What You Should Know About AIDS and Cytomegalovirus (CMV) Retinitis

What is HIV and AIDS?
Infection with the Human Immunodeficiency Virus (HIV) occurs from unprotected sexual contact or injection of blood or blood products (transfusion, sharing of needles). HIV infection is a chronic, slowly progressive, and usually fatal disease. The Acquired Immunodeficiency Syndrome (AIDS) is the final, pre-terminal phase of the HIV illness, often occurring years after  the initial infection.

Current estimates of HIV infection are staggering. Worldwide numbers include 33,400,000 persons living with HIV and 13,900,000 deaths. Nearly 16,000 people become HIV-positive every day. Tragically, over 10,000,000 children have become orphaned due to HIV infection.

What are the eye problems found in AIDS?
There are a myriad of eye infections and tumors found with HIV and AIDS, including Kaposi's sarcoma, molluscum contagiosum, herpes zoster, HIV retinopathy, syphilis, cryptococcus, and toxoplasmosis. The most common vision-threatening infection is an infection of the retina called cytomegalovirus (CMV) retinitis.

Who gets CMV infection and retinitis?
Initial systemic infection with CMV is either asymptomatic or consists of a non-specific viral illness. Fifty to eighty percent of the general population show evidence of prior CMV infection. CMV, similar to HIV, is capable of causing a latent infection that often reactivates in immunocompromised individuals. Nearly all of HIV-positive homosexual males have CMV antibodies and more than half shed virus in the urine or semen.  Manifestations of CMV infection in HIV-infected individuals include CMV wasting syndrome, gastrointestinal findings (esophagitis, gastritis, hepatitis, and colitis), pneumonitis, encephalitis, and retinitis.

CMV retinitis in the pre-AIDS era was a rare complication of leukemia, lymphoma, and iatrogenic immunosuppression following organ transplantation. The AIDS epidemic has dramatically increased the prevalence of CMV retinitis. CMV retinitis occurs in 15-46% of patients with AIDS, although it is the initial manifestation of AIDS in less than 1% of HIV-infected persons.

What are the symptoms of CMV retinitis?
Symptoms of CMV retinitis may include floaters or painless loss of central or peripheral vision. Most patients are asymptomatic unless the optic nerve or macula are involved. All HIV-positive individuals, especially those with depressed T-helper cell counts (below 50-100), should therefore be examined with a dilated retinal examination every three to six months in order to diagnose and treat early infection.

How is CMV retinitis diagnosed?
Although the eyes will always look and feel normal, a thorough dilated retinal examination is needed to diagnose the retinal infection. Diagnosis is based on the clinical findings of hemorrhagic retinal inflammation often following a vascular distribution. If left untreated, the infection will spread throughout the retina and cause blindness.

Normal retina		CMV retinitis

Retinal detachment is a late cause of vision loss, and may develop in eyes with completely inactive infection. The 6-month and 1-year risks of retinal detachment are 11% and 24% respectively. Vitrectomy surgery is often able to reattach the retina with preservation of vision.

What treatments are available for CMV retinitis?
CMV retinitis is a progressive, bilateral, and blinding disease if left untreated.

Treatment with antiviral agents is the only effective means for controlling ocular infection. Since all current drugs are virostatic (suppress, rather than kill the virus), they must be given for the life of the patient. Monthly retinal examinations are necessary to monitor the infection and modify treatment when necessary.

The decisions regarding choice of drug and route of administration are multifactorial and getting more complicated as more options become available. Treatment strategies and management are truly a team effort involving the patient, family members, internist, and retinal specialist.  Current antiviral options include oral Ganciclovir, intravenous therapy (Ganciclovir, Foscarnet, or Cidofovir), and local therapy (Ganciclovir implant, intraocular ganciclovir, foscarnet, cidofovir, or fomivirsen). All have their distinct advantages and disadvantages and none offer the perfect balance of quality of life, efficacy, safety, and cost.

1) Oral anti-CMV therapy.
Oral Ganciclovir is more convenient than intravenous therapy, although intravenous administration is most effective. Mean time to clinical progression is 2 months with oral treatment compared to 3-4 months with intravenous therapy. In general, oral Ganciclovir treatment is an option for peripheral retinitis but is not recommended for more visually threatening disease near the optic nerve or macula.

Valganciclovir (Valcyte) is the oral pro-drug of Ganciclovir. Valganciclovir tablets are equally effective for induction therapy when compared to intravenous Ganciclovir. For patients with active CMV retinitis, the recommended induction dose of Valganciclovir is two 450 mg tablets twice a day for 21 days. Following induction treatment, or for patients with inactive CMV retinitis who require maintenance therapy, the recommended dose is two 450 mg tablets once daily.

2) Intravenous anti-CMV therapy. 
Intravenous therapy not only treats the infected eye, but offers protection against systemic infection and involvement of the other eye. Individuals may also live longer with intravenous treatment.  Patients receiving intravenous Ganciclovir have a shorter life-expectancy than those treated with Foscarnet (8.5 vs. 12.6 months). However, Foscarnet is less well tolerated with many patients preferring Ganciclovir treatment.  Intravenous Cidofovir was recently approved for the treatment of CMV retinitis. Quality of life is improved since the medication is given every 1 to 2 weeks (instead of daily for the other intravenous agents) without the need for an indwelling catheter. All medications are equally effective, with nearly all eyes showing initial control of the infection with reactivation within 3-4 months. Side-effects include bone marrow suppression (Ganciclovir, Cidofovir), kidney toxicity (Foscarnet, Cidofovir), and electrolyte abnormalities (Foscarnet).  Cidofovir also causes eye inflammation (uveitis).

3) Intraocular (local) anti-CMV therapy.
Local therapy provides high intraocular concentrations of antiviral medications, is highly effective in controlling infection, is less costly than systemic treatment, and gives the patient a better quality of life. Antiviral agents used for intraocular therapy include Ganciclovir, Foscarnet, Cidofovir, and Fomivirsen.  However, local therapy provides no protection against infection in the fellow eye (50% within 6 months), nor does it control systemic CMV symptoms. Patients often will therefore need systemic therapy (i.e. oral Ganciclovir) as prophylaxis against infection for the fellow eye.

The Ganciclovir-impregnated implant (Vitrasert), which is sutured into the eye during a 30 minute outpatient surgery, slowly releases Ganciclovir into the eye. It is highly effective and probably superior to the intravenous agents at controlling infection. The implant needs to be replaced every 6-8 months, especially in patients with low T-helper cell counts.

Fomivirsen represents the first of a new class of antisense drugs.  Fomivirsen prevents the CMV virus from forming proteins essential to its growth. Drug resistance is a problem with current antivirals. However, drug resistance cannot develop with antisense drugs. Initial clinical trials evaluated two dosing regimens, one for new and one for previously treated cases of CMV retinitis. Intraocular fomivirsen prevented the progression of CMV retinitis in both of these trials. Retinal detachment was less common than that usually observed with other treatments for CMV retinitis. Ocular side-effects included inflammation (responsive to corticosteroids) and transiently elevated intraocular pressure. There were no systemic toxicities from the ocular injections.

4) Systemic anti-HIV therapy. 
Systemic treatment directed against the HIV virus using a combination of reverse transcriptase inhibitors and protease inhibitors (HAART or highly active anti-retroviral therapy) has created new hope for many infected persons. This therapy results in immunologic, virologic, and clinical improvement along with increased survival.  HAART also may be an effective treatment for CMV retinitis by restoring immune system function and elevating T-helper counts. Many patients previously reliant on anti-CMV therapy can safely be taken off these medications once the T-helper counts rise over 100.

What happens when CMV retinitis fails to respond to initial treatment?
Most patients, particularly those receiving systemic CMV therapy, will reactivate within 3-4 months of initial treatment. Recurrence may be due to either poor penetration of drug into the eye or to the development of resistant strains of CMV. Treatment options for recurrent retinitis include re-induction with the same agent followed by maintenance at a higher dosage, switching to a different drug, combination therapy, or local therapy. Combination therapy with Ganciclovir and Foscarnet is superior than monotherapy for recurrent disease. The mean time to progression is 1-2 months for either Foscarnet or Ganciclovir alone compared to 4.3 months when both agents are given together. The Ganciclovir implant appears to be highly effective for eyes with recurrent CMV retinitis despite systemic treatment.

• CMV retinitis is often asymptomatic.
• Individuals with decreased T-helper counts (especially below 50-100) require dilated retinal examinations every 3-6 months
• Treatment usually controls the infection initially.
• Recurrent infection is common, particularly with patients who are not receiving (or who are resistant to) HAART and receiving intravenous anti-CMV therapy.