Principles of Antiviral Therapy

Acyclovir

Acyclovir is a safe and effective therapy for herpes simplex virus (HSV) infections. The favorable safety profile of acyclovir derives from its requirement for activation to its active form via phosphorylation by a viral enzyme, thymidine kinase (TK). Thus acyclovir can be activated only in cells already infected with HSV that express the viral TK enzyme, a strategy that maximizes selectivity and reduces the potential for cellular toxicity in uninfected cells. Acyclovir is most active against HSV and is also active against varicella-zoster virus (VZV); therapy is indicated for infections with these viruses in a variety of clinical settings. Activity of acyclovir against CMV is less pronounced, and activity against Epstein-Barr virus is minimal, both in vitro and clinically. Therefore, under most circumstances, acyclovir should not be used to treat CMV or Epstein-Barr virus infections.

The biggest impact of acyclovir in clinical practice is in the treatment of primary and recurrent genital HSV infections. Oral nucleoside therapy plays an important role in the management of acute primary genital herpes, treatment of episodic symptomatic reactivations, and prophylaxis against reactivation. Acyclovir is also indicated in the management of suspected or proven HSV encephalitis in patients of all ages and for treatment of neonatal HSV infection, with or without central nervous system (CNS) involvement. With respect to neonatal HSV infection, the routine empirical use of acyclovir as empiric therapy against presumptive or possible HSV infection in infants admitted with fever and no focus in the 1st 4 wk of life is controversial. Acyclovir should be used routinely in infants born to women with risk factors for primary genital herpes or infants presenting with any combination of vesicular lesions, seizures, meningoencephalitis, hepatitis, pneumonia, or disseminated intravascular coagulation. Some advocate initiation of acyclovir in all febrile neonates. Other experts have argued that a selective approach based on the history and physical exam is more appropriate when making decisions about the use of acyclovir in febrile infants. Given the safety of the drug, prudence would dictate the use of acyclovir in such patients if HSV infection cannot be excluded.

Acyclovir is indicated for the treatment of primary HSV gingivostomatitis and for primary genital HSV infection. Long-term suppressive therapy for genital HSV and for recurrent oropharyngeal infections (herpes labialis) is also effective. Acyclovir is also recommended for less commonly encountered HSV infections, including herpetic whitlow, eczema herpeticum, and herpes gladiatorum. In addition, acyclovir is commonly used for prophylaxis against HSV reactivation in SOT and HSCT patients. Severe end-organ HSV disease, including disseminated infection, is occasionally encountered in immunocompromised or pregnant patients, representing another clinical scenario where acyclovir therapy is warranted.

Acyclovir modifies the course of primary VZV infection, although the effect is modest. Acyclovir or another nucleoside analog should always be used in localized or disseminated VZV infections, such as pneumonia, particularly in immunocompromised patients. Primary VZV infection in pregnancy is another setting where acyclovir is indicated; this is a high-risk scenario and can be associated with a substantial risk of maternal mortality, particularly if pneumonia is present.

Acyclovir is available in topical (5% ointment), parenteral, and oral formulations, including an oral suspension formulation for pediatric use. Topical therapy has little role in pediatric practice and should be avoided in favor of alternative modes of delivery, particularly in infants with vesicular lesions compatible with herpetic infection, where topical therapy should never be used. The bioavailability of oral formulations is modest, with only 15–30% of the oral dose being absorbed. There is widespread tissue distribution following systemic administration, and high concentrations of drug are achieved in the kidneys, lungs, liver, myocardium, and skin vesicles. Cerebrospinal fluid concentrations are approximately 50% of plasma concentrations. Acyclovir crosses the placenta, and breast milk concentrations are approximately 3 times plasma concentrations, although there are no data on efficacy of in utero therapy or impact of acyclovir therapy on nursing infants. Acyclovir therapy in a nursing mother is not a contraindication to breastfeeding. The main route of elimination is renal, and dosage adjustments are necessary for renal insufficiency. Hemodialysis also eliminates acyclovir.

Acyclovir has an exceptional safety profile. Toxicity is observed typically only in exceptional circumstances: for example, if administered by rapid infusion to a dehydrated patient or a patient with underlying renal insufficiency, acyclovir can crystallize in renal tubules and produce a reversible obstructive uropathy. High doses of acyclovir are associated with neurotoxicity, and prolonged use can cause neutropenia. The favorable safety profile of acyclovir is underscored by recent studies of its safe use during pregnancy, and suppressive therapy in pregnant women with histories of recurrent genital HSV infection, typically with valacyclovir (see later), has become standard of care among many obstetricians. One uncommon but important complication of long-term use of acyclovir is the selection for acyclovir-resistant HSV strains, which usually occurs from mutations in the HSV TK gene. Resistance is rarely observed in pediatric practice but should be considered in any patient who has been on long-term antiviral therapy and who has an HSV or VZV infection that fails to clinically respond to acyclovir therapy.

Valacyclovir

Valacyclovir is the l -valyl ester of acyclovir and is rapidly converted to acyclovir following oral administration. This agent has a safety and activity profile similar to that of acyclovir but has a bioavailability of >50%, 3-5–fold greater than that of acyclovir. Plasma concentrations approach those observed with intravenous acyclovir. Valacyclovir is available only for oral administration. A suspension formulation is not commercially available, but an oral suspension (25 mg/mL or 50 mg/mL) may be prepared extemporaneously from 500-mg caplets for use in pediatric patients for whom a solid dosage form is not appropriate. Suppressive therapy with valacyclovir is commonly prescribed in the 2nd and 3rd trimesters of pregnancy in women who have a clinical history of recurrent genital herpes. It is important to be aware that perinatal transmission of HSV can occur, leading to symptomatic disease in spite of maternal antenatal antiviral prophylaxis. In such settings, the possibility of emergence of acyclovir-resistant virus should be considered.

Penciclovir and Famciclovir

Penciclovir is an acyclic nucleoside analog that, like acyclovir, inhibits the viral DNA polymerase following phosphorylation to its active form. Compared with acyclovir, penciclovir has a substantially longer intracellular half-life, which in theory can confer superior antiviral activity at the intracellular level; however, there is no evidence that this effect confers clinical superiority. Penciclovir is licensed only as a topical formulation (1% penciclovir cream), and this formulation is indicated for therapy of cutaneous HSV infections. Topical therapy for primary or recurrent herpes labialis or cutaneous HSV infection is an appropriate use of penciclovir in children older than 2 yr of age.

Famciclovir is the prodrug formulation (diacetyl ester) of penciclovir. In contrast to penciclovir, famciclovir may be administered orally and has bioavailability of approximately 70%. Following oral administration, famciclovir is deacetylated to the parent drug, penciclovir. The efficacy of famciclovir for HSV and VZV infections appears equivalent to that of acyclovir, although the pharmacokinetic profile is more favorable. Famciclovir is indicated for oral therapy of HSV and VZV infections. There is currently no liquid or suspension formulation available, and experience with pediatric use is very limited. The toxicity profile is identical to that of acyclovir. In a clinical trial, valacyclovir was found to be superior to famciclovir in prevention of reactivation and reduction of viral shedding in the setting of recurrent genital HSV infection.

Ganciclovir and Valganciclovir

Ganciclovir is a nucleoside analog with structural similarity to acyclovir. Like acyclovir, ganciclovir must be phosphorylated for antiviral activity, which is targeted against the viral polymerase. The gene responsible for ganciclovir phosphorylation is not TK but rather the virally encoded UL97 phosphotransferase gene. Antiviral resistance in CMV can be observed with prolonged use of nucleoside antivirals, and resistance should be considered in patients on long-term therapy who appear to fail to respond clinically and virologically. Ganciclovir is broadly active against many herpesviruses, including HSV and VZV, but is most valuable for its activity against CMV. Ganciclovir was the first antiviral agent licensed specifically to treat and prevent CMV infection. It is indicated for prophylaxis against and therapy of CMV infections in high-risk patients, including HIV-infected patients and SOT or HSCT recipients. Of particular importance is the use of ganciclovir in the management of CMV retinitis, a sight-threatening complication of HIV infection. Ganciclovir is also of benefit for newborns with symptomatic congenital CMV infection and may be of value in partially ameliorating the sensorineural hearing loss and developmental disabilities that are common complications of congenital CMV infection.

Ganciclovir is supplied as parenteral and oral formulations. Ganciclovir ocular implants are also available for the management of CMV retinitis. The bioavailability of oral ganciclovir is poor, <10%, and hence oral ganciclovir therapy has been supplanted by the oral prodrug, valganciclovir, which is well absorbed from the gastrointestinal tract and quickly converted to ganciclovir by intestinal or hepatic metabolism. Bioavailability of ganciclovir (from valganciclovir) is approximately 60% from tablet and solution formulations. Significant concentrations are found in aqueous humor, subretinal fluid, cerebrospinal fluid, and brain tissue (enough to inhibit susceptible strains of CMV). Subretinal concentrations are comparable with plasma concentrations, but intravitreal concentrations are lower. Drug concentrations in the CNS range from 24% to 70% of plasma concentrations. The main route of elimination is renal, and dosage adjustments are necessary for renal insufficiency. Dose reduction is proportional to the creatinine clearance. Hemodialysis efficiently eliminates ganciclovir, so administration of additional doses after dialysis is necessary.

Ganciclovir has several important toxicities. Reversible myelosuppression is the most important toxicity associated with ganciclovir therapy and commonly requires either discontinuation of therapy or the intercurrent administration of granulocyte colony–stimulating factor. There are also the theoretical risks for carcinogenicity and gonadal toxicity; although these effects have been observed in some animal models, they have never been observed in patients. The decision to administer ganciclovir to a pediatric patient is complex and should be made in consultation with a pediatric infectious disease specialist.

Foscarnet

Foscarnet has a unique profile, insofar as it is not a nucleoside analog but rather a pyrophosphate analog. The drug has broad activity against most herpesviruses. Like the nucleoside analogs, foscarnet inhibits viral DNA polymerase. On the other hand, foscarnet does not require phosphorylation to exert its antiviral activity, thus differing from the nucleoside analogs. It binds to a different site on the viral DNA polymerase to exert its antiviral effect and therefore retains activity against strains of HSV and CMV that are resistant to nucleoside analogs. Its clinical utility is as a second-line agent for management of CMV infections in high-risk patients who cannot tolerate ganciclovir and as an alternative for patients with persistent or refractory HSV, CMV, or VZV disease with suspected or documented antiviral drug resistance.

Foscarnet is available only as a parenteral formulation and is a toxic agent that must be administered cautiously. Nephrotoxicity is common, and reversible renal insufficiency is often observed, as evidenced by an increase in serum creatinine. Abnormalities in calcium and phosphorus homeostasis are common, and electrolytes and renal function must be monitored carefully during treatment.