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Herpes labialis in skiers
Herpes labialis in skiers Randomized clinical trial of aeyclovir cream versus placebo G. Wayne Raborn, DDS, MS, dip ABOM, a Alain Y. Martel, MD, CSPQ, FRCPC, b Michael G.A. Grace, PhD, R Eng., a and W.T. McGaw, DDS, MD, MSc, FRCD(C), a Edmonton, Alberta, and Ste-Foy, Quebec, Canada UNIVERSITYOF ALBERTAAND UNIVERSITt~LAVAL
Objective. A randomized, double-blind trial at seven ski sites in Canada and the United States was conducted to compare the effectiveness and the patient tolerance of topically applied 5% acycIovir cream (MAC III formulation) with those of a placebo cream in the prevention of sun-induced herpes labialis lesions. Study Design. All subjects had experienced more than three episodes of sun-induced herpes labialis during the previous year. There were 196 subjects enrolled; 5 did not receive medication, and 10 were excluded from the efficacy analysis for protocol violations. There were 191 subjects in the intent-to-treat analysis, and a separate efficacy analysis was done on 181 subjects. Log rank and Fisher exact tests were used in the analysis. Results. There was no difference between the two groups at baseline with respect to any clinical or demographic factor. There was no substantial difference between the groups with respect to adverse experiences (15 for acyclovir; 13 for the placebo). The acyclovir group had significantly fewer lesions (p < 0.01) than the placebo group (21% vs. 40%) during the 4-day follow-up period. Conclusion. The acyclovir group was significantly better than the placebo group during the follow-up period. The safety record of the drug was satisfactory; there was no difference between acyclovir and the placebo in side effects or pain. Topically applied 5% acyclovir cream is an effective preventive step for'those who are active and exposed to the sun. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84:641-5)
Lifetime prevalence of recurrent herpes labialis in the United States is estimated at between 20% and 40%, with approximately 100 million episodes occurring in the country every year.1 Recurrences of herpes labialis may be induced by emotional stress, high fevers, exposure to ultraviolet light, or nerve or oral tissue trauma. Although most episodes are mild, some may be severe and disfiguring. They often cause psychological distress and physical discomfort while also posing the risk of autoinoculation and transmission. Herpetic keratitis and Whitlow's infection of the fingers are other serious side effects. An estimated 10% of persons with herpes labialis seek medical care specifically for recurrent herpes labialis, and millions attempt some form of treatment. 2 Acyclovir is an acyclic nucleoside analog that displays in vivo antiviral activity against the herpes simplex 1, herpes simplex 2, Epstein-Barr, and varicella zoster viruses. 3 The unique feature of this compound is its affinity for virus-specified thymidine kinase; at the
This research was supported by a grant from Burroughs Wellcome, Canada. aDepartment of Oral Health Sciences, University of Alberta. bLaboratoire et Service d'Infectiologie, Centre de Recherche, Le Centre Hosp. de l'Universit6 Laval. Received for publication Oct. 30, 1996; returned for revision Jan. 9, 1997; accepted for publication Aug. 14, 1997. Copyright © 1997 by Mosby-Year Book, Inc. 1079-2104/97/$5.00 + 0 7/13/85715
same time, it has low human toxicity. The antiviral action of acyclovir derives from the fact that it inhibits viral replication by substitution into the viral DNA molecule and terminating the chain. Over the past several years, researchers have tested several topical acyclovir formulations against herpes labialis with inconsistent results. Notable success with the topical cream formulation, used prophylactically, was reported by Gibson et al. 4 in cases of recurrent lesions. In a study from the United Kingdom, Fiddian et al. 5 reported that the cream was effective in reducing healing and crusting time and in increasing the proportion of aborted lesions. The acyclovir cream formulation has been available in England and continental Europe for several years, even though Shaw et al. 6 reported a failure of the cream formulation in a 1985 trial. In North America, Raborn et al. 7 reported trends toward effectiveness in a trial of the cream. Spruance et al. 8 reported efficacy in the prevention of labialis lesions in Utah skiers with orally administered acyclovir (400 rag). All of these trials involved patients with normal immune systems. In several trials, 9-11 a 5% ointment formulation of acyclovir failed in treatment of herpes labialis in normal volunteers. The major reason suggested for the ointment failure was poor tissue penetration of the acyclovir. 12 In addition, the drug's antiviral effect depends on interruption of viral replication and on early drug therapy in the course of the disease. In contrast, Whitley 641
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et al. 13 demonstrated the effectiveness of the 5% ointment in treatment of individuals with herpes labialis who were immunocompromised. The objective of the present trial was to compare the effectiveness of and patient tolerance for topically applied 5% acyclovir cream (MAC III formulation)* with those of a placebo cream in the prevention of suninduced herpes iabialis lesions.
MATERIAL AND METHODS This double-blind, randomized, placebo-controlled, multicentered trial enrolled subjects at seven ski sites in Canada and the United States. Each center represented a single ski site, and ethics approval was obtained from a Human Subjects Committee at each center. The study was funded by Burroughs Wellcome. Normal, healthy volunteers of either gender who were over the age of 18 years and who had experienced more than three episodes of sun-induced herpes labialis during the previous year met the entry criteria. Pregnant and nursing mothers were excluded; a standard urine pregnancy test was administered to each woman before she was given the study drug. Also excluded were subjects who had received antiviral medication during the week leading up to the study; subjects with known psychiatric disorders; subjects with underlying medical or surgical disorders that might alter their susceptibility to herpes simplex virus infections; and subjects with histories of eczema herpeticum, atopic dermatitis, or other skin conditions that would predispose them to eczema herpeticum.
Treatment procedures The subjects were all people who came to mountain areas to ski. They were entered into the study only if they had had no intensive sun exposure for at least 5 days before they began participating in the study. The subjects were given the study drug to apply 12 hours before intensive sun exposure (in other words, during the evening preceding the day they would start to ski). The study drug was applied five times per day: at bedtime, on waking, and three times during the course of the day at 4-hour intervals. This treatment continued for a period of at least 72 hours, to a maximum of 168 hours. Participants were required to use no analgesics other than acetaminophen and were barred from covering their faces with masks while skiing. The use of sunscreens was not permitted. Subjects were randomly assigned to either acyclovir or a placebo, with randomization done within each center. The subjects and all of the study personnel were blinded as to which treatment was being applied to which person. *Zovirax (GlaxoWellcome, Research Triangle Park, North Carolina).
Clinical evaluation Each subject was contacted daily and examined within 24 hours by a dentist, physician, physician assistant, or nurse if signs or symptoms of recurrent disease appeared. For each lesion, the location was recorded; the size was determined by measurement; and the stage was noted as "erythema," "papule," "vesicle," "ulcerated" or "eroded," "hard crusted," "dry flaking," "residual swelling," or "healed and associated pain." The period of daily sun exposure and the condition of the facial skin were noted. No cultures were required. Each subject was contacted either by mail or by phone 7 to 10 days after completing the study to determine whether there were any problems and to note any formation of lesions since discontinuation of the study drug. Study personnel (physician assistants and nurses) were trained in all evaluation and follow-up procedures. The vast majority of the subjects were monitored by personnel with previous experience in herpes labialis trials. Daily examinations of subjects took place at a central location in each skiing area. All subjects were provided an honorarium for .their time. Information was collected in case report forms, which included measurement techniques that had been shown to be valid and reliable in previous studies. 7,9 Formal calibration of all clinical trial personnel-nurses, physician assistants, and site coordinators (denfists and physicians)--was conducted by the granting agency before the trials. Clinical trial monitors and site coordinators were constantly in communication with study nurses and other clinical personnel to corroborate clinical findings, review patient histories, and make judgement calls with respect to inclusion criteria and other questions. Site visits were made weekly to the remote ski area sites, and cases were reviewed; diagnoses were confirmed by either dentists or physicians.
Statistical analysis Proportions of patients in each treatment group with clinical evidence of herpes labialis during the treatment period and during the 4-day follow-up were analyzed by means of a Fisher exact test. Estimates of time-tofirst-lesion for the treatment period and the treatmentperiod-plus-4-days follow-up were obtained with the Kaplan-Meier product-limit method, and p values were produced by means of a log rank test. For those subjects who experienced pain associated with lesions, duration of pain was analyzed with a log rank test.
RESULTS In this study there were 196 subjects enrolled from seven different sites. Five subjects who were enrolled but did not receive medication were excluded from the
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Table II. Patients in whom lesions formed during treat-
Table I. Demographics by treatment Patient characteristic Age (years) SD Gender (female/male) Race Caucasian Black Asian Self-perceived risk > 50% < 50%
ment*
Acyclovir n=95
Placebo n=96
Probability
37.2 + 10.2 54/41
36.7 __.9.0 49/47
0.52 0.51
95 0 0
94 1 1
0.47
58 37
60 36
0.90
analysis. The remaining 191 subjects (95 treated with acyclovir, 96 given the placebo) constituted the intentto-treat group and were included in the safety and efficacy analysis. Of these 191 subjects, 10 were excluded from the efficacy subset for various protocol violations that ranged from using lipstick while skiing to applying the study medication less than 12 hours before sun exposure. A separate efficacy analysis was conducted for the remaining 181 subjects (91 acyclovir, 90 placebo). There were no major differences among the various ski sites. For the intent-to-treat subjects, there were no differences between the placebo and acyclovir groups for the following factors: age, race, gender, number of recurrences within the past year, and usual duration of lesions. There was no difference between the two groups in their self-perceived assessment of the risk of incurring a herpetic lesion after sun exposure (Table I). For the intent-to-treat subjects, there was no significant difference between the 16% of the acyclovir group and the 25% of the placebo group who experienced lesions during the treatment period (Table II).
Safety analysis There was no significant difference between the acyclovir and placebo groups in adverse events during the treatment period. Twenty-eight subjects (15 acyclovir, 13 placebo) reported at least one adverse experience during treatment.
Efficacy subset The acyclovir group fared significantly better by a log rank test (p < 0.01) than the placebo group during the 4day follow-up period: 21% of the acyclovir subjects and 40% of the placebo subjects had lesions (Table III). The proportion with no lesions during the treatment-periodplus-4-days follow-up period also favored acyclovir (p < 0.01). The amount of pain that patients experienced
No. of patients (%) Study day
Acyclovir (n = 91)
Placebo (n = 90)
Probability
1 2 3 4 5 6 7 8 Totalst
2 (2) 2 (2) 2 (2) 1 (l) 3 (3) 3 (4) 2 (4) 0 (0) 15 (91)
0 (0) 4 (4) 3 (3) 2 (2) 3 (3) 8 (12) 1 (3) 2 (10) 23 (90)
0.24 0.68 1.00 1.00 1.00 0.13 1.00 0.49 0.20
*Fisher exact test; two-sided p values. *Number of subjects decreased each day because of healing; consequently, the denominator for each study day's percentage calculation is less than that for the preceding day.
Table III. Patients in whom lesions formed during fol-
low-up, excluding cases of protocol violation (n = 181)* No. of patients (%) Follow-up day
Acyclovir
Placebo
Probabilty
1 2 3 4
0 (0) 1 (1) 2 (2) 2 (2)
1 (1) 5 (6) 4 (5) 4 (5)
1.00 0.21 0.68 0.68
5
0 (0)
0 (0)
-
18 (21)
35 (40)
Totals (treatment plus follow-up) t
<0.01
*Fisher exact test; two-sided p values. tNumber of subjects decreased each day because of healing; consequently, the denominator for each study day's percentage calculation is less than that for the preceding day.
during treatment was not affected by the study medication. An intent-to-treat analysis provided results similar to those of the efficacy analysis.
DISCUSSION Results from this study seem to complement data published by Spruance et al.8,14 in 1988 and 1991 that acyclovir does not affect the immediate formation of herpes labialis lesions. However, there is a demonstrated effect on lesions formed during the follow-up period. Although the two populations were different, Spruance found no beneficial effect for patients who applied the topical cream after having been exposed to ultraviolet light. These data may indicate a residual antiviral effect, because administration of the drug had been stopped before the effect was noted. Rooney et al. 15 reported a residual antiviral result with oral acyclovir in 400 mg
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ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY December 1997
doses, whereas there was no such result with the placebo. Such a follow-up benefit had not been anticipated in this trial, which preceded that reported by Rooney. The effect of acyclovir had been expected to be limited to the days of application. Rooney was testing oral acyclovir, while our trial was with topical cream. The inability of topical acyclovir cream to positively affect the amount of pain associated with lesions is consistent with the results of previous trials. 6-11 The present trial was not designed to capture the pain effect of the test drug, because subjects were seen only once a day and were not seen at the same time each day. Also, treatment by acyclovir cream in a prophylactic fashion did not have an effect on the number of aborted lesions. This is not surprising, given the information reported by Spruance et al. 14 that the "immediate lesion subgroup" cannot be blocked. By way of explanation, it is postulated that some dormant viruses exist in the dendrites close to the surface. 16 On activation, these viruses replicate, causing the mucous membrane to ulcerate before dormant viruses in the ganglion are activated, begin replication, migrate to the surface, and cause a lesion. At the beginning of the trial it was not possible to identify the patients in whom the virus was latent in the dendrites. Future trial designers might wish to discount those lesions that occur early--within 48 hours of "trigger"--and follow only those lesions that emanate from the latent virus in the nerve ganglion (the so-called "second wave" of lesions). If acyclovir is to be effective, it must be present at appropriate tissue levels during the replication phase of the herpes virus. Even though the cream formulation of acyclovir persists and penetrates at the infected sites more effectively than ointment, it cannot do so at a rate or concentration great enough to alter the course of the disease in a pronounced fashion. Additionally, in herpes simplex labialis, the stratum comeum must be breached to get the active drug to infected tissues. Spruance and Freeman 12 postulate that in its current formulations acyclovir cannot be delivered in sufficient tissue concentrations to produce a clinically significant result. Penetration enhancers might increase the effectiveness of acyclovir in a topical formulation. Viral cultures were not done in this trial because the subjects provided confirmation on recurrences; this is similar to the approach used by Straus 17 and Kaplowitz.18 Because of the large sample size, blinding, and randomization, and in light of the experience of both the staff a n d - - i n particular--the subjects, viral confirmation was not necessary. The safety record of the drug used in the trial was satisfactory, inasmuch as there was no difference in the number of adverse experiences between the patients
treated with acyclovir and those given the placebo. In addition, the types of adverse experiences reported were of a minor nature; they included headache, backache, sore legs, nausea, and stomachache. The development of a resistant strain of herpes simplex virus has not been a major problem, especially for patients with normal immune systems. The literature reveals a paucity of information about whether there has been any resistant-strain development now that acyclovir cream for the treatment of herpes labialis is available in 28 countries (including Great Britain) on an over-the-counter basis. Herpes simplex labialis presents a continuing research challenge because of its prevalence in the population and because of the variable expression of its recurrence. This challenge is enhanced by our current inability to identify individuals who harbor the latent virus in the dendrites close to the surface of their orofacial tissues; these individuals will produce lesions immediately upon trigger, and this is the subset of lesions that is most difficult to affect clinically. The authors thank the following people for their participation: Drs. G. G. Krueger and M. L. Hamill of the University of Utah, Dr. J. Mills of San Francisco General Hospital, Dr. G. J. Mertz of the University of New Mexico, and Dr. H. C. McQuarrie of the University of Utah. REFERENCES
1. Young TB, Rimm EB, D'Alessio DJ. Cross-sectional study of recurrent herpes labialis. Am J Epidemiol 1988;127:612-25. 2. Young SK, Rowe NH, Buchanan RA. A clinical study for the control of facial mucocutaneous herpes virus infections. Oral Surg Oral Med Oral Pathol 1976;41:498-507. 3. Elion GB. The biochemistry and mechanism of action of acyclovir. J AntimicrobChemother 1983;12(suppl B):9-12. 4. Gibson JR, Klaber MR, Harvey SG, TosfiA, Jones D, Yeo JM. Prophylaxis against herpes labialis with acyclovir cream: a placebo controlled study. Dermatologica1986;172:104-7. 5. FiddianAP, Yeo JM, Stubbings R, Dean D. Successful treatment of herpes labialis with topical acyclovir. Br Med J 1983;286: 1699-701. 6. Shaw M, King M, Best JM, Banatvala JE, Gibson JR. Failure of acyclovircream in treatment of recurrent herpes labialis. Br Med J 1985;291:7-9. 7. Raborn GW, McGaw WT, Grace MGA, Samuels S, Percy J. Herpes labialis treatment with 5% modified aqueous cream: a double-blind, randomized trial. Oral Surg Oral Med Oral Pathol 1989;67:676-9. 8. Spruance SL, Hamill ML, Hoge WS, Davis GL, Mills J. Acyclovir prevents reactivation of herpes simplex labialis in skiers. JAMA 1988;260:1597-9. 9. RabornGW, McGawWT, Grace MGA, Houle L. Herpes labialis treatment with acyclovir 5% ointment. J Can Dent Assoc 1989;55:135-7. 10. Spruance SL, Schnipper LE, Overall JC, Kern ER, Wester B, Modlin, et al. Treatment of herpes simplex labialis with topical acyclovirin polyethyleneglycol. J Infect Dis 1982;146:85-90. 11. Spruance SL, Crumpaker CS. Topical 5% acyclovir in polyethylene glycol for herpes simplex labialis: antiviral effect without clinical benefit. Am J Med 1982;73:315-9.Symposium. 12. Spruance SL, Freeman DJ. Topical treatment of cutaneous herpes simplex virus infections. Antiviral Res 1990;14:305-21.
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ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
Volume 84, Number 6 13. Whitley RJ, Levin M, Barton N, Hershey BJ, Davis G, Kenney RE, et al. Infections caused by herpes simplex virus in the immunocompromised host: natural history and topical acyclovir therapy. J Infect Dis 1984;150:323-9. 14. Spruance SL, Freeman DJ, Stewart JCB, McKeough MB, Wenerstrom LG, Krueger GG, et al. The natural history of ultraviolet radiation-induced herpes simplex labialis and response to therapy with peroral and topical formulations of acyclovir. J Infect Dis 1991;163:728-34. 15. Rooney JF, Straus SE, Mannix ML, Wohlenberg CR, Ailing DW, Dumois JA, et al. Oral acyclovir to suppress frequently recurrent herpes labialis: a double-blind, placebo-controlled trial. Ann Intern Med 1993;118:268-72. 16. Spruance SL. Herpes simplex labialis. In: Sacks SL, Straus SE, Whitley RJ, Grifriths PD, et al., editors. Clinical management of herpes viruses. Washington: ISO Press; 1995. p. 6-7.
17. Straus SE, Tariff HE, Sedlin M, Bachrach S, Liniger L, DiGivanna JJ, et al. Suppression of frequently rectm'ing genital herpes: a placebo-controlled double-blind trial of oral acyctovir. N Eng J Med 1984;310:1545-50. 18. Kaplowitz LG, Baker D, Gelb L, Blythe J, Hale R, Frost P, et al. Prolonged continuous acyclovir treatment of normal adults with frequently recurring gential herpes simplex virus infection: the Acyclovir Study Group. JAMA 1991;265:747-51.
Reprint requests: G. Wayne Raborn, DDS, MS, dip ABOM University of Alberta Faculty of Medicine and Oral Health Sciences Edmonton, Alberta T6G 2N8 Canada
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Objective. A randomized, double-blind trial at seven ski sites in Canada and the United States was conducted to compare the effectiveness and the patient tolerance of topically applied 5% acycIovir cream (MAC III formulation) with those of a placebo cream in the prevention of sun-induced herpes labialis lesions. Study Design. All subjects had experienced more than three episodes of sun-induced herpes labialis during the previous year. There were 196 subjects enrolled; 5 did not receive medication, and 10 were excluded from the efficacy analysis for protocol violations. There were 191 subjects in the intent-to-treat analysis, and a separate efficacy analysis was done on 181 subjects. Log rank and Fisher exact tests were used in the analysis. Results. There was no difference between the two groups at baseline with respect to any clinical or demographic factor. There was no substantial difference between the groups with respect to adverse experiences (15 for acyclovir; 13 for the placebo). The acyclovir group had significantly fewer lesions (p < 0.01) than the placebo group (21% vs. 40%) during the 4-day follow-up period. Conclusion. The acyclovir group was significantly better than the placebo group during the follow-up period. The safety record of the drug was satisfactory; there was no difference between acyclovir and the placebo in side effects or pain. Topically applied 5% acyclovir cream is an effective preventive step for'those who are active and exposed to the sun. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84:641-5)
Lifetime prevalence of recurrent herpes labialis in the United States is estimated at between 20% and 40%, with approximately 100 million episodes occurring in the country every year.1 Recurrences of herpes labialis may be induced by emotional stress, high fevers, exposure to ultraviolet light, or nerve or oral tissue trauma. Although most episodes are mild, some may be severe and disfiguring. They often cause psychological distress and physical discomfort while also posing the risk of autoinoculation and transmission. Herpetic keratitis and Whitlow's infection of the fingers are other serious side effects. An estimated 10% of persons with herpes labialis seek medical care specifically for recurrent herpes labialis, and millions attempt some form of treatment. 2 Acyclovir is an acyclic nucleoside analog that displays in vivo antiviral activity against the herpes simplex 1, herpes simplex 2, Epstein-Barr, and varicella zoster viruses. 3 The unique feature of this compound is its affinity for virus-specified thymidine kinase; at the
This research was supported by a grant from Burroughs Wellcome, Canada. aDepartment of Oral Health Sciences, University of Alberta. bLaboratoire et Service d'Infectiologie, Centre de Recherche, Le Centre Hosp. de l'Universit6 Laval. Received for publication Oct. 30, 1996; returned for revision Jan. 9, 1997; accepted for publication Aug. 14, 1997. Copyright © 1997 by Mosby-Year Book, Inc. 1079-2104/97/$5.00 + 0 7/13/85715
same time, it has low human toxicity. The antiviral action of acyclovir derives from the fact that it inhibits viral replication by substitution into the viral DNA molecule and terminating the chain. Over the past several years, researchers have tested several topical acyclovir formulations against herpes labialis with inconsistent results. Notable success with the topical cream formulation, used prophylactically, was reported by Gibson et al. 4 in cases of recurrent lesions. In a study from the United Kingdom, Fiddian et al. 5 reported that the cream was effective in reducing healing and crusting time and in increasing the proportion of aborted lesions. The acyclovir cream formulation has been available in England and continental Europe for several years, even though Shaw et al. 6 reported a failure of the cream formulation in a 1985 trial. In North America, Raborn et al. 7 reported trends toward effectiveness in a trial of the cream. Spruance et al. 8 reported efficacy in the prevention of labialis lesions in Utah skiers with orally administered acyclovir (400 rag). All of these trials involved patients with normal immune systems. In several trials, 9-11 a 5% ointment formulation of acyclovir failed in treatment of herpes labialis in normal volunteers. The major reason suggested for the ointment failure was poor tissue penetration of the acyclovir. 12 In addition, the drug's antiviral effect depends on interruption of viral replication and on early drug therapy in the course of the disease. In contrast, Whitley 641
642
Raborn et al.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY December 1997
et al. 13 demonstrated the effectiveness of the 5% ointment in treatment of individuals with herpes labialis who were immunocompromised. The objective of the present trial was to compare the effectiveness of and patient tolerance for topically applied 5% acyclovir cream (MAC III formulation)* with those of a placebo cream in the prevention of suninduced herpes iabialis lesions.
MATERIAL AND METHODS This double-blind, randomized, placebo-controlled, multicentered trial enrolled subjects at seven ski sites in Canada and the United States. Each center represented a single ski site, and ethics approval was obtained from a Human Subjects Committee at each center. The study was funded by Burroughs Wellcome. Normal, healthy volunteers of either gender who were over the age of 18 years and who had experienced more than three episodes of sun-induced herpes labialis during the previous year met the entry criteria. Pregnant and nursing mothers were excluded; a standard urine pregnancy test was administered to each woman before she was given the study drug. Also excluded were subjects who had received antiviral medication during the week leading up to the study; subjects with known psychiatric disorders; subjects with underlying medical or surgical disorders that might alter their susceptibility to herpes simplex virus infections; and subjects with histories of eczema herpeticum, atopic dermatitis, or other skin conditions that would predispose them to eczema herpeticum.
Treatment procedures The subjects were all people who came to mountain areas to ski. They were entered into the study only if they had had no intensive sun exposure for at least 5 days before they began participating in the study. The subjects were given the study drug to apply 12 hours before intensive sun exposure (in other words, during the evening preceding the day they would start to ski). The study drug was applied five times per day: at bedtime, on waking, and three times during the course of the day at 4-hour intervals. This treatment continued for a period of at least 72 hours, to a maximum of 168 hours. Participants were required to use no analgesics other than acetaminophen and were barred from covering their faces with masks while skiing. The use of sunscreens was not permitted. Subjects were randomly assigned to either acyclovir or a placebo, with randomization done within each center. The subjects and all of the study personnel were blinded as to which treatment was being applied to which person. *Zovirax (GlaxoWellcome, Research Triangle Park, North Carolina).
Clinical evaluation Each subject was contacted daily and examined within 24 hours by a dentist, physician, physician assistant, or nurse if signs or symptoms of recurrent disease appeared. For each lesion, the location was recorded; the size was determined by measurement; and the stage was noted as "erythema," "papule," "vesicle," "ulcerated" or "eroded," "hard crusted," "dry flaking," "residual swelling," or "healed and associated pain." The period of daily sun exposure and the condition of the facial skin were noted. No cultures were required. Each subject was contacted either by mail or by phone 7 to 10 days after completing the study to determine whether there were any problems and to note any formation of lesions since discontinuation of the study drug. Study personnel (physician assistants and nurses) were trained in all evaluation and follow-up procedures. The vast majority of the subjects were monitored by personnel with previous experience in herpes labialis trials. Daily examinations of subjects took place at a central location in each skiing area. All subjects were provided an honorarium for .their time. Information was collected in case report forms, which included measurement techniques that had been shown to be valid and reliable in previous studies. 7,9 Formal calibration of all clinical trial personnel-nurses, physician assistants, and site coordinators (denfists and physicians)--was conducted by the granting agency before the trials. Clinical trial monitors and site coordinators were constantly in communication with study nurses and other clinical personnel to corroborate clinical findings, review patient histories, and make judgement calls with respect to inclusion criteria and other questions. Site visits were made weekly to the remote ski area sites, and cases were reviewed; diagnoses were confirmed by either dentists or physicians.
Statistical analysis Proportions of patients in each treatment group with clinical evidence of herpes labialis during the treatment period and during the 4-day follow-up were analyzed by means of a Fisher exact test. Estimates of time-tofirst-lesion for the treatment period and the treatmentperiod-plus-4-days follow-up were obtained with the Kaplan-Meier product-limit method, and p values were produced by means of a log rank test. For those subjects who experienced pain associated with lesions, duration of pain was analyzed with a log rank test.
RESULTS In this study there were 196 subjects enrolled from seven different sites. Five subjects who were enrolled but did not receive medication were excluded from the
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Table II. Patients in whom lesions formed during treat-
Table I. Demographics by treatment Patient characteristic Age (years) SD Gender (female/male) Race Caucasian Black Asian Self-perceived risk > 50% < 50%
ment*
Acyclovir n=95
Placebo n=96
Probability
37.2 + 10.2 54/41
36.7 __.9.0 49/47
0.52 0.51
95 0 0
94 1 1
0.47
58 37
60 36
0.90
analysis. The remaining 191 subjects (95 treated with acyclovir, 96 given the placebo) constituted the intentto-treat group and were included in the safety and efficacy analysis. Of these 191 subjects, 10 were excluded from the efficacy subset for various protocol violations that ranged from using lipstick while skiing to applying the study medication less than 12 hours before sun exposure. A separate efficacy analysis was conducted for the remaining 181 subjects (91 acyclovir, 90 placebo). There were no major differences among the various ski sites. For the intent-to-treat subjects, there were no differences between the placebo and acyclovir groups for the following factors: age, race, gender, number of recurrences within the past year, and usual duration of lesions. There was no difference between the two groups in their self-perceived assessment of the risk of incurring a herpetic lesion after sun exposure (Table I). For the intent-to-treat subjects, there was no significant difference between the 16% of the acyclovir group and the 25% of the placebo group who experienced lesions during the treatment period (Table II).
Safety analysis There was no significant difference between the acyclovir and placebo groups in adverse events during the treatment period. Twenty-eight subjects (15 acyclovir, 13 placebo) reported at least one adverse experience during treatment.
Efficacy subset The acyclovir group fared significantly better by a log rank test (p < 0.01) than the placebo group during the 4day follow-up period: 21% of the acyclovir subjects and 40% of the placebo subjects had lesions (Table III). The proportion with no lesions during the treatment-periodplus-4-days follow-up period also favored acyclovir (p < 0.01). The amount of pain that patients experienced
No. of patients (%) Study day
Acyclovir (n = 91)
Placebo (n = 90)
Probability
1 2 3 4 5 6 7 8 Totalst
2 (2) 2 (2) 2 (2) 1 (l) 3 (3) 3 (4) 2 (4) 0 (0) 15 (91)
0 (0) 4 (4) 3 (3) 2 (2) 3 (3) 8 (12) 1 (3) 2 (10) 23 (90)
0.24 0.68 1.00 1.00 1.00 0.13 1.00 0.49 0.20
*Fisher exact test; two-sided p values. *Number of subjects decreased each day because of healing; consequently, the denominator for each study day's percentage calculation is less than that for the preceding day.
Table III. Patients in whom lesions formed during fol-
low-up, excluding cases of protocol violation (n = 181)* No. of patients (%) Follow-up day
Acyclovir
Placebo
Probabilty
1 2 3 4
0 (0) 1 (1) 2 (2) 2 (2)
1 (1) 5 (6) 4 (5) 4 (5)
1.00 0.21 0.68 0.68
5
0 (0)
0 (0)
-
18 (21)
35 (40)
Totals (treatment plus follow-up) t
<0.01
*Fisher exact test; two-sided p values. tNumber of subjects decreased each day because of healing; consequently, the denominator for each study day's percentage calculation is less than that for the preceding day.
during treatment was not affected by the study medication. An intent-to-treat analysis provided results similar to those of the efficacy analysis.
DISCUSSION Results from this study seem to complement data published by Spruance et al.8,14 in 1988 and 1991 that acyclovir does not affect the immediate formation of herpes labialis lesions. However, there is a demonstrated effect on lesions formed during the follow-up period. Although the two populations were different, Spruance found no beneficial effect for patients who applied the topical cream after having been exposed to ultraviolet light. These data may indicate a residual antiviral effect, because administration of the drug had been stopped before the effect was noted. Rooney et al. 15 reported a residual antiviral result with oral acyclovir in 400 mg
644 Raborn et al.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY December 1997
doses, whereas there was no such result with the placebo. Such a follow-up benefit had not been anticipated in this trial, which preceded that reported by Rooney. The effect of acyclovir had been expected to be limited to the days of application. Rooney was testing oral acyclovir, while our trial was with topical cream. The inability of topical acyclovir cream to positively affect the amount of pain associated with lesions is consistent with the results of previous trials. 6-11 The present trial was not designed to capture the pain effect of the test drug, because subjects were seen only once a day and were not seen at the same time each day. Also, treatment by acyclovir cream in a prophylactic fashion did not have an effect on the number of aborted lesions. This is not surprising, given the information reported by Spruance et al. 14 that the "immediate lesion subgroup" cannot be blocked. By way of explanation, it is postulated that some dormant viruses exist in the dendrites close to the surface. 16 On activation, these viruses replicate, causing the mucous membrane to ulcerate before dormant viruses in the ganglion are activated, begin replication, migrate to the surface, and cause a lesion. At the beginning of the trial it was not possible to identify the patients in whom the virus was latent in the dendrites. Future trial designers might wish to discount those lesions that occur early--within 48 hours of "trigger"--and follow only those lesions that emanate from the latent virus in the nerve ganglion (the so-called "second wave" of lesions). If acyclovir is to be effective, it must be present at appropriate tissue levels during the replication phase of the herpes virus. Even though the cream formulation of acyclovir persists and penetrates at the infected sites more effectively than ointment, it cannot do so at a rate or concentration great enough to alter the course of the disease in a pronounced fashion. Additionally, in herpes simplex labialis, the stratum comeum must be breached to get the active drug to infected tissues. Spruance and Freeman 12 postulate that in its current formulations acyclovir cannot be delivered in sufficient tissue concentrations to produce a clinically significant result. Penetration enhancers might increase the effectiveness of acyclovir in a topical formulation. Viral cultures were not done in this trial because the subjects provided confirmation on recurrences; this is similar to the approach used by Straus 17 and Kaplowitz.18 Because of the large sample size, blinding, and randomization, and in light of the experience of both the staff a n d - - i n particular--the subjects, viral confirmation was not necessary. The safety record of the drug used in the trial was satisfactory, inasmuch as there was no difference in the number of adverse experiences between the patients
treated with acyclovir and those given the placebo. In addition, the types of adverse experiences reported were of a minor nature; they included headache, backache, sore legs, nausea, and stomachache. The development of a resistant strain of herpes simplex virus has not been a major problem, especially for patients with normal immune systems. The literature reveals a paucity of information about whether there has been any resistant-strain development now that acyclovir cream for the treatment of herpes labialis is available in 28 countries (including Great Britain) on an over-the-counter basis. Herpes simplex labialis presents a continuing research challenge because of its prevalence in the population and because of the variable expression of its recurrence. This challenge is enhanced by our current inability to identify individuals who harbor the latent virus in the dendrites close to the surface of their orofacial tissues; these individuals will produce lesions immediately upon trigger, and this is the subset of lesions that is most difficult to affect clinically. The authors thank the following people for their participation: Drs. G. G. Krueger and M. L. Hamill of the University of Utah, Dr. J. Mills of San Francisco General Hospital, Dr. G. J. Mertz of the University of New Mexico, and Dr. H. C. McQuarrie of the University of Utah. REFERENCES
1. Young TB, Rimm EB, D'Alessio DJ. Cross-sectional study of recurrent herpes labialis. Am J Epidemiol 1988;127:612-25. 2. Young SK, Rowe NH, Buchanan RA. A clinical study for the control of facial mucocutaneous herpes virus infections. Oral Surg Oral Med Oral Pathol 1976;41:498-507. 3. Elion GB. The biochemistry and mechanism of action of acyclovir. J AntimicrobChemother 1983;12(suppl B):9-12. 4. Gibson JR, Klaber MR, Harvey SG, TosfiA, Jones D, Yeo JM. Prophylaxis against herpes labialis with acyclovir cream: a placebo controlled study. Dermatologica1986;172:104-7. 5. FiddianAP, Yeo JM, Stubbings R, Dean D. Successful treatment of herpes labialis with topical acyclovir. Br Med J 1983;286: 1699-701. 6. Shaw M, King M, Best JM, Banatvala JE, Gibson JR. Failure of acyclovircream in treatment of recurrent herpes labialis. Br Med J 1985;291:7-9. 7. Raborn GW, McGaw WT, Grace MGA, Samuels S, Percy J. Herpes labialis treatment with 5% modified aqueous cream: a double-blind, randomized trial. Oral Surg Oral Med Oral Pathol 1989;67:676-9. 8. Spruance SL, Hamill ML, Hoge WS, Davis GL, Mills J. Acyclovir prevents reactivation of herpes simplex labialis in skiers. JAMA 1988;260:1597-9. 9. RabornGW, McGawWT, Grace MGA, Houle L. Herpes labialis treatment with acyclovir 5% ointment. J Can Dent Assoc 1989;55:135-7. 10. Spruance SL, Schnipper LE, Overall JC, Kern ER, Wester B, Modlin, et al. Treatment of herpes simplex labialis with topical acyclovirin polyethyleneglycol. J Infect Dis 1982;146:85-90. 11. Spruance SL, Crumpaker CS. Topical 5% acyclovir in polyethylene glycol for herpes simplex labialis: antiviral effect without clinical benefit. Am J Med 1982;73:315-9.Symposium. 12. Spruance SL, Freeman DJ. Topical treatment of cutaneous herpes simplex virus infections. Antiviral Res 1990;14:305-21.
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Volume 84, Number 6 13. Whitley RJ, Levin M, Barton N, Hershey BJ, Davis G, Kenney RE, et al. Infections caused by herpes simplex virus in the immunocompromised host: natural history and topical acyclovir therapy. J Infect Dis 1984;150:323-9. 14. Spruance SL, Freeman DJ, Stewart JCB, McKeough MB, Wenerstrom LG, Krueger GG, et al. The natural history of ultraviolet radiation-induced herpes simplex labialis and response to therapy with peroral and topical formulations of acyclovir. J Infect Dis 1991;163:728-34. 15. Rooney JF, Straus SE, Mannix ML, Wohlenberg CR, Ailing DW, Dumois JA, et al. Oral acyclovir to suppress frequently recurrent herpes labialis: a double-blind, placebo-controlled trial. Ann Intern Med 1993;118:268-72. 16. Spruance SL. Herpes simplex labialis. In: Sacks SL, Straus SE, Whitley RJ, Grifriths PD, et al., editors. Clinical management of herpes viruses. Washington: ISO Press; 1995. p. 6-7.
17. Straus SE, Tariff HE, Sedlin M, Bachrach S, Liniger L, DiGivanna JJ, et al. Suppression of frequently rectm'ing genital herpes: a placebo-controlled double-blind trial of oral acyctovir. N Eng J Med 1984;310:1545-50. 18. Kaplowitz LG, Baker D, Gelb L, Blythe J, Hale R, Frost P, et al. Prolonged continuous acyclovir treatment of normal adults with frequently recurring gential herpes simplex virus infection: the Acyclovir Study Group. JAMA 1991;265:747-51.
Reprint requests: G. Wayne Raborn, DDS, MS, dip ABOM University of Alberta Faculty of Medicine and Oral Health Sciences Edmonton, Alberta T6G 2N8 Canada
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