Treatment of CMV Retinitis

Treatment for CMV retinitis and systemic CMV infection has markedly improved over the last decade (57). There are two treatment principles for CMV infection. The first principle is to reverse or improve the underlying cause of immunosuppression. This may be possible in some cases by decreasing immunosuppressive medications, for example, after organ transplantation. This is now possible in AIDS by commencing or altering HAART therapy to improve the immune status (4,24). 

Prior to the development of any specific anti-CMV medications, the major approach to CMV retinitis therapy was to alter immune function and this was not particularly successful. In most cases, it was not possible to improve systemic 

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Cidofovir (Fig. 2) has been formally approved for the treatment of CMV retinitis in AIDS patients, where it is administered intravenously at a dose not exceeding 5 mg/kg once weekly during the first two weeks (and every other week thereafter). Cidofovir is also used off label for the treatment of human papilloma virus (HPV) infections (i.e., cutaneous warts, anogenital warts, laryngeal and pharyngeal papilloma), polyomavirus [i.e., progressive (i.e., multifocal leukoencephalopathy (PML)], adenovirus, herpesvirus, and poxvirus (i.e., molluscum contagiosum) infections, where it can be administered intravenously (at a dose of < 5 mg/kg once weekly or every other week) or topically as a 1% gel or cream (De Clercq and Holy 2005). Especially in immunosuppressed patients (i.e., transplant recipients), local treatment of HPV-associated lesions has often yielded spectacular results (Bonatti etal.2007). 

A new antiviral agent, developed for treatment of CMV retinitis, can be administered by intravitreal injection. Formivirsen sodium is a phosphorothioate oligonucleotide that inhibits CMV replication through an antisense mechanism. It is formulated as a sterile and preservative-free solution and supplied in single-use vials (Vitravene ). The product is administered directly into the vitreous cavity posterior to the limbus through a 30-gauge needle. This procedure can be performed on an... 

Cytomegalovirus (CMV) retinitis Treatment of CMV retinitis in patients with AIDS. Combination Combination therapy with ganciclovir for patients who have relapsed after monotherapy with either drug. 

Ganciclovir capsules are indicated only for prevention of CMV disease in patients with advanced HIV infection at risk for CMV disease and for maintenance treatment of CMV retinitis in immunocompromised patients. 

CMV disease Safety and efficacy have not been established for congenital or neonatal CMV disease, nor for the treatment of established CMV disease other than retinitis, nor for use in nonimmunocompromised individuals. The safety and efficacy of oral ganciclovir have not been established for treating any manifestation of CMV disease other than maintenance treatment of CMV retinitis. 

There has been very limited clinical experience using ganciclovir for the treatment of CMV retinitis in patients younger than 12 years of age. 

Foscarnet is indicated for the treatment of CMV retinitis in AIDS patients. Its effectiveness is comparable to that of ganciclovir these drugs are synergistic when given to counteract refractory retinitis. A decreased incidence of Kaposi s sarcoma has been observed in AIDS patients who have undergone foscarnet therapy. 

Intravenous ganciclovir is indicated for the treatment of CMV retinitis in immunocompromised individuals, including those with AIDS, and for the prevention of CMV infection in organ transplant recipients. Oral ganciclovir is less effective than the intravenous preparation but carries a lower risk of adverse effects. It is... 

B. Indications and use Intravitreal Vitravene is indicated for local treatment of CMV retinitis in AIDS patients who are refractory to or intolerant of other treatment or when other treatments are contraindicated. 

Recommended dosage and monitoring requirements For the treatment of CMV retinitis in AIDS patients, the recommended dose of Vitravene is 330 pg (0.05 ml) by intravitreal injection for induction, one dose should be injected every other week for two doses for maintenance, after induction, one dose should be given once every 4 weeks after induction. 

Valganciclovir is indicated for the treatment of CMV retinitis in patients with AIDS and for the prevention of CMV disease in high-risk kidney, heart, and kidney-pancreas transplant patients. Adverse effects, drug interactions, and resistance patterns are the same as those associated with ganciclovir. 

Intravenous cidofovir is effective for the treatment of CMV retinitis and is used experimentally to treat adenovirus infections. Intravenous cidofovir must be administered with high-dose probenecid (2 g at 3 hours before the infusion and 1 g at 2 and 8 hours after), which blocks active tubular secretion and decreases nephrotoxicity. Cidofovir dosage must be adjusted for alterations in the calculated creatinine clearance or for the presence of urine protein before each infusion, and aggressive adjunctive hydration is required. Initiation of cidofovir therapy is contraindicated in patients with existing renal insufficiency. Direct intravitreal administration of cidofovir is not recommended because of ocular toxicity. 

Ganciclovir Cytovene Treatment of CMV retinitis in immunocompromised patients also used to prevent CMV infection after organ transplants... 

To date, the clinical administration of ASOs has focused on local or parenteral routes using simple saline solutions. Intravenous dosing in animals has been shown to lead to an accumulation of oligonucleotide in specific cells, such as endothelial and phagocytic cells, and organs such as the kidneys and liver. These observations suggest optimal targets for clinical applications, for example liver diseases such as hepatitis C or ophthalmic indications such as the intraocular treatment of CMV retinitis. 

The Vitrasert has proved to be safe and effective for treatment of CMV retinitis as an adjimct to continued systemic therapy. Although use of the Vitrasert is relatively safe, it is not free of complications. Adverse events can occur in 10% to 20% of patients and can result in significant loss of vision. Acute and long-term complications associated with the Vitrasert or its surgical procedure include retinal detachment, vitreous hemorrhage, and endophthalmitis. 

Cidofovir is an acyclic nucleotide analogue of the monophosphate of cytosine. When phosphoiylated by host cellular enzymes, the active compound cidofovir diphosphate has broad activity against the herpes viruses, including CMV, HSV 1 and 2, VZV, Epstein-Barr virus, and the BK polyomavirus. Cidofovir has primarily been used in the treatment of CMV retinitis in patients who have failed treatment with ganciclovir or foscarnet and in acyclovir-resistant herpes simplex infections. More recently, there is also a growing experience with the use of this medication in kidney transplant patients who have BK virus-associated nephropathy [31], although this interest has been dampened by significant toxicity and only modest clinical activity [32]... 

Alternative antiviral agents for the treatment of drug-resistant herpesviruses are the acyclic nucleoside phosphonate analogs. The lead compound of this new series of antiviral molecules is cidofovir [(S)-l-(3-hydroxy-2-phosphonylmethoxypropyljcytosine] (HPMPC), which has a broad-spectrum antiviral activity in vitro and in vivo against several DNA viruses. Cidofovir has been approved for the treatment of CMV retinitis in AIDS patients, and it has also been shown to be effective in the treatment of persistent mucocutaneous infections caused by ACVr HSV and ACVr/PFAr HSV (6,7). 

Vitravene (Fomivirsen, an anti-sense oligonucleotide) ISIS pharmaceuticals Treatment of CMV retinitis in AIDS patients... 

CMV disease may still develop or relapse when HAART is not effective or the CD4+ count remains low. As well, incomplete immune recovery may not fully protect against CMV retinitis. Furthermore, HAART medications may not be easily obtained, especially in some underdeveloped countries. For these reasons, CMV retinitis continues to be a prevalent and serious opportunistic infection in AIDS. It is important to be aware of the features and treatment options for this potentially multisystemic infection in AIDS and other immunocompromised individuals. The treatment of CMV retinal infection remains challenging, especially due to the multiple side effects of anti-CMV medications. 

The second intravenous agent approved for the treatment of CMV retinitis was foscarnet. Foscarnet (trisodium phosphoformate) is a synthetic, water-soluble pyrophosphate analogue that inhibits replication of herpesviruses in vitro (3,14). It noncompetitively binds to the exchange site of viral DNA polymerase, thereby... 

Duker JS, Robinson M, Anand R, Ashton P. Initial experience with an eight month sustained-release intravitreal ganciclovir implant for the treatment of CMV retinitis associated with AIDS. Ophthalmic Surg Lasers 1995 26 442-448. 

Musch DC, Martin DF, Gordon JF, et al. Treatment of CMV retinitis with a sustained-release ganciclovir implant. The ganciclovir implant study group. N Engl J Med 1997 115 733-740. 

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