OD News Articles

4th January 2012

New Strategies for HSK

by Salisa Williams, OD Vancouver, Washington

Herpes simplex keratitis (HSK) is the leading infectious cause of blindness in the United States. As the front line of eyecare, optometric physicians play an important role in treating this infection.

The herpes simplex virus (HSV) is a common cause of infection.  Approximately 25% of the population is seropositive for HSV at age 4. This jumps to 100% by age 60. With such prevalence, it may not be surprising that 50,000 new cases occur each year or that 400,000 Americans have had some form of ocular herpes.

Challenging Condition

HSK is challenging for both optometric physicians and patients. After primary ocular infection, the herpes virus becomes latent but episodes of recurrent infection or inflammation are typical and can damage the corneal structure such that corneal transplantation is required. Even after successful transplant surgery, HSK recurrences can lead to corneal graft rejection.

Viroptic and Little Else

Until recently, treatment for HSK was typically limited to Viroptic (trifluridine) eye drops. A thymidine analog, it has been the only topical antiviral for HSV available for many years. While effective, Viroptic has several downsides:

  • It has become less available in pharmacies
  • Requires up to 9 doses per day
  • Requires refrigeration
  • Prolonged use can lead to toxicity of the ocular surface including:

~ epithelial keratitis
~ corneal ulcer
~ follicular conjunctivitis
~ punctal occlusion

Newer Treatment Strategies

Two recent developments offer alternatives to Viroptic:

Oral antivirals – Acyclovir (Zovirax) has been shown to be as effective as Viroptic.

  • Some people would rather take pills than eye drops
  • Dosage is less frequent than trifluridine drops
  • It is available as an inexpensive generic
  • Generally safe and well tolerated

Zirgan (topical ganciclovir gel) – Received FDA approval in 2009 as a safe and effective treatment option.

  • More comfortable than trifluridine drops
  • 5 doses per day vs. 9 for Viroptic
  • No refrigeration needed
  • Increased convenience may result in better compliance
  • Less corneal toxicity than Viroptic
Oral Antiviral Agents

The National Eye Institute’s Herpetic Eye Disease Study (HEDS and HEDS ll) had several interesting findings:

  • Oral acyclovir in a prophylactic dosage of 400mg BID reduced recurrence of any form of ocular herpes in the following year by 41%
  • The above dosage also reduced recurrence of severe forms of ocular herpes, such as stromal keratitis, in the following year by 50%
  • Oral acyclovir was also found to reduce the incidence of epithelial herpetic keratitis from developing into stromal disease or keratitis. No added benefit was found by adding oral acyclovir if the patient was already taking Viroptic.

Some clinicians have adopted an orals only approach to treating HSK—including recurrent and stromal keratitis as well as initial dendritic ulcers. There are several likely reasons, including high rates of Viroptic-associated corneal toxicity, the difficulty in keeping up with 9 doses a day, and the low cost of generic acyclovir.

The dosage for newer oral antivirals—Valtrex (valaciclovir) and Famvir (famcivlovir)—is 3 times a day for 1 week, so compliance may be even better than with acyclovir. In addition, a recent study showed that patients with acute HSK placed on oral antivirals were more than 9 times less likely to experience recurrence.

While researchers and clinicians acknowledge the benefits of oral antivirals, consensus has not been reached that oral antivirals alone should replace topical treatment for dendritic keratitis—particularly initial episodes.

Zirgan—Topical Ganciclovir Gel

Zirgan is the first new topical medication to be approved for treatment of acute herpetic keratitis (dendritic ulcers) in more than 3 decades.

  • It is a potent inhibitor of members of the herpes virus family
  • It is used systemically for the treatment of cytomegalovirus (CMV) retinitis
  • It has been shown to be as safe and effective as topical acyclovir in the treatment of herpetic epithelial keratitis (Note: topical acyclovir is not available in the USA)
  • It is a guanosine derivative that upon phosphorylation inhibits DNA replication by herpes simplex viruses
  • It is more selective than other antiviral drugs and does not target healthy corneal cells
  • It is well tolerated and does not cause toxicity to the ocular surface
Zirgan Efficacy

An open-label, randomized, controlled, multicenter clinical trial involving 164 patients with herpetic keratitis found Zirgan to be as effective as acyclovir ophthalmic ointment 3%.

  • Clinical resolution (healed ulcers) at day 7

~ 77% for Zirgan
~ 72% for acyclovir ointment

In 3 randomized, single-masked, controlled, multicenter clinical trials involving 213 patients, Zirgan was as good as acyclovir ophthalmic ointment 3% in patients with dendritic ulcers.

  • Clinical resolution at day 7

~ 72% for Zirgan
~ 69% for acyclovir ointment

Adverse reactions were mild, the most common being blurred vision (60%), irritation (20%), punctate keratitis (5%), and conjunctival hyperemia (5%).


Zirgan Treatment

The recommended dosing regimen for Zirgan is 1 drop in the affected eye 5 times per day, approximately every 3 hours while awake until the corneal ulcer heals, and then 1 drop 3 times per day for 7 days. Patients should not wear contact lenses if they have signs or symptoms of herpetic keratitis or during the course of therapy with Zirgan.


Zirgan’s advantages, combined with Viroptic’s decreased availability, have led to Zirgan becoming many practitioners’ drug of choice for HSV keratitis. However, even with new treatment strategies, herpetic keratitis can have a prolonged clinical course. And the tendency to cause corneal scarring requires close attention.

Referral for specialty care should be considered when the infection is anticipated to cause loss of acuity, or when no improvement has been seen after several days of treatment. Your close observation and understanding of new treatment strategies will help patients deal with this challenging condition.   

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