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). Acyclovir is most active against HSV and also is active against varicella-zoster virus (VZV); therapy is indicated for these infections under a variety of circumstances. Activity against CMV is less pronounced, and activity against Epstein-Barr virus (EBV) is modest, both in vitro and clinically. Acyclovir should not be used to treat CMV or EBV infections.

The greatest clinical roles for acyclovir are for the treatment of primary and recurrent genital HSV infections, the management of HSV encephalitis, and all manifestations of neonatal HSV infection. The routine empirical use of acyclovir in infants admitted with fever of unknown origin in the first 4-8 wk of life is controversial. Clearly, acyclovir should be routinely empirically used 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 (DIC). Some experts advocate initiation of acyclovir in all febrile infants pending the collection and analysis of viral culture and polymerase chain reaction (PCR) studies. Others 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 the 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, both for genital HSV and recurrent oropharyngeal infections (herpes labialis), is also effective. Long-term suppressive therapy (i.e., for the first 6 mo of life) to prevent recurrent episodes of neonatal HSV infection may be useful in preventing recurrences, although this use is investigational. Acyclovir is also recommended for less commonly encountered HSV infections, including herpetic whitlow, eczema herpeticum, and herpes gladiatorum. Life-threatening HSV disease, including disseminated infection, can occur in immunocompromised or pregnant patients, representing another clinical scenario where acyclovir 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, particularly if pneumonia is present.

Acyclovir is available in topical, 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; indeed, neonatal infection represents a setting in which topical therapy should never be used. The bioavailability of oral formulations is poor, with only 15-30% of the oral formulation 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 (CSF) concentrations are about 50% of plasma concentrations. Acyclovir crosses the placenta, and breast-milk concentrations are about 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 breast-feeding. 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 have been 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 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 it has a bioavailability of >50%, 3-5-fold greater than that of acyclovir. Plasma concentrations approach those observed with intravenous acyclovir. Valacyclovir is only available for oral administration. A suspension formulation is not available. Suppressive therapy with valacyclovir is commonly prescribed in the second and third trimesters of pregnancy in women who have a clinical history of recurrent genital herpes. No cases of neonatal herpes have been described in infants born to women on chronic suppressive nucleoside therapy.

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 >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 de-acetylated 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. The toxicity profile is identical to that of acyclovir.

Ganciclovir

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 the 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. Ganciclovir is broadly active against many herpesviruses, including HSV and VZV, but its greatest value is derived from its activity against CMV. Ganciclovir was the 1st 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 solid organ or hematopoietic stem cell transplant recipients. Of particular importance is the use of ganciclovir in the management of CMV retinitis, a sight-threatening complication of HIV infection. Ganciclovir may be of benefit for newborns with symptomatic congenital CMV infection and may be of particular value in ameliorating the sensorineural hearing loss that is a common complication 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%. An oral prodrug, valganciclovir, is well absorbed from the gastrointestinal tract and quickly converted to ganciclovir by intestinal or hepatic metabolism. Bioavailability of ganciclovir (from valganciclovir) is about 60% from tablet and solution formulations. Significant concentrations are found in aqueous humor, subretinal fluid, CSF, and brain tissue (enough to inhibit susceptible strains of CMV). Subretinal concentrations are comparable to plasma concentrations, but intravitreal concentrations are lower. Drug concentrations in the central nervous system (CNS) range from 24-70% 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 generally should be made in consultation with an infectious diseases 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 2nd-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 only available 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.

Cidofovir

Cidofovir is an acyclic nucleotide analog that requires phosphorylation to its active form, cidofovir diphosphate, to exert its antiviral effect. Analogous to penciclovir, it has an extended intracellular half-life that contributes to its prolonged antiviral activity. Cidofovir is active against HSV, VZV, and CMV. In contrast to most of the other agents with activity against herpesviruses, cidofovir also exhibits broad-spectrum activity against other DNA viruses, most notably the poxviruses. Most clinical experience with cidofovir has been in the management of CMV disease caused by strains with ganciclovir resistance.

Cidofovir is administered intravenously and is cleared renally by tubular secretion. Extensive prehydration and co-administration of probenecid are recommended. Nephrotoxicity is commonly encountered, even with appropriate prehydration, cidofovir must be co-administered with other nephrotoxic medications with care. Other potential toxicities include reproductive toxicity and carcinogenesis.

Trifluridine

Trifluridine is a pyrimidine nucleoside analog with activity against HSV, CMV, and adenovirus. It is formulated as a 1% ophthalmic solution and approved for topical use in the treatment of HSV keratitis and keratoconjunctivitis. Trifluridine is the treatment of choice for HSV keratitis, a disease that should always be managed in consultation with an ophthalmologist.

Vidarabine (ARA-A, Adenine Arabinoside, VIRA-A)

Vidarabine is a nucleoside analog that has activity against HSV. It was the 1st parenteral antiviral agent for HSV infection, although it is no longer available for intravenous administration. A topical preparation remains available to treat HSV keratitis and is considered a 2nd-line agent for this indication.

Fomivirsen

Fomivirsen is a novel anti-CMV compound that is used as a 2nd-line agent for CMV retinitis by direct injection into the vitreous space. It is an antisense 21-mer DNA oligonucleotide that binds directly to complementary messenger RNA. This agent was the first antisense antiviral agent approved by the FDA. The standard dosage is 330 µg via intravitreal injection every 2 wk for 2 doses followed by maintenance therapy of 330 µg every 4 wk. There is no systemic absorption following intravitreal injection.

Ribavirin

Ribavirin is a guanosine analog that has broad-spectrum activity against a variety of viruses, particularly RNA viruses. Its precise mechanism of action is incompletely understood but is probably related to interference with viral messenger RNA processing and translation. Ribavirin is available in oral, parenteral, and aerosolized formulations. Although intravenous ribavirin is highly effective in the management of Lassa fever and other hemorrhagic fevers, this formulation is not licensed for use in the USA. The only licensed formulations in the USA are an aqueous formulation for aerosol administration (indicated for RSV infection) and an oral formulation that is combined with interferon-α for the treatment of hepatitis C. Administration of ribavirin by aerosol should be considered for serious RSV lower respiratory tract disease in immunocompromised children, young infants with serious RSV-associated illness, and high-risk infants and children (children with chronic lung disease or cyanotic congenital heart disease). In vitro testing and uncontrolled clinical studies also suggest efficacy of aerosolized ribavirin for parainfluenza, influenza, and measles infections.

Ribavirin is generally nontoxic, particularly when administrated by aerosol. Ribavirin and its metabolites concentrate in red blood cells and can persist for several weeks and, in rare instances, may be associated with anemia. Conjunctivitis and bronchospasm have been reported following exposure to aerosolized drug. Care must be taken when using aerosolized ribavirin in children undergoing mechanical ventilation to avoid precipitation of particles in ventilator tubing; the drug is not formally approved for use in the mechanically ventilated patient. Concerns regarding potential teratogenicity from animal studies have not been borne out in clinical practice, although care should be taken to prevent inadvertent exposure to aerosolized drug in pregnant health care providers.

Amantadine and Rimantadine

Amantadine and rimantadine are tricyclic amines that are highly similar to each other, both structurally and functionally. Both are indicated for the prophylaxis and therapy of influenza A, and neither has discernible activity against influenza B or any other respiratory viruses. For maximal therapeutic efficacy, therapy should begin as soon as possible and within 48 hr of the onset of symptoms. Influenza immunization is a greatly preferred method of disease control, but these agents are useful for prophylaxis, particularly in unimmunized, high-risk persons during annual seasonal epidemics of influenza.

The mechanism of action of the tricyclic amines against influenza A virus is unclear, but they appear to exert their antiviral effect at the level of uncoating of the virus. Both agents are extremely well absorbed after oral administration and are eliminated via the kidneys (90% of the dose is unchanged), necessitating dosage adjustments for renal insufficiency. The toxicities of the tricyclic amines are modest and include CNS adverse effects such as anxiety, difficulty concentrating, and lightheadedness and gastrointestinal adverse effects such as nausea and loss of appetite. Adverse effects are less common with rimantadine than with amantadine.

Oseltamivir and Zanamivir

Oseltamivir and zanamivir are active against both influenza A and B, although the importance of this broader spectrum of anti-influenza activity in disease control is modest because influenza B infection is typically a much milder illness. Emerging strains of influenza, including H5N1 and the 2009-10 pandemic strain, H1N1 (swine flu), are susceptible to oseltamivir and zanamivir but resistant to amantidine. Therefore, these agents are emerging as the antivirals of choice for influenza infection. Neither agent has appreciable activity against other respiratory viruses. The mechanism of antiviral activity of these agents is via inhibition of the influenza neuraminidase.

Zanamivir has poor oral bioavailability and is licensed only for inhalational administration. With inhaled administration, >75% of the dose is deposited in the oropharynx and much of it is swallowed. The actual amount distributed to the airways and lungs depends on factors such as the patient’s inspiratory flow. About 13% of the dose appears to be distributed to the airways and lungs, with about 10% of the inhaled dose distributed systemically. Local respiratory mucosal drug concentrations greatly exceed the drug concentration needed to inhibit influenza A and B virus. Elimination is via the kidneys, and no dosage adjustment is necessary with renal insufficiency, because the amount that is systemically absorbed is low.

Oseltamivir is administered as an esterified prodrug that has high oral bioavailability. It is eliminated by tubular secretion, and dosage adjustment is required for patients with renal insufficiency. Gastrointestinal adverse effects, including nausea and vomiting, are occasionally observed. The drug is indicated for both treatment and prophylaxis. The usual adult dosage for treatment of influenza is 75 mg twice daily for 5 days. Treatment should be initiated within 2 days of the appearance of symptoms. Recommended treatment dosages for children vary by weight: 30 mg twice a day for children ≤15 kg, 45 mg twice a day for children weighing 15-23 kg, 60 mg twice a day for those weighing 23-40 kg, and 75 mg twice a day for children ≥40 kg. Dosages for chemoprophylaxis are the same for each weight group, but drug should be administered only once daily rather than twice daily. Although the drug is not approved for children <1 year of age, the Centers for Disease Control and Prevention have issued a recommendation that oseltamivir be used in children in this age group for prophylaxis and treatment of H1N1 (swine) influenza. Dosage recommendations are available for this age group at www.cdc.gov/h1n1flu/recommendations.htm. Oseltamivir has been described to produce neuropsychiatric and psychological side effects in some patients; drug should be discontinued if behavioural or psychiatric side effects are observed.

Interferons

Interferons are endogenous immunomodulatory proteins elicited by a variety of infectious and inflammatory stimuli. Interferons exert antiviral activity via induction of multiple effector proteins in virus-infected cells. The interferon that has emerged as an effective antiviral agent is interferon-α, a type I interferon. For therapeutic use, interferons are produced using recombinant techniques. Administration of interferons is via subcutaneous or intramuscular administration, with rapid absorption. The attachment of polyethylene glycol moieties to the interferon, known as pegylation, is an approach that results in a more sustained plasma concentration, thus allowing a weekly subcutaneous dosing schedule.

Interferons are used in the management of hepatitis B, hepatitis C, and HPV infections. The combination of interferon with oral ribavirin results in additional antiviral activity, particularly against hepatitis C virus. Interferons, either by local injection or systemic delivery, are indicated for anogenital warts caused by HPV and for laryngeal and respiratory papillomatosis. Interferons can cause significant systemic toxicities that are dose related, including fever, chills, myalgias, gastrointestinal symptoms, and bone marrow suppression.

Lamivudine

Lamivudine is a reverse transcriptase (RT) inhibitor that is used for management of HIV infection (Chapter 268). Because an RT step is required for replication of hepatitis B virus, it was not surprising that lamivudine was found to have activity against this virus. Lamivudine is useful in the management of hepatitis B infection in children and is available as an oral suspension for pediatric dosing. It is rapidly absorbed following oral administration, with a bioavailability of 80-87%. Lamivudine crosses the placenta and is distributed in breast milk and excreted via the kidneys. A majority of drug is unchanged following oral administration, so dosage adjustment is necessary in the setting of renal insufficiency.

Adefovir Dipivoxil

Adefovir is an acyclic nucleotide analog with activity against human hepatitis B virus. Its mechanism of action appears to be inhibition of the viral DNA polymerase. It is administered orally as a diester prodrug with a bioavailability of approximately 60%. There are few data on the pharmacokinetics of this drug in children. Of concern is the observation of severe exacerbations of liver disease in patients who have discontinued adefovir.