Medication Summary
Experience with antiviral agents for cytomegalovirus (CMV) prophylaxis and CMV therapy is limited in children. Administer anti-CMV therapy only after consultation with an expert familiar with dosages and adverse effects. Antiviral agents may be administered therapeutically for established CMV disease or prophylactically (ie, preemptive therapy) when the risk of development of CMV disease is high (eg, in transplant recipients).
Antiviral Agents
Class Summary
Nucleosides are the only true antiviral agents active against cytomegalovirus (CMV), although immunoglobulins may provide some antiviral effect, particularly in combination with these agents. These agents share a common molecular target, namely, the viral DNA polymerase. Biochemically, ganciclovir is an acyclic nucleoside analog, whereas cidofovir is an acyclic nucleoside phosphonate. Each compound must be phosphorylated to a triphosphate form before it can inhibit the CMV polymerase. A viral gene product, the UL97 phosphotransferase, mediates the monophosphorylation step for ganciclovir. In contrast to these 2 agents, foscarnet is not a true nucleoside analog but can also directly inhibit the viral polymerase.
Ganciclovir is commonly used as preemptive therapy in transplant recipients at high risk of developing disease (eg, a CMV-seronegative recipient of an organ transplant from a CMV-seropositive donor). Oral and intravenous acyclovir have also been used successfully as prophylaxis for solid organ transplantation (seronegative recipient); however, never use acyclovir for CMV therapy in active disease. An oral formulation is approved for use in adult patients infected with HIV who have CMV retinitis; however, the bioavailability is poor, and no data support use in children.
Relatively little information is available concerning the use of ganciclovir in the setting of congenital CMV infection. However, one national collaborative prospective study did demonstrate a benefit of intravenous ganciclovir in infants with symptomatic congenital CMV infection. Antiviral treatment in this study led to improvement or stabilization of hearing. [9] Follow-up studies suggested further neurodevelopmental benefits in treated infants. In light of these data, ganciclovir therapy should probably be offered for all infants with symptomatic congenital CMV infection, toward the goal of improving the neurodevelopmental prognosis of these infants. Ganciclovir therapy should also be used in infants with congenital or perinatally acquired infection with severe end-organ disease, such as pneumonia, hepatitis, or viremia. It is unclear at this time if ganciclovir benefits the long-term prognosis of an infant with asymptomatic congenital CMV infection.
Alternatives to ganciclovir include trisodium phosphonoformate (PFA) and cidofovir. Pediatric experience with these agents is limited. Although potentially useful in the setting of ganciclovir resistance, the toxicities of these antivirals are significant. Use these agents only in pediatric patients in exceptional circumstances. Although they have only a modest level of activity against CMV, high-dose oral acyclovir and valacyclovir have been used for prophylaxis of CMV disease in high-risk individuals but are not suitable for therapy of active disease. Oral therapy with valganciclovir is considered investigational in children.
Ganciclovir (Cytovene)
Ganciclovir is the first compound licensed for the treatment of CMV infections. It is a synthetic acyclic nucleotide structurally similar to guanine. Its structure is similar to that of acyclovir; like acyclovir, it requires phosphorylation for antiviral activity. The enzyme responsible for phosphorylation is the product of the viral UL97 gene, a protein kinase. Resistance may occur with long-term use, generally because of mutations in UL97.
It is indicated in immunocompromised children (eg, HIV infection, posttransplantation, other immunocompromised states) when clinical and virological evidence of specific end-organ disease (eg, pneumonitis, enteritis) is present.
In infants, antiviral therapy with ganciclovir may be of benefit in reducing the prevalence of neurodevelopmental sequelae, in particular sensorineural hearing loss. A study sponsored by the National Institutes of Allergy and Infectious Diseases demonstrated improved hearing-related outcomes in infants with symptomatic congenital CMV treated with ganciclovir. Therefore, therapy in newborns with documented infection should be considered; however, consult an expert.
Cidofovir (Vistide)
Cidofovir is a nucleotide analog that selectively inhibits viral DNA production in CMV and other herpes viral infections.
Foscarnet (Foscavir)
Foscarnet is an organic analog of inorganic pyrophosphate that inhibits replication of known herpesviruses, including CMV, HSV-1, and HSV-2. It inhibits viral replication at the pyrophosphate-binding site on virus-specific DNA polymerases.
Immunoglobulins
Class Summary
These agents are used as passive immunization for the prevention of symptomatic cytomegalovirus (CMV) disease. This strategy has been useful in the control of CMV disease in immunocompromised patients in the prenucleoside antiviral era. It is controversial whether the infusion of CMV immune globulin in women with evidence of a primary CMV infection during pregnancy can prevent transmission and/or improve neurological outcomes in newborn infants, although this intervention is currently being investigated in several clinical trials.
Immune globulin intravenous (Carimune, Gamimune, Gammagard S/D, Gammar-P, Polygam S/D)
The observation that random donor intravenous immune globulin appears to be equal in efficacy to CMV hyperimmunoglobulin suggests that the benefit may be derived from an immunomodulatory effect unrelated to virus neutralization.
Cytomegalovirus immunoglobulin (CytoGam)
A CMV hyperimmunoglobulin has been shown to decrease the prevalence of CMV disease when administered posttransplantation to high-risk transplant recipients when administered alone or in combination with nucleoside antivirals. It may be administered therapeutically in combination with ganciclovir for CMV disease.
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Epidemiology patterns of congenital cytomegalovirus infection. Approximately 10% of cases of congenital cytomegalovirus occur in women with primary infection during pregnancy, and 90% of these infants have neurological sequelae. Although preexisting immunity (eg, maternal recurrent infection) protects against severe disease, approximately 15% of these infants have sequelae, particularly sensorineural hearing loss.
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Cranial CT scan of infant born with symptomatic congenital cytomegalovirus infection. Neurological involvement is evident, manifest as ventriculomegaly and periventricular calcifications.
