Ask the Expert
Is antiviral chemotherapy indicated
for people with recurrent cold sores?
Spotswood L Spruance, MD
University of Utah School of Medicine, Salt Lake City, Utah, USA
Multiple trials of antiviral drugs for recurrent herpes labialis in otherwise healthy, immunocompetent patients
have been conducted in the past 30 years,(1) with largely negative results. Consequently, effective treatments
Much of the difficulty in identifying an efficacious treatment is due to the rapid natural resolution of the disease,
which narrows the window of therapeutic opportunity for chemotherapy. Conversely, antiviral treatment of h. labialis in immunocompromised
patients can effect a dramatic improvement in what can otherwise be a severe and protracted disease course. While
not widely used as such, antiviral agents are also effective as prophylaxis for h. labialis.(2)
Topical acyclovir ointment (Zovirax Ointment 5%, Burroughs Wellcome) is widely used for the treatment of immunocompetent
patients with h. labialis,
but the evidence from multiple clinical trials shows that there is little or no therapeutic effect.(3-5) Only a
few small studies with inconsistent results describe the activity of acyclovir cream 5%,(6-9) which is marketed
for h. labialis
in numerous countries other than the US. Penciclovir, a new antiviral agent, is similar in structure and activity
to acyclovir. Large-scale trials of topical penciclovir cream 1% showed significant improvements in the reduction
of the duration of lesions, pain and viral shedding.(10) This product is presently approved in the UK and approval
in other countries is anticipated.
Poor drug delivery to the basal cell layer of the epidermis has been identified as a contributing factor in the
treatment failure in some h. labialis trials.(11) Skin penetration can be increased geometrically by using dimethyl
sulfoxide (DMSO) or laurocapram as an adjuvant.(12,13) In a study of topical 15% idoxuridine in DMSO,14 patients
receiving idoxuridine healed (defined as loss of crust) 1.7 days (21%) faster (P=0.004) and lost lesion pain 1.2
days (35%) faster (P=0.01) than those in the control groups.
Peroral delivery of drug can assure drug concentrations in lesions that are roughly equivalent to serum levels.(15)
Raborn and coworkers reported a 1- to 1.5-day (12 to 17%) decrease in the healing time of h.
labialis among patients treated with peroral acyclovir (200
mg 5 times/day for 5 days). Our study with peroral acyclovir (400 mg 5 times/day for 5 days)16 confirmed Raborn's
findings (time to loss of crust reduced by 0.9 days [12%]), although the results for the total study group were
Because acyclovir and penciclovir are not well absorbed from the gastrointestinal tract, the manufacturers of both
agents have developed "prodrugs" (modifications of the drug molecules to enhance absorption with subsequent
conversion to the parent compound) to obtain higher blood levels of the agents when administered perorally. Valaciclovir
(Valtrex, Glaxo Wellcome) is the prodrug of acyclovir and famciclovir (Famvir, SmithKline Beecham) is the prodrug
of penciclovir. We conducted a dose-ranging trial of peroral famciclovir for treatment of experimental ultraviolet-radiation-induced
Patients were given 125, 250 or 500 mg of famciclovir or placebo tid for 5 days beginning 2 days after irradiation.
Famciclovir 125 and 250 mg tid healed lesions 1 day faster and 500 mg tid healed lesions 3 days faster, compared
to the placebo-treated group (P<0.05).
In summary, depending on the country, topical treatments are available that have a modest but significant effect
on the course of h. labialis
in immunocompetent patients. For patients seeking a potentially greater therapeutic effect, I recommend famciclovir,
500 mg perorally tid for 5 days. To reduce cost, the duration of famciclovir therapy may be limited to 2 days.
For all treatments, I recommend starting therapy as soon as possible after the onset of signs or symptoms. To accomplish
this, patients will need to purchase the medication in advance. Use of corticosteroids, nonsteroidal antiinflammatory
agents or topical anesthetics have their advocates as well as some rationale (19,20) but further study is needed.
In immunocompromised patients with h. labialis, a wide variety of antiviral agents, given by different routes of administration,
have been found to be effective. Although acyclovir ointment 5% was shown to be of benefit,(21) peroral (400 mg
5 times/day for 10 days) or intravenous (5 mg/kg tid for 7 days) routes are generally preferred because of better
therapeutic activity and the potential for intraoral or esophageal herpes disease in these patients.(22,23) An
open study of intravenous penciclovir (1, 2 or 5 mg/kg bid or tid for 7 days) in 65 immunocompromised patients
with mucocutaneous h. simplex
infections suggested that it compares favorably with intravenous acyclovir.(24) While the only data available is
preliminary, the use of valaciclovir and famciclovir in doses for h.
zoster (1000 and 500 mg perorally tid for 7 to 10 days,
respectively) are other choices. Intravenous foscarnet (40 mg/kg tid for 14 to 21 days) is effective for the treatment
of oral h. simplex infections
in immunocompromised patients and may be used for the treatment of acyclovir-resistant virus strains.(25) The route
of administration, dosage and duration of therapy for these patients should be guided by the severity of the infection.
In the past 13 years, 11 studies have evaluated prophylactic acyclovir for suppression of h.
labialis.(2) Four studies showed inconsistent efficacy of
topical acyclovir, including "escape" lesions outside the zone of application. Prophylactic peroral acyclovir
was evaluated with positive results in 7 studies. The degree of reduction in frequency of lesions ranged from 50
to 78%. Systemic prophylactic therapy may have been more effective than topical because virus replication was suppressed
in the neural ganglia as well as in the periphery.(26)
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