Management of recurrent oral herpes simplex infections

Sook-Bin Woo, DMD,a and Stephen J. Challacombe, PhD, FDSRCS, FRCPath,b Boston, MA,
and London, UK
HARVARD SCHOOL OF DENTAL MEDICINE AND KING’S COLLEGE LONDON DENTAL INSTITUTE
AT GUY’S

The literature has been reviewed for evidence of the efficacy of antiviral agents in both the prophylaxis and
treatment of recurrent oral herpes simplex virus (HSV) infections and discussed by a panel of experts. Emphasis was
given to randomized controlled trials. Management of herpes-associated erythema multiforme and Bell palsy were also
considered. The evidence suggests that 5% acyclovir (ACV) in the cream base may reduce the duration of lesions if
applied early. Recurrent herpes labialis (RHL) and recurrent intraoral HSV infections can be effectively treated with
systemic ACV 400 mg 3 times a day or systemic valacyclovir 500 to 1000 mg twice a day for 3 to 5 days (longer in
the immunocompromised). RHL in the immunocompetent can be effectively prevented with (1) sunscreen alone (SPF
15 or above), (2) systemic ACV 400 mg 2 to 3 times a day, or (3) systemic valacyclovir 500 to 2000 mg twice a day.
Valacyclovir 500 mg twice a day is also effective in suppressing erythema multiforme triggered by HSV. Further
studies are needed to compare treatment efficacy between topical penciclovir, docosanol, and ACV cream for RHL.
(Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103(suppl 1):S12.e1-S12.e18)

Herpes simplex virus-1 (HSV-1), an alpha herpes virus,
is a large DNA virus that causes primary herpetic
gingivostomatitis, mucocutaneous orofacial disease,
and ocular disease; recurrent lesions are common on the
face and on the lips and less common intraorally. Oc-
casional cases are caused by HSV-2; or HSV-1 may
present as a primary genital infection.1 HSV-1 infection
of the cornea (keratitis) is a major cause of infection-
related blindness in the world. HSV transmission is
from direct contact with infected secretions and the
majority of primary infections are subclinical. Data
from the National Health and Nutrition Examination
Survey (NHANES) III revealed that in the United
States, 40% of those under 20 years old are antibody
seropositive for HSV-1, increasing to 65% in those
older than 70 years.2
After primary infection, the virus ascends sensory
axons via retrograde axonal flow, replicates, and estab-
lishes latency within the trigeminal ganglion.3 During
latency, there is down-regulation of the replicative pro-
cess, infectious virus and viral antigens are not detect-
able, and the virus evades immune surveillance. When
an appropriate trigger occurs (such as illness, sunlight,
trauma, emotional stress, or menses), the virus reacti-
vates, replicates in the ganglion, and travels centrifu-
a
Assistant Professor, Department of Oral Medicine, Infection and
Immunity, Harvard School of Dental Medicine.
b
Department of Oral Medicine, King’s College London Dental Insti-
tute at Guys, London, UK.
1079-2104/$ - see front matter
© 2007 Mosby, Inc. All rights reserved.
doi:10.1016/j.tripleo.2006.11.004
gally along the axon to the skin or mucosal site. This is
the “ganglion theory” of reactivation. There, it is di-
rectly cytopathic to the epithelial cells resulting in
vesicles and ulcers. The virus may also establish la-
tency in non-neuronal sites such as within the epithe-
lium of the primary infection although this concept is
controversial.4 A recent study using HSV-induced 3-
dimensional organotypic tissue culture showed typical
lytic changes in skin keratinocytes and expression of
latency associated transcripts (LAT) gene suggesting
the possibility of skin latency at least in vitro.5
Reactivation of HSV can occur as asymptomatic
shedding in secretions such as saliva, or the develop-
ment of clinical lesions that will be termed recrudescent
HSV here. Shedding of HSV-1 has wide variability and
was noted in 1% to 25% of days when oral swabs were
taken.6 Shedding over a 1-week period before and after
dental treatment was reported to range from 8.3% to
10.3% with high genome copies in the saliva.7 Using
polymerase chain reaction (PCR) and samples collected
over many months, 68% of patients had asymptomatic
shedding while 32% had recrudescent lesions.8 Asymp-
tomatic shedding therefore occurs much more fre-
quently than previously thought, and the incidence in-
creases when subjects are sampled over longer periods
of time using more sensitive techniques such as PCR
rather than culture. In general, PCR techniques detect
HSV 3 to 4 times more often than cultures.9,10
Although HSV shedding from the oral cavity occurs at
a lower rate than genital shedding, it is likely that
asymptomatic shedding is a major risk factor for trans-
mission.11 Reactivation also depends on the strain of
HSV-1.12 Interestingly, asymptomatic HSV-2 shedding

S12.e1

S12.e2 Woo and Challacombe
in the oral secretions occurs during new or recurrent
HSV-2 infections in 3.2% of patients, mainly in males
infected with human immunodeficiency virus (HIV).13
Seroconversion is noted only in 75% to 84% of
patients with an oral/lip HSV infection.8,11,14 In one of
these studies, some patients remained seronegative in
spite of developing immune reactive T cells directed
against HSV.14 Serum and salivary neutralizing anti-
bodies do not play a significant role in the control of
recurrent infections, although lactoferrin and hypothio-
cyanite levels were higher in asymptomatic seroposi-
tive subjects.15
Cell-mediated immunity is the primary mechanism
for the control of both initial and recurrent infections
and in the modulation of recurrent HSV infections. This
is borne out by the fact the mucocutaneous HSV infec-
tions are more severe in patients with impaired or
defective cell-mediated immunity but not in patients
with agammaglobulinemia (reviewed by Stanberry
et al.16). In particular, CD8 positive cytotoxic T cells,
natural killer (NK) cells, macrophages and TH1-like
cytokines (interferon [IFN]-gamma and interleukin
[IL]-2 production) may be particularly important in
containment of HSV infections.
Recrudescent HSV-1 lesions in immunocompetent
patients occur at the junction of the vermilion and the
cutaneous lip as recurrent herpes labialis. Intraorally,
they occur almost exclusively on the keratinized mu-
cosa of the hard palate and the attached gingiva, and
occasionally on the dorsum of the tongue, readily dis-
tinguishing them from recurrent aphthous ulcers.17
However, recurrent HSV infections in patients who
have compromised immune systems are often atypical.
Management of recrudescent HSV in this group of
patients is discussed in a later section.
HSV AND OTHER ORAL DISEASES
In a well-controlled study, HSV-1 gene products
were identified in 77% and 57% of the facial nerve
endoneurial fluid and posterior auricular muscle speci-
mens respectively of patients who had Bell’s palsy
(using PCR followed by Southern blot analysis).
This suggests that HSV-1 neuropathic effects may be
an important mechanism in the etiopathogenesis of this
disease.18 Other studies have shown increased shedding
of HSV DNA in patients with Bell’s palsy.19,20 Treat-
ment with acyclovir plus prednisone resulted in better
outcomes than placebo with prednisone21 or no
treatment.22
Although HSV is not cultured from lesions of ery-
thema multiforme, HSV gene products are detected in
71% of patients with recurrent erythema multiforme,
and in 27% of patients with nonrecurrent erythema
multiforme.23 In erythema multiforme with a known
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March 2007
clinical association with herpes, the detection rate is up
to 81%.24 The detection of HSV in dry sockets may
represent shedding after trauma rather than a cause-
effect relationship.25
RECURRENT HERPES LABIALIS
Recurrent herpes labialis (RHL) occurs in 20% to
40% of the population.26-28 The general population
refers to such lesions as “cold sores” or “fever blisters.”
Patients notice a prodrome of tingling, itching, or burn-
ing followed by a papule that progresses to vesicular,
crusted, and healing stages; the outer one third of the
lips are the most frequently affected.29 Those who
experience a prodrome (60%) tend to have larger le-
sions.29 Vesicles develop within hours and progress to
ulceration and crusting within 72 to 96 hours. Such
rapid progression of disease may be a result of multi-
focal inoculation of the lip from a single neuron.29
Infectivity is highest within the first 24 hours of the
appearance of lesions with 80% of vesicles and 34% of
ulcer/crust lesions yielding positive HSV cultures.29
Although larger lesions take longer to heal, the time to
the end of the vesicle stage is not different between
large and small lesions. Because lesions are very short
lived (unless the patient is immunocompromised), the
treatment window is correspondingly short.
Most episodes of RHL are self-limited and mild.
However, under some circumstances, recurrent RHL
can be more than a nuisance including numerous epi-
sodes a year, painful lesions, lesions of long duration;
lesions that are large and unsightly, lesions that trigger
erythema multiforme, and lesions in immunocompro-
mised patients.30 There has therefore been much inter-
est in developing agents that not only effectively treat
outbreaks (by aborting lesions or by reducing the du-
ration and size of lesions, or pain experienced at each
episode), but also agents that suppress outbreaks alto-
gether. In general, prophylaxis regimens for patients
who experience mild outbreaks 1 to 2 times a year
would not be recommended because of the risk of
developing drug-resistant strains29-31 and the cost ver-
sus benefit.
Early treatment agents
In the 1970s, trials using agents such as iodode-
oxyuridine,32 cytosine arabinoside,33 neutral red,34
chloroform,35 and ether36 to treat RHL did not show
efficacy. Lysine at 1000 mg per day versus placebo had
little significant effect on the course of RHL37 while
another study using the same dose showed fewer recur-
rences (by diary) provided serum lysine levels were
kept high.38 Three percent vidarabine gel resulted in
smaller lesions compared with placebo39 while ionto-
phoresis of vidarabine monophosphate resulted in a
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Volume 103, Number 3, Suppl 1
reduced period of viral shedding and time to formation
of dry crust.40 Levamisole (an immunomodulating
agent) treatment (using 50, 100, and 150 mg of drug
versus placebo for 3 days at the onset of lesions)
resulted in increased frequency of episodes with
increasing doses of drug although lesions were less
painful and of shorter duration.41 However, another
placebo-controlled study using levamisole showed a
reduction in frequency of recurrences compared to
prestudy rates.42
These early trials did not use precise measurements,
often lacked controls, and relied overly on subjective
observations by the patient or investigator. Most of
these agents are no longer used today because of the
availability of more efficacious treatment modalities,
although some such as lysine may merit reevaluation
with better-controlled trials.
Stages of RHL infection
Eight stages of RHL have been recognized: pro-
drome, erythema, papule, vesicle, ulcer/soft crust, hard
crust, dry flake (desquamation at the lesion site), and
residual swelling.43 Newer studies use fewer, simplified
end points. Early lesions include prodromal symptoms
and erythema, and late lesions include papular, vesic-
ular, and crusted lesions. End points are measured as
time to loss of hard crust (from onset of papule) and
time to complete healing (restoration of normal skin).
Most of the well-designed clinical trials required pa-
tients to be seen within 12 to 24 hours of the prodrome,
and to be followed daily until loss of hard crust or
complete healing. Other end points that are not consis-
tently measured but are useful include size of lesions,
severity of pain, abortion of lesions (nonprogression
beyond papule stage), and development of satellite
lesions.
Current therapies
For this next section, only placebo-controlled clinical
trials (unless otherwise stated) involving healthy indi-
viduals are discussed. There have been no trials on
subjects under the age of 18, and the term “significant”
refers to statistical significance. The trials varied some-
what in design. RHL may have been established by
history alone and/or with serology. Outbreaks may or
may not be monitored by investigators or be monitored
by diary entries alone. Lesions may or may not be
cultured and compliance with drug use was not always
recorded. In spite of these shortcomings, they provide
important evidence-based data for clinical practice.
Topical acyclovir. Acyclovir (ACV) is a synthetic
acyclic analogue of 2=-deoxyguanosine with inhibitory
activity against HSV-1 and other herpes viruses that
came into use in the 1980s (reviewed by Balfour44).
Woo and Challacombe S12.e3
After 3 phosphorylations (the first by thymidine kinase
produced by the HSV), the ACV triphosphate inserts
into the HSV DNA polymerase and synthesis of viral
DNA stops, terminating chain elongation and HSV
replication.44 ACV therefore has the distinct advantage
of being active primarily in virally infected cells (high
selectivity) and has minimal toxicity in other tissues.
ACV is available in oral and intravenous (IV) prepara-
tions, but after oral administration, the bioavailability
of ACV is only 20%.45
Randomized, placebo-controlled clinical trials have
been performed using 5% ACV in a cream or ointment
base to treat RHL (Table I). Those using an ointment
base of polyethylene glycol 4 to 5 times a day for 5
days showed no difference in lesion duration, pain
duration, or size of lesions between drug and placebo
groups.46,48,49 There was significantly reduced viral
shedding only in a subgroup of patients who began
treatment in the early papular stage.46 Increasing the
concentration of ACV to 10% did not make a differ-
ence.59 Only 1 study using the ointment showed sig-
nificantly shorter time to crust formation and complete
healing.47
In similar treatment trials using 5% ACV in a cream
formulation (in propylene glycol or modified aqueous
cream base) applied 5 times per day for 5 days at the
earliest onset of the prodrome, there was significant
reduction in the duration of vesicles,50 time to crust
formation, and duration of lesions.51,52 The cream also
resulted in more aborted lesions in 1 study,51 although
another study did not show this.52 The reduction in time
to the crust stage was usually by 1 day and total healing
time by 0.5 to 2 days. A double-blind placebo-con-
trolled crossover trial that used the cream prophylacti-
cally showed significantly fewer recurrences and fewer
days with disease and symptoms.53 However, other
similarly conducted studies showed no significant dif-
ference between drug and placebo.54-56 It was subse-
quently shown that ACV penetration in a modified
aqueous cream was 8 times higher than in the oint-
ment.60 A recent study found that ACV cream in 40%
propylene glycol delivered 10-fold more ACV than an
identical formulation containing 15% propylene glycol
in a percutaneous permeation study.61
A trial using 5% ACV in a liposomal carrier (etho-
some) compared with 5% ACV in a cream and placebo
found a significant reduction in time to crusting and
time to loss of crust with the liposomal carrier.57 A
preparation of 5% ACV cream and 1% hydrocortisone
cream was significantly better than placebo in reducing
the frequency of delayed classical lesions and reducing
healing time.58 In Europe, topical ACV is available as
an over-the-counter 5% cream.
 S12.e4
Woo and Challacombe
Table I. Trials using acyclovir ointment and cream
Size of
Author Agent N Time to loss of crust Duration of lesions Duration of pain lesion Others
46
Spruance et al. (1982) 5% ACV in PEG 208 NS NS NS NS Reduced shedding
Fiddian and Ivanyi (1983)47 5% ACV ointment 13 S (3 vs 4 d) S (6 vs 8 d) ND ND S for more aborted lesions
Raborn et al. (1988)48 5% ACV in PEG 60 NS NS NS NS
Raborn et al. (1989)49 5% ACV in ointment 60 NS NS NS S
Van Vloten et al. (1983)50 5% ACV in propylene 30 NS; S for 1st episodes NS; S for 1st episodes NS ND S for decreased time of
glycol; 1 to 3 (5.7 vs 8.3 d) (2.0 vs 2.6 d) vesiculation
episodes
Fiddian et al. (1983)51 5% ACV cream; 2 55 S (1 vs 2 d) S (4 vs 6 d) NS ND S for more aborted lesions
episodes if applied in early stage
(33% vs 8%) – 1st
episodes only
Spruance et al. (2002)52 5% ACV cream; 2 1385 ND S; study 1 (4.3 vs 4.8 d); S; study 1 (2.9 vs 3.2 d); ND NS for more aborted
studies study 2 (4.6 vs 5.2 d) study 2 (3.1 vs 3.5 d) lesions even if applied
early
Gibson et al. (1986)53 5% ACV cream 23 ND ND ND ND S for mean number of
days with lesions and
symptoms; S for fewer
recurrences
Shaw et al. (1985)54 5% ACV cream; 45 NS ND NS ND
crossover trial
Raborn et al. (1989)55 5% ACV in MAC 51 NS NS NS NS
Ottevanger et al. (1996)56* 5% ACV cream in 2 59 NS NS NS NS No placebo was used
formulations
Horwitz et al. (1999)57 5% ACV in ethosome 40 S – only in crossover ND NS ND S for time to crusting
vs ACV cream vs arm; ethosome vs ACV in ethosome vs
placebo; crossover ACV (1.8 vs 3.5 d) ACV cream (4.2 vs
trial 5.9 d)
Evans et al. (2002)58 5% ACV cream and 380 ND S (9.0 vs 10.1 d) NS NS S for reduced frequency
1% HCT of delayed classical
lesions (26% vs 37%)
N, number of patients; ACV, acyclovir; PEG, polyethylene glycol; d, day(s); S, statistically significant at P ⬍ .05 or greater; NS, not significant; ND, not done; MAC, modified aqueous cream;
HCT, hydrocortisone.
*Trial was not placebo-controlled.

March 2007
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Volume 103, Number 3, Suppl 1
The evidence suggests that:
(1) 5% or 10% ACV in ointment base is not efficacious
for treating RHL in healthy patients because of
poor penetration. (IA)
(2) 5% ACV in the cream base may be efficacious in
reducing the duration of lesions especially if ap-
plied early during the prodrome; however, it has
little effect on reducing pain. (IA)
(3) Since statistically significant differences be-
tween drug and placebo are often reported in 1 to
2 days only, patients who have more severe and
longer episodes are the most likely to derive
benefit from therapy.
(4) The use of different carriers (such as liposomal
carriers) and the addition of an anti-inflammatory
agent to ACV may significantly enhance its action.
(IB)
(5) It may be helpful to control trigger factors that
activate the virus since this is an earlier event.
Systemic (oral) ACV. Because of the limited effec-
tiveness of topical ACV, several randomized, double-
blind, placebo-controlled trials were undertaken using
oral ACV for treatment or prophylaxis of RHL (Table
II). In 1 treatment study using 200 mg of ACV 5 times
a day versus placebo, there was significantly shorter
healing time (by approximately 1 day), reduction in
size of lesions, and reduced viral shedding (11% versus
34%).62 In another study using 400 mg of ACV 5 times
a day versus placebo, there was significantly less-fre-
quent HSV shedding (25% versus 48%) and reduction
in duration of pain by 36%. Reduction in healing time
by 27% was seen only in the group that started treat-
ment early in the prodrome or early erythema stage.
However, there was no difference in the frequency of
aborted lesions.43 One study on ACV prophylaxis in
skiers (200 mg twice a day) showed approximately 4
times fewer subjects developed RHL in ACV users
versus placebo users (7% versus 26%), this occurring
only after day 4.64 In a crossover prophylaxis trial using
400 mg ACV twice a day, RHL took significantly
longer to develop in the ACV group (median time
increased by 2.5 times), and there was a 53% reduc-
tion in the number of clinical recurrences and a 71%
reduction in the number of virologically confirmed
recurrences.63
These results are in contrast to the higher efficacy
(80%-90%) seen in oral ACV in suppressing and treat-
ing recrudescent genital HSV.74 This may be because
of difference in susceptibility of HSV-1 and HSV-2,
differences in triggering factors, and/or lower levels
of ACV in oral versus genital secretions. One study
Woo and Challacombe S12.e5
showed that patients who received oral ACV for
treating HSV infection had saliva and vaginal ACV
levels that were 13% and 79% of plasma levels,
respectively.75
Overall, results for treatment of oral herpes infec-
tions appear modest when compared with treatment of
genital herpes infections. Possible explanations that
have been suggested are (1) that the oral viral inoculum
is comparatively larger than the genital at the early
stages, (2) at the time of the earliest sign of infection it
is already too late for virustatic agents to reverse the
damage done by HSV, and (3) the doses used have not
been optimized.43
Role of ultraviolet radiation (UVR) in RHL. Skiers,
who participated in a randomized, double-blind, place-
bo-controlled trial of 200 mg ACV twice a day versus
placebo, exhibited an interesting phenomenon. Within
the first 4 days, there was no difference in the frequency
of recurrences between drug or placebo groups (5 ver-
sus 8 subjects)64 (Table II). However, from days 5
through 7 of treatment, there were 11 cases of recur-
rences in the placebo group and none in the ACV
group. One explanation for this striking difference may be
that active drug levels had not yet reached a high enough
level during the first 4 days. Another is that there was
already present nascent subclinical micro-foci of HSV
infection that had been previously reactivated and were
now present in the lip before treatment initiation.64
To better understand the nature of such lesions,
an experimental model was developed where RHL was
experimentally induced by ultraviolet radiation (ex-
pUVR).65 A small area of the volar surface of the forearm
was exposed to expUVR at different time intervals. The
shortest time that caused a homogeneous erythematous
reaction with distinct margins to develop within 24 hours
was labeled “minimal erythema dose.” To induce RHL,
half of the vermilion of the upper or lower lip where RHL
normally occurred was exposed to 4 times this dose with
the rest of the skin covered with sunscreen.
Immediate and delayed RHL. Using this model in 20
volunteers who were exposed on 3 occasions, 45%, 45%,
and 70% of subjects developed RHL on each of the 3
occasions, and HSV was isolated from 72% of lesions.76
Twenty-one percent were “immediate lesions” that devel-
oped within 2 days and those that developed within 3 to 7
days were called “delayed lesions.” Patients developed
either “immediate” or “delayed” lesions but not both.
There was a significant association of development of
RHL and the luteal phase of the menstrual cycle.76 In
another study where topical or systemic ACV was used in
conjunction with this model (n ⫽ 96), placebo recipients
showed a similar bimodal distribution of RHL with 26%
developing “immediate” lesions.65
Patients treated prophylactically with 200 mg ACV 5
Table II. Trials using oral ACV and valacyclovir*

S12.e6
Time to loss of Time to Size of
Authors Agent N crust normal skin Duration of pain lesions Others
Raborn et al. 200 mg 5 x/d ⫻ 5 d, followed 149 S (8.5 vs 7.0 d) NS NS NS S for reduced frequency of positive HSV
(1987)62

Woo and Challacombe

over 3 episodes cultures (11% vs 34%); S for smaller
lesions for episodes 2 and 3
Spruance et al. 400 mg 5 x/d ⫻ 5 d 174 S only if treated NS S only if treated NS S for reduced frequency of HSV positive
(1990)43 early (5.8 vs early (2.5 vs cultures (25% vs 48%); NS for more
7.9 d) 3.9 d) aborted lesions
Rooney et al. 400 mg 2 x/d ⫻ 4 mo, 20 ND ND ND ND S for median time to recurrence (118 vs 46 d),
(1993)63 crossover mean number of recurrences (0.9 vs 1.8)
and mean no. of HSV ⫹ recurrences (0.4 vs
1.4)
Spruance et al. 200 mg 2 x/d 12 hours prior 147 ND ND ND ND S for fewer recurrences (7% vs 26%)
(1988)64 to UV exposure, up to 7 d
Spruance et al. 200 mg 5 x/d immediately 30 ND ND ND ND S for completely suppressing delayed lesions
(1991)65 after expUVR (100%)
200 mg 5 x/d 7 d prior to 36 NS for suppression of immediate lesions
expUVR
200 mg 5 x/d ⫻ 5 d, 48 h 40 S (6.0 vs S (8.1 vs NS S (52 vs 153 NS for frequency of aborted lesions and
after expUVR 11.6 d) 12.5 d) mm) frequency of HSV ⫹ cultures
Spruance et al. 5% ACV cream after expUVR 90 NS NS NS NS NS for frequency of aborted lesions; S for
(1991)65 frequency of HSV ⫹ culture in delayed
lesions (58% vs 92%)
Duteil et al. Sunscreen vs placebo prior to 19 ND ND ND ND S for frequency of recurrences (5% vs 58%)
(1998)66 expUVR, crossover trial
Rooney et al. Sunscreen vs placebo prior to 38 ND ND ND ND S for frequency of recurrences (75% and 67%
(1991)67 expUVR; crossover trial vs 0%)
Raborn et al. 800 mg ACV 2 x/d ⫻ 3-7 d; 237 ND NS ND S (6.6 mm vs NS for suppression of lesions
(1998)68 natUVR 5.2 mm)
Laiskonis et al. Study 1: 1000 mg 2 x/d ⫻ 1 d 99 ND NS for median NS (both 1.5 d) ND 45.9% aborted lesions
(2002)69* healing time
Study 2: 500 mg 2 x/d ⫻ 3 d 99 48.5% aborted lesions
valacyclovir
Chosidow et al. 500, 1000, or 2000 mg qd 249 NS ND ND ND NS in frequency of aborted lesions
(2003)70 valacyclovir
Spruance et al. Study 1: 2 g 2 x/d ⫻ 1 d Study 1: 292 S (reduced by S (reduced by S (reduced by 0.4- ND NS for aborting lesions
(2003)71 Study 2: 2 g 2 x/d ⫻ 1 d then Study 2: 317 mean of 1.1- mean of 0.8 d)
1 g 2 x/d ⫻ 1 d 1.4 d) 0.8-1.1 d)
valacyclovir
Baker and Eisen 500 mg qd valacyclovir 98 ND ND ND ND S for reduced recurrence (40% vs 62%)
(2003)72
Miller et al. 2 g 2 x/d ⫻ 1 d, 1 g 2 x/d ⫻ 125 ND ND S (mean time to ND S for reduced recurrence of HL (11% vs 21%)

March 2007
(2004)73 1 d valacyclovir; patients pain cessation and reduced HSV shedding (1.6% vs 7.9%)

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about to undergo dental reduced 3.2 vs
treatment 6.2 d)
N, number of patients; ACV, acyclovir; d, day(s); S, statistically significant at P ⬍ .05 or greater; NS, not significant; ND, not done; exp, experimental; UVR, ultraviolet radiation; nat, natural; x/d, times
per day; HSV, herpes simplex virus; HL, herpes labilais.
*All trials were placebo-controlled.
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Volume 103, Number 3, Suppl 1
times a day either 7 days before expUVR exposure for 14
days, or immediately following expUVR exposure for 7
days showed no difference in the frequency of RHL
compared with placebo overall; however, delayed lesions
were completely suppressed65 (Table II). Patients given
the same dose of ACV versus placebo 48 hours after
expUVR showed no difference in frequency of recur-
rences but there was significant reduction in time to
loss of crust and time to complete healing as well as
reduction in lesion size. The use of the ACV cream
versus placebo immediately after expUVR showed
no significant differences in clinical end-point
measures.
A prophylaxis trial where skiers took 800 mg ACV
twice a day 12 to 24 hours before sun exposure
showed only significant difference in lesion size
compared with placebo but no difference in fre-
quency of recurrences or healing time.68 However, the
use of sunscreen only versus placebo showed 95% to
100% suppression of recurrences in 2 crossover trials
using this model.66,67 This study implicates UVR as a
powerful trigger for RHL.
Delayed lesions occur in the same temporal pattern
as do lesions following trigeminal ganglion surgery (3
to 6 days after surgery) and is consistent with viral
reactivation in the ganglion (reviewed by Spruance74).
Some believe that immediate lesions (that occur in
20%-44% of subjects) evolve too quickly after ex-
pUVR or natural UVR to conform to a “ganglion trig-
ger”64,67 and may instead provide evidence of virus in
the epithelium at the time of irradiation, that is, the
“skin trigger” theory.77 Because there is no “travel
time” for axonal transport of the virus, the virus repli-
cates and causes lesions within 24 to 36 hours of the
triggering event. However, this is controversial since
travel time of the virus is 2 to 16 mm per hour
and travel time from the ganglion to the periphery could
take less than 24 hours (reviewed by Miller3).
Nevertheless, the “non-prodromal-classical” lesions
arise as a papule, are of shorter duration, and do not
respond to antiviral therapy. Perhaps the lack of re-
sponse is because the shorter duration of such lesions
does not allow time for treatment effect to show sig-
nificance in trials.74 The occurrence of prodromal
symptoms reflects seeding of the epidermis from in-
fected neurons and “prodromal-classical” lesions are of
longer duration and respond to antiviral therapy.
The evidence suggests:
(1) Systemic (oral) ACV at 200 to 400 mg taken 5
times a day for 5 days to treat RHL reduces healing
time by 1 to 1.5 days, reduces pain by 1 to 1.5 days,
and reduces HSV shedding especially if started
early. (IA) No clinical trials have been performed
Woo and Challacombe S12.e7
on the commonly used dosage of 400 mg 3 times a
day.
(2) Immediate nonprodromal lesions of RHL are dif-
ficult to abort with oral ACV at even 800 mg twice
a day. (IIB)
(3) Virustatic agents have to be started early before a
critical mass of virus has replicated, since once
epithelial cells are damaged, this damage cannot be
reversed.
(4) Systemic (oral) ACV at 200 mg 2 to 5 times a day
may suppress delayed lesions (IA), but 800 mg
twice a day may not suppress RHL although lesions
are smaller. (IIB) No clinical trials have been per-
formed on 400 mg 3 times a day for prophylaxis.
(IA)
(5) Sunscreen alone reduces the incidence of recurrent
RHL. (IA)
Valacyclovir. Valacyclovir is the L-valyl ester and
pro-drug of ACV that is well absorbed after oral ad-
ministration. Its rapid and almost complete conversion
(99%) to ACV in the gastrointestinal tract and liver
results in a 3- to 5-time increase in bioavailability.44
The plasma ACV level following oral administration
of valacyclovir is similar to that achieved with IV
ACV.78,79
In a non-placebo-controlled trial of valacyclovir at
either 1000 mg twice a day for 1 day, or 500 mg twice
a day for 3 days for recurrent orofacial HSV (at least
80% were RHL), 44% of subjects reported abortion of
lesions, especially if the drug was taken in the pro-
drome stage.69 One treatment trial using 1 dose of 500
mg, 1000 mg, or 2000 mg of valacyclovir starting in the
prodrome did not show any difference in the frequency
of aborted lesions compared with placebo for any of the
doses70 (Table II). However, another treatment trial
using 2000 mg of valacyclovir twice a day for 1 or 2
days versus placebo showed a significant reduction in
duration of the episode; 2 days of treatment was not
more efficacious than 1 day of treatment.71 Time to loss
of crust and duration of pain were also significantly
reduced. This dosage regimen, however, did not abort
lesions.
Prophylaxis studies using valacyclovir 500 mg once
a day versus placebo for 16 weeks showed significant
reduction in recurrences (60% versus 38%) and a
longer mean time to recurrence (13 weeks versus 10
weeks)72 (Table II). Another prophylaxis study used
valacyclovir 2000 mg before dental procedures and a
second 2000 mg dose in the evening, with two 1000-mg
doses the following day.73 There were significantly
fewer recurrences in the drug versus placebo group
(11% versus 21%), fewer patients who tested positive
 OOOOE
S12.e8 Woo and Challacombe March 2007

Table III. Trials using penciclovir and famciclovir*

Time to loss Time to Duration of Size of
Authors Agent N of crust normal skin pain lesions Others
Spruance et al. 1% penciclovir 1573 S (HR 1.33) ND S (HR 1.22) ND S for reduced time to
(1997)84 cream every cessation of HSV
2h⫻4d shedding (HR 1.35);
NS for frequency of
aborted lesions
Raborn et al. 1% penciclovir 3057 S (HR 1.31) ND S (HR 1.28) ND NS for frequency of
(2002)85 cream 6 x/d aborted lesions
Boon et al.86 1% penciclovir 553 S (4.8 vs 5.9 d) S (7.6 vs 8.8 d) S (7.0 vs 8.0 d) S (numbers not Not true placebo
(2000) cream every provided) because purified
2h⫻4d water was used
Spruance et al. 125 mg, 250 mg, 248 S for 500 mg ND NS S for 500 mg group NS for frequency of
(2001)87 and 500 mg group vs vs placebo (mean lesions or aborted
famciclovir 3 placebo max area 55 vs lesions
x/d ⫻ 5 d; exp (median time 139 mm)
UVR 4 vs 6 d)
Spruance et al. 500 mg 48 NS NS S (no. of patients S (median max size NS for frequency of
(2000)88 famciclovir with pain 59% 48 vs 162 mm) aborted lesions
3 x/d 0.05% vs 100%)
fluocinonide
gel vs 500 mg
famciclovir
and vehicle
placebo
N, number of patients; ACV, acyclovir; d, day(s); S, statistically significant at P ⬍ .05 or greater; HR, hazard ratio; NS, not significant; ND, not
done; exp, experimental; UVR, ultraviolet radiation; x/d, times per day.
*All were placebo-controlled.

for HSV in the saliva (2% versus 8%), and shorter
duration of pain (3 days versus 6 days).
Achieving and maintaining high concentrations of
ACV in the plasma above the HSV-1 99% inhibitory
concentration during the period of early viral replica-
tion can interrupt the 2 to 3 cycles of viral replication
needed to produce clinically apparent lesions.71,80 Such
levels are attainable with valacyclovir but are not pos-
sible with topical therapy or oral ACV that has low
bioavailability. In general, valacyclovir is well toler-
ated, has minimal toxicity, and resistance to it remains
low.81
The evidence indicates that:
(1) Valacyclovir at 1000 mg twice a day may abort
lesions. (IB)
(2) Valacyclovir at 2000 mg twice a day for even 1 day
shortens the duration of episodes and pain (IB)
(3) Valacyclovir at 500 mg once a day suppresses
recurrences of RHL. (IB)
(4) Valacyclovir at 2000 mg twice a day on the day of
dental procedures followed by 1000 mg twice a day
the day after suppresses HSV recurrences. (IB)
(5) Valacyclovir 500 mg twice a day is effective in
suppressing erythema multiforme triggered by
HSV if ACV fails, probably because of better bio-
availability. (IB)
Penciclovir and famciclovir. Penciclovir, an acyclic
nucleoside analogue similar to ACV, is phosphorylated
by viral thymidine kinase (TK) and also inhibits viral
DNA polymerase.44,82 As such, it too has specific ac-
tion against virally infected cells. It has a higher affinity
for HSV TK than ACV and a prolonged half-life in
HSV-infected cells that is 0 to 20 times longer than
ACV (10-20 hours versus 0.7-1.0 hour), which makes
up for its low potency in inhibiting DNA polymerase
compared to ACV.83 Its long half-life allows for less
frequent dosing.44,84 However, it is poorly absorbed
when given orally and is therefore formulated for IV
and topical use. Its pro-drug, famciclovir (see later in
this section), has better bioavailability (41% versus
9%).
Penciclovir in 1% in an aqueous cream base with
40% propylene glycol was used in 2 large studies of
more than 1000 patients each, with patients applying it
every 2 hours from the prodrome84,85 (Table III). There
was a significant reduction in healing time (hazard ratio
[HR] 1.31-1.33) and duration of pain (HR 1.22-1.28)
between drug and placebo groups regardless of whether
the cream was applied early (prodrome and erythema
stages) or late (papular stage).84 Time to cessation of
HSV shedding was significantly shorter in patients who
applied the cream early.84 Similar findings of reduced
OOOOE
Volume 103, Number 3, Suppl 1
healing time, reduced duration of pain, and reduced
lesion size were noted by Boon et al.86; however, the
placebo was purified water and not the vehicle. Topical
penciclovir is Food and Drug Administration (FDA)-
approved for the treatment of RHL.
A study comparing 1% penciclovir to 3% ACV
cream was difficult to assess because the group con-
sisted of patients with both primary and recrudescent
facial and labial HSV infections.89 Another study com-
paring 5% ACV cream to 1% penciclovir cream
showed significant reduction in both time to crusting
and duration of pain for subjects using penciclovir,90
but it was unclear if this was randomized or blinded.
Famciclovir, a diacetyl-6-deoxy analogue and pro-
drug of penciclovir, is rapidly absorbed after oral ad-
ministration and metabolized by deacetylation in the
gastrointestinal tract, blood, and liver to penciclovir
(see above paragraphs).
Two studies have used this agent for treating RHL.
Using the expUVR model and varying doses of famci-
clovir (125 to 500 mg), there was no difference in the
frequency of recurrence regardless of the dose. How-
ever, the highest dose (500 mg 3 times a day) resulted
in the smallest lesions and shortest median time to
healing91 (Table III). When famciclovir (500 mg 3
times a day) and topical fluocinonide gel was compared
with the same dose of famciclovir and placebo gel, the
combination therapy reduced lesion size and the num-
ber of patients who experienced pain; however, the
number of aborted lesions was not significantly differ-
ent between groups.88
The evidence suggests that:
(1) 1% penciclovir cream is effective in reducing time
to loss of crust, duration of lesions, and duration of
pain. (IA)
(2) Famciclovir at 125 to 500 mg does not suppress
RHL but lesions are smaller and last a shorter
period of time. (IA)
Topical docosanol. N-docosanol is a saturated 22-
carbon alcohol that inhibits HSV replication by inter-
fering with early intracellular events surrounding viral
entry into target cells. Its mechanism of action is still
poorly understood.92 It does not directly disrupt or
inactivate HSV since preincubation with the virus does
not reduce infectivity. It also does not prevent binding
of the virus to target cells indicating that the virus
remains intact and that HSV receptors are neither spe-
cifically nor sterically blocked. It is a highly lipophilic
compound and it targets viruses with lipid-containing
envelopes such as HSV. It probably inhibits fusion of
the HSV envelope with the plasma membrane and
therefore blocks subsequent viral replicative events.93
Because it does not act via thymidine kinase or DNA
Woo and Challacombe S12.e9
polymerase, it is active against ACV-resistant HSV
strains. It is the only over-the-counter drug that is
FDA-approved for the treatment of RHL.
There have only been 2 trials using topical docosanol
to treat RHL (Table IV). One was a randomized, pla-
cebo-controlled crossover trial that showed that treat-
ment with 10% n-docosanol cream, applied 5 times a
day for 10 days, reduced healing time significantly (by
1.6 to 4.6 days) with early treatment (in the prodrome
and erythema stage) having the most benefit.94 The
second, larger, study, using the same dosing schedule,
showed significant reduction in healing time (median
difference of 18 hours) and time to end of the ulcer/soft
crust stage (the most infectious stage) as well as shorter
duration of pain and other symptoms.95 However, the
placebo was polyethylene glycol and not the vehicle for
the active drug.
The evidence suggests that:
(1) 10% docosanol is effective in reducing the healing
time and pain of RHL. (IB)
Topical foscarnet. Foscarnet sodium (trisodium
phosphonoformate hexahydrate) is an organic analogue
of inorganic pyrophosphate. It forms complexes with
viral DNA polymerase and blocks viral DNA exten-
sion.44 Like docosanol, it does not act through the
action of thymidine kinase and is effective for ACV-
resistant HSV infections. There is no oral formulation
and the drug is given IV or topically.
Patients who used 3% foscarnet cream versus pla-
cebo in the early prevesicular stage of RHL exhibited a
shorter time to cessation of HSV shedding (using the
Mantel-Cox regression analysis) and more patients in
the drug group had aborted lesions using the Fisher
Irwin test96 (Table IV). In the expUVR model, 3%
foscarnet cream used to prevent RHL did not lead to
fewer recurrent lesions or more aborted lesions com-
pared with placebo but there was significant reduc-
tion in lesion size and reduced time to healing of
classic lesions by Kaplan Meier survival analysis.97
One disadvantage is that topical foscarnet requires
compounding.
The evidence suggests that:
(1) 3% foscarnet cream reduces HSV shedding, results
in more aborted lesions, and may reduce lesion size
and duration. (IIaB) However, it is recommended
that foscarnet should be used only if lesions are
known to be ACV-resistant.
RECURRENT ERYTHEMA MULTIFORME
Patients who experience recurrent erythema multi-
forme following episodes of recurrent HSV infection
 OOOOE
S12.e10 Woo and Challacombe March 2007

Table IV. Trials of docosanol and foscarnet

Time to loss Time to Duration of
Authors Agent N of crust normal skin pain Lesion size Others
Habbema et al. 10% n-docosanol 63 S (5.7 vs 7.3 d) ND ND ND S is most marked if
(1996)94 cream, crossover applied early
5 x/d ⫻ max 10 d
Sacks et al, 10% docosanol 737 S@ (3.6 vs 3.9 d) S (4.1 vs 4.8 d) S (2.2 vs 2.7 d) ND NS for frequency of
(2001)95* cream 5 x/d ⫻ aborted lesions;
max 10 d placebo was
polypethylene
glycol and not
vehicle
Lawee et al. 3% foscarnet every 149 NS NS NS NS S for shorter time to
(1988)96 2h⫻5d cessation of HSV
shedding if
applied early;
S for more aborted
lesions if applied
early
Bernstein et al. 3% foscarnet; 302 S (by Kaplan NS NS S (mean of NS for frequency of
(1997)97 expUVR every Meier analysis) 48 vs 81 mm) lesions;
2h⫻7d NS for frequency of
aborted lesions
N, Number of patients; d, day(s); S, statistically significant at P ⬍ .05 or greater; NS, not significant; ND, not done; exp, experimental; UVR,
ultraviolet radiation; x/d, times per day; @, time to loss of soft crust.
*Not placebo-controlled.

showed suppression of both RHL lesions and erythema
multiforme on oral ACV at doses of 400 mg twice a
day.98 Seventy percent of patients showed continuously
suppressed erythema multiforme compared with 0% of
those on placebo (n ⫽ 20).98 In a case of HSV-induced
recurrent erythema multiforme, valacyclovir at 500 mg
twice daily completely suppressed HSV and recurrent
erythema multiforme after ACV at 400 mg twice a day
failed to do so.99
Valacyclovir, 500 mg twice a day, is effective in sup-
pressing erythema multiforme triggered by HSV if ACV
fails, probably because of better bioavailability. (IB)
IMMUNOCOMPROMISED HOSTS
Recrudescent HSV-1 in the immunocompromised
host, such as those with acquired immunodeficiency
syndrome (AIDS), those undergoing cytoreductive
therapy, or those on immunosuppressive drugs (espe-
cially after organ transplantation) may develop any-
where in the oral cavity as single or multiple ul-
cers.100,101 They often occur on the nonkeratinized
tissues and when single, resemble recurrent aphthous
ulcers; only 13% are associated with RHL.102 They
may be large, progressive, and persistent, and diagnosis
is often delayed because of the atypical presentation.
Ulcers that developed during chemotherapy for hema-
tological malignancies were positive for HSV by cul-
ture in 48% to 61% of cases.100,103,104 In 1 study of
patients after marrow transplantation, 82% shed
HSV.105 Predisposing factors include a pretransplanta-
tion diagnosis of leukemia, being in remission at the
time of transplantation, and the use of chemoradiother-
apy.101 Oral recrudescent HSV may lead to HSV vire-
mia and life-threatening disseminated disease.106
TREATMENT OF HSV INFECTIONS
Topical 5% ACV ointment versus placebo was used
to treat 63 patients post–renal transplantation or with
leukemia who developed recurrent HSV infections
(more than 70% were RHL).107 Patients with lesions
greater than 50 mm2 in area benefited the most in terms
of pain resolution, time to healing, and cessation of
HSV shedding (mean difference of 6 days). Only 70%
of patients had healed lesions by day 21. IV ACV (250
mg/m2 every 8 hours) versus placebo used to treat 97
immunocompromised patients (after marrow and other
organ transplantation) showed reduced duration of
HSV shedding (2.8 versus 16.8 days), faster healing
(9.3 versus 13.5 days), and reduced pain.108 This was
confirmed in other studies.109,110 Because patients un-
dergoing chemotherapy for hematologic malignancies
have a high tendency to develop recrudescent HSV
infections, management was directed toward prophy-
laxis in this group of patients.
PROPHYLAXIS OF HSV INFECTIONS
Subsequent studies of systemic ACV used to sup-
press HSV recrudescence in patients undergoing bone
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Volume 103, Number 3, Suppl 1
marrow transplantation or chemotherapy for leukemia
showed dramatic results (80% to 100% suppression
compared with placebo).111-115 These trials used vary-
ing doses of ACV such as IV doses of 250 mg/m2 every
8 to 12 hours or oral doses at 200 to 400 mg 5 times
a day.
Valacyclovir at 1g twice a day compared with IV
ACV 250 mg/m2 twice a day completely suppressed
recrudescent HSV in 30 patients undergoing autolo-
gous stem cell transplantation.116 The pharmacy cost of
oral valacyclovir was approximately one third that of
using IV ACV. In another suppression trial of a similar
population, 500 mg of valacyclovir twice a day (n ⫽
108) versus historical controls on IV ACV 5 mg/kg
twice a day (n ⫽ 43) found rates of HSV reactivation to
be 2.0% and 2.7% respectively; all recrudescent lesions
in patients on valacyclovir were genital in nature while
those on ACV were oral in nature.117 However, cul-
tures were not done on all patients. Fifteen percent of
patients had oral intolerance or oral mucositis after
valacyclovir and had to be switched to IV ACV.
Valacyclovir at 500 mg twice a day in another
prophylaxis trial was compared with historical controls
of ACV given 4 times a day (600 mg oral or
125 mg/m2IV) for patients undergoing autologous bone
marrow transplantation (n ⫽ 60).118 None of the pa-
tients developed oral or oropharyngeal HSV infection
while receiving either treatment. Thirty-seven percent
of the patients on oral valacyclovir had to switch to IV
ACV because of nausea and vomiting. Another study
where patients undergoing induction or consolidation
therapy for leukemia (n ⫽ 81) were given 500 mg or
1000 mg of valacyclovir orally 3 times a day resulted in
100% suppression of recrudescent HSV.119
In 1 trial of IV penciclovir (5 mg/kg) 2 or 3 times a
day versus IV ACV (5 mg/kg) 3 times a day to treat
patients with hematological malignancies or post–
organ transplantation who develop mucocutaneous
HSV infection (n ⫽ 342), penciclovir at both dosing
regimens and ACV showed comparable efficacy with
20% of patients in each of the 3 groups developing oral
HSV. Penciclovir given 2 times a day has a more
convenient dosing schedule compared with ACV.120
Patients undergoing solid organ transplantation are
generally not given prophylaxis but all recrudescent
lesions are treated with courses of oral ACV, valacy-
clovir, or famciclovir. Patients who undergo head and
neck radiation may also show recrudescence of HSV
intraorally and are treated only as they occur.121,122
Most of the studies on treatment and prophylaxis in
patients with AIDS are directed toward perianal and
genital disease. Famciclovir at 500 mg twice a day
versus placebo taken for 8 weeks reduced oral shedding
of HSV-1 (5% and 35% of subjects, respectively).123
Woo and Challacombe S12.e11
High doses of valacyclovir (up to 8000 mg per day for
months) used for CMV prophylaxis in patients with
AIDS have been associated with a thrombotic microan-
giopathy-like illness with features of thrombotic throm-
bocytopenic purpura or hemolytic uremic syndrome.124
Such doses are not usually used for HSV prophylaxis.
The evidence suggests:
(1) Prophylaxis with ACV 200 to 400 mg (either IV or
orally) 3 to 5 times a day or 500 to 1000 mg of
valacyclovir 2 to 3 times a day successfully sup-
presses recrudescent HSV in patients undergoing
hematopoietic stem cell transplantation. However,
optimum dosing is not well defined.125 (IA)
(2) IV penciclovir at 5 mg/kg 2 or 3 times a day also
effectively treated HSV. (IB)
RESISTANCE TO ACV AND OTHER
ANTIVIRAL DRUGS
Resistance to the ACV family of drugs is caused by
deficiency in thymidine kinase (the most frequent
cause), decreased activity of thymidine kinase, thymidine
kinase with altered substrate specificity, or viral DNA
polymerase with altered substrate specificity.126,127 ACV-
resistant HSV in patients with RHL is low and varies
from 0.1% to 0.7% (reviewed by Bacon et al.83). One
study of 207 patients found ACV-resistant HSV iso-
lates in 4.7% of immunocompromised patients but none
in immunocompetent patients.128 Another study that
evaluated 3900 isolated strains of HSV from 15 virol-
ogy laboratories found that 0.32% of immunocompe-
tent patients and 3.5% of immunocompromised patients
had ACV-resistant strains.129
Patients who had undergone bone marrow transplan-
tation showed the highest prevalence of resistance
(10.9%), whereas those infected with HIV had a prev-
alence of 4.2%. Overall, the prevalence of resistance is
4.1% to 7.1% in immunocompromised patients.83 Com-
parable rates were seen in a study of 2145 HSV isolates in
11 penciclovir trails where penciclovir resistance was
noted in 0.22% and 2.1% of immunocompetent and im-
munocompromised patients respectively.130
Multidrug resistance has also been reported. In 38%
of patients who showed ACV resistance, treatment with
foscarnet led to 61% developing resistance to foscar-
net.129 Similarly, a survey from 68 European transplan-
tation centers found that 25% of centers reported resis-
tant strains to herpes viruses and foscarnet therapy was
effective in only 17% of patients.131 Systemic cidofovir
was effective in only 71% of patients with ACV and
foscarnet-resistant oral HSV in spite of in vitro suscep-
tibiolities in patients who had undergone allogeneic
stem cell transplantation.132

S12.e12 Woo and Challacombe
Cidofovir
Cidofovir is an acyclic nucleotide analogue of de-
oxycytidine monophosphate that is active against her-
pes viruses and is licensed for treating CMV retinitis in
patients with AIDS.133 It is phosphorylated by host (not
viral) thymidine kinase and should therefore be active
in aciclovir-resistant infections. It has a long intracel-
lular half-life but is slowly and poorly absorbed into
cells, is not bioavailable when taken orally, and is
nephrotoxic.134 It needs to be infused with probenecid
and vigorous hydration and requires only weekly dos-
ing. The lipid esters of this drug are 100 times more
potent than unmodified or even cyclic cidofovir and are
active against herpes virus isolates that are resistant to
aciclovir, ganciclovir, or foscarnet.134
There is a case report of topical 1% cidofovir cream
that was successful in treating facial HSV infection
after poor response to ACV (oral and IV), foscarnet,
and fluorothymidine in a child with AIDS.135 There is
a second case report of 3% topical cidofovir gel
that resolved oral HSV ulcers that were ACV- and
foscarnet-resistant in a patient after bone marrow trans-
plantation.136 Systemic cidofovir successfully treated
another case of ACV and foscarnet-resistant HSV sto-
matitis.137 Topical cidofovir is particularly useful and
well-studied in the treatment of ACV-resistant genital
and perianal HSV infections in patients with AIDS.133
This may yet emerge as an important drug as more
patients develop or acquire ACV-resistant strains of
HSV. One disadvantage is that cidofovir needs to be
compounded.
Other agents
Imiquimod, an immune modifier in the imidazoquino-
line family, used in a 5% cream formulation for treatment
of RHL, resulted in a severe local inflammatory response
leading to early termination of the study although patients
on active drug had an increased median time to next
recurrence of RHL versus vehicle (91 days versus 50
days).138 Imiquimod has been shown to resolve genital
HSV lesions.139 Resiquimod, a related drug, used in gel
form (0.01% or 0.05%) has shown efficacy in suppressing
episodes of genital HSV infections when used 1 to 3 times
a week, and its efficacy against RHL should be tested.87
Resiquimod induces endogenous production of interferon-
alpha and IL-12 and is thought to lead to local Th1-
dominance and cell-mediated immunity that effectively
treats infections such as those caused by the human pap-
illoma virus.
Subunit HSV vaccines have focused on 2 envelope
glycoproteins. Glycoproteins B and D are major targets
for neutralizing antibodies, are immunogenic, and confer
protection in animal studies. They are formulated with an
adjuvant to further enhance immunogenicity.16 One of
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March 2007
these glycoprotein D adjuvant vaccines has been shown to
be efficacious against genital HSV infections in women
and stage III trials are ongoing.140 The use of nucleic
acid– based vaccines is a new strategy in early develop-
ment.16
A solution of 15% idoxuridine in 80% dimethyl sul-
foxide and 5% water used in 301 patients showed signif-
icant reduction in the duration of pain (by 1.5 days) and
reduction in time to loss hard crust (by 3.3 days) if the
drug is applied in the prodrome or erythema stage.141 This
product is commercially available in Europe but not in the
United States. Dimethyl sulfoxide had been shown to
produce lens changes in animals but many studies in
humans have not shown adverse effects in the eye.141
Undecylenic acid is a monounsaturated fatty acid
present in human sebum and postulated to aid in skin
defense against infection. Its antiviral activity is thought to
be due to removal of essential viral envelope glycopro-
teins. In 560 patients with RHL, it was reported that 15%
undecylenic acid cream versus placebo significantly re-
duced the mean duration of viral shedding (by 14 hours)
but not the time to crusting, healing, or pain.142 This
product is not commercially available.
Thymopentin (synthetic thymopoietin which induces
T-cell precursors to differentiate and mature) was shown
in a placebo-controlled trial (n ⫽ 36) to increase the
symptom-free period, increase time to relapse (6 weeks
versus 17 weeks), and reduce the duration of relapses.143
Other agents are reviewed by Cassady and Whitley.144
Positive clinical outcomes have been reported with
various other agents such as 7% tannic acid145; 1.8%
topical tetracaine146; balm mint extract147; Longo Vital, a
vitamin of ground herbs, flowers, and seeds148; and propo-
lis ointment, a preparation of a resinous substrate collected
by honeybees to seal and sterilize their hives.149
FUTURE RESEARCH
More studies are needed to address the question of why
seroconversion does not occur in all patients who have
been exposed to the virus. Studies to identify genetic
factors that modify immune response, latency, and metab-
olism of antiviral drugs are ongoing. With more sensitive
techniques such as PCR, other ulcerative conditions (such
as recurrent oral erythema multiforme) should be investi-
gated to see if HSV is the etiologic agent, and whether
treatment with new antiviral medications would be help-
ful. Further work regarding the controversial concept of
nonganglionic latency would be welcome. Better-con-
trolled clinical trials may show that older treatments such
as lysine may be efficacious for RHL.
Further controlled clinical trials in humans are
needed to compare treatment efficacy between penci-
clovir, docosanol, and ACV cream for RHL. The use of
combination therapy such as hydrocortisone in associ-
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Volume 103, Number 3, Suppl 1
Table V. Summary of evidence-based management
recommendations for treatment or prophylaxis of oral
recurrent herpes simplex infections
A. Treatment of RHL in the immunocompetent host
(1) 1% penciclovir cream applied every 2 hours from the time
of prodrome until lesions are healed.
(2) 10% docosanol cream applied every 2 hours from the time
of prodrome until lesions are healed.
(3) 5% ACV cream applied every 2 hours from the time of
prodrome until lesions are healed.
(4) 400 mg of systemic (oral) ACV 3 times a day for 5 to 7
days; it is unclear if 800 mg twice a day would also be
efficacious.
(5) 500 to 2000 mg of valacyclovir twice a day for 1 day or
500 mg of famciclovir 2 to 3 times a day for 3 days are
also effective in aborting lesions.
B. Prophylaxis of RHL in the immunocompetent host*
(1) Sunscreen alone (SPF 15 or above).
(2) Systemic (oral) ACV 400 mg 2 to 3 times a day.
(3) Systemic (oral) valacyclovir 500 to 2000 mg twice a day.
The duration of prophylaxis would depend on trigger factors
such as UV exposure or dental treatment.
C. Treatment of recrudescent HSV infections in the
immunocompromised host*
(1) Systemic (oral) ACV 400 mg 3 times a day for 10 days or
longer (often up to several weeks).
(2) Systemic (oral) valacyclovir 500-1000 mg twice a day for
10 days or longer (often up to several weeks).
(3) Famciclovir has been recommended as an alterative at 500
mg 2 times a day by the Centers for Disease Control and
Prevention for up to 1 year.
D. Prophylaxis of recrudescent HSV infections in the
immunocompromised host
(1) Systemic (oral) ACV 400-800 mg 3 times a day.
(2) Systemic (oral) valacyclovir 500-1000 mg twice a day.
(3) Systemic (oral) famciclovir 500-1000 mg twice a day.
RHL, recurrent herpes labilialis; ACV, acyclovir; UV, ultraviolet;
HSV, herpes simplex virus; PCR, polymerase chain reaction.
*Diagnosis should always be confirmed with a culture, PCR or other
direct test for HSV for atypical intraoral lesions. If lesions do not heal
within 7-10 days, lesions should be recultured or biopsied, and
sensitivity testing to ACV performed. An important cause of apparent
ACV resistance is co-infection of the oral ulcers with another agent,
especially cytomegalovirus or deeply invasive fungi. Patients who
have compromised renal function should have their doses of ACV
adjusted accordingly.
ation with either topical or systemic agents may be
more effective than the antiviral agent alone. Novel
carriers that allow better penetration of the drug across
the skin barrier may also improve efficacy of some of
the topical agents.57,150 Trials to evaluate suppression
and treatment efficacy between oral famciclovir and
valacyclovir in varying doses for varying durations
should also be performed.
SUMMARY OF RECOMMENDATIONS
A summary of all the recommendations for both
treatment and prophylaxis in immunocompetent and
Woo and Challacombe S12.e13
immunocompromised patients, based on the clinical
trials and discussed at the World Workshop on Oral
Medicine, is shown in Table V.
For the immunocompromised patients, it is important
to monitor patients to be sure that lesions heal within 7
to 10 days. If they do not, lesions should be recultured
or biopsied, and sensitivity testing to ACV performed.
If HSV strains are ACV-resistant, patients should be
referred to their treating physician for foscarnet or
cidofovir treatment. An important cause of apparent
ACV resistance is coinfection of the oral ulcers with
another agent, especially cytomegalovirus or deeply
invasive fungi; these organisms are readily identifiable
on biopsy and not necessarily on culture.
Patients who have compromised renal function, espe-
cially after renal transplantation or long-term use of neph-
rotoxic drugs, should have their doses of ACV reduced to
approximately 50%. Formulae to calculate this based on
creatinine clearance and age should be consulted.
We are pleased acknowledge the contributions of Dr
Sean Meehan and the remainder of “Group 1” panel
members who made the workshop so productive and
enjoyable and of Dr Peter Lockhart and his team for
facilitating the conference and proceedings.
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