CE: Tripti; ICU/290410; Total nos of Pages: 5;

ICU 290410

REVIEW

CURRENT
OPINION Management of herpes simplex virus
epithelial keratitis
Mehdi Roozbahani and Kristin M. Hammersmith

Purpose
To review recent advancements in the management of herpes simplex virus (HSV) epithelial keratitis.
Recent findings
Trifluridine eye drop, acyclovir (ACV) ointment, ganciclovir gel, and oral ACV are still the main therapeutic
agents. Cryopreserved amniotic membrane has been recently used as an adjuvant treatment. Resistance to
ACV has become a concerning issue. The animal models of HSV vaccine are able to reduce HSV keratitis.
New antivirals are under development.
Summary
Current cases of HSV epithelial keratitis are manageable with available medications, but new
advancements are required to decrease disease burden in the future. HSV vaccine can be revolutionary.
Keywords
antiviral, epithelial keratitis, herpes simplex virus, resistance, vaccine

INTRODUCTION infection. Whereas innate immunity is involved

Herpes simplex virus (HSV) causes broad spectrum
of medical problems which mostly involve central
nervous system, eye, mouth, genitalia, and skin.
HSV-1 and HSV-2 belong to human herpes virus
family. While both HSV-1 and HSV-2 can involve
eye, most cases of keratitis are attributed to HSV-1
[1]. Mixed infections with HSV-1 and HSV-2 have
been reported [2]. HSV-1 is the most common cause
of infectious keratitis around the globe. Based on
anatomical location, HSV keratitis is divided into
epithelial, stromal, and endothelial keratitis.
On a global scale, about one million people suffer
from new or recurrent HSV epithelial keratitis every
year [3], which may significantly impair their quality
of life [4]. In Herpetic Eye Disease Study (HEDS), HSV
epithelial keratitis was the most common HSV eye
involvement, which was seen in 79% of subjects [5].
In a survey that was performed in Mayo clinic, Flor-
ida, the United States, from 1976 to 2007, dendritic
epithelial keratitis was the most common initial pre-
sentation of acute herpetic eye disease, which was
reported in 59% of cases. The incidence of new cases
was 11.8 per 100,000 population in the study [6].
PATHOGENESIS
Humans are the only host for HSV. Both innate and
adaptive immune responses will be activated by HSV
with active viral load, adaptive immune response
plays a role in progression, latency, and spread of
virus [7]. HSV epithelial keratitis can manifest dur-
ing primary or recurrent infection. Primary eye
infection happens with or without concurrent ble-
pharoconjunctivitis [8]. Recurrent epithelial kerati-
tis can be due to the reactivation of previous
epithelial or nonepithelial HSV. It can also happen
in a patient who has been previously affected by
HSV at a nonocular site [9,10].
Primary infection usually occurs in early child-
hood. About 90% of people older than age 60 are
seropositive for HSV-1 [6]. HSV-1 enters into the
mucous membrane and epithelial cells of host by
direct contact [9]. The virus moves retrograde
through axons to reach trigeminal ganglia, where
it develops a life-long latency. Other than sensory
ganglia, cornea has been shown to be a site of
latency [11,12]. Although there are controversies
Cornea Service, Wills Eye Hospital, Sidney Kimmel Medical College at
Thomas Jefferson University, Philadelphia, PA, USA
Correspondence to Mehdi Roozbahani, MD, 840 Walnut Street, Suite
920, Philadelphia, PA, USA. Tel: +1 215 928 3180;
fax: +1 215 928 3854;
e-mail: mroozbahani@willseye.org; meroozbeh@yahoo.com
Curr Opin Ophthalmol 2018, 29:000–000
DOI:10.1097/ICU.0000000000000483

1040-8738 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-ophthalmology.com

Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: Tripti; ICU/290410; Total nos of Pages: 5;
ICU 290410
Corneal and external disorders
KEY POINTS
 GCV gel, TFT, and topical and oral ACV have almost
the same therapeutic effect on HSV epithelial keratitis.
 New antivirals with novel mechanism of actions other
than nucleoside analogs are developing.
 Preliminary results suggested that HSV vaccine can
prevent primary and recurrent HSV keratitis on
animal models.
 After previous use of amniotic membrane in the
treatment of HSV stromal keratitis, it was tried as an
adjuvant in the management of HSV epithelial keratitis.
about the reasons for the reactivation of virus, fever,
ultraviolet light, contact lens wear, using prosta-
glandin eye drops, recent eye surgery, and immuno-
suppressive therapy have been attributed to
reactivation of HSV epithelial keratitis. Reactivation
can induce different types of keratitis other than first
presentation [3]. Potentially blinding complications
of HSV-1 almost always happen after the reactiva-
tion rather than primary acute infection [13].
PRESENTATION
Herpes simplex virus epithelial keratitis is usually the
most painful type of HSV keratitis. Pain makes
patients seek for treatment probably earlier than
the other types of herpetic keratitis. Other symptoms
include photophobia, foreign body sensation, tear-
ing, conjunctival injection, and decreased vision.
The diagnosis is made by slit-lamp examination.
Dendritic and geographic ulcers are two types of
HSV epithelial keratitis [14]. They are simply recog-
nizable with typical pattern after fluorescein staining.
This characteristic feature almost always eliminates
further tests like culture, PCR, immunofluorescence
assay (IFA), and immunochromatographic assay,
which may be used for the other types of herpetic
eye disease. It is usually a unilateral disease other than
those with atopy or decreased immunity [15,16].
Primary HSV epithelial keratitis starts with pin
point 30–35 micron vesicles on the corneal surface,
which are infected epithelial cells [10]. After 12–
24 h, the infected cells swell up. Increased volume
would lead to disruption of the superficial layer and
release the virus into adjacent areas. It develops to
stellate erosion and finally converts to a typical
dendritic involvement with fluorescein stain [1,17].
Differential diagnosis for HSV epithelial keratitis
include other keratitis caused by herpes virus family
like Varicella zoster virus (VZV), cytomegalovirus
(CMV), Epstein–Barr virus (EBV), or adenovirus,
2 www.co-ophthalmology.com
Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
which are differentiated with ancillary tests. Other
nonviral conditions like limbal stem cell deficiency
(LSCD), dry eye syndrome, drug-induced corneal
changes, and hereditary metabolic diseases (like
thyrosinemia) can cause ‘pseudo-dendrites.’ Acan-
thamoeba keratitis should be considered in all cases
particularly among contact lens wearers [18].
TREATMENT
Herpes simplex virus epithelial keratitis has been
attributed to direct virus invasion and active infec-
tion within corneal epithelium. Although sponta-
neous recovery is seen in 50% of patients, treatment
with antivirals should be administered to decrease
discomfort, minimize visual loss, and reduce recur-
rence rate [19]. Idoxuridine was introduced in 1962
as the first topical antiviral. Currently, trifluridine
(TFT), ganciclovir (GCV), and acyclovir (ACV) are
available topical medications, and ACV, valacyclo-
vir (VACV), and famciclovir (FCV) are the most
accessible systemic antivirals in the United States
[14]. Oral ACV, TFT, and topical GCV have been
equally effective to treat HSV epithelial keratitis
[3,20–23]. After being phosphorylated and activated
by viral thymidine kinase, all of these medications
inhibit viral DNA replication. Topical ACV has not
been available in the United States, but it is widely
used in other parts of the world [14]. Trifluridine and
GCV are the only US Food and Drug Administration
(FDA)-approved medications for the topical treat-
ment of HSV epithelial keratitis. Whereas oral anti-
virals are widely used for the treatment of HSV
epithelial keratitis, none of them have been
approved by US FDA for this purpose [22].
Based on the disease condition, either topical or
systemic antivirals are used for the treatment of HSV
epithelial keratitis. Topical antivirals and oral ACV
have shown almost similar therapeutic effects for
years. A combination of topical and systemic anti-
virals or even augmenting treatment with epithelial
debridement was reported [19–22,24,25]. It is
unclear whether these modalities can fortify the
treatment [19]. Cycloplegic drops and topical anti-
biotics may be added, but corticosteroid is contra-
indicated while the epithelium has not been healed
yet. Long-term prophylactic treatment after the first
episode of HSV epithelial keratitis for the purpose of
halting recurrences is not recommended [23].
Oral ACV is used for the treatment of HSV
epithelial and stromal keratitis in children and
adults, particularly after the HEDS [23,24,26]. A
prodrug of ACV (introduced as VACV) is another
nucleoside analog with enhanced oral bioavailabil-
ity. It needs lower frequency of administration and
has been approved by US FDA for reducing genital
Volume 29  Number 00  Month 2018
CE: Tripti; ICU/290410; Total nos of Pages: 5;
ICU 290410
Herpes simplex virus epithelial keratitis Roozbahani and Hammersmith
herpes recurrences. The therapeutic effects of sys-
temic VACV for the management of HSV epithelial
keratitis has been established on animal models
[27,28]. Komoto et al. [29] in 2015 compared the
effects of ACV ointment, oral VACV, and oral FCV
(orally bioavailable penciclovir prodrug) for the
treatment of HSV epithelial keratitis on mice. Tear
cultures revealed that following treatment, HSV-1
was not detectable in the topical ACV group and oral
VACV group on day 4, and in the oral FCV group on
day 6. The authors concluded that a 5-day treatment
course with any of these medications would be
enough for the treatment of HSV epithelial keratitis.
There is only one available clinical trial on humans
with regard to administration of VACV for the treat-
ment of HSV epithelial keratitis. In that study, Sozen
et al. [30] demonstrated that VACV was better than
topical ACV, because faster epithelial healing and
lower photophobia score were seen in the VACV
group. FCV has never been studied for the treatment
of HSV epithelial keratitis on humans, but it was
effective for this purpose in an animal model [31].
Ganciclovir is a broad-spectrum antiviral that
selectively inhibits viral DNA polymerase after being
phosphorylated with HSV. GCV ophthalmic gel
0.15% has been approved by US FDA in 2009 as
Zirgan (Baush and Lomb Inc., Rochester, New York,
USA) for the treatment of HSV epithelial keratitis.
GCV gel has been shown to be effective as other
topical antivirals with a better tolerability and lower
adverse effects. GCV has become a first choice for
the treatment of HSV epithelial keratitis by many
ophthalmologists. However, GCV may not be used
as it is expected because it is more expensive than
the well known ACV [32].
After promising application of self-retained cry-
opreserved amniotic membrane (CAM) for the treat-
ment of complex herpetic corneal infections [33–
36], it has been limitedly used for the treatment of
HSV epithelial keratitis more recently. Sheha et al.
&
[37 ] reported a case of recurrent HSV epithelial
keratitis, which was treated with debridement and
CAM. The patient had a history of three episodes of
HSV epithelial keratitis in the past year that had
been treated with debridement and topical ACV
during acute phase and prophylactic oral ACV
between episodes. For the new episode of HSV epi-
thelial keratitis, following debridement and placing
CAM (PROKERA SLIM, Bio-Tissue Incorporation,
Miami, Florida, USA), systemic ACV was prescribed,
but was not used by the patient. After 5 days, cornea
healed completely and CAM was removed. After
18 months follow-up, the patient did not experience
another HSV epithelial keratitis even without taking
prophylactic antiviral. The authors attributed their
results to the potential antiviral effects of CAM.
1040-8738 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
They explained that in addition to the known
anti-inflammatory effects of CAM, it can be a poten-
tial antiviral agent due to interferon and cystatin E
in its structure. In another experience with CAM,
Cheng and Tseng [38] reported four cases of primary
or recurrent HSV epithelial keratitis, who were
treated with epithelial debridement, CAM, and oral
ACV. After 5  3.7 days, all patients were healed and
remained symptom-free through 2.7 to 50.8 months
follow-up.
Whereas antivirals eliminate active viral replica-
tion within epithelial cells, debridement removes
infected cell load, and amniotic membrane re-estab-
lishes epithelial healing. Amniotic membrane inhib-
its differentiation of corneal fibroblast into
myofibroblast and reduces scar formation in such
a way [39]. It also promotes epithelial healing by
providing growth factors and anti-inflammatory
effects. Direct antiviral activity of amniotic mem-
brane is still questionable [34,40].
COMPLICATIONS
Decreased corneal sensation is a concerning compli-
cation after HSV epithelial keratitis. Recently, Moein
&&
et al. [41 ] in a prospective study evaluated central
corneal nerve changes after HSV epithelial keratitis.
The authors revealed that after a mean follow-up of
3.1 years, statistically significant regeneration of
subbasal nerve happened. However, this number
was statistically lower than the age-matched control
group. Moreover, statistically significant improve-
ment in corneal sensation was not seen. Decreased
sensation can enhance the risk of other complica-
tions like bacterial super-infection and dry eye. It
has been shown that unilateral, recurrent HSV kera-
titis can lead to bilateral lacrimal dysfunction and
impaired tear secretion [42]. Prolonged epithelial
defect can happen due to drug resistance, toxicity
from topical medications, inflammation from active
viral replication, and concurrent use of steroid drops
[19]. A central subepithelial scar can cause vision
reduction and glare.
DRUG RESISTANCE
Since ACV has been used for the treatment of variety
of diseases for years, developing resistance is not
surprising. Studies revealed that antiviral resistance
is 0.1–6.4% in immunocompetent patients, whereas
it was reported as high as 36% in immunocompro-
&
mised cases [1,43]. Recently, Rousseau et al. [44 ], in
a prospective study, revealed that HSV-1 resistance
to ACV is a significant cause of failure of prophylaxis
in patients with HSV keratitis, and it is associated
with longer disease duration. Due to increasing
www.co-ophthalmology.com 3
CE: Tripti; ICU/290410; Total nos of Pages: 5;
ICU 290410
Corneal and external disorders
resistance to ACV and cross-resistance between dif-
ferent antivirals, an alternative for the treatment of
HSV should be considered [45].
FUTURE
In the future, we will need new antivirals with novel
mechanism of action other than nucleoside analogs.
Cui et al. [46] investigated the role of tripartite motif
protein 32 (TRIM32) in promotion of natural anti-
viral proteins like interferon (IFN)-b in corneal epi-
thelial cells. Their results suggested TRIM32 as a
promising therapeutic target for the treatment of
HSV keratitis. Bhela and Rouse [47] revealed that
small nuclear RNA (miRNA) can be used as thera-
peutic tool for HSV treatment and the prevention of
virus reactivation. Zinser et al. [45] has introduced
SC93305 as a novel potent antiviral substance which
was effective against ACV resistance HSV, especially
in immunocompromised individuals. Amenavemir
and pritelivir are two helicase-primase inhibitors
passing phase II and III clinical trials. These new
antivirals are not dependent on the virus thymidine
kinase for activation [48,49].
In the light of successful development of VZV
vaccine, promising efforts for developing a vaccine
for HSV has been performed. The effective vaccine
for HSV should prevent the reactivation of latent
viruses and/or inhibit primary infections. Dong et al.
[50] reported that glycoprotein C (gC)-based vaccine
was effectively able to prevent primary HSV keratitis
in mice by inducing humoral and cellular immune
response. Royer et al. [51] investigated that a live
attenuated HSV vaccine can remarkably protects
mice eyes against HSV-1 associated ocular compli-
cations by impending viral replication, dissemina-
tion, and latency via humoral immunity. Srivastava
et al. [52] suggested the potential effect of asymp-
tomatic CD8þ T-cell epitope based vaccines against
recurrent ocular herpes.
CONCLUSION
In the past few years, medical treatment of HSV
epithelial keratitis has not changed. No novel topi-
cal or systemic antiviral has been introduced in the
market which was widely used. Recently, new
modalities like CAM have been used for the man-
agement of HSV epithelial keratitis. Moreover, HSV
vaccine on animal models suggested promising
results for the prevention of HSV keratitis. Up to
February 2018, there was no active research study
about HSV epithelial keratitis on the US National
Library of Medicine website (clinicaltrial.gov),
World Health Organization International Clinical
Trials Registry Platform (ICTRP), European Clinical
4 www.co-ophthalmology.com
Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Trial Registration webpage (EU Clinical Trial Regis-
ter), and Australian-New Zealand Clinical Trial Reg-
istry (ANZCTR). This lack of new researches on this
topic, which is the most prevalent type of herpetic
eye disease, is concerning. Although there are new
antivirals and HSV vaccines in development, there
are still some questions which should be answered.
Famous antivirals like VACV and FCV have not been
evaluated in strong clinical trials targeting HSV
epithelial keratitis. Interestingly, oral ACV has not
been compared with GCV gel in any clinical trial.
Latest published study about GCV gel, which is the
newest topical antiviral, goes back to year 2013 [53].
Moreover, exact indications for selecting topical
instead of systemic antivirals are unclear. Whereas
the vast majority of cases are manageable with exist-
ing medications, apparently, there is not enough
motivation to enhance current management. With
emerging drug resistance, particularly between
immunocompromised patients, we should consider
new agents and modalities to improve the manage-
ment of patients with HSV epithelial keratitis.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. Farooq AV, Shukla D. Herpes simplex epithelial and stromal keratitis: an
epidemiologic update. Surv Ophthalmol 2012; 57:448–462.
2. Kaneko H, Kawana T, Ishioka K, et al. Evaluation of mixed infection cases with
both herpes simplex virus types 1 and 2. J Med Virol 2008; 80:883–887.
3. Wilhelmus KR. Antiviral treatment and other therapeutic interventions for
herpes simplex virus epithelial keratitis. Cochrane Database Syst Rev 2015;
1:CD002898.
4. Reynaud C, Rousseau A, Kaswin G, et al. Persistent impairment of quality of
life in patients with herpes simplex keratitis. Ophthalmology 2017;
124:160–169.
5. Herpetic Eye Disease Study Group. Predictors of recurrent herpes simplex
virus keratitis. Cornea 2001; 20:123–128.
6. Young RC, Hodge DO, Liesegang TJ, et al. Incidence, recurrence, and
outcomes of herpes simplex virus eye disease in Olmsted County, Minnesota,
1976-2007: the effect of oral antiviral prophylaxis. Arch Ophthalmol 2010;
128:1178–1183.
7. Rolinski J, Hus I. Immunological aspects of acute and recurrent herpes simplex
keratitis. J Immunol Res 2014; 2014:513560.
8. Darougar S, Wishart MS, Viswalingam ND. Epidemiological and clinical
features of primary herpes simplex virus ocular infection. Br J Ophthalmol
1985; 69:2–6.
9. Kaye S, Choudhary A. Herpes simplex keratitis. Prog Retin Eye Res 2006;
25:355–380.
10. Tabery HM. Epithelial changes in early primary herpes simplex virus keratitis.
Photomicrographic observations in a case of human infection. Acta Ophthal-
mol Scand 2000; 78:706–709.
Volume 29  Number 00  Month 2018
CE: Tripti; ICU/290410; Total nos of Pages: 5;
ICU 290410
Herpes simplex virus epithelial keratitis Roozbahani and Hammersmith
11. Kennedy DP, Clement C, Arceneaux RL, et al. Ocular herpes simplex virus
type 1: is the cornea a reservoir for viral latency or a fast pit stop? Cornea
2011; 30:251–259.
12. Polcicova K, Biswas PS, Banerjee K, et al. Herpes keratitis in the absence of
anterograde transport of virus from sensory ganglia to the cornea. Proc Natl
Acad Sci USA 2005; 102:11462–11467.
13. BenMohamed L, Osorio N, Srivastava R, et al. Decreased reactivation of a
herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT)
mutant using the in vivo mouse UV-B model of induced reactivation. J
Neurovirol 2015; 21:508–517.
14. White ML, Chodosh J. Herpes Simplex Virus Keratitis: A Treatment Guideline.
AAO Compendium of Evidence-Based Eye Care; 2014. Available at: http://
www.aao.org/clinical-statement/herpes-simplex-virus-keratitis-treatment-
guideline. [Accessed 26 October 2015].
15. Rezende RA, Hammersmith K, Bisol T, et al. Comparative study of ocular
herpes simplex virus in patients with and without self-reported atopy. Am J
Ophthalmol 2006; 141:1120–1125.
16. Borkar DS, Gonzales JA, Tham VM, et al. Association between atopy and
herpetic eye disease: results from the pacific ocular inflammation study. JAMA
Ophthalmol 2014; 132:326–331.
17. Tabery HM. Early epithelial changes in recurrent herpes simplex virus keratitis:
a noncontact photomicrographic study in vivo in the human cornea. Acta
Ophthalmol Scand 1998; 76:349–352.
18. Gulmez Sevim D, Gumus K, Cavanagh HD. Corneal pseudodendritic lesions
masquerading as herpetic keratitis in a patient with tyrosinemia type I. Eye
Contact Lens 2017; 43:e7–e9.
19. Ching SST, Feder RS, Hindman HB, et al. Herpes simplex epithelial keratitis.
Preferred Practice Pattern clinical questions. Am Acad Ophthalmol 2012; 1–8.
20. Hovding G. A comparison between acyclovir and trifluorothymidine ophthal-
mic ointment in the treatment of epithelial dendritic keratitis. A double blind,
randomized parallel group trial. Acta Ophthalmol 1989; 67:51–54.
21. Hoh HB, Hurley C, Claoue C, et al. Randomised trial of ganciclovir and
acyclovir in the treatment of herpes simplex dendritic keratitis: a multicentre
study. Br J Ophthalmol 1996; 80:140–143.
22. Collum LM, McGettrick P, Akhtar J, et al. Oral acyclovir (Zovirax) in herpes
simplex dendritic corneal ulceration. Br J Ophthalmol 1986; 70:435–438.
23. The Herpetic Eye Disease Study Group. A controlled trial of oral acyclovir for
the prevention of stromal keratitis or iritis in patients with herpes simplex virus
epithelial keratitis. The Epithelial Keratitis Trial. Arch Ophthalmol 1997;
115:703–712.
24. Herpetic Eye Disease Study Group. Oral acyclovir for herpes simplex virus
eye disease: effect on prevention of epithelial keratitis and stromal keratitis.
Arch Ophthalmol 2000; 118:1030–1036.
25. Parlato CJ, Cohen EJ, Sakauye CM, et al. Role of debridement and trifluridine
(trifluorothymidine) in herpes simplex dendritic keratitis. Arch Ophthalmol
1985; 103:673–675.
26. Schwartz GS, Holland EJ. Oral acyclovir for the management of herpes
simplex virus keratitis in children. Ophthalmology 2000; 107:278–282.
27. Higaki S, Itahashi M, Deai T, et al. Effect of oral valaciclovir on herpetic
keratitis. Cornea 2006; 25(10 Suppl 1):S64–S67.
28. Itahashi M, Higaki S, Shimomura Y. Effects of anti herpetic drugs on mice with
herpetic epithelial keratitis after reactivation of herpes simplex virus type 1.
Semin Ophthalmol 2008; 23:241–247.
29. Komoto S, Higaki S, Fukuda M, et al. Effects of antiviral medications on
herpetic epithelial keratitis in mice. Jpn J Ophthalmol 2015; 59:194–200.
30. Sozen E, Avunduk AM, Akyol N. Comparison of efficacy of oral valacyclovir
and topical acyclovir in the treatment of herpes simplex keratitis: a randomized
clinical trial. Chemotherapy 2006; 52:29–31.
31. Loutsch JM, Sainz B Jr, Marquart ME, et al. Effect of famciclovir on herpes
simplex virus type 1 corneal disease and establishment of latency in rabbits.
Antimicrob Agents Chemother 2001; 45:2044–2053.
32. Chou TY, Hong BY. Ganciclovir ophthalmic gel 0.15% for the treatment of
acute herpetic keratitis: background, effectiveness, tolerability, safety, and
future applications. Ther Clin Risk Manag 2014; 10:665–681.
33. Shi W, Chen M, Xie L. Amniotic membrane transplantation combined with
antiviral and steroid therapy for herpes necrotizing stromal keratitis. Ophthal-
mology 2007; 114:1476–1481.
1040-8738 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
34. Sangwan VS, Basu S. Antimicrobial properties of amniotic membrane. Br J
Ophthalmol 2011; 95:1–2.
35. Witherel CE, Yu T, Concannon M, et al. Immunomodulatory effects of human
cryopreserved viable amniotic membrane in a pro-inflammatory environment in
vitro. Cell Mol Bioeng 2017; 10:451–462.
36. Kalogeropoulos D, Geka A, Malamos K, et al. New therapeutic percep-
tions in a patient with complicated herpes simplex virus 1 keratitis: a case
report and review of the literature. Am J Case Rep 2017; 18:
1382 – 1389.
37. Sheha H, Tighe S, Cheng AMS, et al. A stepping stone in treating dendritic
& keratitis. Am J Ophthalmol Case Rep 2017; 7:55–58.
This is the first study on the application of amniotic membrane as an adjuvant for
the management of HSV epithelial keratitis.
38. Cheng AMS, Tseng SCG. Self-retained amniotic membrane combined with
antiviral therapy for herpetic epithelial keratitis. Cornea 2017; 36:
1383–1386.
39. Tseng SC, Espana EM, Kawakita T, et al. How does amniotic membrane
work? Ocul Surf 2004; 2:177–187.
40. Kantarci FA, Faraji AR, Ozkul A, et al. Evaluation of the effects of acyclovir and/
or human amniotic membrane on herpes virus culture and quantitative virus
inactivity by real-time polymerase chain reaction. Int J Ophthalmol 2014;
7:626–631.
41. Moein HR, Kheirkhah A, Muller RT, et al. Corneal nerve regeneration after
&& herpes simplex keratitis: an in vivo confocal microscopy study. Ocul Surf
2018; 16:218–225.
A recent prospective study about the destructive effects of HSV epithelial keratitis
on the corneal sensation.
42. M’Garrech M, Rousseau A, Kaswin G, et al. Impairment of lacrimal secretion in
the unaffected fellow eye of patients with recurrent unilateral herpetic keratitis.
Ophthalmology 2013; 120:1959–1967.
43. Piret J, Boivin G. Antiviral resistance in herpes simplex virus and varicella-
zoster virus infections: diagnosis and management. Curr Opin Infect Dis
2016; 29:654–662.
44. Rousseau A, Boutolleau D, Titier K, et al. Recurrent herpetic keratitis despite
& antiviral prophylaxis: a virological and pharmacological study. Antiviral Res
2017; 146:205–212.
A recent study about the effect of resistance to ACV on the clinical course of
patients.
45. Zinser E, Krawczyk A, Muhl-Zurbes P, et al. A new promising candidate to
overcome drug resistant herpes simplex virus infections. Antiviral Res 2018;
149:202–210.
46. Cui H, Liu Y, Huang Y. Roles of TRIM32 in corneal epithelial cells after
infection with herpes simplex virus. Cell Physiol Biochem 2017; 43:
801–811.
47. Bhela S, Rouse BT. Are miRNAs critical determinants in herpes simplex virus
pathogenesis? Microbes Infect 2018; https://doi.org/10.1016/j.mi-
cinf.2017.12.007. [Epub ahead of print]
48. Birkmann A, Zimmermann H. Drugs in development for herpes simplex and
varicella zoster virus. Clin Pharmacol Ther 2017; doi: 10.1002/cpt.647 [Epub
ahead of print]
49. Jiang YC, Feng H, Lin YC, et al. New strategies against drug resistance to
herpes simplex virus. Int J Oral Sci 2016; 8:1–6.
50. Dong LL, Tang R, Zhai YJ, et al. DNA vaccine expressing herpes simplex virus
1 glycoprotein C and D protects mice against herpes simplex keratitis. Int J
Ophthalmol 2017; 10:1633–1639.
51. Royer DJ, Gurung HR, Jinkins JK, et al. A highly efficacious herpes
simplex virus 1 vaccine blocks viral pathogenesis and prevents
corneal immunopathology via humoral immunity. J Virol 2016; 90:
5514 – 5529.
52. Srivastava R, Khan AA, Huang J, et al. A herpes simplex virus type 1 human
asymptomatic CD8þ T-cell epitopes-based vaccine protects against ocular
herpes in a ‘humanized’ HLA transgenic rabbit model. Invest Ophthalmol Vis
Sci 2015; 56:4013–4028.
53. Lin T, Gong L, Sun XH, et al. Effectiveness and safety of 0.15% ganciclovir in
situ ophthalmic gel for herpes simplex keratitis: a multicenter, randomized,
investigator-masked, parallel group study in Chinese patients. Drug Des Dev
Ther 2013; 7:361–368.
www.co-ophthalmology.com 5