Double-blind, randomized, placebo-controlled study of topical 5% acyclovir-1% hydrocortisone cream (ME-609) for treatment of UV radiation-induced herpes labialis.

Abstract

Immunopathology is recognized as an important component of infectious disease manifestations, and corticosteroids have been used as an adjunct to antimicrobial therapy for a variety of conditions. Antiviral therapy of herpes labialis has been shown to result in only a small reduction in the time to healing and the duration of pain. To determine if topical application of a combination product containing 5% acyclovir and 1% hydrocortisone (ME-609) could provide benefit to herpes labialis patients, 380 immunocompetent adults with a history of herpes labialis were exposed to experimental UV radiation (UVR) to induce a recurrence. On day 2, just before the appearance of the majority of lesions ("delayed" lesions), subjects were randomized to receive active medication or vehicle control six times per day for 5 days. Overall, 120 of 380 patients developed delayed classical lesions, of whom 50 of 190 (26%) had been treated with ME-609 and 70 of 190 (37%) had received placebo (a reduction of 29% [P = 0.02]). Healing time, measured as the time to normal skin, was reduced by treatment with ME-609 (9.0 days for treated patients versus 10.1 days for the controls [P = 0.04]). There was a trend toward a reduction in the maximum lesion size in the ME-609 recipients compared to that in the controls (43 versus 60 mm(2), respectively [P = 0.07]). The treatment had no effect on lesion pain, but ME-609 treatment reduced the number of patients with moderate or severe tenderness. Compared to treatment with a placebo, treatment with the combination antiviral-immunomodulatory cream provided benefit to patients with experimental UVR-induced herpes labialis, reducing classical lesion incidence, healing time, lesion size, and lesion tenderness. ME-609 is a novel product that merits further evaluation as a treatment for cold sores.

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ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 2002, p. 1870–1874
0066-4804/02/$04.00?0DOI: 10.1128/AAC.46.6.1870–1874.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.
Vol. 46, No. 6
Double-Blind, Randomized, Placebo-Controlled Study of Topical 5%
Acyclovir–1% Hydrocortisone Cream (ME-609) for Treatment of UV
Radiation-Induced Herpes Labialis
T. G. Evans,1* D. I. Bernstein,2G. W. Raborn,3J. Harmenberg,4,5J. Kowalski,4,5and S. L. Spruance6
University of Rochester, Rochester, New York1; Children’s Hospital Research Foundation, Cincinnati, Ohio2; University of Alberta,
Edmonton, Alberta, Canada3; Medivir AB, Huddinge,4and Karolinska Institute, Stockholm,5Sweden;
and University of Utah, Salt Lake City, Utah6
Received 12 November 2001/Returned for modification 4 January 2002/Accepted 14 March 2002
Immunopathology is recognized as an important component of infectious disease manifestations, and
corticosteroids have been used as an adjunct to antimicrobial therapy for a variety of conditions. Antiviral
therapy of herpes labialis has been shown to result in only a small reduction in the time to healing and the
duration of pain. To determine if topical application of a combination product containing 5% acyclovir and 1%
hydrocortisone (ME-609) could provide benefit to herpes labialis patients, 380 immunocompetent adults with
a history of herpes labialis were exposed to experimental UV radiation (UVR) to induce a recurrence. On day
2, just before the appearance of the majority of lesions (“delayed” lesions), subjects were randomized to receive
active medication or vehicle control six times per day for 5 days. Overall, 120 of 380 patients developed delayed
classical lesions, of whom 50 of 190 (26%) had been treated with ME-609 and 70 of 190 (37%) had received
placebo (a reduction of 29% [P ? 0.02]). Healing time, measured as the time to normal skin, was reduced by
treatment with ME-609 (9.0 days for treated patients versus 10.1 days for the controls [P ? 0.04]). There was
a trend toward a reduction in the maximum lesion size in the ME-609 recipients compared to that in the
controls (43 versus 60 mm2, respectively [P ? 0.07]). The treatment had no effect on lesion pain, but ME-609
treatment reduced the number of patients with moderate or severe tenderness. Compared to treatment with a
placebo, treatment with the combination antiviral-immunomodulatory cream provided benefit to patients with
experimental UVR-induced herpes labialis, reducing classical lesion incidence, healing time, lesion size, and
lesion tenderness. ME-609 is a novel product that merits further evaluation as a treatment for cold sores.
Treatment of herpes simplex virus (HSV) infections with
antiviral drugs has been a major challenge for investigators for
more than 30 years. The benefits of treatment of recurrent
HSV infection have been modest in contrast to the benefits of
treatment of primary infection. The main clinical benefit in the
treatment of recurrences has been the modest reduction in
lesion healing time of approximately 10 to 15% (5, 10). Re-
current disease differs from the primary episode in that the
virus is cleared much more rapidly, usually within 3 days or
less. Although the immune response is quicker and more ef-
fective in controlling recurrent disease, it also may be respon-
sible for most of the clinical symptoms, which persist for up to
a week after the virus can no longer be isolated (6, 9). Thus, a
combined modality of therapy aimed at both an antiviral effect
and an immunomodulatory effect has been proposed in a num-
ber of studies (1, 9).
The availability of a small-animal model for evaluation of
the effects of treatment on the severity of recurrent lesions has
been a limiting factor in evaluations of therapy. A novel animal
model of recurrent HSV disease was recently developed by the
use of zosteriform HSV infection in mice combined with adop-
tive transfer of immunity (1). This model mimics both the
clinical parameters of reactivated HSV infection and the ef-
fects of antiviral treatment. Using this model, Awan et al. (1, 2)
evaluated many combinations of antiviral agents and immuno-
modulators. In those studies, the combination of 5% acyclovir
and 1% hydrocortisone in a topical cream (referred to as
ME-609) was shown to be optimal.
Multiple parameters have been used to assess herpes labialis
lesions (3, 5, 8, 9). These include the incidence of lesions, the
proportion of aborted lesions (lesions that do not develop
beyond the initial phase of a lesion with edema and redness,
known as the papule stage), the maximal lesion area, the de-
gree of pain, and the time to healing (measured as the time to
the complete loss of a hard crust or the time to normal skin).
No previously published trials of episodic treatment of humans
have shown a consistent influence of antiviral therapy on the
incidence of lesions or the proportion of aborted lesions.
The objective of the present clinical trial was to provide a
proof of concept as to whether a combination of an antiviral
agent with an immunomodulatory agent can provide benefits
to patients with recurrent HSV infections. To carefully control
patient self-medication and lesion severity assessments, we ex-
posed patients with a history of recurrent herpes labialis to
experimental UV radiation (UVR) and treated the induced
recurrences (7).
MATERIALS AND METHODS
Study medication. The clinical trial material consisted of 5% acyclovir and 1%
hydrocortisone (ME-609) or a placebo. The appearances of the two creams were
* Corresponding author. Present address: Division of Infectious
Diseases, University of California, Davis, 4150 V St., PSSB 500, Sacra-
mento, CA. Phone: (916) 734-3741. Fax: (916) 734-7766. E-mail: tgevans
@ucdavis.edu.
1870

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similar. Both creams were produced and packed in identical plastic containers by
CCS, Borlänge, Sweden.
Patient population. The study was conducted at four major university clinics in
North America. To be eligible, patients had to be ?18 years of age and had to
have a history of recurrent herpes labialis after exposure to sunlight in the
previous 12 months or to have had two or more cold sores in the previous 12
months. In addition, women of childbearing age had a documented negative
pregnancy test and used an acceptable method of birth control. All patients were
generally healthy, had a Fitzpatrick skin type category of 1 to 4, and signed an
informed consent form approved by the local institutional review board. The
patient could not have participated in any herpes UVR reactivation study within
the previous 3 months or have had an episode of herpes labialis within 30 days
before enrollment in the study.
MED determination and UVR exposure. At the screening visit, the patient’s
sensitivity to UVR was evaluated by determination of the minimal erythema dose
(MED), as described previously (8). In short, the forearm is irradiated with a
FS20 T12 sunlamp (National Biologic Corp., Twinsburg, Ohio) at a distance of
19 cm for 1, 2, 3, 4, 5, or 6 min. The power at the irradiation site was measured
with a handheld meter and averaged approximately 1 mW/cm2; the power did not
differ between the two treatment groups. Patients who did not develop a reaction
following 6 min of exposure were excluded from further study. The lips of the
patients were exposed to UVR (study day 0) within 7 days of the initial reading.
The half of the lips (either the lower lip, the upper lip, or the right or left portions
of both the lower and upper lips) that was regarded as the usual site of recur-
rence was exposed to UVR as described above for a duration four times the
MED, as described previously (3, 8, 11). The remainder of the lips and the
perioral skin outside this zone were covered with a para-aminobenzoic acid-
containing sunscreen with a sun protection factor of at least 30.
Study procedure and lesion evaluation. After the screening history, local
examination, pregnancy test, signing of the informed consent, and MED deter-
mination, eligible patients were randomized 1:1 to the two treatment groups
without stratification. The containers were dispensed by study personnel such
that neither the patients nor the investigators were aware of the treatment
assignments. On the morning of the second day after UVR exposure, patients
were instructed to apply the study medication (ME-609 or the corresponding
placebo) six times daily for 5 days to the whole area that was exposed to UVR.
If patients developed a lesion, treatment was continued until healing (complete
loss of the hard crust) or for a maximum of 5 days. Patients returned to the clinic
on study day 1, 3, 7 or 8, and 15 and were evaluated for the development of
lesions. “Immediate lesions” were defined as those that arose within 2 days of
UVR, and “delayed lesions” were those that occurred 2 to 7 days after exposure
to UVR. Immediate lesions are of uncertain etiology and pathophysiology and
have not responded to antiviral drugs in previous studies (3, 7, 11). Therefore,
only lesions that developed during the 2- to 7-day period following UVR expo-
sure (delayed lesions) were evaluated. If a lesion that was deemed to be due to
HSV developed, the patients were monitored daily until crusting of the lesion or
the development of a hard crust and then every second day thereafter until the
return of normal skin.
The first delayed lesion to develop was defined as the study lesion. Lesions
other than the study lesion and other changes in the status of the skin or lip were
noted but were not monitored in the present study. Only one lesion per patient
was thus included in the evaluation presented here. Lesions were further cate-
gorized as aborted (those that did not progress beyond the papule stage) or
classical (those that progressed to vesicles, ulcers, or hard-crust stages or a
combination of such stages).
During the study the patients were instructed to record on patient diary cards
lesion stage, the presence or absence of pain and tenderness, and the severity of
pain and tenderness three times daily. Clinical assessment of lesion severity was
performed by the investigator after the patient was consulted and included
observations of lesion stage, measurement of the lesion area (defined as the
product of the length and the width), and assessment of pain and tenderness.
Lesion stages were prodrome, erythema, papule, vesicle, ulcer or soft crust, hard
crust, residual swelling or dry flaking, and normal skin, as described previously (7,
11). Two predefined definitions of healing were used: return to normal skin and
loss of a hard crust. Pain and tenderness were recorded as mild, moderate, or
severe. The duration of pain and tenderness was recorded from its first occur-
rence until its first recorded permanent absence. Tenderness was defined as
unpleasant effects upon touching the affected region, while pain was used to
describe the global unprovoked soreness. The patients were also asked to assess
whether the current episode was better, the same, or worse than their usual
recurrences.
Virus isolation. Specimens of the lesions for virus isolation were obtained
during the vesicle and ulcer stages through the use of cotton swabs. The speci-
mens were processed as described elsewhere (3). In short, the swabs were
immediately placed into viral transport medium, inoculated onto tissue cultures
at each study site, and observed for at least 7 days for evidence of a cytopathic
effect.
Data analysis. The population of interest was the patients who developed
delayed classical lesions. The lesion variables examined included development of
delayed classical lesions, time to healing (defined as the time to the loss of a hard
crust or the time to normal skin), maximum lesion area, pain, tenderness, dura-
tion of individual lesion stages including aborted lesions that did not progress
past the papule stage, positive virus cultures, and patient assessment.
The time to the loss of a hard crust and the time to normal skin were analyzed
by analysis of variance by adjusting for differences between study sites with
log-transformed (e-log) data. Censured data were not observed in this analysis.
The following other variables were also analyzed by analysis of variance, adjust-
ing for differences between study sites: time to normal skin on square root-
transformed data, maximum lesion size, and duration of pain and duration of
tenderness with log-transformed (e-log) data. The incidence of delayed classical
lesions, the frequency of pain, and the frequency of tenderness were analyzed by
logistic regression. The severity of tenderness, the severity of pain, and the
patient’s opinion of the lesion were analyzed by use of a logit model. The
transformation of all variables was followed by a check for the normality of
the data. All tests were two sided, with significance being a P value of 0.05. The
statistical analysis software used was STATISTICA (version 5.5; StatSoft Inc.,
Tulsa, Okla.).
RESULTS
Characteristics of the study population. In total, 417 pa-
tients were enrolled in the study. Thirty-seven patients under-
went evaluation for determination of the MED but were not
subsequently exposed to UVR (mainly due to failed determi-
nation of the MED) and thus were not treated with the study
medication. A total of 380 patients were exposed to UVR and
treated with at least one dose of study medication (safety
population) (Table 1). A total of 145 (38.2%) of these patients
developed a lesion. Twenty-one of the 145 patients (14.5%)
developed lesions immediately before the start of administra-
tion of the study medication. These lesions were noted but
were not monitored. One hundred twenty patients (31.6%)
developed delayed classical lesions (intent-to-treat [ITT] pop-
ulation). All data shown are derived from the ITT population.
Evaluation of the per-protocol population revealed similar re-
sults.
Overall, 80% of the patients were females. The average age
was 39 years (age range, 18 to 76 years), and the mean number
of herpes labialis episodes per year prior to the study was 5.3.
The average duration of UVR exposure was 13 min (range, 4
TABLE 1. Patient disposition and type of developed lesion
Patient disposition
No. of patients
ME-609
group
Placebo
group
All
Randomized 209208 417
Not exposed to UVR 19 1837
Safety population 190 190380
Did not develop lesion
ITT population
Delayed classical lesions
Delayed aborted lesions
Immediate lesions
123
67
50
112
78
70
235
145
120
31
7
4
1421
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to 24 min) in the two treatment groups. There were no notable
differences between the two treatment groups.
Development and evaluation of lesions. Only 50 of 190 pa-
tients (26%) developed delayed classical lesions (lesions that
developed between 46 h and 7 days following UVR exposure)
during treatment with ME-609, whereas 70 of 190 patients
(37%) treated with placebo cream developed delayed classical
lesions, a reduction of 29% (P ? 0.022). In addition, three
patients in the ME-609 group and one patient in the placebo
group experienced delayed lesions that did not progress be-
yond the papule stage (delayed aborted lesion). As shown in
Fig. 1, 101 of the 120 patients in the study (84%) with delayed
classical lesions exhibited lesions that appeared on the first or
second day after the initiation of therapy (2 to 3 days after
UVR exposure). Only 17 patients treated with ME-609 re-
ported the occurrence of a delayed classical lesion during the
first day of treatment, whereas 40 patients treated with placebo
reported the occurrence of a delayed classical lesion during the
first day of treatment, a reduction of 58%. The reduction in the
incidence of a delayed classical lesion during the first day of
treatment with ME-609 thus explains the overall reduction of
incidence in the entire study.
The 50 patients in the ME-609 treatment group who devel-
oped delayed classical lesions had a median time to healing to
normal skin of 9.0 days, whereas the time was 10.1 days (P ?
0.037) for the 70 placebo-treated patients who developed de-
layed classical lesions (Table 2). Similarly, the healing time
measured as the time to the loss of the hard crust was reduced
19% by ME-609 treatment, from 6.8 to 5.4 days, although this
reduction did not reach statistical significance (P ? 0.084). The
Kaplan-Meier curves of time to normal skin are shown in Fig.
2.
ME-609 treatment also reduced the median maximal lesion
area of the delayed classical lesions by 28% (P ? 0.072). The
mean durations of the lesion stages in patients with delayed
classical lesions are shown in Fig. 3. The major effect of ME-
609 treatment was on the vesicle and crusting stage, whose
durations were reduced by a total of 1.6 days (25%) compared
with the durations in patients who received the placebo treat-
ment.
The present study is the first study of herpes labialis to divide
unpleasant sensations into pain, which was an overall measure
of unprovoked soreness, and tenderness, which described un-
pleasantness upon touch of the region of a lesion. Pain was
evaluated as the proportion of patients who developed classical
delayed lesions and who reported pain. In addition, the sever-
ity of pain and the duration of pain were also studied. No
statistically significant treatment effects with respect to pain
were observed in the study. Eighty-one percent of placebo
recipients and 76% of those receiving ME-609 developed pain.
Moderate pain developed in 26 and 36% of the placebo and
FIG. 1. Start of lesions shown as time from UVR exposure in
patients developing classical lesions, per treatment group. Day zero
includes the first 24 h following UVR exposure. ?, ME-609; I, pla-
cebo.
FIG. 2. The Kaplan-Meier curve (ITT population) for time to nor-
mal skin in patients with delayed classical lesions, per treatment group.
Cum. prop., cumulative proportion; thick line, ME-609; thin line, pla-
cebo.
TABLE 2. Treatment effects (ITT population) with respect to development of delayed classical lesions and all lesions
VariableME-609 group Placebo groupImprovement (%)P value
Incidence of delayed classical lesions (no. of
patients with lesions/total no. evaluated)
Median time to loss of hard crust (days [range])
Median time to normal skin (days [range])
Median maximum lesion area (mm2[range])
50/190 70/190 28.6 (1.69a)
0.022
5.4 (1.6–13.2)
9.0 (4.0–19.1)
43.5 (6–450)
6.8 (1.9–19.6)
10.1 (1.9–24.3)
60.0 (4–364)
19.2
11.2
27.5
0.084
0.037
0.072
aOdds ratio.
1872EVANS ET AL.ANTIMICROB. AGENTS CHEMOTHER.

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the ME-609 groups, respectively, and severe pain developed in
11 and 4% of the placebo and the ME-609 groups, respectively.
Forty-two of the patients who were treated with ME-609 and
who developed delayed classical lesions experienced tender-
ness, whereas 65 patients who were in the control group and
who developed delayed classical lesions experienced tender-
ness (odds ratio, 2.94; P ? 0.11) (Table 3). In addition, only 18
of the ME-609-treated patients experienced tenderness of
moderate or severe intensity, whereas 38 patients in the pla-
cebo group experienced tenderness of moderate or severe in-
tensity. The overall severity of tenderness was reduced by an
odds ratio of 2.33 (P ? 0.018). In addition, there was a trend
toward a reduction in the median duration of tenderness in the
ME-609-treated patients from 5.0 to 4.0 days (P ? 0.078). Only
8 of the ME-609-treated patients who developed delayed clas-
sical lesions graded their current episode as “worse than their
usual recurrences,” whereas 24 patients in the placebo group
gave their lesions such a grade. The overall patient opinion of
the current episode was more favorable for the patients treated
with ME-609 than for those treated with placebo, with an odds
ratio of 2.78 (P ? 0.006) (Table 3).
Virologic evaluations. Viral swabs from 34 of 49 (69%) ME-
609-treated patients with delayed classical lesions and 54 of 70
(77%) of the placebo-treated patients with delayed classical
lesions were positive for virus isolation at least once (P was not
significant). The times to cessation of viral shedding were sim-
ilar for both groups (data not shown).
Adverse events. The incidence and nature of adverse events
were similar for both treatment groups. The treatment was well
tolerated, and there were no serious adverse events.
DISCUSSION
A large number of individuals suffer from recurrent herpes
labialis and seek treatment. A wide variety of treatment mo-
dalities have been used, including pain relievers, antivirals,
moisturizers, or combinations of these agents. Therapy with
topical acylovir ointment alone has little to no benefit in the
treatment of recurrent cold sores. Topical penciclovir cream
and acyclovir cream have been shown to reduce the time to
healing by less than 1 day (4, 10).
The signs and symptoms of herpes labialis are in part due to
the inflammatory response that ensues following viral reacti-
vation. Accordingly, combination therapy with drugs with im-
munomodulatory properties such as topical corticosteroids
along with antiviral agents may have added clinical benefit
compared to the use of antivirals alone. In the study reported
here we have shown that the combination of an antiviral and an
immunomodulatory cream (ME-609) reduced the severity of
experimental UVR-induced herpes labialis, as defined by clas-
sical lesion incidence, healing time, lesion size, and lesion ten-
derness. In the present study, the incidence of delayed classical
lesions was reduced by 29% when the ME-609 combination
treatment was used compared with the incidence with the use
of a placebo. Numerous previous studies have clearly shown
that episodic treatment with antiviral drugs alone does not
influence the incidence of the classical and aborted lesions that
develop (3, 5, 8, 10, 11).
The prevention of classical cold sores was achieved in a
clinical model of viral reactivation in which treatment was
given from the morning of the second day following the UVR
exposure, at a time just prior to the onset of the majority of
lesions induced in this model. The events that follow UVR
exposure and that lead to reactivation of virus in the trigeminal
nerve are rapid (within hours in animal models), and treatment
started on the morning of the second day would be unlikely to
affect these early events. Treatment starting on the morning of
the second day after UVR exposure may correspond to very
early episodic treatment, similar to therapy initiated for the
treatment of naturally occurring lesions during the prodromal
symptom phase of disease.
The use of the antiviral properties of acyclovir in combina-
tion with the immunomodulatory properties of hydrocortisone
in the treatment of recurrent HSV disease is a novel concept
FIG. 3. Median durations of lesion stages in patients (ITT popula-
tion) with delayed classical lesions. The papule stage (I) is the time
from the start of a lesion (papule) to the time of observation of the first
vesicle. The vesicle stage (0) is the time of observation of the first
vesicle to the time of the first sign of crusting. The crusting stage (u)
is the time from the first sign of crusting to the time of the loss of the
hard crust. The healing stage (?) is the time from the loss of the hard
crust to normal skin.
TABLE 3. Treatment effects (ITT population) of secondary
parameters with respect to delayed classical lesions
Variable
ME-609
group
Placebo
group
Odds
ratio
P value
No. of patients experiencing
tenderness
42 652.94 0.110
Severity of tenderness
(no. of patients)
None
Mild
Moderate
Severe
85
24
14
4
27
29
9
2.330.018
Patient opinion of the episode
(no. of patients)
Better than usual
Same as usual
Worse than usual
3229
17
24
9
8
2.780.006
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Page 5

previously tested in a smaller pilot study (9). That study differs
from the one reported here in terms of both the medications
used and the timing of treatment. Spruance and McKeough (9)
exposed 49 patients to UVR in order to induce herpes labialis.
All patients were instructed to start treatment with study drugs
for 5 days at the first sign or symptom of a recurrence and
received high-dose famciclovir (500 mg three times daily
orally) in conjunction with either a potent corticosteroid cream
(0.05% Lidex gel three times daily) or a placebo cream. Be-
cause treatment was initiated at the start of the occurrence of
a lesion in the pilot study, the incidence of recurrences could,
by definition, not be altered by treatment. The most beneficial
outcome in that study was an aborted lesion, which is a lesion
that does not progress to the typical lesion stages of classical
herpes labialis (vesicle, ulcer, crust). The investigators found
that 41% of the patients treated with the combination therapy
developed aborted lesions, whereas 8% of the patients in the
arm that received famciclovir only developed aborted lesions.
The results of the present study together with the results of the
pilot study indicate that as many as one-third of the patients
with herpes labialis have episodes that may be prevented or
aborted by combination therapy.
The combination treatment (ME-609) used in our study
reduced the healing times for the 50 patients who developed
delayed classical lesions approximately 11 to 19% compared
with the healing times for the 70 placebo-treated patients. In
addition to the benefit provided by the 29% decrease in the
incidence of delayed classical lesions, ME-609 thus also re-
duced the healing times and maximal lesion sizes in the pa-
tients who did develop lesions, notwithstanding treatment. The
reduction in healing times found in the present study is similar
to the reduction in healing times found in large-scale field trials
of the treatment of herpes labialis with topical formulations of
antiviral compounds such as acyclovir and penciclovir (4, 10).
Corticosteroids would not be expected to accelerate wound
healing, and indeed, this was the outcome in both the present
study and the pilot study with famciclovir-corticosteroid cream
(Lidex gel). The results of efficacy in a presumptive treatment
trial with the UVR model do not necessarily imply efficacy in
a natural history study. Nevertheless, because of the promising
results obtained with the UVR model described here, a study
evaluating early treatment of naturally occurring recurrent
herpes simplex infections is warranted.
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