) retinitis is the most common serious ocular complication of AIDS. The majority of disease is related to reactivation of latent infection. However, the introduction of potent combination antiretroviral therapy (ART) regimens in 1996 has led to changes in the incidence, natural history, management, and sequelae of CMV retinitis .
The clinical manifestations, pathogenesis, risk factors, and diagnosis of CMV retinitis are discussed here. The treatment of CMV retinitis and the use of antiretroviral therapy for the treatment of HIV are reviewed separately. (See "Treatment of AIDS-related cytomegalovirus retinitis" and "Selecting antiretroviral regimens for the treatment-naïve HIV-infected patient" and "Selecting an antiretroviral regimen for treatment-experienced HIV-infected patients who are failing therapy".)
CMV IN THE ERA OF POTENT COMBINATION ART
Cytomegalovirus (CMV) retinitis was first reported as a complication of AIDS in 1982. Prior to the availability of potent combination antiretroviral therapy (ART) in 1996, CMV retinitis occurred in 21 to 44 percent of patients with AIDS, primarily in those with a CD4 T lymphocyte count below 50 cells/microL [2-4]. In early case series, patients who survived beyond six months without CMV-specific treatment became severely visually impaired or blind. The median time to progression of disease into previously uninvolved areas of the retina while on CMV-specific antiviral therapy was 47 to 104 days, mean survival after diagnosis was 6 to 10 months, and indefinite maintenance therapy was essential .
However, the introduction of potent combination ART has had a dramatic impact on CMV disease in the HIV-infected patient. CMV disease essentially occurs only in patients with advanced immunosuppression, such as those who are either not receiving or have failed to respond to ART .
Incidence — In the era prior to the availability of potent ART regimens, the incidence of CMV retinitis was high. As an example, in one observational study, approximately 25 percent of AIDS patients with a CD4 count <200 cells/microL developed CMV retinitis during four years of follow-up . In addition, in the placebo arm of a clinical trial of oral ganciclovir prophylaxis, which enrolled AIDS patients with a CD4 count of <50 cells/microL or patients with a history of an AIDS-defining opportunistic infection and a CD4 count <100 cells/microL, the incidence of CMV retinitis was 24 percent after only 12 months of follow-up .
Subscribers log in hereLiterature review current through: Jun 2017. | This topic last updated: May 17, 2016.References
- Goldberg DE, Smithen LM, Angelilli A, Freeman WR. HIV-associated retinopathy in the HAART era. Retina 2005; 25:633.
- Hoover DR, Saah AJ, Bacellar H, et al. Clinical manifestations of AIDS in the era of pneumocystis prophylaxis. Multicenter AIDS Cohort Study. N Engl J Med 1993; 329:1922.
- Gallant JE, Moore RD, Richman DD, et al. Incidence and natural history of cytomegalovirus disease in patients with advanced human immunodeficiency virus disease treated with zidovudine. The Zidovudine Epidemiology Study Group. J Infect Dis 1992; 166:1223.
- Studies of Ocular Complications of AIDS Research Group, AIDS Clinical Trials 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.
- Jabs DA, Van Natta ML, Kempen JH, et al. Characteristics of patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Am J Ophthalmol 2002; 133:48.
- Hoover DR, Peng Y, Saah A, et al. Occurrence of cytomegalovirus retinitis after human immunodeficiency virus immunosuppression. Arch Ophthalmol 1996; 114:821.
- Spector SA, McKinley GF, Lalezari JP, et al. Oral ganciclovir for the prevention of cytomegalovirus disease in persons with AIDS. Roche Cooperative Oral Ganciclovir Study Group. N Engl J Med 1996; 334:1491.
- Holland GN. AIDS and ophthalmology: the first quarter century. Am J Ophthalmol 2008; 145:397.
- Yust I, Fox Z, Burke M, et al. Retinal and extraocular cytomegalovirus end-organ disease in HIV-infected patients in Europe: a EuroSIDA study, 1994-2001. Eur J Clin Microbiol Infect Dis 2004; 23:550.
- Sugar EA, Jabs DA, Ahuja A, et al. Incidence of cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Am J Ophthalmol 2012; 153:1016.
- Schwarcz L, Chen MJ, Vittinghoff E, et al. Declining incidence of AIDS-defining opportunistic illnesses: results from 16 years of population-based AIDS surveillance. AIDS 2013; 27:597.
- Heiden D, Ford N, Wilson D, et al. Cytomegalovirus retinitis: the neglected disease of the AIDS pandemic. PLoS Med 2007; 4:e334.
- Pathanapitoon K, Ausayakhun S, Kunavisarut P, et al. Blindness and low vision in a tertiary ophthalmologic center in Thailand: the importance of cytomegalovirus retinitis. Retina 2007; 27:635.
- Ford N, Shubber Z, Saranchuk P, et al. Burden of HIV-related cytomegalovirus retinitis in resource-limited settings: a systematic review. Clin Infect Dis 2013; 57:1351.
- Tun N, Smithuis FM, London N, et al. Mortality in patients with AIDS-related cytomegalovirus retinitis in Myanmar. Clin Infect Dis 2014; 59:1650.
- Jacobson MA, Zegans M, Pavan PR, et al. Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy. Lancet 1997; 349:1443.
- Komanduri KV, Feinberg J, Hutchins RK, et al. Loss of cytomegalovirus-specific CD4+ T cell responses in human immunodeficiency virus type 1-infected patients with high CD4+ T cell counts and recurrent retinitis. J Infect Dis 2001; 183:1285.
- Deayton JR, Wilson P, Sabin CA, et al. Changes in the natural history of cytomegalovirus retinitis following the introduction of highly active antiretroviral therapy. AIDS 2000; 14:1163.
- Roels P. Ocular manifestations of AIDS: new considerations for patients using highly active anti-retroviral therapy (HAART). Optometry 2004; 75:624.
- Kempen JH, Jabs DA, Wilson LA, et al. Risk of vision loss in patients with cytomegalovirus retinitis and the acquired immunodeficiency syndrome. Arch Ophthalmol 2003; 121:466.
- Holbrook JT, Jabs DA, Weinberg DV, et al. Visual loss in patients with cytomegalovirus retinitis and acquired immunodeficiency syndrome before widespread availability of highly active antiretroviral therapy. Arch Ophthalmol 2003; 121:99.
- Jabs DA, Van Natta ML, Thorne JE, et al. Course of cytomegalovirus retinitis in the era of highly active antiretroviral therapy: 1. Retinitis progression. Ophthalmology 2004; 111:2224.
- Kempen JH, Min YI, Freeman WR, et al. Risk of immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis. Ophthalmology 2006; 113:684.
- Kempen JH, Jabs DA, Wilson LA, et al. Incidence of cytomegalovirus (CMV) retinitis in second eyes of patients with the acquired immune deficiency syndrome and unilateral CMV retinitis. Am J Ophthalmol 2005; 139:1028.
- Jabs DA, Van Natta ML, Thorne JE, et al. Course of cytomegalovirus retinitis in the era of highly active antiretroviral therapy: 2. Second eye involvement and retinal detachment. Ophthalmology 2004; 111:2232.
- Jabs DA, Holbrook JT, Van Natta ML, et al. Risk factors for mortality in patients with AIDS in the era of highly active antiretroviral therapy. Ophthalmology 2005; 112:771.
- Whitcup SM. Cytomegalovirus retinitis in the era of highly active antiretroviral therapy. JAMA 2000; 283:653.
- Wohl DA, Kendall MA, Owens S, et al. The safety of discontinuation of maintenance therapy for cytomegalovirus (CMV) retinitis and incidence of immune recovery uveitis following potent antiretroviral therapy. HIV Clin Trials 2005; 6:136.
- Jacobson MA, Maecker HT, Orr PL, et al. Results of a cytomegalovirus (CMV)-specific CD8+/interferon- gamma+ cytokine flow cytometry assay correlate with clinical evidence of protective immunity in patients with AIDS with CMV retinitis. J Infect Dis 2004; 189:1362.
- Weinberg A, Tierney C, Kendall MA, et al. Cytomegalovirus-specific immunity and protection against viremia and disease in HIV-infected patients in the era of highly active antiretroviral therapy. J Infect Dis 2006; 193:488.
- Li TS, Tubiana R, Katlama C, et al. Long-lasting recovery in CD4 T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease. Lancet 1998; 351:1682.
- Keane NM, Price P, Lee S, et al. Restoration of CD4 T-cell responses to cytomegalovirus is short-lived in severely immunodeficient HIV-infected patients responding to highly active antiretroviral therapy. HIV Med 2004; 5:407.
- Sinclair E, Tan QX, Sharp M, et al. Protective immunity to cytomegalovirus (CMV) retinitis in AIDS is associated with CMV-specific T cells that express interferon- gamma and interleukin-2 and have a CD8+ cell early maturational phenotype. J Infect Dis 2006; 194:1537.
- Jacobson MA, Tan QX, Girling V, et al. Poor predictive value of cytomegalovirus (CMV)-specific T cell assays for the development of CMV retinitis in patients with AIDS. Clin Infect Dis 2008; 46:458.
- Rook AH, Manischewitz JF, Frederick WR, et al. Deficient, HLA-restricted, cytomegalovirus-specific cytotoxic T cells and natural killer cells in patients with the acquired immunodeficiency syndrome. J Infect Dis 1985; 152:627.
- Walter EA, Greenberg PD, Gilbert MJ, et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 1995; 333:1038.
- Schrier RD, Freeman WR, Wiley CA, McCutchan JA. Immune predispositions for cytomegalovirus retinitis in AIDS. The HNRC Group. J Clin Invest 1995; 95:1741.
- Bronke C, Palmer NM, Jansen CA, et al. Dynamics of cytomegalovirus (CMV)-specific T cells in HIV-1-infected individuals progressing to AIDS with CMV end-organ disease. J Infect Dis 2005; 191:873.
- Weinberg A, Bosch R, Bennett K, et al. Regulatory T cells and the risk of CMV end-organ disease in patients with AIDS. J Acquir Immune Defic Syndr 2014; 66:25.
- Sezgin E, Jabs DA, Hendrickson SL, et al. Effect of host genetics on the development of cytomegalovirus retinitis in patients with AIDS. J Infect Dis 2010; 202:606.
- Holland GN, Tufail A, Jordan MC. Cytomegalovirus diseases. In: Ocular Infection and Immunity, Pepose JS, Holland GN, Wilhelmus KR (Eds), CV Mosby, St. Louis 1996. p.1088.
- Spector SA, Hsia K, Crager M, et al. Cytomegalovirus (CMV) DNA load is an independent predictor of CMV disease and survival in advanced AIDS. J Virol 1999; 73:7027.
- Spector SA, Wong R, Hsia K, et al. Plasma cytomegalovirus (CMV) DNA load predicts CMV disease and survival in AIDS patients. J Clin Invest 1998; 101:497.
- Wohl DA, Kendall MA, Andersen J, et al. Low rate of CMV end-organ disease in HIV-infected patients despite low CD4+ cell counts and CMV viremia: results of ACTG protocol A5030. HIV Clin Trials 2009; 10:143.
- Hodge WG, Boivin JF, Shapiro SH, et al. Iatrogenic risk factors for cytomegalovirus retinitis. Can J Ophthalmol 2005; 40:701.
- Hodge WG, Boivin JF, Shapiro SH, et al. Clinical risk factors for cytomegalovirus retinitis in patients with AIDS. Ophthalmology 2004; 111:1326.
- Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. http://aidsinfo.nih.gov/contentfiles/lvguideline s/adult_oi.pdf (Accessed on March 04, 2016).
- Holland GN, Vaudaux JD, Jeng SM, et al. Characteristics of untreated AIDS-related cytomegalovirus retinitis. I. Findings before the era of highly active antiretroviral therapy (1988 to 1994). Am J Ophthalmol 2008; 145:5.
- Holland GN, Buhles WC Jr, Mastre B, Kaplan HJ. A controlled retrospective study of ganciclovir treatment for cytomegalovirus retinopathy. Use of a standardized system for the assessment of disease outcome. UCLA CMV Retinopathy. Study Group. Arch Ophthalmol 1989; 107:1759.
- Cytomegalovirus (CMV) culture results, drug resistance, and clinical outcome in patients with AIDS and CMV retinitis treated with foscarnet or ganciclovir. Studies of Ocular Complications of AIDS (SOCA) in collaboration with the AIDS Clinical Trial Group. J Infect Dis 1997; 176:50.
- Jabs DA, Gilpin AM, Min YI, et al. HIV and cytomegalovirus viral load and clinical outcomes in AIDS and cytomegalovirus retinitis patients: Monoclonal Antibody Cytomegalovirus Retinitis Trial. AIDS 2002; 16:877.
- Goldberg DE, Wang H, Azen SP, Freeman WR. Long term visual outcome of patients with cytomegalovirus retinitis treated with highly active antiretroviral therapy. Br J Ophthalmol 2003; 87:853.
- Holland GN. Immune recovery uveitis. Ocul Immunol Inflamm 1999; 7:215.
- Nguyen QD, Kempen JH, Bolton SG, et al. Immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis after highly active antiretroviral therapy. Am J Ophthalmol 2000; 129:634.
- Thorne JE, Jabs DA, Kempen JH, et al. Causes of visual acuity loss among patients with AIDS and cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Ophthalmology 2006; 113:1441.
- Schrier RD, Song MK, Smith IL, et al. Intraocular viral and immune pathogenesis of immune recovery uveitis in patients with healed cytomegalovirus retinitis. Retina 2006; 26:165.
- Robinson MR, Csaky KG, Lee SS, et al. Fibrovascular changes misdiagnosed as cytomegalovirus retinitis reactivation in a patient with immune recovery. Clin Infect Dis 2004; 38:139.
- Karavellas MP, Azen SP, MacDonald JC, et al. Immune recovery vitritis and uveitis in AIDS: clinical predictors, sequelae, and treatment outcomes. Retina 2001; 21:1.
- Raina J, Bainbridge JW, Shah SM. Decreased visual acuity in patients with cytomegalovirus retinitis and AIDS. Eye (Lond) 2000; 14 ( Pt 1):8.
- 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.
- Henderson HW, Mitchell SM. Treatment of immune recovery vitritis with local steroids. Br J Ophthalmol 1999; 83:540.
- Karavellas MP, Plummer DJ, Macdonald JC, et al. Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy. J Infect Dis 1999; 179:697.
- Wright ME, Suzman DL, Csaky KG, et al. Extensive retinal neovascularization as a late finding in human immunodeficiency virus-infected patients with immune recovery uveitis. Clin Infect Dis 2003; 36:1063.
- Arevalo JF, Mendoza AJ, Ferretti Y. Immune recovery uveitis in AIDS patients with cytomegalovirus retinitis treated with highly active antiretroviral therapy in Venezuela. Retina 2003; 23:495.
- Song MK, Azen SP, Buley A, et al. Effect of anti-cytomegalovirus therapy on the incidence of immune recovery uveitis in AIDS patients with healed cytomegalovirus retinitis. Am J Ophthalmol 2003; 136:696.
- CMV IN THE ERA OF POTENT COMBINATION ART
- Effect on clinical presentation
- Morbidity and mortality
- CMV specific immune responses
- RISK FACTORS
- CMV viremia
- Iatrogenic risk factors
- CLINICAL MANIFESTATIONS
- CMV IMMUNE RECOVERY UVEITIS
- SOCIETY GUIDELINE LINKS
- SUMMARY AND RECOMMENDATIONS