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Herpes Simplex
Virus and Varicella-Zoster Virus
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Acyclovir is the most useful agent for the treatment of herpes
simplex virus (HSV) and varicella-zoster virus (VZV) infections.
Acyclovir is a synthetic purine nucleoside analog that has specificity
for the viral thymidine kinase, which phosphorylates the drug to
the monophosphate form. The drug is then further phosphorylated
by host cell thymidine kinases to the triphosphate form, which inhibits
the viral DNA polymerase. Acyclovir is most active against HSV-1
and HSV-2. It also has substantial activity against VZV but requires
approximately 10-fold higher concentrations to inhibit replication
as compared with HSV.4 Acyclovir is not effective
against cytomegalovirus (CMV) infection, because CMV replication
does not require thymidine kinase. Acyclovir inhibits Epstein-Barr
virus (EBV) in vitro, but has limited efficacy in treating clinical
EBV disease. Topical antiviral agents available to treat keratoconjunctivitis
caused by HSV include trifluorothymidine, iododeoxyuridine, and
vidarabine ophthalmic drops.5 The topical formulation
of acyclovir has limited efficacy in mucocutaneous disease. Newer
topical formulations of penciclovir and docosanol also have limited
activity against mucocutaneous HSV disease.
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The decision to treat HSV-1, HSV-2, and VZV infections depends
on whether the infection is primary or recurrent; the clinical presentation;
and host factors, such as age and underlying conditions. Primary
infections are more often treated than recurrent infections because
of the absence of viral-specific immunity. Because neonates and
other immunodeficient hosts infected with HSV or VZV can experience
substantial morbidity and mortality, antiviral therapy for these
patients is recommended.
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Acyclovir is safe and generally well tolerated, although patients
should be monitored for potential side effects. Neurotoxicity (paresthesias
and other neurologic symptoms such as tremor, ataxia, and hallucinations)
can occur in patients receiving acyclovir, particularly if renal impairment
is present. In addition, if acyclovir is administered with an inadequate
volume of fluid or too rapidly, it can precipitate in the renal
tubules, causing acute renal injury. Serum creatinine should be
monitored in patients treated with acyclovir, especially if more
than 5 to 7 days of therapy is anticipated. The dosage should be
reduced if the serum creatinine concentration is above 1.5 mg/dL.
Acyclovir can reduce the white cell count, but this is reversible
with dose reduction or discontinuation. Acyclovir also can cause
gastrointestinal symptoms, including anorexia, nausea, vomiting,
and diarrhea.
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Acyclovir is available in oral formulations; however, less than
20% of an orally administered dose is absorbed. Therefore,
oral administration is appropriate only for nonlife-threatening
infections. Valacyclovir is the l-valyl ester of
acyclovir, which is rapidly converted to acyclovir by hepatic first-pass
metabolism after oral administration. Its bioavailability after oral
administration exceeds 50%.6 Although
valacyclovir has been used in adults for the treatment and suppression
of genital herpes infections, there is currently no oral suspension available
for children, and pediatric pharmacokinetic data are limited.
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The diagnosis of infection caused by HSV-1 or HSV-2 in neonates
is an indication for intravenous antiviral therapy. The use of high-dose intravenous
acyclovir (60 mg/kg/day) has favorably impacted
the mortality and morbidity of herpes encephalitis.7 Antiviral
therapy also is indicated for immunocompromised children with primary
HSV-1 or HSV-2 infection. Although the risk of life-threatening
dissemination is low, even among severely compromised patients,
severe local symptoms can persist for 2 weeks or longer.
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Acyclovir can be considered for treatment of serious herpes simplex
virus infections in other patients in whom the indications are less
well established. Examples of such patients include otherwise healthy
children with severe herpes gingivostomatitis and children with
eczema herpeticum. If the patient is hospitalized, intravenous acyclovir
may be used, but if the patient is ambulatory, oral therapy may
be appropriate. Acyclovir in the oral capsule formulation is licensed
for treating primary and recurrent genital herpes simplex
virus infection, usually caused by HSV-2. The recommended dosage
for adults and adolescents is 200 mg 5 times per day. Sexually active
teenagers or abused children may present with this infection and
should be treated if the clinical symptoms are significant and the
child is able to take capsules. Severe primary genital herpes simplex
virus should be treated with intravenously administered acyclovir.
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Alternatives to acyclovir for herpes simplex virus infections
include penciclovir and its oral diacetyl ester prodrug, famciclovir.
Both drugs have the same spectrum of activity as acyclovir. Following
oral administration, famciclovir is converted by the liver into
the active drug, penciclovir. Its bioavailability is ~70%.
Famciclovir has been used in the suppression of genital herpes.8
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HSV isolates resistant to acyclovir, on the basis of mutations
in the viral thymidine kinase or viral DNA polymerase genes, have been
reported. Although these isolates have demonstrated diminished virulence
in animal models, they have been associated with progressive mucosal
infections in immunocompromised hosts. Alternative antiviral agents
to consider for the therapy of patients infected with acyclovir-resistant
isolates include foscarnet and cidofovir.9 Foscarnet
is an inorganic pyrophosphate analog that has activity against all
human herpesviruses. It must be given intravenously because of its
poor bioavailability. Side effects of foscarnet include significant
nephrotoxicity and electrolyte disturbances, including symptomatic
derangements of both calcium and phosphate. Cidofovir is an acyclic
phosphonate nucleotide analog that does not require viral thymidine
kinase to convert it to its active form. Therefore, it is well suited
to treat viruses that are resistant to acyclovir because of alterations
in viral thymidine kinase. Cidofovir has a very long half-life because
it accumulates intracellularly; it can be given once per week. Cidofovir
therapy is associated with significant nephrotoxicity.
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Acyclovir has good activity in vitro against varicella-zoster
virus, but its use in acute varicella should be limited to patients
at high risk for severe disease, such as children older than age
12 or immunocompromised individuals. If acyclovir is administered
within 24 hours of the onset of rash, a more rapid decrease in fever
and a modest reduction in the total number of lesions can be expected.
Acyclovir also is effective in the treatment of reactivated varicella-zoster
virus. For immunocompromised patients with zoster who have a high
risk of dissemination, high-dose intravenous acyclovir should be
administered. In healthy individuals, treatment with acyclovir can
decrease acute pain but may not have an impact on the development
of postherpetic neuralgia. Oral valacyclovir or famciclovir is approved
for the treatment of herpes zoster in adults, but no pediatric formulations
are available for these drugs.10