Original Article
Acyclovir for the Prevention of Recurrent Herpes Simplex Virus Eye Disease
N Engl J Med 1998; 339:300-306July 30, 1998
- Abstract
Background
Long-term treatment with antiviral agents has been shown to prevent recurrences of genital and orofacial herpes simplex virus (HSV) disease, but it is uncertain whether prophylactic treatment can prevent recurrences of ocular HSV disease.
Methods
We randomly assigned 703 immunocompetent patients who had had ocular HSV disease within the preceding year to receive 400 mg of acyclovir or placebo orally twice daily. The study outcomes were the rates of development of ocular or nonocular HSV disease during a 12-month treatment period and a 6-month observation period.
Results
The cumulative probability of a recurrence of any type of ocular HSV disease during the 12-month treatment period was 19 percent in the acyclovir group and 32 percent in the placebo group (P<0.001). Among the 337 patients with a history of stromal keratitis, the most common serious form of ocular HSV disease, the cumulative probability of recurrent stromal keratitis was 14 percent in the acyclovir group and 28 percent in the placebo group (P=0.005). The cumulative probability of a recurrence of nonocular (primarily orofacial) HSV disease was also lower in the acyclovir group than in the placebo group (19 percent vs. 36 percent, P<0.001). There was no rebound in the rate of HSV disease in the six months after treatment with acyclovir was stopped.
Conclusions
After the resolution of ocular HSV disease, 12 months of treatment with acyclovir reduces the rate of recurrent ocular HSV disease and orofacial HSV disease. Long-term antiviral prophylaxis is most important for patients with a history of HSV stromal keratitis, since it can prevent additional episodes and potential loss of vision.
Media in This Article
Figure 1
Kaplan–Meier Estimates of the Cumulative Probability of a Recurrence of Ocular HSV Disease, According to Treatment.Table 1
Base-Line Characteristics of the Patients.Article Activity
- Article
Herpes simplex virus (HSV) is a leading cause of corneal opacification and infection-related visual loss. An estimated 400,000 Americans have had ocular HSV disease, and there are nearly 50,000 new and recurrent cases each year in the United States.1
After the initial exposure and primary, often asymptomatic infection, HSV establishes a latent infection in the trigeminal or other sensory ganglia. Recurrent viral shedding can lead to disease of one or both eyes. Superficial ocular infection can involve the eyelids (blepharitis), conjunctiva (conjunctivitis), or corneal surface (dendritic or epithelial keratitis). Deeper involvement of the cornea (stromal keratitis) or anterior uvea (iritis) represents a more serious form of the disease that can cause permanent visual loss. No treatment has been demonstrated to prevent recurrences of ocular HSV disease, and neither antiviral drugs nor other treatments are routinely prescribed after the resolution of acute HSV eye infections.
Acyclovir is a potent and specific antiviral agent that is effective in the treatment of and prophylaxis against nonocular HSV infection. Controlled trials have established that oral acyclovir significantly reduces the rate of recurrent genital2,3 and orofacial4,5 HSV infections in otherwise healthy persons. Some studies in animals have shown that systemic acyclovir can suppress experimental reactivation of ocular HSV disease,6 but others have not shown a benefit.7 Although preliminary reports have suggested that such an approach may help prevent ocular HSV disease in humans,8-10 clinical confirmation in a well-designed study has been lacking. Therefore, we conducted a randomized, placebo-controlled trial to determine whether treatment with 400 mg of oral acyclovir twice daily for one year would prevent ocular recurrences in immunocompetent persons who had had an episode of ocular HSV within the preceding year.
Methods
The study was conducted at 74 clinical sites. The protocol and informed-consent forms were approved by the institutional review boards at the participating institutions, and all patients gave written informed consent. The study was overseen by an independent data and safety monitoring committee. Details of the protocol have been published previously11 and are summarized below.
Patients
Eligible patients were 12 years of age or older and had had an episode of ocular HSV disease (i.e., blepharitis, conjunctivitis, epithelial keratitis, stromal keratitis, or iritis) in one or both eyes within the preceding 12 months, but their disease had been inactive and untreated during the 30 days before the study began. Patients were excluded if they were receiving antiviral or immunosuppressive therapy or had a history of immune dysfunction, renal insufficiency, allergy or adverse reaction to acyclovir, or keratoplasty or keratorefractive surgery of the involved eye. All sexually active patients of reproductive age agreed to use contraception during the one-year treatment period and for three months thereafter.
Review of the patients after randomization revealed that 15 did not fulfill all the eligibility criteria: 8 had insufficient documentation of their most recent episode of ocular HSV disease or had not had active disease within the 12 months before enrollment, 6 had either had active ocular HSV disease or received topical antiviral or corticosteroid treatment within 30 days before enrollment, and 1 had been given a misdiagnosis.
Treatment Assignment and Monitoring
A permuted-block design, with a separate sequence of computer-generated random numbers for each of eight geographic regions, was used to assign patients in approximately equal numbers to the two treatment groups. One group received 400 mg of acyclovir (Zovirax, Glaxo Wellcome, Research Triangle Park, N.C.) orally twice daily for 12 months (administered as two capsules, each containing 200 mg of acyclovir, 162 mg of lactose, cornstarch, magnesium stearate, and sodium lauryl sulfate). The other group received two placebo capsules (Glaxo Wellcome) twice daily that contained 218 mg of lactose and were identical in appearance and taste to the capsules containing active drug. Treatment (acyclovir or placebo) was continued for the full 12 months regardless of whether there was a recurrence. In the event of a recurrence of ocular HSV disease, the use of topical treatment was left to the discretion of the investigator. Patients and clinic personnel were unaware of the patients' treatment assignments; the data analysts and monitoring committee were not masked.
We assessed compliance with the treatment protocol by counting the number of capsules remaining in each bottle when it was returned. If a bottle was not returned by the patient, compliance was estimated from the patient's report and from medication cards used by the patient to record when medication was taken.
At each study visit, patients were asked whether any adverse events had occurred since the last visit and were asked to call and report any adverse events that occurred between visits.
Outcomes
Whether patients had a recurrence of active ocular HSV disease was assessed by an experienced ophthalmologist using slit-lamp biomicroscopy. Examinations were performed after 1, 3, 6, 9, and 12 months of treatment; during the post-treatment observation period, after months 13, 15, and 18; and any time new ocular symptoms developed. Recurrences were classified as infections of the ocular surface (blepharitis, conjunctivitis, or epithelial keratitis), stromal keratitis (corneal stromal inflammatory infiltrate or corneal edema associated with endothelial inflammatory precipitates), or iritis. Nonocular HSV infections were recorded solely on the basis of patients' reports and were classified as orofacial or genital or as affecting some other cutaneous site.
Statistical Analysis
We estimated that a total of 696 patients were required for the study to detect with a power of 80 percent a treatment effect of 50 percent, with a probability of a type I error of 5 percent (two-tailed), given a projected rate of recurrence of 15 percent at one year in the placebo group. The calculation was adjusted to account for the possibility that 10 percent of the enrolled patients had not actually had previous ocular HSV disease and that 10 percent of the patients would be lost to follow-up. Primary analyses included all randomized patients and followed the intention-to-treat principle. All reported P values are two-tailed. Interim analyses were performed at six prespecified intervals according to the method of Lan and DeMets.12
The primary outcome was the recurrence of any type of ocular HSV disease during the 12-month treatment period. Analyses were also performed with development of stromal keratitis as the outcome variable, since this is the form of the disease that is most likely to cause permanent loss of vision. The cumulative probability of a recurrence was calculated for each treatment group with the Kaplan–Meier product-limit method, and values in the two groups were compared with the Mantel log-rank test.13 Data on patients who were withdrawn from the trial or were lost to follow-up before having a recurrence were censored at the time of the last completed examination. Unadjusted and adjusted rate ratios were determined from a proportional-hazards model.14 The assumption of proportional hazards was tested for the treatment groups with a time-dependent covariate and found to be appropriate.
Comparisons of categorical variables were made with Fisher's exact test or a chi-square test, and continuous variables were assessed with either a t-test or the Wilcoxon rank-sum test, as appropriate.
Results
Between September 1992 and December 1996, 703 patients entered the trial, with 357 assigned to the acyclovir group and 346 to the placebo group. The base-line characteristics of the two groups were similar (Table 1Table 1
Base-Line Characteristics of the Patients.).Follow-up
During the 18-month study, 88 percent of protocol-specified visits were completed by patients in the acyclovir group and 86 percent by those in the placebo group. Among the 486 patients who did not have a recurrence of ocular HSV disease during the trial, follow-up was incomplete for 64 (13 percent). Five patients died during the course of the study of causes unrelated to study participation (in the acyclovir group, one died of colon cancer and one of emphysema; in the placebo group, one each died of prostate cancer, liver cancer, and non-Hodgkin's lymphoma).
Patients with incomplete follow-up data were more likely to be black than patients with complete follow-up data (17 percent vs. 8 percent, P=0.03) and were younger (mean [±SD] age, 44±18 vs. 49±18 years; P=0.02).
Compliance and Adverse Effects
No serious adverse effects were attributable to treatment; however, 32 patients (15 in the acyclovir group and 17 in the placebo group) discontinued treatment because of side effects (Table 2Table 2
Reasons for Early Discontinuation of Treatment.). The treatment assignment was unmasked for one of these patients, who was in the acyclovir group, after erythema nodosum developed.Among the 575 patients (82 percent of the 703 patients) who completed the full 12-month course of treatment, 89 percent of patients in the acyclovir group and 87 percent of patients in the placebo group were at least 80 percent compliant in taking the oral study medication; 72 percent and 68 percent, respectively, were at least 90 percent compliant. In the acyclovir group, the compliance rate was similar for the patients who had a recurrence of ocular HSV disease during the 12-month treatment period and for those who did not: 90 percent and 89 percent, respectively, were at least 80 percent compliant.
Recurrences of Ocular HSV Disease
Treatment Period
The cumulative probability of a recurrence of ocular HSV disease during the 12-month treatment period was significantly lower in the acyclovir group than in the placebo group (19 percent vs. 32 percent; rate ratio, 0.55; 95 percent confidence interval, 0.41 to 0.75; P<0.001) (Figure 1Figure 1
Kaplan–Meier Estimates of the Cumulative Probability of a Recurrence of Ocular HSV Disease, According to Treatment. and Table 3Table 3
Recurrences of Ocular HSV Disease during the 12-Month Treatment Period.). Adjustment for base-line covariates did not substantially change the results. The results were similar when the data were analyzed according to whether the patients were enrolled at a university-affiliated or community-based clinical center (data not shown). In both treatment groups, the number of past episodes of ocular HSV disease was strongly associated with the likelihood of a recurrence (P=0.04 in the acyclovir group and P=0.006 in the placebo group). The magnitude of the relative treatment effect was similar irrespective of the number of past episodes of ocular HSV disease (Table 3). Sixteen patients in the acyclovir group (4 percent) and 30 in the placebo group (9 percent) had more than one recurrence during the 12-month treatment period.Stromal keratitis was the initial recurrence during the 12-month treatment period in 27 patients in the acyclovir group (8 percent) and in 46 patients in the placebo group (13 percent), whereas epithelial keratitis was the initial recurrence in 31 patients in the acyclovir group (9 percent) and 39 patients in the placebo group (11 percent) (Table 4Table 4
Types of Ocular Involvement in Initial Recurrences of HSV Disease.). Acyclovir reduced the risk of stromal keratitis only among the 337 patients who had had at least one prior episode of stromal keratitis (Table 3). Among such patients, the cumulative probability of a recurrence of HSV stromal keratitis during the 12-month treatment period was 14 percent in the acyclovir group and 28 percent in the placebo group (rate ratio, 0.48; 95 percent confidence interval, 0.29 to 0.80; P=0.005), whereas among patients with no history of stromal keratitis, the cumulative probability of stromal keratitis was 4 percent in the acyclovir group and 3 percent in the placebo group. In no subgroup of patients without a history of stromal keratitis (on the basis of the base-line characteristics given in Table 1) was acyclovir effective in preventing stromal keratitis.Observation Period
During the 6-month observation period after the 12-month treatment period, there were no significant differences between groups in the frequency of recurrences of ocular HSV disease. Among the patients who were followed up for at least 12 months, 45 of the 335 acyclovir-treated patients (13 percent) had a recurrence during the 6-month observation period, as compared with 43 of the 315 placebo-treated patients (14 percent, P=1.0).
Recurrences of Nonocular HSV Disease
The orofacial region was by far the most common location of nonocular HSV infection. During the 12-month treatment period, at least one nonocular HSV infection occurred in 71 patients (20 percent) in the acyclovir group (62 orofacial, 3 genital, 1 at another site, and 5 at more than one site) and 122 patients (35 percent) in the placebo group (111 orofacial, 4 genital, and 7 at more than one site). The cumulative probability of a nonocular recurrence during the 12-month treatment period was 19 percent in the acyclovir group and 36 percent in the placebo group (rate ratio, 0.51; 95 percent confidence interval, 0.38 to 0.69; P<0.001). Among patients with a history of orofacial HSV infection, the cumulative probability of an orofacial recurrence during the 12-month treatment period was 29 percent among 170 patients in the acyclovir group and 50 percent among 177 patients in the placebo group (rate ratio, 0.52; 95 percent confidence interval, 0.37 to 0.74; P<0.001). Among patients with no such history, the cumulative probability of orofacial infection was 11 percent among 187 patients in the acyclovir group and 21 percent among 169 patients in the placebo group (rate ratio, 0.48; 95 percent confidence interval, 0.27 to 0.84; P=0.01). Sixteen patients in the acyclovir group (4 percent) and 49 patients in the placebo group (14 percent) had both ocular and nonocular infections (although not necessarily simultaneously) (P<0.001).
During the observation period, nonocular HSV infections occurred in 87 of the 335 patients still in follow-up in the acyclovir group (26 percent) and in 80 of the 315 patients in the placebo group (25 percent) (P=0.93).
Discussion
This study of 703 patients who had had an episode of ocular HSV disease during the year preceding the trial demonstrated that oral acyclovir reduced the incidence of ocular recurrences during a 12-month treatment period by nearly half. A reduction of similar magnitude in the rate of orofacial HSV recurrences was also found; the rate of genital HSV infections was too low for us to assess whether treatment was beneficial. Acyclovir treatment was generally well tolerated, with no serious adverse effects. The benefit was not sustained after treatment was stopped, but there was also no acute rebound effect.
The two treatment groups were similar, and there was no evidence of confounding in the analyses. Masking was well maintained, and the placebo capsules included a lactose filler that served to mimic the gastrointestinal side effects of the acyclovir formulation used in the study. The percentage of patients with incomplete follow-up was similar in the two groups. Most patients (82 percent) received the full 12 months of treatment and their rates of compliance were satisfactory. The characteristics of our patients appear similar to the reported profile of people with ocular HSV disease.1,15 The generalizability of our results is enhanced by the participation in the trial of patients at both university-affiliated and community-based clinical centers, since the results were similar for both subgroups of patients.
Our finding that prophylactic treatment with oral acyclovir resulted in a 45 percent decrease in the rate of recurrence of ocular HSV disease as compared with placebo is similar to the reported reductions of 50 to 78 percent in the rate of orofacial recurrences4 and of 80 percent in the rate of genital recurrences16 with acyclovir prophylaxis. At the time the trial was initiated, acyclovir was the only commercially available oral antiherpetic medication. The treatment regimen was empirically selected on the basis of previous trials of prophylaxis against nonocular HSV disease. It is not known whether a shorter treatment period, a different dose of acyclovir, or another antiviral agent would provide similar benefit.
In summary, our results show that long-term treatment with acyclovir helps prevent recurrences of ocular HSV disease and orofacial HSV infections in patients with a history of ocular HSV disease. Since the form that a recurrence of ocular HSV disease takes is strongly associated with the form of previous episodes, prolonged acyclovir therapy should provide the greatest clinical benefit for patients with a history of stromal keratitis because it should reduce the likelihood of the corneal scarring and loss of vision that can result from recurrent episodes of stromal keratitis. The role of prophylaxis is less clear for patients who have had only superficial forms of ocular HSV disease (epithelial keratitis, conjunctivitis, and blepharitis), since these forms generally resolve with short-term topical antiviral therapy and cause little permanent damage.17 In general, our results should apply to patients who have had an episode of ocular HSV disease within the year before treatment but not necessarily to those who are immunosuppressed.
Supported by cooperative agreements (EY09686, EY09687, EY09691, EY09692, EY09693, EY09694, EY09695, EY09696, and EY09697) with the National Eye Institute, National Institutes of Health.
Kirk R. Wilhelmus, M.D., M.P.H., Roy W. Beck, M.D., Ph.D., Pamela S. Moke, M.S.P.H., Chandler R. Dawson, M.D., Bruce A. Barron, M.D., Dan B. Jones, M.D., Herbert E. Kaufman, M.D., Natalie Kurinij, Ph.D., R. Doyle Stulting, M.D., Ph.D., Joel Sugar, M.D., Elisabeth J. Cohen, M.D., Robert A. Hyndiuk, M.D., and Penny A. Asbell, M.D., as authors of the study, assume full responsibility for the overall content and integrity of the manuscript.
Source Information
Address reprint requests to Dr. Roy W. Beck at the Jaeb Center for Health Research, 3010 E. 138th Ave., Suite 9, Tampa, FL 33613.
Members of the Herpetic Eye Disease Study Group are listed in the Appendix.
Appendix
The following centers and persons participated in the Herpetic Eye Disease Study: Louisiana State University Eye Center, New Orleans: B. Barron, K. Edwards, S. Massare, M. McGovern, D. Williams, S. Capps, D. Dragon, C. Fitzmorris, E. Graul, Jr., M. Insler, H. Kaufman, A. Lacoste, C. McCaa, R. Selser, Jr., N. Wagner, J. Yokubaitis; Cullen Eye Institute, Baylor College of Medicine, Houston: K. Wilhelmus, L. Todaro, S. Woodside, C. Bowman, J. Chodosh, R. Gilliam, J. Goosey, D. Jones, C. Kirkland, Jr., R. Lehmann, A. Matoba, R. Pitts, P. Scott, S. Smith, T. Wolf, R. Yee; Francis I. Proctor Foundation, University of California, San Francisco: C. Dawson, S. Banuvar, S. Osaki, F. Cohen, G. Barth, R. Biswell, E. Cunningham, D. DeMartini, D. Gritz, W. Hodge, D. Holsclaw, D. Hwang, C. Knox, T. Lietman, T. Margolis, I. Schwab, L. Schwartz, M. Sherman, B. Silverstein, D. Vastine, M. Volpicelli, J. Whitcher, S. Wilson, I. Wong; Emory Eye Center, Emory University, Atlanta: R. Stulting, L. DuBois, R. Baldassare, B. Bertram, H. Chopra, S. Croll, R. DiIorio, J. Gussler, S. Hamilton, G. John, J. McCann, J. Meyer, P. Mitchell, D. Palay, R. Ramirez, R. Reed, R. Serros, L. Taub, K. Thompson, K. Walter; University of Illinois at Chicago Eye Center, Chicago: J. Sugar, R. Rodiek, C. Bouchard, R. Dennis, R. Feder, M. Hennessey, D. Lubeck, S. McLeod, D. Meisler, D. Morimoto, P. Morimoto, J. Rubenstein, H. Tessler; Eye Institute, Medical College of Wisconsin, Milwaukee: R. Hyndiuk, C. Samson, N. Barney, F. Brightbill, J. DeCarlo, E. Fogel, S. Gainey, S. Koenig, D. Kontra, D. Krebs, D. Lewellen, S. Patalano, P. Rice, M. Sanderson, K. Wienkers, M. Yeomans; Wills Eye Hospital, Philadelphia: E. Cohen, S. Marshall, I. Rodriguez, P. Phipps, A. Altman, R. Bailey, K. Fung, S. Hannush, K. Heffler, H. Ingraham, J. Kesselring, V. Kowal, P. Laibson, N. Martin, M. Naidoff, S. Orlin, I. Raber, C. Rapuano, R. Rubinfeld, M. Sulewski; Mount Sinai Medical Center, New York: P. Asbell, N. Justin, R. Azueta, M. Arroyo, S. Celanges, D. Annunziato, S. Epstein, B. Barker, E. Brocks, N. Choo, W. Constad, G. D'Aversa, M. Dunn, B. Gorman, M. Leopold, M. Newton, V. Perez-Arroyo, W. Schwartz, G. Sternberg, I. Udell; National Coordinating Center: Jaeb Center for Health Research, Tampa, Fla.: R. Beck, P. Moke, R. Blair, S. Cole, H. Gillespie, L. Lester, M. Mhamdi, E. Tan; University of California, San Francisco: W. Hauck, L. Gee, J. Hidayat; National Eye Institute: N. Kurinij; Data and Safety Monitoring Committee: S. Bangdiwala (chairman), W. Barlow, J. Chandler, M. Lemp, A. Nesburn, D. Patrick, J. Sutphin, Jr., S. Watson.
- References
References
1
Liesegang TJ , Melton LJ 3rd,Daly PJ ,Ilstrup DM . Epidemiology of ocular herpes simplex: incidence in Rochester, Minn, 1950 through 1982. Arch Ophthalmol 1989;107:1155-1159
Web of Science | Medline2
Mertz GJ ,Jones CC ,Mills J , et al. Long-term acyclovir suppression of frequently recurring genital herpes simplex virus infection: a multicenter double-blind trial. JAMA 1988;260:201-206
CrossRef | Web of Science | Medline3
Mattison HR ,Reichman RC ,Benedetti J , et al. Double-blind, placebo-controlled trial comparing long-term suppressive with short-term oral acyclovir therapy for management of recurrent genital herpes. Am J Med 1988;85:Suppl 2A:20-25
CrossRef | Web of Science | Medline4
Spruance SL ,Hamill ML ,Hoge WS ,Davis LG ,Mills J . Acyclovir prevents reactivation of herpes simplex labialis in skiers. JAMA 1988;260:1597-1599
CrossRef | Web of Science | Medline5
Rooney JF ,Straus SE ,Mannix ML , et al. Oral acyclovir to suppress frequently recurrent herpes labialis: a double-blind, placebo-controlled trial. Ann Intern Med 1993;118:268-272
Web of Science | Medline6
Blatt AN ,Laycock KA ,Brady RH ,Traynor P ,Krogstad DJ ,Pepose JS . Prophylactic acyclovir effectively reduces herpes simplex virus type 1 reactivation after exposure of latently infected mice to ultraviolet B. Invest Ophthalmol Vis Sci 1993;34:3459-3465
Web of Science | Medline7
Kaufman HE ,Varnell ED ,Centifanto-Fitzgerald YM ,DeClercq E ,Kissling GE . Oral antiviral drugs in experimental herpes simplex keratitis. Antimicrob Agents Chemother 1983;24:888-891
Web of Science | Medline8
Colin J ,Robinet A ,Malet F . Preventive treatment of herpetic keratitis with acyclovir tablets. J Fr Ophtalmol 1993;16:6-9
Web of Science | Medline9
Simon AL ,Pavan-Langston D . Long-term oral acyclovir therapy: effect on recurrent infectious herpes simplex keratitis in patients with and without grafts. Ophthalmology 1996;103:1399-1405
Web of Science | Medline10
Rodriguez A ,Power WJ ,Neves RA ,Foster CS . Recurrence rate of herpetic uveitis in patients on long-term oral acyclovir. Doc Ophthalmol 1995;90:331-340
CrossRef | Web of Science | Medline11
Manual of operations: Herpetic Eye Disease Study: prevention studies. Springfield, Va.: National Technical Information Service, August 1, 1994. (Accession #PB97-112999).
12
Lan KKG ,DeMets DL . Discrete sequential boundaries for clinical trials. Biometrika 1983;70:659-663
CrossRef | Web of Science13
Mantel N . Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50:163-170
Medline14
Cox DR . Regression models and life-tables. J R Stat Soc [B] 1972;34:187-22015
Liesegang TJ . Epidemiology of ocular herpes simplex: natural history in Rochester, Minn, 1950 through 1982. Arch Ophthalmol 1989;107:1160-1165
Web of Science | Medline16
Whitley RJ ,Gnann JW Jr . Acyclovir: a decade later. N Engl J Med 1992;327:782-789[Erratum, N Engl J Med 1993;328:671.]
Full Text | Web of Science | Medline17
The Herpetic Eye Disease Study Group
Web of Science | Medline
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K Ziahosseini, K Ikram. (2009) Current clinical practice of consultant ophthalmologists in treating herpetic eye disease in the United Kingdom. Eye 23:4, 993-994
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Relief Jones, Louis R. Pasquale, Deborah Pavan-Langston. (2008) Herpes Simplex Virus: An Important Etiology for Secondary Glaucoma. International Ophthalmology Clinics 47:2, 99-107
CrossRef28
Herbert E. Kaufman, Emily D. Varnell, Bryan M. Gebhardt, Hilary W. Thompson, Ephraim Atwal, Helga Rübsamen-Waigmann, Gerald Kleymann. (2008) Efficacy of a Helicase-Primase Inhibitor in Animal Models of Ocular Herpes Simplex Virus Type 1 Infection. Journal of Ocular Pharmacology and Therapeutics 24:1, 34-42
CrossRef29
Alessandro Lambiase, Marco Coassin, Nicola Costa, Paolo Lauretti, Alessandra Micera, Emiliano Ghinelli, Luigi Aloe, Paolo Rama, Stefano Bonini. (2007) Topical treatment with nerve growth factor in an animal model of herpetic keratitis. Graefe's Archive for Clinical and Experimental Ophthalmology 246:1, 121-127
CrossRef30
Eric E. Gabison, Nicolas Alfonsi, Serge Doan, Louis Racine, Gilles Sultan, Christophe Baudouin, Thanh Hoang-Xuan. (2007) Archipelago Keratitis. Ophthalmology 114:11, 2000-2005
CrossRef31
Elisabetta Miserocchi, Giulio Modorati, Laura Galli, Paolo Rama. (2007) Efficacy of Valacyclovir vs Acyclovir for the Prevention of Recurrent Herpes Simplex Virus Eye Disease: A Pilot Study. American Journal of Ophthalmology 144:4, 547-551.e1
CrossRef32
Fujie Xu, Francis K. Lee, Rhoda A. Morrow, Maya R. Sternberg, Kristina E. Luther, Gary Dubin, Lauri E. Markowitz. (2007) Seroprevalence of Herpes Simplex Virus Type 1 in Children in the United States. The Journal of Pediatrics 151:4, 374-377
CrossRef33
Joon Seo Hwang, Won Ryang Wee, Jin Hak Lee, Mee Kum Kim. (2007) Clinical Analysis of Herpetic Keratitis in Korea. Journal of the Korean Ophthalmological Society 48:9, 1212
CrossRef34
David C Ritterband. (2006) Herpes simplex keratitis: classification, pathogenesis and therapy. Expert Review of Ophthalmology 1:2, 241-256
CrossRef35
Suzanne Luck, Mike Sharland, Paul Griffiths, Sian M Jenkins. (2006) Advances in the antiviral therapy of herpes virus infection in children. Expert Review of Anti-infective Therapy 4:6, 1005-1020
CrossRef36
Laura M Kasman, Joseph M Biber, David T Vroman. (2006) Immunoglobulin Gene Implicated in Murine Herpes Stromal Keratitis Is Not Associated With the Human Disease. Cornea 25:9, 1069-1071
CrossRef37
Renata A. Rezende, Tiago Bisol, Kristin Hammersmith, Christopher J. Rapuano, Ana Luisa H. Lima, Guy F. Webster, Juliana F. Freitas, Peter R. Laibson, Elisabeth J. Cohen. (2006) Efficacy of Oral Antiviral Prophylaxis in Preventing Ocular Herpes Simplex Virus Recurrences in Patients With and Without Self-Reported Atopy. American Journal of Ophthalmology 142:4, 563-567.e1
CrossRef38
Laura K. Green, Deborah Pavan-Langston. (2006) Herpes Simplex Ocular Inflammatory Disease. International Ophthalmology Clinics 46:2, 27-37
CrossRef39
Jay S. Pepose, Tammie L. Keadle, Lynda A. Morrison. (2006) Ocular Herpes Simplex: Changing Epidemiology, Emerging Disease Patterns, and the Potential of Vaccine Prevention and Therapy. American Journal of Ophthalmology 141:3, 547-557.e2
CrossRef40
Pierre-Yves Robert, Anja Liekfeld, Sylvia Metzner, Sylvie Ranger-Rogez, Jean-Paul Adenis, François Denis, Christian Hartmann, Uwe Pleyer. (2006) Specific antibody production in herpes keratitis: intraocular inflammation and corneal neovascularisation as predicting factors. Graefe's Archive for Clinical and Experimental Ophthalmology 244:2, 210-215
CrossRef41
Igor Kaiserman, Nadia Kaiserman, Sasson Nakar, Shlomo Vinker. (2005) Herpetic Eye Disease in Diabetic Patients. Ophthalmology 112:12, 2184-2188
CrossRef42
Bryan M. Gebhardt, Emily D. Varnell, Herbert E. Kaufman. (2005) Inhibition of Cyclooxygenase 2 Synthesis Suppresses Herpes simplex Virus Type 1 Reactivation. Journal of Ocular Pharmacology and Therapeutics 21:2, 114-120
CrossRef43
Arun Chakrabarty, Karl Beutner. (2004) Therapy of other viral infections: herpes to hepatitis. Dermatologic Therapy 17:6, 465-490
CrossRef44
B. Bodaghi. (2004) Les uvéites virales. Journal Français d'Ophtalmologie 27:5, 528-537
CrossRef45
M. Labetoulle. (2004) Actualités thérapeutiques de l’herpès cornéen. Journal Français d'Ophtalmologie 27:5, 547-557
CrossRef46
C. Fardeau. (2004) Rétinites nécrosantes herpétiques. Journal Français d'Ophtalmologie 27:5, 538-546
CrossRef47
Christopher J Rapuano. (2004) EFFECT OF ORAL ACYCLOVIR AFTER PENETRATING KERATOPLASTY FOR HERPETIC KERATITIS. Evidence-Based Eye Care 5:2, 84-85
CrossRef48
Penny J McAllum, Charles NJ McGhee. (2003) Prescribing trends in infectious keratitis: a survey of New Zealand ophthalmologists. Clinical and Experimental Ophthalmology 31:6, 496-504
CrossRef49
Jeroen van Rooij, Wilhelmina J Rijneveld, Lies Remeijer, Henny J.M Völker-Dieben, Catrien A Eggink, Annette J.M Geerards, Paul G.H Mulder, Peter Doornenbal, W.Houdijn Beekhuis. (2003) Effect of oral acyclovir after penetrating keratoplasty for herpetic keratitis. Ophthalmology 110:10, 1916-1919
CrossRef50
Thomas J Liesegang. (2003) Discussion by. Ophthalmology 110:10, 1919
CrossRef51
G. A. E. Wong, S. B. Kaye, R. Parslew. (2003) Reactivation of herpes simplex keratitis during TL01 phototherapy for psoriasis. Clinical and Experimental Dermatology 28:4, 453-454
CrossRef52
Y. Jerold Gordon, Kathleen A. Yates, Francis S. Mah, Eric G. Romanowski. (2003) The Effects of Xalatan ® On the Recovery of Ocular Herpes Simplex Virus Type 1 (HSV-1) in the Induced Reactivation and Spontaneous Shedding Rabbit Models. Journal of Ocular Pharmacology and Therapeutics 19:3, 233-245
CrossRef53
Omesh P. Gupta. (2003) Prevention of Herpes Simplex Virus Eye Disease: A Cost-Effectiveness Analysis. Evidence-Based Eye Care 4:2, 104-105
CrossRef54
DOREEN L. TEOH, SALLY REYNOLDS. (2003) Diagnosis and management of pediatric conjunctivitis. Pediatric Emergency Care 19:1, 48-55
CrossRef55
Anne-Marie Fillet. (2002) Prophylaxis of Herpesvirus Infections in Immunocompetent and Immunocompromised Older Patients. Drugs & Aging 19:5, 343-354
CrossRef56
Samir A Melki, Dimitri T Azar. (2001) LASIK Complications. Survey of Ophthalmology 46:2, 95-116
CrossRef57
Deepinder K Dhaliwal, Eric G Romanowski, Kathleen A Yates, Dean Hu, Francis S Mah, Douglas N Fish, Y.Jerold Gordon. (2001) Valacyclovir inhibition of recovery of ocular herpes simplex virus type 1 after experimental reactivation by laser in situ keratomileusis. Journal of Cataract & Refractive Surgery 27:8, 1288-1293
CrossRef58
Kevin E Kip, Frances Cohen, Stephen R Cole, Kirk R Wilhelmus, Donald L Patrick, R.Clifford Blair, Roy W Beck. (2001) Recall bias in a prospective cohort study of acute time-varying exposures. Journal of Clinical Epidemiology 54:5, 482-487
CrossRef59
Nigel H Barker, Timothy RM Henderson, Carolyn A Ross, Douglas J Coster, Keryn A Williams. (2000) Current Australian practice in the prevention and management of corneal allograft rejection. Clinical and Experimental Ophthalmology 28:5, 357-360
CrossRef60
Bo Cui, Daniel J.J Carr. (2000) A plasmid construct encoding murine interferon beta antagonizes the replication of herpes simplex virus type I in vitro and in vivo. Journal of Neuroimmunology 108:1-2, 92-102
CrossRef61
Rebecca H. Burpo. (2000) Common Antiviral Agents Used in Women's and Children's Care, Part 1. Journal of Obstetric, Gynecologic, <html_ent glyph="@amp;" ascii="&"/> Neonatal Nursing 29:2, 181-190
CrossRef62
Sudha Sudesh, Peter R. Laibson. (1999) The impact of the Herpetic Eye Disease Studies on the management of herpes simplex virus ocular infections. Current Opinion in Opthalmology 10:4, 230-233
CrossRef63
Curtis E Margo. (1999) The Placebo Effect. Survey of Ophthalmology 44:1, 31-44
CrossRef64
Jabs, Douglas A., . (1998) Acyclovir for Recurrent Herpes Simplex Virus Ocular Disease. New England Journal of Medicine 339:5, 340-341
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