Efficacy of valacyclovir vs acyclovir for the prevention of recurrent herpes simplex virus eye disease: a pilot study.
ABSTRACT To compare the efficacy of one-year treatment with valacyclovir vs acyclovir in preventing recurrence of the herpes simplex virus (HSV) eye disease.
Prospective, randomized, clinical trial pilot study.
Fifty-two immunocompetent patients with a history of recurrent ocular HSV disease were treated at the Ocular Immunology Service, San Raffaele Hospital, Milan, Italy. Twenty-six patients were randomized to the valacyclovir group (one 500 mg tablet daily), and 26 patients were randomized to the acyclovir group (one 400 mg tablet twice daily). The recurrence rate of ocular HSV disease during 12 months of treatment and drug-related side effects were monitored.
Recurrence of any type of ocular HSV disease during the 12-month treatment period was 23.1% in the valacyclovir group, compared with 23.1% in the acyclovir group. No difference between the two groups was observed regarding the nature, frequency, or severity of adverse events. The most frequent adverse events were nausea and headache.
One-year suppression therapy with oral valacyclovir (500 mg tablet daily) was shown to be as effective and as well tolerated as acyclovir (400 mg tablet twice daily) in reducing the rate of recurrent ocular HSV disease.
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ABSTRACT: Abstract Purpose: To describe a series of 5 patients with herpes simplex virus keratitis (HSK) and rheumatoid arthritis (RA) under immunosuppressive treatment. Methods: Retrospective study. Detailed data were obtained regarding symptoms and signs at the initial evaluation, treatment, microbiological diagnostic tests, evolution, and outcomes. Results: Five patients with HSK and RA were identified. Bilateral involvement occurred in 2 patients (40%). Epithelial keratitis was diagnosed in 5 eyes. Three eyes showed severe melting with eye perforation. Gram-positive bacterial co-infections were common in the group with stromal keratitis. We did not find differences in the evolution of the disease based on anti-rheumatoid treatment. Conclusions: The characteristics of HSK in patients with RA differed from HSK in immunocompetent patients. The stromal keratitis cases were very aggressive and difficult to manage, with perforation and gram-positive bacterial co-infection as frequently associated conditions. Prophylactic therapy at standard doses was unsuccessful to avoid recurrences.Ocular immunology and inflammation. 08/2014;
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ABSTRACT: To evaluate the potential utility of collagen-based corneal implants with anti-Herpes Simplex Virus (HSV)-1 activity achieved through sustained release of LL-37, from incorporated nanoparticles, as compared with cell-based delivery from model human corneal epithelial cells (HCECs) transfected to produce endogenous LL-37.Translational vision science & technology. 05/2014; 3(3):4.
Efficacy of Valacyclovir vs Acyclovir for the Prevention
of Recurrent Herpes Simplex Virus Eye Disease:
A Pilot Study
ELISABETTA MISEROCCHI, GIULIO MODORATI, LAURA GALLI, AND PAOLO RAMA
● PURPOSE: To compare the efficacy of one-year treat-
ment with valacyclovir vs acyclovir in preventing recur-
rence of the herpes simplex virus (HSV) eye disease.
● DESIGN: Prospective, randomized, clinical trial pilot
● METHODS: Fifty-two immunocompetent patients with
a history of recurrent ocular HSV disease were treated at
the Ocular Immunology Service, San Raffaele Hospital,
Milan, Italy. Twenty-six patients were randomized to the
valacyclovir group (one 500 mg tablet daily), and 26
patients were randomized to the acyclovir group (one 400
mg tablet twice daily). The recurrence rate of ocular
HSV disease during 12 months of treatment and drug-
related side effects were monitored.
● RESULTS: Recurrence of any type of ocular HSV
disease during the 12-month treatment period was 23.1%
in the valacyclovir group, compared with 23.1% in the
acyclovir group. No difference between the two groups
was observed regarding the nature, frequency, or severity
of adverse events. The most frequent adverse events were
nausea and headache.
● CONCLUSIONS: One-year suppression therapy with
oral valacyclovir (500 mg tablet daily) was shown to be as
effective and as well tolerated as acyclovir (400 mg tablet
twice daily) in reducing the rate of recurrent ocular HSV
disease.(Am J Ophthalmol 2007;144:547–551. © 2007
by Elsevier Inc. All rights reserved.)
and developing nations throughout the world, affecting
some 450,000 people with 50,000 new and recurrent cases
each year.1,2Few studies have evaluated the epidemiologic
features of herpes keratitis in Europe; the largest and most
recent study, carried out in France, reported that the
overall incidence of herpetic keratitis is 31.5 per 100,000
HE HERPES SIMPLEX VIRUS (HSV) IS THE LEADING
cause of corneal opacity and secondary visual loss in
the United States, other industrialized countries,
person-years, 13.2 per 100,000 person-years for new cases,
and 18.3 per 100,000 person-years for recurrences.3
Despite the availability of antiviral agents that are
effective in treating HSV eye disease, visual impairment
resulting from corneal scarring and uncontrolled intraoc-
ular inflammation can occur in many patients. The most
important and challenging problem in patients with recur-
rent ocular HSV is to limit and suppress recurrences to
avoid permanent visual loss. An analysis of the natural
history of ocular herpes simplex infection shows that the
number of recurrent episodes increases after onset: 9.6% at
one year, 22.9% at two years, and 63.2% at 20 years.1,4
Acyclovir is an antiviral drug that selectively targets
virus-infected cells and has been shown to be effective in
treating and preventing genital herpes5–7and orofacial
herpes.8It also has been evaluated in the therapy and
prophylaxis of HSV eye disease in a series of clinical trials
known as the Herpetic Eye Disease Study (HEDS).9,10The
HEDS recently showed that long-term prophylactic treat-
ment with oral acyclovir for more than 12 months reduces
ocular HSV recurrence.11
Valacyclovir is the prodrug of acyclovir and is converted
rapidly to acyclovir after oral administration. The resulting
acyclovir bioavailability is three to five times more than
that of oral acyclovir. This higher plasma concentration of
acyclovir obtained from the oral administration of valacy-
clovir is similar to that achieved with intravenous acyclo-
vir.12Furthermore, intraocular and corneal concentrations
of acyclovir are known to correlate with plasma concen-
trations.12The purpose of this pilot study was to compare
the efficacy of one-year treatment with oral valacyclovir
(500 mg daily) vs oral acyclovir (400 mg twice daily) in
preventing the recurrence of HSV eye disease.
PATIENTS WITH HSV EYE DISEASE REFERRED TO THE OCU-
lar Immunology and Uveitis Service at the San Raffaele
Hospital in Milan, Italy, were enrolled in the study and
were followed up from February 2004 through May 2005.
● INCLUSION CRITERIA: Eligible patients were more
than 18 years of age and had recurrence of ocular HSV
disease in one or both eyes in the preceding 12 months.
Accepted for publication Jun 1, 2007.
From the Department of Ophthalmology and Visual Sciences, San
Raffaele Scientific Institute, Milan, Italy (E.M., G.M., P.R.); and the
Clinic of Infectious Diseases, Vita-Salute San Raffaele University, Milan,
Inquiries to Elisabetta Miserocchi, Department of Ophthalmology and
Visual Sciences, San Raffaele Scientific Institute, Via Olgettina 60,
20132 Milan, Italy; e-mail: firstname.lastname@example.org
© 2007 BY ELSEVIER INC. ALL RIGHTS RESERVED.
Their disease, however, had been inactive and untreated
for at least one month before the beginning of the study.
Patients with renal or liver dysfunction and proven allergy
to acyclovir were excluded from the study. Women of
childbearing age who were not using effective contracep-
tion methods, were pregnant, or were breast-feeding were
not included in the study.
● STUDY DESIGN: This was a prospective, randomized
study. The patients were assigned randomly to the two
different groups on the basis of a computer-generated list
prepared by our statistician. The primary study end point
was to assess the recurrence rate of ocular HSV disease in
the group of patients treated with acyclovir compared with
the group of patients treated with valacyclovir. Recurrence
was classified as infection of the ocular surface (blepharitis,
conjunctivitis, or keratitis) and anterior uveitis. An expe-
rienced ophthalmologist (G.M.) who was unaware of the
assigned treatment assessed all episodes of recurrence.
Another experienced ophthalmologist (E.M.) performed a
complete ophthalmological evaluation and a review of
each patient’s system to detect possible treatment-related
side effects. Evaluations were scheduled at one, three, six,
nine, and 12 months after treatment began. The secondary
objective of the study was the evaluation of treatment
tolerance in both groups of patients by analyzing treat-
ment-related side effects.
● TREATMENT ASSIGNMENT: Patients were randomized
into two different treatment groups. Group 1 received one
500 mg tablet of valacyclovir daily and group 2 received
one 400 mg tablet of acyclovir twice daily for 12 months.
Laboratory parameters (complete cell blood count and
liver and renal function tests) were evaluated at baseline
and then repeated every three months to monitor drug
● STATISTICAL ANALYSIS: The study was designed as an
exploratory proof-of-concept one, and no formal sample
size calculation was performed; the number of subjects was
planned on a feasibility basis. The Fisher Exact test was
used as appropriate to compare the proportions of the two
patient groups. Mean values of normally distributed con-
tinuous variables were compared using the Student t test.
A TOTAL OF 52 IMMUNOCOMPETENT PATIENTS WITH A
history of recurrent ocular HSV disease were included in
the study; 26 patients were randomized to the valacyclovir
group (one 500 mg tablet daily) and 26 were randomized to
the acyclovir group (one 400 mg tablet twice daily). All
patients were white and their demographic characteristics
are shown in Table 1.
● RECURRENCE OF OCULAR HSV DISEASE: The study
showed no significant frequency differences between
groups in the recurrence of ocular HSV disease at the end
of follow-up; the recurrence rate of any type of ocular HSV
disease was 23.1% in the valacyclovir group (six of 26
patients) and 23.1% in the acyclovir group (six of 26
patients; P ? 1.0). In the valacyclovir group, one patient
had recurrence of herpetic blepharoconjunctivitis and
three patients experienced recurrence of keratitis (three
cases of stromal keratitis). Two patients experienced re-
currence of anterior uveitis at three and six months,
respectively, after treatment began. In the acyclovir group,
recurrence of keratitis occurred in three patients (two cases
of epithelial keratitis and one case of disciform keratitis),
whereas there was recurrence of anterior uveitis in three
patients (Table 2).
● TREATMENT TOLERANCE: The incidence of adverse
events was comparable in both groups, and both drugs were
well tolerated during the 12-month treatment period.
There was no clinically significant difference between the
groups in the nature, frequency, or severity of the adverse
events. No serious adverse reactions occurred during treat-
ment, and none of the patients discontinued the drug
because of drug intolerance. The most frequent treatment-
related side effects encountered in both groups were
gastrointestinal upset (three cases of nausea and vomiting
in the valacyclovir group and four such cases in the
acyclovir group), headache (five cases in the valacyclovir
TABLE 1. Valacyclovir vs Acyclovir for the Prevention of
HSV Eye Disease: Characteristics of Patients
(Mean ? Standard Deviation)
Characteristics of Patients
(n ? 52)
(n ? 26)
(n ? 26)
HSV ? herpes simplex virus.
TABLE 2. Valacyclovir vs Acyclovir for the Prevention of
Recurrent HSV Eye Disease: Types of Recurrences
Type of Ocular HSV Recurrence
(n ? 26)
(n ? 26)
HSV ? herpes simplex virus.
AMERICAN JOURNAL OF OPHTHALMOLOGY
group and three cases in the acyclovir group). Two patients
in both groups reported abdominal pain, which was more
evident during the first month of treatment, but did not
need to discontinue the drug. In the acyclovir group, two
patients experienced temporary hair loss during treatment.
Complete cell blood count, serum creatinine, and liver
function test analyses were carried out regularly, and none
of the patients studied demonstrated laboratory abnormal-
ities during the treatment period.
HSV IS A MAJOR CAUSE OF CORNEAL SCARRING AND VI-
sual loss. The morbidity from recurrent herpetic episodes is
high, with resulting corneal scarring and opacities being
the possible causes of severe visual impairment.1,2,4,13,14
Acyclovir, a specific and selective inhibitor of the
replication of herpes viruses, has been used safely and
effectively for more than a decade in the prevention and
treatment of genital and orofacial herpes.5,6,8This drug has
been evaluated in the therapy and prophylaxis of HSV eye
disease in a series of clinical trials known collectively as
HEDS.9,10Recently, HEDS investigated whether the long-
term use of oral acyclovir would reduce the risk of
recurrent HSV eye disease.11Acyclovir safely and effec-
tively suppresses recurrent HSV eye disease during a
12-month treatment period, reducing the risk of any
recurring ocular disease.11Although acyclovir displays
potent inhibitory activity against all herpes viruses in
vitro, sensitivity to the drug varies greatly from virus to
virus. The limitations of acyclovir in treating infections
caused by HSV include the development of resistant
isolates and relatively poor oral bioavailability.15
Research during the last decade therefore has focused on
the development of an acyclovir prodrug, valacyclovir,
which would retain the safety and efficacy profiles of
acyclovir while greatly improving oral bioavailability. Va-
lacyclovir is rapidly and almost completely hydrolyzed to
acyclovir and results in acyclovir bioavailability that is
three to five times more than that of oral acyclovir.12
Bioavailability is 12% after administration of a single dose
of 800 mg acyclovir; after a single 1000-mg dose of
valacyclovir, the acyclovir bioavailability is 54.2%. The
plasma acyclovir concentration obtained is comparable
with the levels reached with intravenous acyclovir
The favorable safety profile and increased systemic
exposure make this drug a particularly ideal candidate for
the treatment of herpes-group viral infections. It is cur-
rently approved for the treatment of herpes zoster infec-
tions and recurrent genital herpes in immunocompetent
adults.17–19The efficacy of valacyclovir in the suppression
of recurrent genital herpes has been demonstrated in
different clinical trials; once-daily suppressive therapy with
500 mg valacyclovir for one year effectively prevents
genital herpes recurrence, with 65% to 69% of patients
remaining recurrence free during the study.17In another
large-scale, placebo-controlled study by Spruance and
associates, 500 or 1000 mg valacyclovir therapy provided a
clinically significant benefit to patients that included the
shortening of the duration of genital lesions, duration of
pain and discomfort, and virus shedding.19Adverse reac-
tions to studied valacyclovir treatment for genital herpes
are mild and comparable with the side effects in the
placebo group, most frequently headache, nausea, and
diarrhea. The use of valacyclovir for ocular herpetic disease
was evaluated by Colin and associates, who suggested that
valacyclovir is as effective as acyclovir in preventing the
ocular complications of herpes zoster ophthalmicus.16
In the present study, we compared the efficacy of
prophylactic treatment with 500 mg daily of valacyclovir
and 400 mg twice daily of acyclovir to prevent the
recurrence of ocular HSV disease. The hypothesis was to
assess if the two treatment arms have similar efficacy in
terms of recurrence rate. This pilot study was designed on
the basis of HEDS, and the valacyclovir administration
dose was assessed from the current guidelines for suppres-
sion of recurrent genital herpes (500 mg once daily).19
During the 12-month treatment period, the recurrence
rate of any type of ocular HSV disease was 23.1% in the
group of patients taking 500 mg valacyclovir daily (six of
26 patients) and 23.1% in the group of patients taking 400
mg acyclovir twice daily (six of 26 patients). These
findings are similar to other studies in the literature,
suggesting a prophylactic role of long-term antiviral treat-
Various studies have shown the efficacy of long-term
oral prophylaxis with acyclovir in reducing the recurrence
rate of ocular herpes simplex eye disease compared with
placebo; the cumulative probability of a recurrence of any
type of ocular HSV disease can range from 19%9,10to
36%.11Other studies have confirmed this beneficial role of
antiviral prophylaxis in reducing the number of episodes of
ocular HSV (reduction of 48% and 47%, respectively, in
both nonatopic and atopic patients).21In our sample,
treatment tolerance of valacyclovir and acyclovir was
comparable in both groups of patients and can be consid-
ered acceptable; the most frequent adverse reactions dur-
ing treatment were gastrointestinal disturbances (vomiting
or nausea) and headache. No serious adverse events
occurred during the study. The convenient once daily
regimen may increase the compliance with valacyclovir.
Guidelines for compliance improvement include single
rather than multiple medication doses. The more fre-
quently a medication needs to be taken, the greater the
likelihood a dose will be missed or will be administered at
an incorrect time.22Omission of a dose of acyclovir poses
a risk to patients with a history of recurrent HSV ocular
disease because serum acyclovir concentrations, which are
much lower than those achieved with valacyclovir, can
VALACYCLOVIR AND ACYCLOVIR IN HSV EYE DISEASE
VOL. 144, NO. 4
decrease below the IC50for HSV isolates, possibly contrib-
uting to treatment failure.6
The safety findings reported for once daily valacyclovir
in the present study are comparable with the previous
evaluation of long-term valacyclovir treatment.17–19De-
spite the clear benefits of valacyclovir in the management
of genital and ocular HSV disease, such treatment may be
considered expensive by family practitioners and therefore
We must recognize that valacyclovir costs compared
with acyclovir costs necessary to treat HSV eye disease are
higher for long-term prophylactic treatment. Lairson and
associates conducted a cost-effectiveness analysis on the
prevention of HSV eye disease; they estimated that
chronic suppressive oral acyclovir costs 8,532 USD per
ocular HSV episode averted.23The incremental cost per
infection averted would decline by up to 51% if antiviral
prophylaxis were more effective and by up to 87% if
patients had a higher risk of recurrence. Targeting prophy-
laxis to patients with a history of stromal keratitis is not
more cost effective than providing oral acyclovir for
patients with any prior HSV eye disease. The authors
concluded that herpetic eye disease is costly to treat and to
prevent. Because long-term prophylactic treatment with
oral antiviral drugs is not a cost-effective option for all
patients with previous HSV eye disease, therapeutic deci-
sions must be made on a case-by-case basis; prophylactic
therapy may be appropriate for patients with sight-threat-
ening recurrences, frequent episodes, or other reasons for a
reduced quality of life caused by ocular herpes.
The potential clinical benefits of valacyclovir are likely
to be apparent in the case of acyclovir-resistant herpes
virus infections, where high-dose systemic or intravenous
treatment with acyclovir has been necessary and where the
resistance has been attributed to inadequate exposure of
the drug. Because optimal levels of acyclovir are achieved
with a simpler dosing regimen of valacyclovir, compliance
may be improved in many patients, thus reducing the
incidence of a resistant virus. A compound with improved
absorption and bioavailability theoretically would extend
the therapeutic usefulness of the drug. Simplified dosing
regimens would increase compliance, and the higher
plasma concentration would minimize the potential for
suboptimal treatment of the less sensitive herpes viruses.
To summarize, in this pilot study, the one-year suppres-
sion treatment with oral valacyclovir (500 mg daily) was as
effective as acyclovir (400 mg twice daily) in reducing the
rate of recurrent ocular HSV disease. The results of this
trial will be used to plan further adequately powered
randomized clinical trials to confirm this hypothesis.
THE AUTHORS INDICATE NO FINANCIAL SUPPORT OR FINANCIAL CONFLICT OF INTEREST. ALL OF THE AUTHORS WERE
involved in design and conduct of study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the
manuscript. The study and data accumulation were in conformity with country and state laws. Informed consent was obtained from the patients and
the study adhered to the tenets of the Declaration of Helsinki. Institutional review board approval was not obtained for the present study.
The authors would like to thank Michael John, University Hospital San Raffaele, Milan, Italy for the English language editing of the manuscript.
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VALACYCLOVIR AND ACYCLOVIR IN HSV EYE DISEASE
VOL. 144, NO. 4
Elisabetta Miserocchi, MD, graduated from medical school in Milan, Italy in 1996 and performed two years of
ophthalmology residency in her country, followed by two years of ocular immunology research fellowship at the
Massachusetts Eye and Ear Infirmary, Boston, Massachusetts with Dr Stephen Foster. Dr Miserocchi is currently working
at the San Raffaele University Hospital in Milan, in the Ocular Immunology and Uveitis Service, where she is actively
seeing patients with intraocular inflammation and ocular surface diseases.
AMERICAN JOURNAL OF OPHTHALMOLOGY