The topical agent trifluridine and newer antiviral agents acyclovir, brivudine, and ganciclovir, are efficacious treatments for Herpes simplex virus (HSV) epithelial keratitis. Oral antiviral agents are efficacious treatments for HSV epithelial keratitis. The combined treatment of interferon and an antiviral agent may speed the healing process and may be appropriate for recalcitrant cases. Debridement is an alternative treatment to chemotherapeutic drugs, but it is more efficacious when followed by antiviral treatment. (Strong recommendation, moderate quality)

Epithelial keratitis is the most prevalent form of HSV, accounting for 50% to 80% of ocular herpes cases. Worldwide, approximately 1 million cases of new or recurrent HSV epithelial keratitis occur each year. Without treatment, only half of herpetic corneal surface infections heal within 2 weeks. Controversy remains as to what treatment is the most efficacious in treating HSV epithelial keratitis.

Topical antiviral agents: Topical antiviral agents trifluridine, acyclovir, brivudine, and ganciclovir were almost equally efficacious in treating epithelial keratitis, helping 90% of the total corneas treated in 52 studies to heal within 2 weeks. Formulations or dosages of topical antiviral agents were rarely compared in the studies. Acyclovir and brivudine appear to be similar in efficacy and were not significantly different from trifluridine. While use of ganciclovir was associated with a better outcome than acyclovir, similar healing rates were found at 7 days. The ganciclovir/acyclovir comparison was limited by insufficient data. The benefit of using a second antiviral agent, either topical or oral, is unclear.

Forty of the 88 trials that examined topical antivirals reported adverse reactions from antiviral use. Adverse reactions from topical antivirals included stinging upon installation, allergic blepharoconjunctivitis, superficial keratopathy, and toxo-allergic follicular conjunctivitis. Among the trials that resulted in adverse reactions, the median percentage of eyes that resulted in superficial keratopathy or punctate epithelial erosions was as follows: acyclovir, 10%; ganciclovir, 4%; trifluridine, 4%; and brivudine, 0%. However, because the number of studies and number of participants varied for each drug, these figures do not accurately depict the safety of the antivirals.

Oral antiviral agents: The use of oral acyclovir alone was found to be as efficacious as topical antiviral therapy. The role of oral acyclovir in treating herpetic eye disease is consistent with the findings of evidence-based reviews on the episodic dosing of oral antivirals for labial or genital herpes.

Few trials compared the healing rates of combined oral and topical antiviral treatment to topical antiviral therapy alone. Among those that did, oral antiviral therapy used in conjunction with topical acyclovir was as efficacious - but not more efficacious - than topical antiviral treatment alone.

Topical interferon therapy: Topical interferon therapy was shown to be as efficacious as antiviral agents, both when used alone and when used in conjunction with debridement. While few studies compared different types or formulations of interferon, higher interferon concentrations were generally shown to be more efficacious than lower concentrations - those below 1 million IU/ml. However, studies could not clearly demonstrate a dose-response relationship for progressively increasing interferon dosages. The form of interferon - interferon-α, interferon-β, recombinant interferon, or naturally derived interferon - did not result in any differences in efficacy.

Interferon-antiviral combination therapy: Studies of interferon-antiviral combination treatments were inconsistent, possibly because interferon concentrations varied by study. Interferon-antiviral combination therapy was not significantly better than use of antiviral agents alone at 14 days, but evidence suggests earlier and faster healing using interferon-antiviral combination therapy compared to antiviral monotherapy. Data on the safety of interferon therapy was not provided.

Debridement: Corneal epithelial debridement was found to be more efficacious when followed by use of an antiviral agent or interferon, although the efficacy of this treatment remains inconclusive due to trial heterogeneity on healing rates and no discernible difference in healing rates at the two-week mark compared to antiviral monotherapy. The risks of debridement - damaging the Bowman's layer or causing further corneal inflammation or scarring - have been debated for years, but there is currently no evidence to support these claims.

Supplemental agents: There is inadequate evidence indicating the efficacy of a cytokine growth factor or nonsteroidal anti-inflammatory drug following antiviral therapy; the usefulness of other immunomodulators remains unclear.

Prolonged epithelial defects in HSV: Prolonged epithelial defects in HSV epithelial keratitis may occur as a result of the inhibitory effect of inflammatory cells on corneal epithelial wound healing, as suggested by prolonged healing noted in the setting of peripheral lesions and in those with underlying stromal inflammation. Other causes of prolonged epithelial defects include epithelial toxicity from topical antiviral agents and virological resistance to the therapeutic agent. HSV strains that are not readily susceptible to acyclovir and other antivirals are becoming increasingly prevalent, and may require the selection of an alternative antiviral for treatment. Viral resistance may develop in immunocompromised patients - including patients with bone marrow transplants, cancer, or AIDS - and in patients with intermittent antiviral therapy. Secondary bacterial infections rarely occur.

Healing corneal epithelial defects can result in epithelial abnormalities that may be confused with HSV epithelial keratitis. Eyes with recurrent erosion syndrome may have epithelial irregularities that resemble HSV dendrites, but also often have a history of multiple recurrences that may mimic HSV epithelial keratitis.

HSV PPP Clinical Question Authors/Reviewers

Steven S. T. Ching, MD
Robert S. Feder, MD
Holly B. Hindman, MD
Francis S. Mah, MD
Kirk R. Wilhelmus, MD

Preferred Practice Patterns Committee Members

Christopher J. Rapuano, MD, Chair
David F. Chang, MD
Emily Y. Chew, MD
Robert S. Feder, MD
Stephen D. McLeod, MD
Bruce E. Prum, Jr., MD
C. Gail Summers, MD
David C. Musch, PhD, MPH, Methodologist

Secretary for Quality of Care

Anne L. Coleman, MD, PhD - Director, H. Dunbar Hoskins Jr., MD Center for Quality Eye Care

Academy Staff

Alicia Kraig
Flora C. Lum, MD
Nancy Collins, RN, MPH

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Copyright © March 2012 American Academy of Ophthalmology®

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In compliance with the Council of Medical Specialty Societies' Code for Interactions with Companies, relevant relationships with industry occurring from January 2011 to March 2012 are listed. The Academy has Relationship with Industry Procedures to comply with the Code.

David F. Chang, MD: Alcon Laboratories, Inc. - Consultant/Advisor; Bausch & Lomb - Lecture Fees

Emily Y. Chew, MD: No financial relationships to disclose

Steven S. T. Ching, MD: No financial relationships to disclose

Robert S. Feder, MD: No financial relationships to disclose

Holly B. Hindman, MD: No financial relationships to disclose

Francis S. Mah, MD: No financial relationships to disclose

Stephen D. McLeod, MD: No financial relationships to disclose

David C. Musch, PhD, MPH: No financial relationships to disclose

Bruce E. Prum, Jr., MD: No financial relationships to disclose

Christopher J. Rapuano, MD: Alcon Laboratories, Inc. - Lecture Fees; Bausch & Lomb - Consultant/Advisor, Lecture Fees

C. Gail Summers, MD: No financial relationships to disclose

Kirk R. Wilhelmus, MD: No financial relationships to disclose

Anne L. Coleman, MD, PhD: No financial relationships to disclose

Academy Staff: No financial relationships to disclose