Cytomegalovirus retinitis and the acquired immunodeficiency syndrome--bench to bedside: LXVII Edward Jackson Memorial Lecture

Abstract

Purpose: To update information on cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) and to integrate information on its pathogenesis and clinical outcomes.

Design: Literature review.

Methods: Selected articles from the medical literature, particularly large epidemiologic studies, including the Johns Hopkins Cytomegalovirus Retinitis Cohort Study, the Longitudinal Study of the Ocular Complications of AIDS, and the Cytomegalovirus Retinitis and Viral Resistance Study, were reviewed. Clinical information is discussed in light of knowledge on CMV, its pathogenesis, and its interactions with human immunodeficiency virus (HIV).

Results: Cytomegalovirus uses several mechanisms to evade the immune system and establish latent infection in immunologically normal hosts. With immune deficiency, such as late-stage AIDS, CMV reactivates, is disseminated to the eye, and establishes a productive infection, resulting in retinal necrosis. HIV and CMV potentiate each other: CMV accelerates HIV disease, and CMV retinitis is associated with increased mortality. Randomized clinical trials have demonstrated the efficacy of treatments for CMV retinitis. Systemically administered treatment for CMV retinitis decreases AIDS mortality. Highly active antiretroviral therapy (HAART) effectively suppresses HIV replication, resulting in immune recovery, which, if sufficient, controls retinitis without anti-CMV therapy. Resistant CMV, detected in the blood, correlates with resistant virus in the eye and is associated with worse clinical outcomes, including mortality. Host factors, including host genetics and access to care, play a role in the development of CMV retinitis.

Conclusions: Clinical outcomes of CMV retinitis in patients with AIDS are dependent on characteristics of the virus and host and on HIV-CMV interactions.

Figure 1

Cytomegalovirus retinitis.

Figure 2

Annual number of new cases of cytomegalovirus (CMV) retinitis at the Johns Hopkins Medical Institutions (JHMI). Informal surveys suggest that these data represent ~90% of the new cases of CMV retinitis in the Baltimore metropolitan area.

Figure 3

Immune recovery uveitis among patients with cytomegalovirus retinitis. Adapted from Jabs DA, Ahuja A, VanNatta M, Lyon A, Srivastava S, Gangaputra S for the Studies of the Ocular Complications of AIDS Research Group. Course of cytomegalovirus retinitis in the era of highly active antiretroviral therapy: five-year outcomes. Ophthalmology (in press). Used with permission.

Figure 4

Retinitis progression among patients with cytomegalovirus retinitis. Adapted from Jabs DA, Ahuja A, VanNatta M, Lyon A, Srivastava S, Gangaputra S for the Studies of the Ocular Complications of AIDS Research Group. Course of cytomegalovirus retinitis in the era of highly active antiretroviral therapy: five-year outcomes. Ophthalmology (in press). Used with permission.

Figure 5

Incidence of resistant cytomegalovirus among patients with cytomegalovirus retinitis, comparing patients diagnosed pre-1996 (hatched line) to those diagnosed in 1996 or later (solid line). From Martin BK, Ricks MO, Forman MS, Jabs DA for the Cytomegalovirus Retinitis and Viral Resistance Research Group. Change over time in incidence of ganciclovir resistance in patients with cytomegalovirus retinitis. Clin Infect Dis 2007;44(7):1001-8. Used with permission.

Figure 6

Visual impairment (worse than 20/40 visual acuity) in eyes of patients with newly-diagnosed cytomegalovirus retinitis in the HAART era. Adapted from Jabs DA, Ahuja A, VanNatta M, Lyon A, Srivastava S, Gangaputra S for the Studies of the Ocular Complications of AIDS Research Group. Course of cytomegalovirus retinitis in the era of highly active antiretroviral therapy: five-year outcomes. Ophthalmology (in press). Used with permission.

Figure 7

Blindness (visual acuity 20/200 or worse) in eyes of patients with newly-diagnosed cytomegalovirus retinitis in the HAART era. Adapted from Jabs DA, Ahuja A, VanNatta M, Lyon A, Srivastava S, Gangaputra S for the Studies of the Ocular Complications of AIDS Research Group. Course of cytomegalovirus retinitis in the era of highly active antiretroviral therapy: five-year outcomes. Ophthalmology (in press). Used with permission.

Figure 8

Mortality among patients with AIDS in the era of highly active antiretroviral therapy. CMVR = cytomegalovirus retinitis. From Jabs DA, Holbrook JT, Van Natta ML, et al. for the Studies of the Ocular Complications of AIDS Research Group. Risk factors for mortality in patients with AIDS in the era of highly active antiretroviral therapy. Ophthalmology 2005;112(5):771-9. Used with permission.

Figure 9

Mortality among patients with newly-diagnosed cytomegalovirus retinitis in the HAART era. Adapted from Jabs DA, Ahuja A, VanNatta M, Lyon A, Srivastava S, Gangaputra S for the Studies of the Ocular Complications of AIDS Research Group. Course of cytomegalovirus retinitis in the era of highly active antiretroviral therapy: five-year outcomes. Ophthalmology (in press). Used with permission.

Figure 10

Immune recovery among patients with newly-diagnosed cytomegalovirus retinitis. Adapted from Jabs DA, Ahuja A, VanNatta M, Lyon A, Srivastava S, Gangaputra S for the Studies of the Ocular Complications of AIDS Research Group. Course of cytomegalovirus retinitis in the era of highly active antiretroviral therapy: Five-year outcomes. Ophthalmology (in press). Used with permission.

Figure 11

Effect of cytomegalovirus “viral load” on mortality among patients with newly-diagnosed cytomegalovirus retinitis. From Jabs DA, Martin BK, Forman MS, Ricks MO for the Cytomegalovirus Retinitis and Viral Resistance Research Group. Cytomegalovirus (CMV) blood DNA load, CMV retinitis progression, and occurrence of resistant CMV in patients with CMV retinitis. J Infect Dis 2005;192(4):640-9. Used with permission.

Figure 12

Effect of systemic anti-cytomegalovirus therapy on mortality among patients with cytomegalovirus retinitis. From Kempen JH, Jabs DA, Wilson LA, Dunn JP, West SK, Tonascia J. Mortality risk for patients with cytomegalovirus retinitis and acquired immune deficiency syndrome. Clin Infect Dis 2003;37(10):1365-73. Used with permission.

Figure 13

Effect of resistant cytomegalovirus on mortality among patients with cytomegalovirus retinitis. From Jabs DA, Martin BK, Forman MS for the Cytomegalovirus Retinitis and Viral Resistance Research Group. Mortality associated with resistant cytomegalovirus among patients with cytomegalovirus retinitis and AIDS. Ophthalmology 2010;117(1):128-132. Used with permission.