CITATION: Spruance SL. 1996. Ask the Expert. APUA Newsletter 14(3):7.


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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 are limited.

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 not significant.

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
h. labialis.(17,18) 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)

References

  1. Overall JC, Jr. In: Galasso GJ, Merigan TC, Buchanan RA, editors. Antiviral Agents and Viral Diseases of Man. 2nd ed. New York, NY: Raven Press, 1984:247-312.
  2. Spruance SL. J Med Virol 1993;41 (suppl) 1:27-32.
  3. Raborn GW, McGaw WT, Grace M, Houle L. Can Dent Assoc J 1989;55:135-7.
  4. Spruance SL, Crumpacker CS, Schnipper LE, et al. Antimicrob Agents Chemother 1984;25:553-5.
  5. Spruance SL, Schnipper LE, Overall Jr JC, et al. J Infect Dis 1982;146:85-90.
  6. Raborn GW, McGaw WT, Grace M, Percy J, Samuels S. Oral Surg Oral Med Oral Pathol 1989;67:676-9.
  7. Van Vloten WA, Swart RNJ, Pot F. J Antimicrob Chemother 1983;12:89-93.
  8. Shaw M, King M, Best JM, et al. Br Med J 1985;291:7-9.
  9. Engler H, Zawatsky R, Kirchner H, Armerding D. Arch Virol 1982;74:239-47.
  10. Spruance SL. Dermatology 2000 1996. Abstract.
  11. Spruance SL. Semin Dermatol 1992;11:200-6.
  12. Freeman DJ, Sheth NV, Spruance SL. Antimicrob Agents Chemother 1986;29:730-2.
  13. Sheth NV, Freeman DJ, Higuchi WI, Spruance SL. Int J Pharmaceut 1986;28:201-9.
  14. Spruance SL, Stewart JCB, Freeman DJ, et al. J Infect Dis 1990;161:191-7.
  15. De Miranda P, Blum MR. J Antimicrob Chemother 1983;12:29-37.
  16. Spruance SL, Stewart JCB, Rowe NH, et al. J Infect Dis 1990;161:185-90.
  17. Alenius S. Arch Virol 1980;65:149-56.
  18. Green JA, Weiss PN, Spruance SL. J Immunol 1983;l3l:2827-9.
  19. Bratcher DF, Harrison CJ, Bourne N, Stanberry LR, Bernstein DI. J Gen Virol 1993;74:1951-4.
  20. Spruance SL, Evans TG, McKeough MB, et al. Antiviral Res 1995;28:39-55.
  21. Whitley RJ, Levin M, Barton N, et al. J Infect Dis 1984;150:323-9.
  22. Shepp DH, Newton BA, Dandliker PS, Flournoy N, Meyers JD. Ann Intern Med 1985;102:783-5.
  23. Wade JC, Newton B, McLaren C, et al. Ann Intern Med 1982;96:265-9.
  24. Vartivarian S, Toth B, Eron L. Intersci Conf Antimicrob Agents Chemother 1995. Abstract.
  25. Naik HR, Siddique N, Chandrasekar PH. Clin Infect Dis 1995;6:1514-5.
  26. Demangone M, Hill JM, Kwon BS. Antiviral Res 1987;7:237-43.
 

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