Treatment of CMV Retinitis

Cytomegalovirus (CMV) retinitis is among the most common opportunistic infections in patients with AIDS [Trans Am Ophthalmol Soc, 93, 623, 1995]. The incidence of CMV retinitis is approximately 10% per year in patients with CD4 counts <100 cells/mm3 and 20% per year in patients with CD4 counts <50 cells/mm3 [J Infect Dis, 166, 1223, 1992; J Acquir Immune Def Syn, 5, 1069, 1995]. Over the past year there has been a substantial decrease in the incidence of CMV retinitis at several AIDS centers throughout the United States, presumably due to the availability of effective combination antiretroviral therapy. The likely reason for this decrease is the reduction in the number of patients with low CD4 cell counts as a consequence of the use of these more effective regimens. Whether the incidence will climb again and when this increase might happen remain to be determined. During 1996, the ganciclovir intraocular device (Vitrasert) and intravenous cidofovir (Vistide) were approved by the Food and Drug Administration, increasing the number of FDA-approved treatment options for CMV retinitis to five (intravenous ganciclovir, oral ganciclovir, the ganciclovir intraocular device, intravenous foscarnet, and intravenous cidofovir). With the addition of these agents, there has been an evolution in the treatment of CMV retinitis. One of the goals of the changing approach is elimination of the central venous catheter. Intravenous ganciclovir and foscarnet require daily intravenous infusions and the placement of a central venous catheter for a long-term intravenous access. Conversely, the newer agents (oral ganciclovir, ganciclovir intraocular device, and intravenous cidofovir) do not require placement of the central venous catheter. Central venous catheters are associated with complication rates of 1.3 to 1.5 complications per person/year [New Engl J Med, 326, 213, 1992]. One study showed that the probability of a catheter complication was directly related to the duration of catheter use and that approximately two-thirds of patients with a catheter present for one year suffered at least one complication [Trans Am Ophthalmol Soc, 93, 623, 1995]. Hence, the desire to develop regimens which avoid placement of a central venous catheter.

Oral Ganciclovir

Oral ganciclovir has been approved for maintenance therapy of patients with CMV retinitis and is used after induction with intravenous ganciclovir. The dose of oral ganciclovir generally used is 1 gram three times daily. Although earlier published studies [N Engl J Med, 333, 615, 1995; AIDS, 9, 471, 1995] suggested that oral ganciclovir might have similar efficacy to intravenous ganciclovir as maintenance therapy, a study presented at the 1996 International AIDS Meeting reported that oral ganciclovir, at the current dose, was less effective than intravenous ganciclovir [Abstracts of the XI International Conference on AIDS, 2, 225, 1996]. Higher oral doses appear to be more effective than the currently-approved dose. Because it is less effective than intravenous ganciclovir, and because given enough time, treatment with intravenous ganciclovir is associated with relapse in almost all cases [Trans Am Ophthalmol Soc, 93, 623, 1995; Ophthalmology, 101, 1250, 1994], many clinicians will use oral ganciclovir as maintenance therapy only for patients with peripheral disease. Patients with peripheral disease are not at an immediate risk of loss of vision and usually can tolerate a relapse without loss of visual acuity. Conversely, patients with posteriorly located disease are at greater risk of loss of visual acuity and are less likely to be able to tolerate a relapse. An orally bioavailable prodrug of ganciclovir is currently under development, but as of January 1997 it is not yet available.

Ganciclovir Intraocular Device

The ganciclovir intraocular device is a reservoir of ganciclovir which is surgically implanted into the eye and releases ganciclovir at a steady rate over a period of six to eight months. The ganciclovir intraocular device achieves drug levels in the eye that are approximately four times greater than those achieved with intravenous ganciclovir. Furthermore, the ganciclovir intraocular device does not have the same intraocular peaks and troughs of drug levels associated with the intermittent administration of systemically administered drugs. Controlled trials of the ganciclovir intraocular device have suggested that it is highly effective for controlling CMV retinitis [Arch Ophthalmol, 112, 1531, 1994]. The median time to progression in patients with newly-diagnosed disease is approximately seven months (compared to two months with systemically administered monotherapy), reflecting the time when the device runs out of drug. The device can be replaced, and scheduled replacements every six to seven months may prevent clinical relapse in most patients. Surgical implantation of the device is associated with the typical risks of surgery, including bacterial endophthalmitis and vitreous hemorrhage, but the rates are low (<1% of surgical procedures for bacterial endophthalmitis). Although there was an initial concern that implantation of the ganciclovir intraocular device may increase the rate of retinal detachments in patients with CMV retinitis, more recent uncontrolled case series have suggested that the rate of retinal detachments may not be substantially increased and may, in the long run, be decreased. However, there are no long-term comparative studies of the device versus systemically-administered drugs to determine the relative detachment rates. Because it is local therapy, the ganciclovir intraocular device does not control systemic disease. As such, patients treated only with the ganciclovir intraocular device are at risk of development of disease in the contralateral eye and for the development of visceral disease. One study estimated the six-month incidence of contralateral ocular disease at 50% and of visceral disease at 31% of patients treated only with the device [Arch Ophthalmol, 112, 1531, 1994]. One theoretically attractivecombination is the use of the ganciclovir intraocular device for control of the ocular disease and oral ganciclovir to prevent the development of contralateral ocular or visceral disease. A Roche-sponsored study of this regimen is underway as of January 1997, but data are not yet available from this study. Many clinicians, anticipating the results of this study, have shifted to the use of the device coupled with oral ganciclovir as a preferred form of therapy. Should the Roche study not show that this form of therapy is effective both for the eye and for systemic complications, then this approach will need to be rethought. At Johns Hopkins, most patients are now being offered a combination of the ganciclovir intraocular device plus oral ganciclovir as first-line therapy.

Cidofovir

Cidofovir is a nucleotide analog which has a prolonged duration of effect. It can be given as an intermittent intravenous infusion. It is generally given at a dose of 5 mg/kg once weekly for two weeks as induction therapy followed by maintenance therapy at 5 mg/kg every two weeks. Preliminary studies have suggested that both this dose and the 3 mg/kg maintenance dose are effective, but that the 3 mg/kg dose may be less effective than the 5 mg/kg maintenance dose. Cidofovir is associated with nephrotoxicity and requires the coadministration of saline hydration and probenecid. Because of the need for probenecid and saline hydration, administration requires the better part of the day. Careful attention must be paid to both the serum creatinine and to the urinalysis. Proteinuria is thought to herald the development of more serious nephrotoxicity, and the development of proteinuria which does not clear with hydration generally necessitates discontinuation of the drug. Patients receiving nephrotoxic drugs, such as amphotericin-B or aminoglycoside antibiotics, should not be treated with cidofovir. Cidofovir should not be used in patients with preexisting renal impairment. Several drug interactions with probenecid have been reported so that concurrent medications should be carefully reviewed in patients being considered for treatment with cidofovir. An intolerance to probenecid generally results in discontinuation of cidofovir therapy. However, because of its intermittent administration, cidofovir generally does not require the placement of a central venous catheter. No studies comparing cidofovir to intravenous ganciclovir or foscarnet have been performed; therefore, its efficacy relative to these agents both in terms of controlling CMV retinitis and of preventing visceral complications remains to be determined. Furthermore, because of the potential for irreversible nephrotoxicity, its use must be carefully monitored [J Infect Dis, 171, 788, 1995]. Cidofovir also has been used in patients who have suffered frequent relapses on other agents and who appear to be resistant to ganciclovir.

Other Available Treatments

Intravenous ganciclovir and foscarnet remain useful agents in the treatment of CMV retinitis. In patients with posteriorly-located and immediately vision-threatening lesions, intravenous ganciclovir may be initiated until the patient can receive implantation of a ganciclovir intraocular device. Our own practice has been to switch patients to oral ganciclovir maintenance once the device has been surgically implanted in the affected eye(s). If the patient has visceral disease, then long-term systemic therapy may be required. The CMV Retinitis Retreatment Trial demonstrated that the combination of intravenous ganciclovir and intravenous foscarnet was substantially more effective than monotherapy with either drug alone [Arch Ophthalmol, 114, 23, 1996]. Patients who appear to be ganciclovir resistant may be particularly likely to benefit from combination therapy. In some cases this approach may take the form of the ganciclovir intraocular device combined with intravenous foscarnet. Intravitreous injection of foscarnet and ganciclovir have also been used in selected cases [Ophthalmology, 98, 1348, 1991; Brit J Ophthalmol, 78, 120, 1994]. Intravitreous therapy generally requires the injection of either ganciclovir or foscarnet two to three times weekly for induction and once weekly for maintenance. In some situations, intravitreous injections may be combined with systemic therapy in patients who appear to have rapidly relapsing disease. Often patients who appear to be ganciclovir resistant and systemically intolerant of foscarnet will receive intravitreous foscarnet as an adjunct to therapy. Because of the need for only a single surgery every six to seven months with the ganciclovir intraocular device versus weekly injections, in the United States the ganciclovir intraocular device is usually preferred over ganciclovir injections. In those areas where the cost of the ganciclovir intraocular device poses a problem for availability, intravitreous injections are used more frequently. In addition, other agents are in various stages of development. The intra-vitreally-injected antisense compound fomivirsen is undergoing clinical trials and may have utility in patients who appear to be resistant to currently approved agents, in that its method of inhibiting viral replication is different from other agents.

In conclusion, there are now several treatment options available for patients with CMV retinitis. Although treatment must be individualized, treatments which avoid the placement of a central venous catheter appear to have certain advantages. The ganciclovir intraocular device appears to be highly effective for control of CMV retinitis but probably requires additional treatment with systemically administered agents in order to avoid the development of contralateral ocular or visceral complications.