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Case 7: Discussion - Cytomegalovirus Retinitis

Epidemiology and Risk of Developing CMV Retinitis

Cytomegalovirus (CMV) retinitis is the most common serious manifestation of CMV infection among HIV-infected persons[1,2]In HIV-infected adults, CMV disease almost always represents reactivation with dissemination in persons with latent CMV infection[3]. 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[3]. Multiple studies have shown that most patients with CMV retinitis have a CD4 count less than 50 cells/mm3[3,4]. 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[3]. In the modern era of potent antiretroviral therapy, the incidence of CMV retinitis has declined dramatically[5],with most contemporary cases involving patients who are not taking antiretroviral therapy or have repeatedly failed antiretroviral therapy. Issues related to prevention of and screening for CMV retinitis will be addressed in a separate case.

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[3]. 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)[1,6]. 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[1,6]. 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[7]. 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[3]. 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[1]. 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[1].

Studies of Therapy for CMV Retinitis

Multiple therapies have been studied and established as effective for initial therapy of acute CMV retinitis, including (a) intravenous ganciclovir (Cytovene)[8,9], (b) intravenous foscarnet (Foscavir)[10], (c) intravenous cidofovir (Vistide)[11,12], (d) sustained release ganciclovir intraocular implant (Vitrasert) alone or with oral ganciclovir (Cytovene)[8,13,14], and (e) oral valganciclovir (Valcyte)[9]. 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. The ganciclovir implant (Figure 7) used in these studies provides local sustained release of ganciclovir for 6 to 8 months. Key studies involving treatment for HIV-associated CMV retinitis have established the following: (1) the ganciclovir intraocular implant is more effective than intravenous ganciclovir for treating the affected eye (Figure 8)[8]; (2) ganciclovir implant alone is ineffective in preventing contralateral retinitis and extraocular disease (Figure 9)[8,9]; (3) the ganciclovir implant plus oral ganciclovir is more effective than the implant alone in preventing new CMV disease[14]; and (4) oral valganciclovir alone is at least as effective as intravenous ganciclovir (Figure 10)[9].

Recommendations for Initial (Induction) Therapy

Management of CMV retinitis consists of initial therapy (also known as induction therapy), typically 14 to 21 days,followed by maintenance therapy[1]. The recommendations from the CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America 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 11)[3]. These recommendations note that certain HIV specialists recommend oral valganciclovir plus the intraocular ganciclovir implant for initial therapy (especially for patients with immediate site-threatening retinitis), but that other experts recommend the use of oral valganciclovir alone for initial therapy[3]. Insertion (and removal) of the ganciclovir pellet requires access to an ophthalmologist experienced with this procedure, and it is associated with significant risk of ocular morbidity, including retinal detachment[15], cataract formation, vitreous hemorrhage, and endophthalmitis. In addition, although the intraocular implanted ganciclovir pellet provides high concentration of ganciclovir locally, concurrent systemic therapy is strongly recommended to prevent disease in the contralateral eye, as well as to prevent CMV disease in other organs[16]. For patients who do not have site-threatening lesions most experts prefer oral valganciclovir alone as initial therapy, mainly because of its ease of administration and lack of requirement for ophthalmologic surgery or placement of an indwelling intravenous catheter[3]. 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[7,17]. Although the optimal timing for initiating antiretroviral therapy in the setting of a new opportunistic infection remains unclear[3], immediately starting antiretroviral therapy may increase the risk of immune reconstitution uveitis (iritis or vitritis). Some experts believe that anti-CMV therapy is unnecessary in patients with small peripheral lesions who are starting antiretroviral therapy, but most recommend therapy for these lesions until the CD4 increases to greater than 100 cells/mm3 for at least 3 to 6 months[3]. Intravenous ganciclovir is infrequently used except in 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)[3]. Thereafter, ophthalmologic follow-up should take place at approximately monthly intervals while the patient is receiving therapy[3]. 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.

Chronic Maintenance Therapy

After the 14 to 21 days of initial therapy, patients should transition to maintenance therapy (Figure 12). The use of once daily oral valganciclovir has become the preferred maintenance therapy for CMV retinitis[3]. When employed for chronic suppression, the ganciclovir intraocular implant requires replacement every 6 to 8 months. Repeated removal and replacement of the ganciclovir implant increases the risk of ocular morbidity. For those who remain immunosuppressed (CD4 count less than 100 to 150 cells/mm3), maintenance therapy is continued indefinitely. In most circumstances, patients receiving effective antiretroviral therapy may discontinue chronic maintenance CMV therapy if they have inactive retinitis and they maintain a CD4 count greater than 100 to 150 cells/mm3 for at least 6 months; this decision, however, should be made in consultation with an ophthalmologist and should take into consideration the severity of the retinal disease[3].

Immune Reconstitution Disease

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[18,19,20]. 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[3]. This reaction is most likely to occur 4 to 12 weeks after starting antiretroviral therapy[3]. Immune recovery uveitis is usually managed using topical periocular corticosteroids, with or without a brief course of systemic corticosteroids[3]. In addition, patients without known CMV retinitis have developed clinical manifestations of CMV retinitis within 8 weeks of initiating antiretroviral therapy. In this situation, presumably the immune recovery leads to an inflammatory response that unmasks subclinical CMV retinitis.

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    Figure 1 - Retinal Anatomic Zones Figure 1
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    Figure 2 - Normal Retina Figure 2
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    Figure 3 - Cytomegalovirus Retinitis, Central Portion of Retina Figure 3
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    Figure 4 - Cytomegalovirus Retinitis, Brushfire Pattern Figure 4
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    Figure 5 - Cytomegalovirus Retinitis, Smoldering Lesion Figure 5
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    Figure 6 - HIV Retinopathy Figure 6
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    Figure 7 - Ganciclovir Implant Before and After Intraocular Insertion Figure 7
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    Figure 8 - Ganciclovir Intraocular Implant versus Intravenous Ganciclovir for Patients with Newly Diagnosed Cytomegalovirus Retinitis Figure 8
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    Figure 9 - Development of New Cytomegalovirus Disease (at any site) in Patients with Cytomegalovirus Retinitis who Received Ganciclovir Implant plus Placebo, Ganciclovir Implant plus Oral Ganciclovir, or Intravenous Ganciclovir Figure 9
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    Figure 10 - Oral Valganciclovir versus Intravenous Ganciclovir for Patients with Newly Diagnosed Cytomegalovirus Retinitis Figure 10
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    Figure 11 - Induction Therapy for Cytomegalovirus RetinitisFigure 11
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    Figure 12 - Maintenance Therapy for Cytomegalovirus RetinitisFigure 12