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Review of antiviral agents for treatment of pediatric HSV infection
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Several pharmacotherapeutic agents are commercially available in the United States for the treatment of infection caused by the herpesvirus family. Of these agents, only a relative few, however, have been well studied or are labeled by the FDA for use in infants and children with disease from infection with herpes simplex virus. In the past few years, several important studies and clinical reports describing the use of these antiviral drugs have been published, and they are reviewed here.
Agents for infection with HSV
Acyclovir, the most well-studied antiviral agent to treat HSV infection in children, has been available since 1982. Acyclovir is an acyclic guanine nucleoside and functions to inhibit HSV DNA synthesis once the virus enters host cells. This action of viral replication inhibition is therapeutically useful in infants and children; yet, acyclovir’s pharmacokinetic profile can limit its therapeutic usefulness. When given orally, acyclovir is not well absorbed (10% to 30%, with decreasing absorption as dosing increases). Oral acyclovir is dosed three to five doses per day, and thus may pose practical concerns with adequate adherence.
Valacyclovir is a pro-drug of acyclovir, and when given orally, it is metabolized to acyclovir by intestinal and hepatic enzymatic hydrolysis. In contrast to acyclovir, valacyclovir is very well absorbed orally (a threefold to fivefold increase in bioavailability compared with acyclovir). However, valacyclovir has not been as well studied for use in children in contrast to acyclovir; it is FDA-labeled for the treatment of herpes labialis (cold sores) in older children (aged 12 years and older) and for the treatment of chicken pox in immunocompetent children aged 2 years and older. Valacyclovir is commercially available as a tablet (Valtrex, GlaxoSmithKline; and generic), although a recipe to compound a 25 mg/mL or 50 mg/mL suspension for use in infants and children aged 3 months and older is available in the package insert.
Edward A. Bell
Valacyclovir is labeled for twice-daily (herpes labialis) or thrice-daily (chicken pox) dosing. Famciclovir (Famvir, Novartis) is another antiviral agent available to treat HSV infection. Famciclovir is also considered a pro-drug and is metabolized to the active form, penciclovir. Famciclovir is not labeled for use in the pediatric population and has not been well studied in children. Its labeled uses in adults include treatment of herpes labialis, genital herpes infection and herpes zoster infection.
Acyclovir and valacyclovir
Acyclovir has been well studied in infants and children and is most often the antiviral of choice for infants and children with primary and recurrent HSV infection. Acyclovir is commercially available as an oral tablet or capsule, oral buccal tablet, oral suspension and IV solution in generic and name-brand (Zovirax, GlaxoSmithKline) dosage forms. Valacyclovir is labeled for use in younger, immunocompetent children (aged 2 years and older) with chicken pox. Valacyclovir is additionally labeled for use in children aged at least 12 years with herpes labialis (2 g twice daily for 1 day). Recommendations listed in the 2012 Red Book describe potential advantages of valacyclovir, compared with acyclovir, when treating select immunocompromised children with chicken pox (eg, HIV-infected individuals with relatively normal concentrations of CD4+ T-lymphocytes; children with leukemia and good follow-up), due to improved oral bioavailability. This use is off-label, however.
Although acyclovir can effectively manage recurrent genital HSV infections, its poor bioavailability limits its potential effectiveness, as three to five daily doses are required. Valacyclovir has not been studied in children younger than 18 years and is labeled for twice-daily dosing in adults with recurrent HSV episodes. Chronic suppressive therapy can be initiated with twice-daily acyclovir (older children and adults) and once-daily dosing with valacyclovir (adults). Although acyclovir is available as topical cream and ointment formulations, use of these dosage forms when treating herpes labialis or genital HSV infections is not recommended, according to the 2012 Red Book.
Penciclovir is additionally available as a topical cream (Denavir, Prestium Pharma). It is FDA-labeled in older children (aged 12 years and older) for recurrent herpes labialis, although it is also not recommended in the 2012 Red Book.
As infection with HSV in the neonatal period often produces significant morbidity and mortality, recent studies have been conducted to evaluate the benefit of additional treatment beyond 14- to 21-day IV acyclovir treatment courses in neonates with HSV disease. In a study published in 2011, Kimberlin and colleagues compared orally administered acyclovir with placebo in neonates with HSV disease and central nervous system (CNS) or skin, eye and mouth involvement in a randomized, blinded manner. After completion of a 14- to 21-day regimen of IV acyclovir, study patients were given either oral acyclovir or placebo for 6 months. Neonates with CNS involvement in the study who received acyclovir displayed significantly higher Bayley mental development scores at 12 months as compared with neonates receiving placebo.
Effective treatments available
In summary, infection with HSV may result in significant morbidity and mortality in infants and children. Identification of young infants at risk for HSV infection is important; a clinical report to assist pediatric clinicians with managing these infants was published in Pediatrics in 2013. Acyclovir can effectively treat primary and recurrent HSV infection, although its pharmacokinetic profile may limit its use in select patients and indications, due to poor bioavailability and the need for frequent dosing. Valacyclovir, a pro-drug of acyclovir, is better absorbed when given orally and can be dosed less often, although data to support is efficacy in infants and children are not as strong.
Although valacyclovir is not commercially available as a liquid dosage form, an oral liquid suspension can be compounded from a known recipe. When acyclovir is used for long-term viral suppression, monitoring for neutropenia and maintenance of adequate hydration to limit nephrotoxicity are recommended.
Kimberlin DW. N Engl J Med. 2011;365:1284-1292.
Kimberlin DW. Pediatrics. 2013;131:e635-e646.
Pinninti SG. Pediatr Clin North Am. 2013;60:351-365.
Disclosure: Bell reports no relevant financial disclosures.