Epidemiology and Risk of Developing CMV Retinitis
Cytomegalovirus (CMV) retinitis is the most common serious manifestation of CMV infection among HIV-infected persons.[,] In HIV-infected adults, CMV disease almost always represents reactivation with dissemination in persons with latent CMV infection. In the United States, the likelihood of having established CMV infection varies based on the mode of HIV acquisition, with positive anti-CMV IgG antibodies found in greater than 90% of homosexual men, 70% of injection-drug users, and 50% of heterosexuals who do not inject drugs. The risk of developing CMV retinitis depends on the degree of immunosuppression. Prior to the widespread use of effective antiretroviral therapy, approximately 30% of patients with AIDS would develop CMV retinitis. Multiple studies have shown that most patients with CMV retinitis have a CD4 count less than 50 cells/mm3.[,] Investigators have also identified HIV RNA levels greater than 100,000 copies/ml and disseminated Mycobacterium avium complex as risk factors for the development of CMV retinitis. In the modern era with widespread use of potent antiretroviral therapy, the incidence of CMV retinitis has declined dramatically, with most contemporary cases involving patients who are not taking antiretroviral therapy or have repeatedly failed antiretroviral therapy. The most reliable and effective way to prevent HIV-infected patients from developing CMV retinitis is to use antiretroviral therapy and maintain a CD4 count greater than 100 cells/mm3. This discussion will not address additional issues related to the prevention of and screening for CMV retinitis.
Clinical Manifestations of CMV Retinitis
Among HIV-infected persons, CMV can cause a broad array of clinical manifestations, including retinitis, esophageal ulcers, colitis, and encephalitis. The development of CMV retinitis is the most common clinical manifestation of end-organ CMV disease in HIV-infected persons. The initial symptoms of CMV retinitis typically include one or more of the four "F's": floaters, flashes, field deficits, or failing vision. The symptoms usually start in one eye. Patients do not have pain related to the lesions, nor do they present with redness of the eye. Investigators have utilized a standardized system to define three distinct anatomical zones of the retina: zone 1 (central retina), zone 2 (mid peripheral), and zone 3 (far peripheral) (Figure 1).[,]) Zone 1 consists of the critical central region surrounding the optic nerve head (within 1500 um) and fovea (within 3000 um), but encompasses less than 10% of the entire retina. Zone 2 extends from the edge of zone 1 to a circle defined by the ampullae of the vortex veins. Zone 3 extends from the edge of zone 2 to the ora serrata and includes the area of attachment of the vitreous base.[,] Zone 1 (central) lesions are considered as immediate sight-threatening, and typically these lesions have affected central vision or may rapidly do so. Patients with retinitis beginning outside of the central (zone 1) region often have absence of any major symptoms, except for a peripheral field defect. At the time of initial presentation with active CMV retinitis, approximately 30% of patients have visual acuity of 20/50 or worse, and 17% have 20/200 or worse. Patients with a low CD4 cell count should be educated about the symptoms of CMV retinitis and instructed to seek urgent eye evaluation if they experience those symptoms.
Diagnosis of CMV Retinitis
The diagnosis of CMV retinitis is a clinical diagnosis based on characteristic findings observed during a dilated funduscopic examination by an ophthalmologist. With a handheld monocular direct ophthalmoscope, the user can visualize all of zone 1 (including the optic nerve head and the macula), less than half of zone 2, and none of zone 3 (Figure 2). Patients with a CD4 count less than 50 cells/mm3 and new symptoms suggestive of CMV retinitis, should be referred for immediate funduscopic examination by an ophthalmologist, preferably one who has experience with the diagnosis of CMV retinitis.Typically, CMV retinal lesions appear as areas of yellow-white necrosis with edema located along the distribution of retinal vessels (Figure 3); in some patients, the findings may include exudates and vascular sheathing. The lesions often have a granular appearance with variable amounts of associated hemorrhage. As the retinitis expands, it takes on a brushfire pattern, with an active white or yellow leading edge and a darker, atrophic, scarred area present behind the active edge (Figure 4). In some instances, patients can have smoldering lesions outside of zone 1 that may be more difficult to diagnose (Figure 5). In addition, other lesions can be misdiagnosed as CMV retinitis, including HIV-associated retinopathy (Figure 6), toxoplasmosis, and varicella-zoster retinitis. In general, laboratory tests, such as CMV serology, antigen detection, PCR, or viral blood cultures, do not play a role in the acute evaluation in this setting. In routine cases, it is not necessary to obtain a retinal biopsy or attempt to identify CMV in the eye to make the diagnosis. In unusual cases where the diagnosis is not clear or a patient does not respond to initial therapy, identifying CMV DNA in vitreous or aqueous humor, or rarely in tissue obtained via endoretinal biopsy, may help to establish the diagnosis.
Studies of Therapy for CMV Retinitis
Multiple therapies have been studied and established as effective for initial therapy of acute CMV retinitis, including intravenous ganciclovir (Cytovene),[,] intravenous foscarnet (Foscavir), intravenous cidofovir (Vistide),[,] oral valganciclovir (Valcyte), sustained release ganciclovir intraocular implant (Vitrasert) alone or with oral ganciclovir (Cytovene),[,,] and intravitreal ganciclovir or foscarnet.[,] Although oral ganciclovir was used in some of the earlier studies (and shown to have some efficacy), oral valganciclovir has completely replaced oral ganciclovir in clinical practice. In addition, studies have shown that oral valganciclovir alone is at least as effective as intravenous ganciclovir (Figure 7). The ganciclovir implant (Figure 8), which provides via local sustained release of intraocular ganciclovir for 6 to 8 months, demonstrated excellent efficacy in several studies,[,,] but unfortunately it is no longer commercially available in the United States.
Recommendations for Induction Therapy for CMV Retinitis
Management of CMV retinitis consists of initial therapy (also known as induction therapy), typically 14 to 21 days, followed by maintenance therapy. The recommendations from the 2013 guidelines for the prevention and treatment of opportunistic infections recommends state "the choice of initial therapy for CMV retinitis should be individualized based on the location and severity of the lesion(s), the level of underlying immune suppression, and other factors such as concomitant medications and ability to adhere to treatment" (Figure 9). In general, systemic antiviral therapy is recommended to prevent disease in the contralateral eye, diminish the risk of developing CMV disease in other organs, and improve survival.[,] For patients with immediate site-threatening lesions (adjacent to the optic nerve or fovea), the opportunistic infections guidelines recommend using intravitreal ganciclovir or foscarnet given in combination with systemic antiviral therapy. Administering intravitreous therapy via injection of ganciclovir or foscarnet requires access to an ophthalmologist experienced with this procedure, and it is associated with significant risk of ocular morbidity if not performed correctly. Oral valganciclovir is the preferred systemic agent since it has comparable efficacy as intravenous therapy and obviates the need for placement of an indwelling intravenous catheter. For patients who have peripheral lesions, the guidelines recommend using oral valganciclovir alone as initial therapy. Patients not on antiretroviral therapy at the time of the diagnosis of CMV retinitis will usually show reduced risk of relapse and lower risk of visual impairment if they also receive (and respond to) antiretroviral therapy.[,] Use of antiretroviral therapy, however, may induce CMV-related immune reconstitution uveitis (iritis or vitritis), although the incidence of this appears to be low. The optimal timing for initiating antiretroviral therapy in the setting of a new opportunistic infection remains unclear, but most experts would not wait more than 2 weeks after starting therapy for CMV retinitis. Some experts have suggested that anti-CMV therapy is unnecessary in patients with small peripheral lesions who are starting antiretroviral therapy, but this strategy has several disadvantages and the guidelines do not recommend using antiretroviral therapy alone as an approach to treat even very mild CMV retinitis. Intravenous ganciclovir is infrequently used, but it provides a good option for patients who cannot take oral therapy. Primarily because of its toxicity, intravenous foscarnet is generally reserved for patients who cannot tolerate oral valganciclovir or for those who have resistant or refractory disease.
Monitoring Patients on Therapy
Patients undergoing treatment for CMV retinitis require close follow-up by an ophthalmologist experienced in managing CMV retinitis and by an HIV provider. Specifically, ophthalmologic follow-up is recommended after the patient completes induction therapy (a visible response to treatment takes approximately 2 weeks). Thereafter, ophthalmologic follow-up should take place at approximately monthly intervals while the patient is receiving therapy. Ideally, these visits should include drawings and photographs of the patient's retinal lesions for serial comparison. All systemic agents used to treat CMV retinitis have major toxicities and require laboratory monitoring. During initial induction therapy, patients receiving ganciclovir, valganciclovir, or foscarnet should have twice weekly monitoring of complete blood counts, serum electrolytes, and renal function. Patients should undergo evaluation for any signs or symptoms that might suggest immune reconstitution uveitis.
Chronic Maintenance Therapy (Secondary Prophylaxis) for CMV Retinitis
After the 14 to 21 days of initial therapy, patients should transition to maintenance therapy (Figure 10). The use of once daily oral valganciclovir has become the preferred maintenance therapy for CMV retinitis. Intravitreal injections are not typically continued during the chronic maintenance period. For those who remain immunosuppressed (CD4 count less than 100 to 150 cells/mm3) maintenance therapy is continued indefinitely. Patient may stop chronic maintenance therapy if the following criteria are met: they have received therapy for CMV retinitis for at least 3 to 6 months, there is no signs of active CMV retinitis, and their CD4 count has increased to greater than 100 cells/mm3 for longer than 3 to 6 months in response to antiretroviral therapy. This decision, however, should be made in consultation with an ophthalmologist and should take into consideration the severity of the retinal disease. Patients who stop CMV therapy should have routine ophthalmologic examinations every 3 months.
Management of Immune Reconstitution Uveitis
Patients on treatment for CMV retinitis and who initiate antiretroviral therapy are at risk for developing immune recovery uveitis, an immunologic reaction to CMV manifested as iritis, vitritis, macular edema, or the formation of epiretinal membranes.[,,] The risk of immune recovery uveitis is greatest in those patients who have a brisk and substantial increase in CD4 cell count after initiating antiretroviral therapy. This reaction is most likely to occur 4 to 12 weeks after starting antiretroviral therapy, but cases have been reported in which immune reconstitution uveitis developed more than a year after successful treatment of CMV retinitis. Immune recovery uveitis is usually managed using topical periocular corticosteroids, with or without a brief course of systemic corticosteroids. In addition, patients without known CMV retinitis have developed clinical manifestations of CMV retinitis within 8 weeks of initiating antiretroviral therapy, a phenomenon referred to as unmasking CMV immune reconstitution syndrome. In this situation, presumably the immune recovery leads to an inflammatory response that unmasks subclinical CMV retinitis.