Treatment of Cytomegalovirus Retinitis in Patients with AIDS

Cytomegalovirus (CMV) is among the most common opportunistic infections in patients with the acquired immunodeficiency syndrome (AIDS) [1-3]. In the era of prophylaxis for Pneumocystis carinii pneumonia, disease caused by CMV has been reported to affect as many as 45% of patients with AIDS at some time during the course of disease [2]. Although CMV may affect the eyes, gastrointestinal tract, lungs, and central nervous system, CMV retinitis accounts for 85% of all CMV disease in patients with AIDS [3]. Untreated CMV retinitis spreads through the retina and causes total retinal destruction and blindness [4, 5]. Hence, CMV retinitis is a major cause of morbidity in patients with AIDS.

As of 1 May 1996, the treatments approved by the Food and Drug Administration (FDA) for CMV retinitis were intravenous ganciclovir, intravenous foscarnet, oral ganciclovir (for maintenance therapy), and the sustained-release ganciclovir intraocular device. Intravenous cidofovir was recommended for approval by the FDA Antiviral Advisory Committee in March 1996 but has not yet received full approval. Systemically administered drugs for treatment of CMV retinitis are given in two steps: An initial high dose is given to control the infection (induction), and then a lower dose is given to prevent relapse (maintenance). Although it suppresses viral replication, treatment does not eliminate CMV from the retina [6]; thus, discontinuation of therapy results in prompt relapse of retinitis. Both intravenous ganciclovir [4, 5, 7] and intravenous foscarnet [8] are effective for induction and maintenance therapy for CMV retinitis. The Studies of Ocular Complications of AIDS Foscarnet Ganciclovir Cytomegalovirus Retinitis Trial showed that the two drugs were equally effective in controlling CMV retinitis [9] but that foscarnet was associated with longer survival [10], presumably because of the modest antiretroviral effect. As noted by Masur and colleagues in this issue [11], the advent of combination therapy for human immunodeficiency virus (HIV) with more potent drugs and introduction of protease inhibitors is likely to reduce the importance of the anti-HIV effect of foscarnet. Oral ganciclovir has limited bioavailability but is approved for use as maintenance therapy after intravenous induction. Two published studies [12, 13] report that the short-term efficacy of oral ganciclovir is similar to that of intravenous ganciclovir when the two are used as maintenance therapy. However, a difference between fundus photograph reading center and clinician evaluations of the relative efficacy of the two formulations, as well as subsequent clinical experience, suggest that oral ganciclovir may be less effective in the long run. Many clinicians avoid using oral ganciclovir in patients with lesions that are an immediate threat to vision (that is, those adjacent to the optic nerve or fovea).

Despite long-term maintenance therapy, most patients with CMV retinitis have relapse [5, 9]. Although it can be controlled by reinduction, the interval between relapses decreases with successive relapses [9]. The CMV Retinitis Retreatment Trial [14] evaluated various treatment regimens for patients who had had relapse of retinitis and reported that the combination of ganciclovir and foscarnet was substantially more effective at controlling retinitis than was monotherapy with either drug. Combination therapy was not more toxic than monotherapy but was less convenient because of the required two infusions.

A major problem with systemically administered drugs for CMV retinitis is limited intraocular penetration [15]. The efficacy of combination therapy for relapse of retinitis presumably results in part from the synergistic effect of the two drugs on CMV [14]. Local administration into the eye offers the therapeutic advantage of producing high intraocular levels of the drugs. Unfortunately, the short intraocular half-life of intravitreous injections of ganciclovir or foscarnet requires twice-weekly injections for induction and once-weekly injections for maintenance. As noted by Masur and colleagues [11], the time to relapse with this form of therapy is similar to that seen with intravenous therapy. The sustained-release ganciclovir intraocular device effectively controls retinitis and appears to suppress viral replication until the drug is depleted [16]. However, cytomegalovirus causes systemic infection, even in patients in whom retinitis is the only clinically evident disorder [17], and intraocular therapy does not prevent contralateral ocular disease and visceral disease. Of patients treated only with the ganciclovir intraocular device, contralateral disease occurred in 50% after 6 months, and visceral CMV disease occurred in 31% [16]. Hence, a combination of local therapy plus a conveniently administered systemic therapy (possibly oral ganciclovir) may be an attractive approach.

Cidofovir is a nucleotide analogue that has a long intracellular half-life and a long-lasting effect; it can thus be given systemically as an intermittent intravenous infusion. The data cited by Masur and colleagues [11] support the efficacy of systemically administered cidofovir. Intravitreous administration of cidofovir has also been shown to have a prolonged duration of effect, with a median time to relapse of approximately 8 weeks [18, 19]. Administration of high doses (100 µg) of intravitreous cidofovir has been associated with hypotony (low intraocular pressure) and visual loss [18], but administration of a 20-µg dose appears to be relatively safe.

Also in this issue, Rahhal and coworkers [20] report their experience in a series of 22 patients with AIDS and CMV retinitis. The patients received repetitive injections of 20 µg of cidofovir at 5- to 6-week intervals. The authors report that this therapy successfully controlled retinitis and prevented relapse.

Several caveats remain, however. The study was a consecutive series from one center, and no other published articles have replicated these results (an industry-sponsored study of intravitreous cidofovir is now under way). No controlled studies of this method of treatment and no studies comparing it with other forms of therapy have been done. The average follow-up period in the study [19] was less than 5 months; hence, the long-term (for example, 1-year) outcomes are unavailable. Intravitreous administration of cidofovir has toxic side effects, including hypotony and uveitis. However, the data suggest, despite these shortcomings, that CMV retinitis can be controlled by repetitive intravitreous injections of cidofovir. As with the other forms, this type of local therapy does not treat systemic infection, and rates of contralateral ocular disease and visceral disease in patients treated with intravitreous cidofovir are likely to be similar to those reported in well-designed studies of local therapy [16]. However, intermittent intravitreous injections of cidofovir combined with a conveniently administered systemic agent (to prevent systemic disease) may be an attractive therapeutic option in the future.

In conclusion, CMV retinitis is a major cause of illness in patients with AIDS. Newer therapies, particularly those directed at achieving high local concentrations of drugs in the eye, appear promising for control of retinitis. A combination of local and systemic therapies is probably needed, given the systemic implications of CMV disease. Successful primary prophylaxis remains a long-term goal.

• Copyright ©2004 by the American College of Physicians