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Practical Management of CMV Retinitis

Infection with cytomegalovirus (CMV) patients with AIDS and can result in several clinical illnesses, including chorioretinitis, esophagitis, colitis, and several neurologic disorders. During the last two years, there has been a dramatic decline in new cases of CMV retinitis as benefit of highly active antiretroviral therapy (HAART). This benefit may require several months of HAART before it is observed and disappears after discontinuation.

Chorioretinitis

Retinitis is the most common disease due to CMV in patients with AIDS. Retinitis is occasionally the presenting manifestation of AIDS, but it more commonly occurs months to years after the diagnosis of AIDS has been established. Retinitis usually begins unilaterally, but untreated, progression to bilateral involvement is common because of the associated viremia. Systemic CMV infection may also be present with involvement.

Differentiating suspected CMV retinitis lesions from cotton wool spots is essential. Cotton wool spots appear as small, fluffy, white lesions with indistinct margins and are not associated with exudates or hemorrhages. They are common in AIDS patients, usually asymptomatic, do not progress.

Therapeutic Agents

Ganciclovir

Structure and Mechanism of Action. Ganciclovir is a nucleoside analogue that differs from acyclovir by a single carboxyl side chain. This structural change confers on the drug approximately 50 times more activity against CMV than acyclovir. Acyclovir has low activity against CMV, since it is not well phosphorylated in CMV-infected cells. This is due to the absence of the gene for thymidine kinase (TK) in CMV. Ganciclovir, however, is active against CMV because it does not require TK for phosphorylation. Instead, another viral-encoded phosphorylating enzyme (UL97) is present in CMV infected cells. It is capable of phosphorylating ganciclovir and converting it to the monophosphate. Then cellular enzymes convert it to the active compound, ganciclovir triphosphate. Ganciclovir triphosphate acts to inhibit the viral DNA polymerase.

Pharmacology and Dosage. Intravenous and oral ganciclovir are now available for clinical use. When administered by intravenous infusion.

Initial response in retinitis (improvement or stabilization in vision of ophthalmoscopic appearance) occurs in approximately 75% of treated patients. By comparison, the disease is relentlessly progressive in 90% of patients if left untreated. Visual field defects present at the onset of therapy do not reverse, but a decrease in visual acuity caused by edema of the macula may improve with treatment.

Intravitreal Treatment. Intravitreal delivery is effective and relatively safe, although it does not treat the systemic CMV disease that is frequently present in patients with retinitis. Sustained intravitreal release by a surgically implantable device indicates that local therapy.

The currently available oral ganciclovir may be considered for maintenance therapy (not induction) in patients who do not have immediate sight-threatening disease (ie, retinitis near the macula or the optic nerve), since it is not quite as effective.

Prevention of CMV Disease. Two separate trials have evaluated the use of oral ganciclovir as a primary prophylactic agent against CMV disease.

A trial by Spector et al (Syntex 1654) was a double-blind, placebo-controlled study of 725 patients who had serologic tests positive for HIV and anti-CMV antibody and had <50 CD4+ cells/ÁL or <100 CD4+ cells/ÁL plus a previous opportunistic infection. Patients were randomized in a 2:1 fashion to receive either 1000 mg of oral ganciclovir three times daily or an identical-appearing placebo.

Other manifestations of CMV disease (eg, esophagitis, other gastrointestinal [GI] manifestations, hepatic effects, polyradiculopathy) occurred too infrequently to demonstrate a significant difference between the two groups.

Surprisingly, the two groups had a similar occurrence of nausea and diarrhea. The major adverse events were hematologic, with more neutropenia in the ganciclovir-treated group. The use of filgrastim, a marker for the occurrence of neutropenia, was significantly higher in the treated group than in the placebo group. There was no difference between the two treatment groups in the occurrence of anemia, but use of eryrhropoetin was also significantly higher in the oral ganciclovir group. With oral therapy, there was also a statistically significant greater frequency of serum creatinine concentrations above 1.5mg/dL than with placebo, suggesting that there may be nephrotoxicity associated with ganciclovir, at least in the oral form.

Another study has also evaluated primary prophylaxis of symptomatic CMV disease in AIDS patients.

Hematopoiesis. Sixteen percent of patients receiving ganciclovir develop neutrophil counts of less than 500/ÁL. Neutropenia may occur early but often develops during prolonged therapy. The leukopenia is usually reversible especially with the use of cytokines.

Other organ systems. Adverse effects on the central nervous system (CNS) occur in 17% of AIDS patients. Confusion is the most common symptom, occurring in 3% of patients, and 2% of patients experience convulsions, dizziness, headaches, or abnormal thinking. Overall, 15% of patients have gastrointestinal disturbances. Nausea is the most frequent complaint (5%), followed by vomiting (4%), abnormal liver function test (3%), and diarrhea (2%).

Gonadal toxicity. In preclinical animal studies, it was determined that ganciclovir is a potent inhibitor of spermatogenesis. Sperm counts in humans before and during ganciclovir therapy, however, have been performed too infrequently to provide meaningful information on spermatogenesis. Patients wishing to reproduce should use ganciclovir only for the strongest indications.

Foscarnet

Foscarnet is a pyrophosphate that inhibits the DNA polymerase of herpes viruses. Specifically, the drug blocks the pyrophosphate-binding site of the viral DNA polymerase, preventing cleavage of pyrophosphate from nucleoside triphosphates.

Cidofovir

Cidofovir, or HPMPC, represents a departure from previous nucleoside analogues since it appears to the cell as a nucleotide. It has a phosphonate moiety attached to a cytosine analogue and does not require phosphorylation by viral-encoded enzyme.