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Clinical Sciences |

Modalities to Decrease Stromal Herpes Simplex Keratitis Reactivation Rates FREE

John D. Sheppard, MD; Michael L. Wertheimer, MD; Stephen V. Scoper, MD
[+] Author Affiliations

Author Affiliations: Thomas R. Lee Center for Ocular Pharmacology (Dr Sheppard) and Department of Ophthalmology (Drs Sheppard and Wertheimer), Eastern Virginia Medical School, and Virginia Eye Consultants (Drs Sheppard and Scoper), Norfolk.


Arch Ophthalmol. 2009;127(7):852-856. doi:10.1001/archophthalmol.2009.163.
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Published online

Objective  To evaluate the efficacy of adjunctive treatments to decrease herpes simplex keratitis (HSK) recurrences in patients with simultaneous stromal HSK and dry eye disease.

Methods  This was a nonrandomized, single-center, retrospective, comparative analysis. Forty-two patients were diagnosed with unilateral HSK and dry eye disease. Of the 42 patients, 22 were treated with ipsilateral punctal occlusion by thermal cautery and 10 were treated with topical administration of cyclosporine, 0.05%, ophthalmic emulsion twice a day. Another group of 10 patients had previously undergone punctal occlusion and had cyclosporine ophthalmic emulsion twice a day added. All patients continued the use of oral acyclovir or valacyclovir hydrochloride and topical steroids. The frequency and duration of HSK recurrences were monitored for 1 year after initiation of treatment, and the rates were compared with those in the prior year.

Results  The thermal cautery and topical cyclosporine groups experienced HSK recurrences for mean durations of 7.1 and 5.8 mo/y before treatment, respectively, and these were reduced to 1.1 mo/y after treatment in both groups. Topical administration of cyclosporine further reduced the duration of HSK recurrences in patients with prior thermal cautery from an average of 1.3 mo/y before the addition of cyclosporine to 0.8 mo/y after the addition of cyclosporine.

Conclusion  Permanent punctal occlusion by thermal cautery and the use of topical cyclosporine independently reduced recurrences of stromal HSK.

Figures in this Article

Herpes simplex virus (HSV) is the most common cause of corneal blindness and blindness resulting from infection in the United States and developed countries.1,2 The prevalence of ocular HSV was 0.15% in 1988, and it may be greater now owing to the increased prevalence of HSV in the general population.2 The recurrence rate of ocular HSV within 2 years ranges from 23% to 33%, and about 20% to 25% of those with ocular HSV infections develop T-cell–mediated stromal herpes simplex keratitis (HSK).2,3 In addition to the stromal inflammation associated with HSK, these patients have been shown to have decreased tear production and dry eyes.4

A need exists for safe and effective prophylactic treatments to prevent or minimize the corneal scarring, vision loss, discomfort, and glaucoma that often result from HSK recurrences and stromal disease. The antiviral compound acyclovir had a beneficial effect for patients with ocular HSV relative to placebo in a randomized, double-masked trial, but the ability of acyclovir to prevent stromal disease remains controversial.2,57 Topical administration of corticosteroids in conjunction with oral antivirals has been proven to reduce the persistence or progression of HSK compared with placebo.8 However, prolonged use of topical steroids introduces the well-established increased risks of ocular infection, cataract, delayed wound healing, and glaucoma. In a 1999 study,9 topical administration of a pharmacy-prepared suspension of cyclosporine, 2%, in peanut oil resolved stromal HSK in 10 of 14 patients, but the lack of a commercially available ophthalmic formulation of cyclosporine until 2001 probably discouraged further investigation of its potential therapeutic benefit. However, Rao10 recently reported that topical cyclosporine, 0.05%, although in an off-label use of the medication, was an effective alternative to topical steroids in patients with stromal HSK shown to be nonresponsive to prednisolone acetate.

To address the tear production deficit associated with stromal HSK and examine its link to recurrence rates, this retrospective study investigated the efficacy of both ipsilateral punctal occlusion by thermal cautery and topical administration of cyclosporine, 0.05%, ophthalmic emulsion for the treatment of patients diagnosed with both stromal HSK and dry eye disease.

This was a nonrandomized, retrospective, comparative analysis set in a private academic medical school–based referral practice. Information from 42 patients with unilateral HSK and dry eye disease was collected by consecutive retrospective record review in compliance with Health Insurance Portability and Accountability Act guidelines. Herpes simplex keratitis was diagnosed by at least 1 of the following criteria: stromal scarring, history of dendritic keratitis, corneal hypoesthesia, or clinical response to antivirals for the treatment of HSK. Dry eye disease was diagnosed by at least 1 of the following criteria: poor tear meniscus, Schirmer test score of 10 mm or less, or punctate epitheliopathy. Immunocompromised patients were excluded from the study.

We obtained informed consent and divided patients into 3 treatment groups (Table 1): patients in group 1 were treated by ipsilateral punctal occlusion by thermal cautery at the beginning of the study (n = 22); patients in group 2 were treated with cyclosporine, 0.05%, ophthalmic emulsion (Restasis) twice a day (n = 10); and patients in group 3 had undergone punctal occlusion by thermal cautery prior to the study and were subsequently treated with cyclosporine, 0.05%, ophthalmic emulsion twice a day (n = 10). All patients continued the use of oral acyclovir or valacyclovir hydrochloride throughout the study. Patients were also given the minimal amount of topical steroid deemed necessary, either prednisolone acetate, 1% (Pred Forte), or loteprednol etabonate, 0.5% (Lotemax). Treatment groups were not age or sex matched. Investigators and patients were not masked with respect to treatments.

Table Graphic Jump LocationTable 1. Annual Duration of Herpes Simplex Keratitis Recurrences

We observed the patients for at least 1 year. Outcome assessments were made by one of us (J.D.S.). We compared the frequency and duration of HSK recurrence with the same patient's record from the year preceding treatment. We defined recurrences either as a clinical need for increased topical steroid or oral antiviral therapy above baseline maintenance therapy or as clinically increased corneal inflammation, persistent epitheliopathy, or decreased vision. Baseline minimal maintenance therapy for most patients consisted of a single daily dose of either 400 mg of acyclovir or 500 mg of valacyclovir hydrochloride, plus a single daily dose of topical loteprednol etabonate, 0.5%, or prednisolone acetate, 1%.

Statistical significance was analyzed by paired t tests. Any adverse effects that had been noted in the patients' medical records were recorded.

Patients with unilateral HSK and dry eye disease were treated as described in Table 1. The frequency and duration of HSK recurrences were monitored for at least 1 year after initiation of the punctal occlusion or cyclosporine treatments and were compared with the frequency and duration of HSK recurrences in the prior year.

The frequency of HSK recurrences was reduced in patients treated by punctal cautery from 2.1 recurrences per year before treatment to 0.45 recurrences per year after treatment (P = .01) (Figure). Similarly, administration of topical cyclosporine reduced the annual frequency of HSK recurrences from 1.8 to 0.43 (P = .02) (Figure). Patients who had thermal cautery prior to this analysis had a lower pretreatment frequency of recurrences, 0.58 per year, as expected (Figure). Treatment of patients with prior thermal cautery by topical administration of cyclosporine further reduced their frequency of HSK recurrences to 0.40 per year (P = .05) (Figure).

Place holder to copy figure label and caption
Figure.

Frequency of herpes simplex keratitis recurrences for 1 year before permanent cautery or topical cyclosporine treatment and at least 1 year after initiation of treatment. *P = .01. †P = .02. ‡P = .05.

Graphic Jump Location

The mean annual duration of single or multiple recurrences in patients with unilateral HSK and dry eye disease was also reduced by adjunctive occlusion or cyclosporine treatments. Punctal cautery reduced the mean duration of HSK recurrences from 3.4 months per recurrence before treatment to 2.4 months per recurrence after treatment (P = .05). Multiplying these values by the number of recurrences per year yields a mean annual HSK recurrence duration of 7.1 mo/y before thermal cautery and 1.1 mo/y after thermal cautery (Table 1). Topical administration of cyclosporine reduced HSK recurrences from 3.2 to 2.5 months (P = .03). The mean annual HSK recurrence duration was 5.8 mo/y before initiation of topical cyclosporine and 1.1 mo/y after initiation of topical cyclosporine (Table 1). Patients who had thermal cautery prior to this analysis had a mean duration of 2.2 months per recurrence before treatment, which decreased to 2.0 months with the addition of topical administration of cyclosporine. These patients had HSK recurrence durations of 1.3 mo/y before analysis and 0.8 mo/y after the addition of topical cyclosporine treatment (Table 1).

Topical steroid use decreased in all of the 3 treatment groups relative to steroid use during the year prior to analysis, but these decreases were not statistically significant. No significant changes in best-corrected visual acuity or intraocular pressure were found in any of the treatment groups. No serious adverse effects of the adjunctive cyclosporine or occlusion treatments were reported.

Recurrences of HSK due to reactivation of latent viruses may lead to progressive corneal scarring, corneal ectasia, neurotrophic keratopathy, vision loss, uveitis, cataract, and glaucoma. To minimize ocular damage, it is desirable to limit the frequency and duration of HSK recurrences. The results of this study demonstrate that prophylactic adjunctive treatments with thermal punctal cautery or topical administration of cyclosporine in patients with simultaneous stromal HSK and dry eye disease each provide significant benefit by minimizing HSK frequency and duration of recurrences for at least 1 year compared with the 1-year period prior to treatment. Topical cyclosporine appeared to provide some additional benefit to patients who had already undergone thermal cautery.

Cyclosporine, 0.05%, was approved by the US Food and Drug Administration for the treatment of dry eye disease and ocular surface inflammation based on its efficacy and safety in large clinical trials.11,12 Cyclosporine is an immunomodulator that inhibits activation of T cells. Understanding that the pathological mechanism of stromal HSK is not active viral infection but viral antigens initiating a T-lymphocytic destruction of the stroma helps predict the potential success of cyclosporine for stromal HSK. It is important to note that systemic plasma concentrations of cyclosporine after topical administration of cyclosporine, 0.05%, were below the limit of detection (0.1 ng/mL [to convert to nanomoles per liter, multiply by 0.832]) in all patients tested.11,13

Studies have documented that topically administered steroids are effective treatments for stromal inflammation associated with HSK but because of well-known adverse effects are relatively undesirable for long-term therapy.8 Besides the previously discussed risks associated with long-term use, topical steroids are immunosuppressive and therefore predispose to herpetic reactivation when administered alone without concomitant oral antiviral therapy. Our study found, in addition to a therapeutic benefit of thermal cautery and topical cyclosporine, that steroid use was decreased in all of the 3 unmasked treatment groups, although these decreases were not statistically significant. Clearly, the investigators in this analysis intended throughout to decrease topical steroid administration to the lowest effective frequency possible. However, they may have been biased to become more aggressive with steroid withdrawal than otherwise, anticipating subsequent analysis of the interventions addressed in this study. Cyclosporine has been used as a steroid-sparing agent in the treatment of many other immunologic diseases, and the potential steroid-sparing effect of cyclosporine may limit herpetic reactivation associated with topical steroid exposure.

Although limited by its nonrandomized, retrospective design, the results of this study support the hypothesis that cautery and topical cyclosporine independently and concomitantly decrease HSK recurrences. It could be postulated that thermal cautery facilitates therapy by simply enhancing topically applied drug levels on the ocular surface and that both thermal cautery and cyclosporine therapeutic effects targeting dry eye improve tear film quality and decrease ocular surface irritation, thereby suppressing well-known triggers for HSV reactivation. The immunomodulatory effects of cyclosporine limiting the underlying mechanism of stromal HSK and potentially limiting topical steroid exposure are also potential mechanisms for this new adjunctive therapy.

One treatment is not more efficacious than the other based on evidence presented herein. In addition, the therapeutic benefit obtained with topical cyclosporine, 0.05%, in this study is consistent with that found in a previous study of HSK using topical cyclosporine, 2%.9

A second limitation is that the treatments were not masked because the surgical intervention of permanent occlusion by thermal cautery could not be obscured from physicians and patients. Also, cyclosporine prescriptions were not masked from the treating physician.

Another limitation is that participants had both HSK and dry eye disease; thus, it is unknown whether the therapeutic benefits of thermal cautery and topical cyclosporine found here would apply to patients with HSK alone. It should be noted, however, that reduced tear production and dry eyes are strongly associated with HSK, suggesting that most patients with HSK may have both conditions.4

Finally, this analysis did not completely differentiate between patients with solely stromal disease and those with epithelial disease plus stromal HSK. Thus, additional trials to address the wide variety of HSK manifestations may further guide clinicians in the care of these patients.

The recurrence rates and durations for patients in this analysis were high, reflective of a tertiary referral population already frustrated by inadequate responses to initial therapeutic attempts. Thus, the efficacy of the adjunctive therapies used in this analysis from this clinical practice cannot necessarily be inferred for patients with milder or less problematic HSK. In addition, this analysis did not use silicone punctal plugs because plug caps may lead to conjunctival irritation as well as accumulation of protein and ocular surface floral bacteria. It is therefore not known whether the use of silicone punctal plugs would incur the same benefits as permanent thermal punctal cautery.

Ideally, recurrent stromal HSK episodes should be limited with an individually tailored, minimally sufficient, preventive clinical regimen. This prophylactic regimen would include many elements such as appropriately frequent slitlamp evaluations, maintenance oral antiviral therapy, topical corticosteroid drops limited in frequency by concomitant topical cyclosporine therapy, ipsilateral punctal occlusion, and avoidance of stress factors known to induce keratitis relapses. Because each episode of reactivation can potentially cause significant structural damage to the central cornea and visual axis, relapse prevention portends invaluable preservation of health care resources as well as visual function. The cost of the preventive regimen can be at least estimated using readily available information (Table 2).

Table Graphic Jump LocationTable 2. Costs of Preventive Regimens

Comparing maintenance treatment as recommended in this article with standard treatment, yearly costs could be as shown in Table 3 assuming that relapse care dosages are maintained for 6 months, that no relapses occur while the patient receives preventive maintenance therapy with occlusion and Restasis, and that 1 relapse occurs per year when the patient receives no preventive maintenance. The preventive maintenance strategy with occlusion and Restasis costs about the same as a wait-and-see relapse care strategy under these assumptions. The costs of permanent corneal damage are not included in this scenario. Preventive maintenance therapy using bilateral Restasis treatment and ipsilateral thermocautery occlusion preceded by a collagen plug trial appears to be cost-effective in this scenario during the first year and potentially even more cost-effective in subsequent years. Other methods of punctal occlusion such as argon laser thermocautery are less effective and more costly than the traditional thermocautery with a hyfrecator used throughout this study.15

Table Graphic Jump LocationTable 3. Costs of Preventive Maintenance and Relapse Care

Similar comparisons can be made using Pred Forte eyedrops or generic prednisolone acetate eyedrops vs oral Valtrex (valacyclovir hydrochloride) therapy. The relative savings would be proportionate and thus comparable to our initial scenario prescribing Lotemax drops and generic oral acylovir, our preferred regimen.

In summary, the adjunctive treatments for HSK and dry eye disease evaluated in this retrospective analysis significantly reduced the frequency and duration of HSK recurrences. Based on these results, adjunctive therapy with both punctal occlusion by thermal cautery and topical administration of cyclosporine, 0.05%, should be considered for any patient with HSK and dry eye disease.

Correspondence: John D. Sheppard, MD, Virginia Eye Consultants, 241 Corporate Blvd, Norfolk, VA 23502 (docshep@hotmail.com).

Submitted for Publication: November 16, 2008; final revision received January 29, 2009; accepted February 6, 2009.

Financial Disclosure: The authors have no financial interest in the treatments investigated in this study. Dr Sheppard serves as an advisor, speaker, and clinical researcher for Allergan, Inc, the manufacturer of cyclosporine, 0.05%, ophthalmic solution (Restasis).

Funding/Support: This work was supported in part by the Thomas R. Lee Center for Ocular Pharmacology and the Virginia Eye Foundation.

Role of the Sponsor: The Thomas R. Lee Center for Ocular Pharmacology and the Virginia Eye Foundation had no role in the design or conduct of this research.

Additional Contributions: Sandeep Samudre, PhD, provided statistical analysis.

Judge  AAssil  K Herpes simplex. http://www.emedicine.com/oph/topic256.htm. Accessed September 24, 2005
Liesegang  TJ Herpes simplex virus epidemiology and ocular importance. Cornea 2001;20 (1) 1- 13
PubMed
Doymaz  MZRouse  BT Herpetic stromal keratitis: an immunopathologic disease mediated by CD4+ T lymphocytes. Invest Ophthalmol Vis Sci 1992;33 (7) 2165- 2173
PubMed
Keijser  Svan Best  JAVan der Lelij  AJager  MJ Reflex and steady state tears in patients with latent stromal herpetic keratitis. Invest Ophthalmol Vis Sci 2002;43 (1) 87- 91
PubMed
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 [published correction appears in Arch Ophthalmol. 1997;115(9):1196]. Arch Ophthalmol 1997;115 (6) 703- 712
PubMed
Herpetic Eye Disease Study Group, Acyclovir for the prevention of recurrent herpes simplex virus eye disease. N Engl J Med 1998;339 (5) 300- 306
PubMed
Barron  BAGee  LHauck  WW  et al.  Herpetic Eye Disease Study: a controlled trial of oral acyclovir for herpes simplex stromal keratitis. Ophthalmology 1994;101 (12) 1871- 1882
PubMed
Wilhelmus  KRGee  LHauck  WW  et al.  Herpetic Eye Disease Study: a controlled trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology 1994;101 (12) 1883- 1896
PubMed
Heiligenhaus  ASteuhl  KP Treatment of HSV-1 stromal keratitis with topical cyclosporin A: a pilot study. Graefes Arch Clin Exp Ophthalmol 1999;237 (5) 435- 438
PubMed
Rao  SN Treatment of herpes simplex virus stromal keratitis unresponsive to topical prednisolone 1% with topical cyclosporine 0.05%. Am J Ophthalmol 2006;141 (4) 771- 772
PubMed
Sall  KStevenson  ODMundorf  TKReis  BLCsA Phase 3 Study Group, Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease [published correction appears in Ophthalmology. 2000;107(7):1220]. Ophthalmology 2000;107631- 639
PubMed
Barber  LDPflugfelder  SCTauber  JFoulks  GN Phase III safety evaluation of cyclosporine 0.1% ophthalmic emulsion administered twice daily to dry eye disease patients for up to 3 years. Ophthalmology 2005;112 (10) 1790- 1794
PubMed
Small  DSAcheampong  AReis  B  et al.  Blood concentrations of cyclosporine a during long-term treatment with cyclosporine A ophthalmic emulsions in patients with moderate to severe dry eye disease. J Ocul Pharmacol Ther 2002;18 (5) 411- 418
PubMed
 Drugstore.com online pharmacy. http://www.drugstore.com. Accessed April 22, 2009
Hutnik  CMProbst  LE Argon laser punctal therapy vs thermal cautery for the treatment of aqueous deficiency dry eye syndrome. Can J Ophthalmol 1998;33 (7) 365- 372
PubMed

Figures

Place holder to copy figure label and caption
Figure.

Frequency of herpes simplex keratitis recurrences for 1 year before permanent cautery or topical cyclosporine treatment and at least 1 year after initiation of treatment. *P = .01. †P = .02. ‡P = .05.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Annual Duration of Herpes Simplex Keratitis Recurrences
Table Graphic Jump LocationTable 2. Costs of Preventive Regimens
Table Graphic Jump LocationTable 3. Costs of Preventive Maintenance and Relapse Care

References

Judge  AAssil  K Herpes simplex. http://www.emedicine.com/oph/topic256.htm. Accessed September 24, 2005
Liesegang  TJ Herpes simplex virus epidemiology and ocular importance. Cornea 2001;20 (1) 1- 13
PubMed
Doymaz  MZRouse  BT Herpetic stromal keratitis: an immunopathologic disease mediated by CD4+ T lymphocytes. Invest Ophthalmol Vis Sci 1992;33 (7) 2165- 2173
PubMed
Keijser  Svan Best  JAVan der Lelij  AJager  MJ Reflex and steady state tears in patients with latent stromal herpetic keratitis. Invest Ophthalmol Vis Sci 2002;43 (1) 87- 91
PubMed
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 [published correction appears in Arch Ophthalmol. 1997;115(9):1196]. Arch Ophthalmol 1997;115 (6) 703- 712
PubMed
Herpetic Eye Disease Study Group, Acyclovir for the prevention of recurrent herpes simplex virus eye disease. N Engl J Med 1998;339 (5) 300- 306
PubMed
Barron  BAGee  LHauck  WW  et al.  Herpetic Eye Disease Study: a controlled trial of oral acyclovir for herpes simplex stromal keratitis. Ophthalmology 1994;101 (12) 1871- 1882
PubMed
Wilhelmus  KRGee  LHauck  WW  et al.  Herpetic Eye Disease Study: a controlled trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology 1994;101 (12) 1883- 1896
PubMed
Heiligenhaus  ASteuhl  KP Treatment of HSV-1 stromal keratitis with topical cyclosporin A: a pilot study. Graefes Arch Clin Exp Ophthalmol 1999;237 (5) 435- 438
PubMed
Rao  SN Treatment of herpes simplex virus stromal keratitis unresponsive to topical prednisolone 1% with topical cyclosporine 0.05%. Am J Ophthalmol 2006;141 (4) 771- 772
PubMed
Sall  KStevenson  ODMundorf  TKReis  BLCsA Phase 3 Study Group, Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease [published correction appears in Ophthalmology. 2000;107(7):1220]. Ophthalmology 2000;107631- 639
PubMed
Barber  LDPflugfelder  SCTauber  JFoulks  GN Phase III safety evaluation of cyclosporine 0.1% ophthalmic emulsion administered twice daily to dry eye disease patients for up to 3 years. Ophthalmology 2005;112 (10) 1790- 1794
PubMed
Small  DSAcheampong  AReis  B  et al.  Blood concentrations of cyclosporine a during long-term treatment with cyclosporine A ophthalmic emulsions in patients with moderate to severe dry eye disease. J Ocul Pharmacol Ther 2002;18 (5) 411- 418
PubMed
 Drugstore.com online pharmacy. http://www.drugstore.com. Accessed April 22, 2009
Hutnik  CMProbst  LE Argon laser punctal therapy vs thermal cautery for the treatment of aqueous deficiency dry eye syndrome. Can J Ophthalmol 1998;33 (7) 365- 372
PubMed

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