EyeNet Magazine


 
Ophthalmic Pearls: Retina
How to Treat Cytomegalovirus Retinitis
By Bradley T. Smith, MD, and Carl D. Regillo, MD
Edited By Ingrid U. Scott, MD, MPH, and Sharon Fekrat, MD
 
 

Cytomegalovirus retinitis usually results from reactivation of a latent CMV infection secondary to immunodeficiency and accounts for 90 percent of the infectious retinopathies in AIDS patients. Before the introduction of highly active antiretroviral therapy, 30 percent of patients with AIDS developed CMV retinitis. Fortunately, HAART has reduced that incidence by three-quarters. However, CMV retinitis remains a concern for HIV-infected individuals who are not in treatment or who have failed anti-HIV therapy, whose CD4 lymphocytes have fallen below 50/mm³, who have a plasma HIV-1 RNA level greater than 100,000 copies/mL or who have been previously diagnosed with opportunistic infections.

Clinical Findings
Patients with CMV retinitis may be asymptomatic, or they may complain of floaters, photopsia and/or scotomata. The retinal lesions usually consist of perivascular infiltration with associated retinal hemorrhage and vascular sheathing. Vitritis is not a common finding given the immunocompromised state of these patients, but it may occur with immune recovery. The two forms of CMV retinitis are:

  • The indolent form, limited to the periphery and appearing more granular with less hemorrhage than
  • The fulminant form, which can involve the macula, having a more intense retinal infiltration with a greater degree of intraretinal hemorrhage. 

Diagnosis
Ophthalmoscopy revealing the characteristic appearance of CMV retinitis is diagnostic.

However, it is important to consider other causes. These include acute retinal necrosis, progressive outer retinal necrosis, toxoplasmosis, syphilis, HIV retinitis as well as other bacterial and fungal infections. Consider immunoglobulin G levels or polymerase chain reaction analysis (PCR) for CMV in problematic instances such as the patient with a vitreous hemorrhage precluding a fundus view. Diagnostic vitrectomy with tissue biopsy looking for inclusion bodies may also be helpful.

Treatment
HAART is by far the most important weapon in the treatment of CMV retinitis. Sustained immune reconstitution (maintaining CD4 cells above 100/ mm³) may allow discontinuation of anti-CMV treatment that otherwise must be continued indefinitely to suppress the virus.1

Specific anti-CMV treatment should be individualized based on the location and severity of the retinitis, level of underlying immune suppression, concomitant medications and ability to comply with treatment. Therapy is induced at high doses for two to three weeks or until the retinitis stabilizes. (See the table below for current options and dosing regimens.)

Treatment Options and Dosing Regimens

SYSTEMIC
Intravenous ganciclovir
 
 Induction: 5 mg/kg twice daily for two weeks
 Maintenance: 5 mg/kg/day
Oral ganciclovir   
 Induction: not recommended
 Maintenance: 1 g three times a day
Oral valganciclovir   
 Induction: 900 mg twice daily for two weeks
 Maintenance: 900 mg/day
Intravenous foscarnet  
 Induction: 60 mg/kg every eight hours for 14 days
 Maintenance: 90 mg/kg/day
Intravenous cidofovir  
 Induction: 5 mg/kg weekly for two weeks
 Maintenance: 3 mg/kg every two  weeks
 Give probenecid 2 g orally three hours before and an additional 1 g  at two and
 eight hours after each infusion

OCULAR
Intravitreal ganciclovir
 
 Induction: 2 mg twice weekly for three weeks
 Maintenance: 2 mg weekly
Ganciclovir implant  
 Induction: 4.5 mg implant
 Maintenance: replace every six to eight months
Intravitreal foscarnet  
 Induction: 2.4 mg twice weekly for three weeks
 Maintenance: 2.4 mg weekly
Intravitreal cidofovir   
 Induction: 20 µg
 Maintenance: repeat every five to  six weeks
Intravitreal fomivirsen  
 Induction: 300 µg every two weeks for four weeks
 Maintenance: 300 µg every four weeks

Note: The manufacturer’s instructions regarding dosage, administration and monitoring should be followed precisely. 


Systemic Treatment
Ganciclovir is administered intravenously, and the dose must be adjusted in patients with renal insufficiency. Ganciclovir undergoes phosphorylation to the active form after uptake by CMV-infected cells, making it susceptible to resistance when the UL97 mutation is present. Oral ganciclovir is not as effective in delaying disease progression as is IV ganciclovir. However, it causes less neutropenia and does not carry the risks associated with indwelling catheters. It may be appropriate as prophylactic therapy or as treatment in those patients with early, stable, peripheral CMV retinitis that is not immediately sight threatening. Note that if immune recovery is sufficient on HAART, reimplantation of a ganciclovir device (see below) or continuation of specific anti-CMV therapy may not be necessary.

Valganciclovir is an oral prodrug of ganciclovir and has been shown to be equally efficacious.2 Bone marrow suppression can occur with either drug, so blood counts should be measured twice weekly during induction and weekly during maintenance therapy. If neutropenia occurs, a colony-stimulating factor should be added and other drugs with myelosuppressive effects (including some antiretrovirals) should be discontinued, or an alternative anti-CMV drug substituted.

Foscarnet does not require intracellular phosphorylation to inhibit DNA polymerase and so it is effective against many resistant strains of CMV. Induction requires a large fluid infusion. Maintenance therapy requires an indwelling catheter and a daily two-hour infusion. Renal toxicity is common, but appropriate dose calculation based on creatinine clearance and adequate hydration can help prevent this side effect. Renal function and electrolytes should be evaluated twice weekly with appropriate dose adjustment based on creatinine levels. Foscarnet was shown to provide a greater survival advantage than ganciclovir in the Study of the Ocular Complications of AIDS trial,3 but this advantage has waned in the HAART era. Combination therapy with ganciclovir and foscarnet is effective, but quality of life suffers greatly given the time required for the infusions.

Cidofovir is also effective against many resistant strains of CMV since it does not require immediate phosphorylation. However, renal toxicity is even more common with this drug and so should be avoided in patients already taking a nephrotoxic medication or in those with a history of renal insufficiency. Urine protein and creatinine levels should be checked 48 hours before injection and the dose adjusted accordingly. Its less frequent dosing schedule compared with foscarnet makes an indwelling catheter unnecessary and so may be more attractive for those interested in maximizing quality of life. Its toxicity may be reduced by a saline bolus and adequate hydration, plus concomitant use of probenecid (beware in patients with allergy to sulfa) to inhibit renal uptake.

Intraocular Treatment
Intraocular anti-CMV therapy provides higher targeted concentrations of drug compared with systemic therapy. However, the patient is not then protected systemically (e.g., against CMV esophagitis or colitis) and the fellow eye remains vulnerable to reactivated CMV infection. 

The ganciclovir implant has demonstrated effective local control of CMV retinitis for up to six to eight months before replacement is required.4 It is especially useful when sight is immediately threatened or when systemic therapy is not adequate. However, risks of vitreous hemorrhage, retinal detachment and endophthalmitis require a more judicious use of implants. Because of these risks, it is recommended that efficacy first be established with several injections of intravitreal ganciclovir. 

Intravitreal foscarnet, like ganciclovir, requires weekly injections, making it intolerable to some patients.

Intravitreal cidofovir injections can result in hypotony and uveitis even in the fellow eye. Both of these injectable drugs also carry a risk of complications such as retinal detachment and endophthalmitis, although those occur less often than with the ganciclovir implant. 

Intravitreal fomivirsen is a synthetic antisense oligonucleotide that binds specifically to viral mRNA to inhibit protein expression. It has recently been proven effective in the treatment of patients with newly diagnosed CMV retinitis and for those in whom CMV retinitis has reactivated or persisted despite previous treatment. Like other intravitreal antivirals, it is considered a second-line agent, given the bimonthly induction injections followed by monthly maintenance doses.

Resistance and Relapse
It is impossible to totally eradicate CMV since all patients harbor a resistant colony. Resistance is defined as persistent active retinitis despite six weeks of induction therapy and occurs in 25 to 35 percent of patients by nine months of therapy. Resistance increases with longer-term therapy, and the UL97 mutation is the culprit in most cases. Management includes combining therapies such as foscarnet with ganciclovir, or adding an implant or intravitreal injection to systemic therapy. In some cases it may be prudent to switch therapies altogether. 

Almost all patients with a CD4 count less than 100 will relapse. This can be subtle clinically, so comparison of serial photos is necessary. Relapse is defined as a quiescent CMV retinitis that becomes active. It may be that the intravitreal drug concentration is subtherapeutic, so don’t assume resistance. Consider PCR sequencing for detection of the UL97 mutation if the patient has clearly relapsed. In the meantime, the current therapy should be continued at the induction schedule. The most important factor in treating resistance and relapse is to ensure HAART compliance.

Complications
As a patient’s immune system recovers, it recognizes CMV antigens as foreign. Immune recovery uveitis (IRU) can occur months to years after a patient begins treatment with HAART. IRU represents the leading cause of new visual loss in patients with AIDS through mechanisms such as cystoid macular edema, epiretinal membranes and cataracts. The treatment of IRU is one of the few indications for corticosteroids in an AIDS patient, and a depot injection of steroid should be considered before cataract extraction. The diagnosis of IRU should only be made when the retinitis is inactive, the CD4 cell counts have increased, and there is no evidence of an additional infectious etiology. 

It is estimated that 18 to 26 percent of eyes with CMV retinitis develop a rhegmatogenous retinal detachment due to multiple necrotic holes. Methods of repairing detachments depend on the status of the macula and activity of the retinitis. Pars plana vitrectomy with silicone oil tamponade is useful for macula-off retinal detachments in the setting of an active retinitis. The oil should remain in the eye until the immune system has recovered and the retinitis is quiescent. Vitrectomy with SF6 gas tamponade may be used if the retinitis is not active. Laser demarcation is useful for preventing detachment of the macula only when the retinitis is inactive and the area of prior retinitis and associated rhegmatogenous retinal detachment are relatively limited. Adjunct scleral buckling procedures which require many sutures are often not necessary.

Minimizing intraoperative suturing will help to reduce the risk of needle sticks. Retinal detachments in HIV patients with a history of CMV retinitis are rarely complicated by proliferative vitreoretinopathy.

Follow-Up
In general anti-CMV therapy should be maintained until patients have been compliant with HAART for at least 18 months, there are documented CD4 counts greater than 100 for at least three months, and the retinitis is quiescent with prolonged relapse-free intervals. Treatment success is suggested by reaction of the retinal pigment epithelium, no advancement of the linear border, and no expansion of any area of retinitis or atrophy by greater than 750 micrometers on serial fundus photographs. 

CMV retinitis is the most common ocular infection in people with AIDS. Those with CD4 counts less than 50 should have a dilated exam every three months since many patients with active retinitis may be asymptomatic. Patients should be instructed on the importance of strict adherence to HAART and any specific anti-CMV treatment. Any change in vision or ocular symptoms should be reported promptly.

_______________________________
1 Whitcup, S. M. et al. JAMA 1999;282: 1633–1637.
2 Martin, D. F. et al. N Engl J Med 2002;346: 1119–1126.
3 Jabs, D. A. et al. N Engl J Med 1992;326(4): 213–220.
4 Martin, D. F. et al. Arch Ophthalmol 1994; 112(12):1531–1539.

_______________________________
Dr. Smith is a senior ophthalmology resident and Dr. Regillo is a professor of ophthalmology. Both are at Wills Eye Hospital in Philadelphia.

AAO Annual Meeting: Chicago 2005

Two related posters will be presented in Chicago:

Poster #343 “Ocular Lesions in HIV-Infected Patients in the Era of Highly Active Anti-Retroviral Therapy in Western India” is to be presented by Alay S. Banker, MD, on Monday, Oct. 17, from 11 a.m. to 12:30 p.m. in Hall A.

Poster #378 “Pathologic Findings of Choroidal Melanoma in Patients With HIV” is to be presented by Scott R. Witherspoon, MD, on Monday, Oct. 17, from 11 a.m. to 12:30 p.m. in Hall A.

For more information about the posters to be presented during this year’s meeting, visit www.aao.org/meetings/annual_meeting/program, and scroll down for the “Posters” link.

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