New Treatment Guidelines for Opportunistic Infections Recommend Valganciclovir for AIDS-related CMV Retinitis

The US Centers for Disease Control and Prevention (CDC), The National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America have issued new recommendations for the treatment of 28 AIDS-related opportunistic infections (OIs).

The new guidelines, “Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents,” are intended for clinicians and other health-care providers and include evidence-based guidelines for the treatment of 28 opportunistic infections.

Among the OIs covered by the new recommendations is cytomegalovirus (CMV) retinitis, a condition that can lead to partial or total blindness. Valganciclovir (Vacyte), a potent oral treatment for AIDS-related CMV retinitis, received positive recommendations in the new treatment guidelines that were issued last month by the CDC and published in the CDC’s Morbidity and Mortality Weekly Report.

"Even though advances in HAART have transformed the HIV landscape, opportunistic infections are still a threat, due to increasing antiretroviral resistance and the large number of HIV positive people remaining undiagnosed and untreated," said W. Robert Lange, MD, Medical Director, Roche. "Valgaciclovir is a potent and convenient treatment option, both for the induction and maintenance phases of therapy."

About CMV

Cytomegalovirus (CMV), a member of the herpes family of viruses, infects approximately 50 to 75 percent of the U.S. adult population and 90 percent of people with HIV. In individuals with healthy immune systems, CMV exists in the body in a dormant state.

However, among individuals with compromised immune systems, the virus can become active and cause disease. CMV retinitis, which damages eyesight and can cause blindness, is the most common CMV-related condition in people living with AIDS, affecting between 10 and 25 percent of persons with late-stage AIDS.

When a person living with AIDS develops CMV retinitis, the infection usually gets worse over time, quickly in some patients and slowly in others. If the disease is not treated, patients may lose some or all of their vision. In early stages, patients may not perceive symptoms of CMV retinitis, but as the condition progresses, visual problems, such as blind spots, distorted vision and noticeable blurring occur. Because these problems can be associated with diseases other than CMV retinitis, an ophthalmologist must make the diagnosis of the condition.

Clinical Manifestations of CMV Retinitis

Retinitis is the most common clinical manifestation of CMV end-organ disease. CMV retinitis usually occurs as unilateral disease, but in the absence of therapy, viremic dissemination results in bilateral disease in the majority of patients.

Peripheral retinitis might be asymptomatic or present with floaters, scotomata, or peripheral visual field defects. Central retinal lesions or lesions impinging on the macula are associated with decreased visual acuity or central field defects. The characteristic ophthalmologic appearance of CMV lesions includes perivascular fluffy yellow-white retinal infiltrates, typically described as a focal necrotizing retinitis, with or without intraretinal hemorrhage, and with little inflammation of the vitreous unless immune recovery with potent ART intervenes.

Blood vessels near the lesions might appear to be sheathed. Occasionally, the lesions might have a more granular appearance.

In the absence of ART or specific anti-CMV therapy, retinitis invariably progresses, usually within 10--21 days after presentation. Progression of retinitis occurs in "fits and starts" and causes a characteristic brushfire pattern, with a granular, white leading edge advancing before an atrophic, gliotic scar.

Treatment Recommendations

The choice of initial therapy for CMV retinitis should be individualized based on the location and severity of the lesion(s), the level of underlying immune suppression, and other factors such as concomitant medications and ability to adhere to treatment.

Oral valganciclovir, intravenous ganciclovir, intravenous ganciclovir followed by oral valganciclovir, intravenous foscarnet, intravenous cidofovir, and the ganciclovir intraocular implant coupled with valganciclovir are all effective treatments for CMV retinitis.

The ganciclovir intraocular implant plus oral valganciclovir is superior to once daily intravenous ganciclovir (and presumably to once-daily oral valganciclovir) for preventing relapse of retinitis. For this reason, certain HIV specialists recommend the intraocular implant plus valganciclovir as the preferred initial therapy, particularly for patients with immediately sight-threatening lesions (adjacent to the optic nerve or fovea); others prefer oral valganciclovir alone.

Among patients with peripheral lesions that are not immediately sight-threatening, oral valganciclovir is preferable to the ganciclovir intraocular implant, intravenous ganciclovir, or intravenous foscarnet because of its greater ease of administration and lack of surgical or catheter-associated complications. However, any of the treatment regimens can be chosen because epidemiologic studies and clinical trials have not demonstrated substantially reduced rates of loss of visual acuity among patients treated with the ganciclovir implant compared with those treated with systemic therapies.

Certain clinicians would not treat small peripheral CMV retinitis lesions if ART is to be initiated soon because immune recovery might ultimately control the retinitis. However, immune recovery uveitis might be more common among patients given less aggressive anti-CMV therapy. Therefore, treatment of CMV retinitis until sufficient immune recovery occurs (i.e., CD4⁺ T lymphocyte count >100 cells/µL for 3--6 months) is still preferred.

Valganciclovir Toxicities

The clinical toxicity of valganciclovir, which is metabolized to ganciclovir, includes granulocytopenia, anemia and thrombocytopenia. In animal studies ganciclovir was carcinogenic, teratogenic and caused aspermatogenesis.

Valganciclovir should not be administered if the absolute neutrophil count is less than 500 cells/µL, the platelet count is less than 25,000/µL or the hemoglobin is less than 8 g/dL. Didanosine (Videx) blood levels can be significantly increased when didanosine is taken with Valganciclovir. Cytopenias may be exacerbated by zidovudine (Retrovir).

Other side effects occurring with a frequency of ≥5% may include diarrhea, fever, nausea, neutropenia, headache, vomiting, insomnia, abdominal pain, retinal detachment, peripheral neuropathy and paresthesia.

02/02/05

Reference
C A Benson, J E Kaplan, H Masur, A Pau, and K K Holmes. Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents. Morbidity and Mortality Weekly Report (MMWR) 53(RR15): 1-112. December 17, 2004.