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REVIEW
URRENT
C
OPINION
Herpetic eye disease study: lessons learned
Tanja Kalezic a, Mostafa Mazen b, Eric Kuklinski b, and Penny Asbell b
Purpose of review
Ophthalmic herpes simplex virus (HSV) of the anterior segment is responsible for a range of corneal
complications such as scarring, thinning, neovascularization, and severe loss of vision. This review provides
current guidelines for treating anterior segment disease related to HSV.
Recent findings
We first review findings from the Herpetic Eye Disease Study (HEDS) clinical trials, and then review new
topical and antiviral therapies developed since the HEDS studies. The development of vaccines to prevent
recurrent episodes of herpetic infection is briefly reviewed. New corneal surgical procedures, developed
since HEDS, may put patients at risk for ocular HSV disease: cross-linking and excimer refractive surgery.
Summary
HEDS established the standard of HSV ocular therapy and is still valid today. However, newer antivirals
may provide easier compliance with improved bioavailability, efficacy, dosage, and tolerability. Further
research is needed to prevent latency of HSV, decrease recurrences, and more effectively treat necrotizing
keratitis associated with HSV.
Keywords
antivirals, herpes simplex virus, HSV, keratitis
INTRODUCTION
Herpetic eye disease is the most common infectious
cause of corneal blindness in the USA [1,2 ]. Herpes
infections have been recognized for many centuries:
from Hippocrates’ description of skin lesions that
‘creep and crawl,’ to Vidal who noted human-tohuman transmission in 1893 and Lowenstein who
found transmission of herpes simplex virus in a
laboratory setting in 1919 [3].
Herpes simplex virus (HSV) is a prevalent viral
pathogen infecting approximately 90% of the
world’s population [4–6]. Whereas oral and genital
lesions are the most common manifestations, HSV
type 1 (HSV-1) can also cause disease in the lids,
conjunctiva, cornea, uveal tract, and retina [5].
Clinical manifestations of primary ocular HSV infections are rare and usually occur early in life [5,6].
Every year in the USA, approximately 500 000 new
cases of active ocular herpes simplex infection are
reported [7,8]. However, only 20–30% have ocular
clinical manifestations [9]. Usually, it occurs as a
unilateral case, but 1.3–12% can be bilateral, especially in younger patients [10]. The most recent
survey conducted by National Health and Nutrition
Evaluation revealed a seroprevalence of HSV-1 in
53.9% of 14–49-year-olds in the United States from
2005 to 2010. It is estimated that 90% of adults
50 years or older are seropositive for the HSV [7,11].
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Herpes simplex virus is responsible for a variety
of ocular diseases in the anterior and posterior
segment, but most commonly it involves the anterior segment and manifests as an epithelial keratitis,
stromal keratitis, endotheliitis, and/or iritis [12,13].
Epithelial disease typically presents as dendritic disease, but can progress to geographic keratitis, which
often has elements of a neurotrophic ulcer.
There are two manifestations of stromal disease
from HSV: necrotizing stromal keratitis which
occurs from direct viral invasion, and immune stromal keratitis (interstitial) as a result of immune
reaction within the stroma itself [14,15]. Necrotizing stromal keratitis is characterized as an ulceration
and necrosis with infiltration of the stroma beneath
an overlying epithelial defect [16–18]. On the contrary, immune stromal keratitis is stromal inflammation (focal, multifocal, or diffuse), and the
a
University of Belgrade, Faculty of Medicine, Clinic for Eye Disease,
Clinical Center of Serbia, Belgrade, Serbia and bDepartment of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, New
York, USA
Correspondence to Tanja Kalezic, Clinic for Eye Disease, University of
Belgrade, Faculty of Medicine, Belgrade, Serbia. Tel: +381638148843;
e-mail: tanjakalezic@gmail.com
Curr Opin Ophthalmol 2018, 29:000–000
DOI:10.1097/ICU.0000000000000482
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KEY POINTS
The review focuses on treatment of HSV infection of the anterior segment, especially the cornea.
New therapeutic options, such as valacyclovir and
gancyclovir, which are more efficacious and less toxic
than trifluridine, have become available since HEDS.
HERPETIC EYE DISEASE STUDY
Topical antivirals currently available include acyclovir
3% ointment, gancyclovir 0.15% gel and trifluridine
1% solution. Oral antivirals include acyclovir,
valacyclovir and famcyclovir.
Prophylaxis with oral antivirals is suggested in patients
with a history of HSV keratitis/iritis, especially if
excimer laser for LASIK, PRK, or corneal cross-linking
being considered.
Steroids for HSV stromal herpes keratitis have
advantages such as inhibition of cellular response,
opacification, scarring and inhibition of
neovascularization. However, disadvantages are
stimulation of viral replication, exacerbation, corneal
thinning and finally steroid induced glaucoma and
cataracts.
HSV leads to latency and recurrent disease. At present,
there is no treatment to eradicate latent virus. Oral
antivirals can reduce recurrences, but only when they
are in use. Although no vaccine is currently available,
research is underway.
overlying epithelium is typically intact. Other clinical findings include anterior chamber inflammation, ciliary flush, stromal edema, immune ring,
and, most importantly, neovascularization, which
may occur at any level of the cornea leading to
stromal scarring, thinning, and severe loss of vision
[15,18,19].
Herpes simplex virus replication usually leads to
host cell death. However, HSV in neural cells can be
less destructive, allowing the virus to remain dormant in an infected patient without producing any
signs and/or symptoms. This is known as latency.
Recent studies explain the role of viral transcripts
called latency-associated transcripts (LATs), which
are the key in inducing and maintaining viral
latency [7]. For recurrent ocular HSV disease, the
trigeminal ganglion is the main source of recurrent
infection. Many factors have been reported as triggers for recurrent disease, including exposure to
ultraviolet light, psychological stress, ocular surgery, trauma, and hormonal fluctuation [5,20,21].
Herpes simplex virus also mimics many other
eye diseases, and is often on the differential diagnosis of any kind of inflammatory eye disease of the
anterior segment that has an unclear cause. This
may include marginal ulcer, pseudodendrites, limbitis, and infectious keratitis, such as acanthamoeba
corneal infections.
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The Herpetic Eye Disease Study (HEDS) was a series
of randomized, double-masked, placebo-controlled
clinical trials funded by the National Eye Institute
(NEI) that studied various approaches to treating
ocular HSV, and is still considered the gold
standard for clinical care for anterior segment
HSV disease [22].
Herpetic Eye Disease Study: topical steroids
in stromal keratitis
Patients received either topical steroids or placebo
starting eight times per day and tapered over the
following weeks. All patients also received topical
antiviral, trifluridine. Corticosteroid group showed
68% more reduction in progression of stromal keratouveitis. The study also showed that postponing
topical steroids for a few weeks led to delayed resolution of stromal keratitis, but had no detrimental
effect as assessed by visual outcome at 6 months.
This study concluded that steroid use can reduce
progression and speed recovery, but with no effect
on the visual outcome [23]. At 6 months after randomization, no clinically or statistically significant
difference in visual outcome was seen between the
placebo and the steroid group.
The use of anti-inflammatory therapy for herpes
simplex stromal keratitis is still controversial. Corticosteroids suppress inflammation by interfering
with normal immunological response. They suppress the local antibody- forming B lymphocytes,
but this effect lasts only as long as the treatment
[23]. Corticosteroids are contraindicated during herpes simplex viral infection of the ocular surface, but
are used to suppress herpes simplex stromal keratitis. Corticosteroid therapy may need to be tapered
very slowly for most patients with herpes simplex
stromal keratitis because of risk of recurrence or
making the present keratitis worse.
Herpetic Eye Disease Study: oral acyclovir
for herpes simplex virus stromal keratitis
Patients received either 400 mg oral acyclovir or
placebo 5 times daily for 10 weeks and follow up
for 6 months. All patients also received standard
regimen of topical corticosteroids, solution prednisolone phosphate 1% eight times daily for 1 week,
tapered to six times daily for second week, on third
week tapered to four times daily, on fourth week two
times daily, and on fifth week once a day. At sixth
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week, a 0.125% solution of corticosteroids was given
four times daily, on seventh week two times daily,
and from eighth to tenth week, it was once a day.
From week 11 to 26, it was not given to participants.
Trifluridine was used four times a day for first
3 weeks, tapered to two times daily until the tenth
week and then stopped. Treatment failure was
observed later in the acyclovir group (84 days) vs.
the placebo group (62 days).
The trial, however, concluded that oral acyclovir
did not significantly improve the outcome of the
stromal keratitis as measured by the time to resolution and visual outcome, respectively [24].
history of active ocular HSV disease within the past
year. The recurrence rate of any type of ocular HSV
disease during that period of treatment was 19% in
the acyclovir group compared with 32% in the
placebo group. The magnitude of absolute benefit
was greatest among patients with the highest number of prior episodes of ocular HSV disease. The
benefit in preventing stromal keratitis was seen
solely among patients with a history of stromal
keratitis. This HEDS study concluded that the
long-term use of oral acyclovir therapy reduces
the rate of recurrent HSV epithelial keratitis and
stromal keratitis by about 50% [27].
Herpetic Eye Disease Study: oral acyclovir
for herpes simplex virus iritis
Herpetic Eye Disease Study: predictors of
recurrent herpes simplex virus keratitis
Patients received either 400 mg oral acyclovir or
placebo 5 times daily for 10 weeks. Follow up examinations were performed weekly during the treatment period, every 2 weeks for 6 weeks posttreatment, and then at 26 weeks. All patients also
received standard regimen of topical corticosteroids
and trifluridine. Treatment failure occurred in 50%
of patients in acyclovir group and 68% of patents in
the placebo group. Although the number of patients
was too small to achieve statistically significant
results, the trend in this study of oral acyclovir
suggested that it may be beneficial but this trend
was noted only after 3 weeks of treatment [25].
The HEDS research group assessed how previous
HSV eye disease affects the risk of recurrent HSV,
and evaluated if any demographic or other predictors play a role in recurrent HSV disease. During
18 months of follow-up, 18% developed recurrent
epithelial keratitis and 18% developed recurrent
stromal keratitis. The risk of epithelial keratitis
was similar among patients who reported previous
epithelial keratitis and among those who did not. In
contrast, previous stromal keratitis increased the
risk of stromal keratitis 10-fold, and the risk was
strongly related to the number of previous episodes.
Demographic and other predictors such as age, sex,
ethnicity, and nonocular herpes were not significantly associated with recurrences, and no seasonal
effects were observed [28].
Herpetic Eye Disease Study: oral acyclovir
for prevention of stromal keratitis or iritis in
patients with epithelial herpes simplex virus
keratitis
Patients with HSV epithelial keratitis of 1 week or
less duration were treated with topical trifluridine
and were randomly assigned to receive 400 mg oral
acyclovir five times a day or placebo for 3 weeks and
follow up for 12 months. Stromal keratitis or iritis
developed in 11% of the acyclovir group and in 10%
of the placebo group. The development of stromal
keratitis or iritis was more frequent in patients with a
history of HSV stromal keratitis or iritis than in those
without such a history (23 vs. 9%). No apparent
benefit of a 3-week course of oral acyclovir in preventing HSV stromal keratitis or iritis was seen
during the 1 year of follow-up [26].
Herpetic Eye Disease Study: oral acyclovir
for prevention of recurrent herpes simplex
virus and prophylaxis
Patients were assigned either 400 mg oral acyclovir
twice per day or placebo for 12 months, if they had a
Herpetic Eye Disease Study: psychological
stress and other potential triggers for
recurrences of herpes simplex virus
Patients were examined with a history of ocular HSV
in the previous year and observed for 15 months.
The participants recorded if psychological stress,
systemic infection, sunlight exposure, menstrual
period, contact lens wear, and/or eye injury
occurred in the week prior to the onset of a recurrence. Psychological stress did not appear to be a
trigger for recurrences of HSV eye disease [29].
During the study, a systemic infection was
reported on 13% of the weekly logs, sun exposure
of more than 21 h in a week on 7%, and contact lens
wear in 10%. None of these potential triggers were
found to be associated with recurrences. Although
no association was found between the onset of the
menstrual period and a recurrence, the study’s
power was too low for any assessment. Similarly,
eye injuries were reported too infrequently to have a
valid conclusion [29].
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Table 1. Topical antivirals for ocular herpes simplex virus
Drug/concentration
Epithelial keratitis
Gancyclovir 0.15% gel
Five times a day, after healing
three times a day for 7 days
Acyclovir 3% ointment
Five times a day
Trifluridine 1% solution
Nine times a day, every 2 h
Data from [30].
NEW TREATMENTS SINCE HERPETIC EYE
DISEASE STUDY
Treatment options today for HSV keratitis and/or
iritis include topical [30] and oral antivirals [30]
(Tables 1 and 2).
Topical treatments for herpes simplex virus
Trifluridine is a synthetic pyrimidine nucleoside
that has been US FDA-approved since 1980
(Table 1) [30]. It was originally developed as an
anticancer agent and later was noted to be an effective antiviral [31]. At the time of the HEDS studies, it
was the most widely prescribed topical antiviral
agent for treatment of HSV keratitis in USA. However, side effects such as punctate keratopathy, allergic conjunctivitis, and toxicity to the ocular surface
have led to the decline of its use as new topical
antivirals have become available [32].
Two new topical antivirals against HSV have
become available since the HEDS study: gancyclovir
and acyclovir.
Acyclovir is a nucleoside analog that is selectively phosphorylated by the thymidine kinase
induced by the HSV in infected cells [33]. It is highly
specific for herpes infected cells. The DNA polymerase of HSV has 10–30 times greater affinity for
acyclovir than that of uninfected cells [34].
Gancyclovir ophthalmic gel 0.15% is a synthetic
purine nucleoside and analog of guanosine. It is
similar to acyclovir, because it is phosphorylated
only in infected cells and inhibits synthesis of viral
DNA. It also contributes to less toxicity, so it is well
tolerated in contrast to trifluridine, which causes
conjunctival and corneal toxicity. Furthermore,
gancyclovir gel has similar toxicity to artificial tears,
while providing prolonged corneal contact time,
and a long and stable shelf life [35–37].
These two agents – acyclovir and gancyclovir –
are considered more specific and less toxic for the
anterior segment. Both agents are not activated by
phosphorylation in host cells, but only in virusinfected cells containing viral thymidine kinase,
earning the name ‘selective antiviral agents.’
Acyclovir ointment has been shown to be more
efficacious and less toxic in comparative studies to
other nonselective antivirals such as vidarabine or
idoxuridine [38–40]. Trifluridine and acyclovir
appeared more effective than vidarabine. No significant differences were found in comparisons between
acyclovir ointment and trifluridine [41].
A comparative study between gancyclovir gel
0.15% and acyclovir ointment 3% showed similar
therapeutic efficacy and similar healing rates [41].
Gancyclovir gel 0.15% was significantly better tolerated by patients and has been approved by US FDA
in the USA since 2009. Acyclovir ointment for ocular
use is not US FDA-approved in the USA, but is
available in Europe and other areas of the world.
Oral antivirals for herpes simplex virus
treatment
New oral antivirals, such as valacyclovir and famcyclovir, have easier dosing regimens compared to oral
acyclovir (Table 2) [30]. Acyclovir itself is poorly
Table 2. Oral antivirals in ocular herpes simplex virus
Drug/route
Epithelial keratitis
Stromal keratitis
Prophylaxis
Acyclovir
Dendritic: 400 mg, 3–5 times/day, 7–10 days
Geographic: 800 mg, five times/day, 14–21
days
400 mg b.i.d.
1 year
Valacyclovir
Dendritic: 500 mg, two times per day, 7–10
days
Geographic: 1 g, three times per day, 14–21
days
Without ulcer: 400 mg, b.i.d.
With ulcer: 800 mg, 3–5 times/day, 7–10
days
Endotheliitis: 400 mg, 3–5 times/day
Without ulcer: 500 mg, once a day
With ulcer: 1 g, three times per day, 7–10
days
Endotheliitis: 500 mg, two times/day
Famcyclovir
Dendritic: 250 mg, two times/day, 7–10 days
Geographic: 500 mg, two times/day, 14–21
days
Without ulcer: 250 mg, two times/day
With ulcer: 500 mg, two times/day, 7–10 days
Endotheliitis: 250 mg, two times/day
250 mg 2 times/
day
1 year
500 mg once a
day
1 year
Data from [30].
HSV, herpes simplex virus.
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absorbed in the gastrointestinal tract; its oral bioavailability is 10–20%. In contrast, valacyclovir is
more than 10 times more permeable than acyclovir.
Valacyclovir’s oral bioavailability is more than 55%,
which allows comparable blood levels to parenteral
acyclovir. The mechanism of both famcyclovir and
valacyclovir is inhibition of viral DNA polymerase,
similar to acyclovir. Dosage modification is required
in patients with renal impairment, because there is a
risk of renal toxicity. It is suggested to measure the
peak plasma concentration level associated with
oral intake of valacyclovir [42 ].
As noted in the Table 1, oral antivirals can be
used instead of topical treatment for HSV keratitis
and may be preferred if significant ocular surface
disease and/or inability to use topical medications.
Valacyclovir is a prodrug converted in vivo to
acyclovir. It is more bioavailable (50%) than acyclovir, better tolerated, has fewer side effects, and is
easier to use because of the lower dose per day and
decreased frequency needed.
Famcyclovir is another alternative to acyclovir
and valacyclovir. It is a guanosine analog antiviral
drug used for the treatment of various herpes virus
infections, most commonly for herpes zoster. It is a
prodrug form of pencyclovir with improved
oral bioavailability.
Oral acyclovir has been reported to be as effective as topical antivirals for epithelial keratitis
(400 mg, five times daily for 10 days); oral acyclovir
is the preferred treatment in patients unable to
tolerate topical medications and with good renal
function. The use of systemic acyclovir is preferred
over topical agents in the treatment of HSV keratitis,
particularly for patients with pre-existing ocular
surface disease who are at high risk for toxicity from
topical medications, for patients who are immunocompromised, and for pediatric patients. Some
physicians prescribe both oral and topical antiviral
agents in conjunction when treating infectious HSV
keratitis [43,44].
Newer oral antiviral drugs, such as valacyclovir
and famciclovir, further simplify the dosing regimens; however, the optimal dose for ocular disease
has not been determined [42 ,45].
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of 80 genes [45]. It also has an outer lipid bi-layer
embedded with glycoproteins (gB, gC, gD, gH) which
facilitate virus to host cell attachment, fusion, and
permeability [46]. This is an important concept in
understanding the therapy for herpetic infection
because both topical and oral agents rely on their
anti-DNA transcription properties to achieve effectiveness. Therapeutic agents inhibit the viral DNA,
stopping protein synthesis and replication.
Clinical trials for HSV vaccines have been ongoing for more than three decades, yet none have
reported data on the eye. HSV-1 specifies at least
11 glycoproteins that are expressed in infected cells.
Most of the research on subunit vaccines have used
HSV envelope glycoproteins, specifically glycoprotein gB and/or gD, as immunogens, because these
are the dominant targets for neutralizing antibody
production in HSV-infected people [45]. Glycoprotein gD received the greatest attention as a subunit
vaccine candidate [46]. A major concern associated
with the use of live recombinant or attenuated virus
vaccines is the possibility that nonvirulent strains of
HSV-1 can give rise to a virulent HSV-1 strain in vivo
via recombination or mutation.
CD8 T cells of the adaptive immune response
function to inhibit viral reactivation within the
trigeminal ganglion using nonlytic mechanisms.
Therefore, a therapeutic vaccine designed to boost
the CD8 T-cell response within latently infected
ganglia may achieve inhibition of viral reactivation
and subsequent corneal inflammation without the
need for daily oral medication [46].
Nesburn and Mohamed [47–49] developed a
novel approach using several immune white-cell
parts from the two most responsive glycoproteins
(gB and gD) expressed by the herpes virus, allowing
researchers to develop a candidate vaccine to target
them [48,49]. Consistent with this hypothesis, a
small controlled trial in humans demonstrated a
significant reduction in HSV-1 ocular recurrences
following subcutaneous administration of heatinactivated HSV-1 [18,47,48].
RISK OF HERPES SIMPLEX VIRUS
REACTIVATION WITH NEW CORNEAL
PROCEDURES
ONGOING RESEARCH
Key unsolved issues for herpetic disease are the
development of latency and recurrent disease. Current research investigates HSV vaccine strategies
with the goal of inhibiting viral reactivation within
the trigeminal ganglia and preventing reactivation
events.
The herpes viruses are classified as DNA viruses
[18]. HSV has a linear double stranded DNA composed
Refractive surgery with excimer laser
(laser-assisted in situ keratomileusis/
photorefractive keratectomy)
The safety of laser-assisted in situ keratomileusis
(LASIK) or photorefractive keratectomy (PRK) is still
unknown in patients with HSV-1. Excimer laser PRK
is a surgical procedure utilizing a 193 nm ultraviolet
light to alter the curvature of the cornea and hence
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correct vision. Reactivation of ocular herpes simplex
keratitis following such excimer laser PRK has been
reported [50,51]. History of ocular HSV is considered
a relative contraindication for excimer treatment to
the eye. Perioperative and postoperative antiviral
therapy should be given to all patients with a history
of ocular HSV infection. Patients should be well
informed regarding the remote risk of HSV reactivation following LASIK or PRK [20,50].
Cross-linking of the cornea with ultraviolet
light
Corneal collagen cross-linking (CXL) using UVA and
riboflavin has been found to be effective in halting
the progression of keratoconus. A UVA surface dose of
5.4 J/cm2 is used for CXL [51]. Corneal collagen CXL
arrests further progression of corneal collagen thinning that is otherwise progressive in keratoconus
stromal collagen, thereby increasing the biomechanical stability of the cornea. CXL is used off-label for
infection of the cornea, and also as pre-excimer laser
surgery to possibly reduce the risk of ectasia [52,53].
Several papers have been published that report development of HSV keratitis following CXL [52,53]. It has
been shown that exposure to ultraviolet light can
reactivate latent HSV infection [53,54]. Moreover, the
epithelial debridement, damage to the corneal
nerves, and use of topical steroid drops have been
proposed as risk factors [54]. It has been suggested
that prophylactic antiviral therapy may decrease the
possibility of herpetic keratitis after CXL in patients
with a history of herpetic disease [55–57].
CONCLUSION
Herpetic Eye Disease Study clinical trials have established the gold standard for clinical treatment of
ocular HSV for the anterior segment. New therapeutic options have become available since HEDS, such
as topical gancyclovir and valacyclovir, which are
more efficacious and less toxic than triflurdine
[36,40,41,42 ]. Patients with HSV keratitis need to
be monitored closely in an outpatient clinic until
the disease is inactive. Any suspicious corneal infiltrate in the presence of HSV epithelial keratitis
should be cultured for possible secondary microbial
infection. Contact lens wear should be used with
caution. Inactive keratitis or a history of previous
HSV disease is also considered a relative contraindication to LASIK, PRK, or CXL. Although no vaccine
is currently available, research is underway.
&
Acknowledgements
None.
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Financial support and sponsorship
The study has no financial interest or funding received.
Conflicts of interest
Penny A. Asbell: Receives research funding from the
National Eye Institute and Office of Dietary Supplements
of the National Institutes of Health (U10EY022881),
MC2 Therapeutics and Novartis; is a consultant for
Novartis, ScientiaCME, Shire, and WebMD; has received
travel/financial compensation from Novartis, Santen,
ScientiaCME, and Shire.
Tanja Kalezic: No financial disclosures.
Mostafa Mazen: No financial disclosures.
Eric Kuklinski: Receives research funding from the
National Eye Institute and Office of Dietary Supplements
of the National Institutes of Health (U10EY022881),
and MC2 Therapeutics
No financial interest or funding received.
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&
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