Viroptic: an effective treatment for herpes simplex ocular infections

Viroptic (trifluridine 1%, Glaxo) is an antiviral that is currently the drug of choice for treating primary keratoconjunctivitis and recurrent epithelial keratitis caused by herpes simplex virus (HSV) type 1 (oral) or type 2 (genital). It is also indicated for treating HSV keratitis that has not responded to idoxuridine or vidarabine (Vira-A, Parke-Davis). It is not indicated for other common forms of viral conjunctivitis.

Viroptic is preserved with 0.001% thimerosal and supplied as a sterile ophthalmic solution in a 7.5-mL plastic bottle. Viroptic is an analog of thymidine, which inhibits DNA synthesis and thus viral replication.

Primary/recurrent episodes

Herpes simplex infection may be either a primary or recurrent episode and usually presents as a unilateral red eye. Primary infection typically occurs before the age of 15. After this age, up to 90% of individuals will show serological evidence of exposure to HSV. Patients may complain of pain, light sensitivity, decreased vision and a skin rash.

In primary HSV, there is usually a mixed follicular and papillary conjunctivitis, which may be accompanied by vesicular eruptions on the eyelids that progress to pustules. Dendritic ulcers are rarely associated with a primary HSV infection. If keratitis is present, it is usually punctate in appearance.

There is often a tender, enlarged pre-auricular lymph node on the same side as the affected eye. If the initial presentation is a conjunctivitis with no corneal involvement, one drop of Viroptic five times a day may be sufficient treatment. However, if there is an associated keratitis, the maximum dosage of one drop every 2 hours (up to nine times daily) should be used.

Reactivation of the virus

Following resolution of a primary HSV infection, the virus becomes latent in the trigeminal ganglia. It may be reactivated by stress, immunocompromise or systemic illness. Virus produced in the trigeminal ganglion can move through the sensory nerves to infect the cornea. Corneal sensitivity may be reduced and should be evaluated before anesthetic is applied.

Secondary HSV infection usually presents in the form of a small, single, dendritic corneal ulcer or multiple ulcers. These ulcers are thin, linear, branching lesions, often with terminal end bulbs. The centers of these ulcers typically stain brightly with fluorescein, while the edges stain well with rose bengal.

The ulcers may progress from the typical dendritic pattern to a "geographic" or "ameoboid" pattern. This progression can occur with misdiagnosis and subsequent treatment with topical steroids, which are contraindicated in active HSV keratitis.

HSV keratitis should be treated with one drop of Viroptic to the affected eye every 2 hours while awake for a maximum daily dose of nine drops until the ulcer has completely re-epithelialized (usually 1 to 2 weeks).

Resolution of the ulcer

Following resolution of the ulcer, the dosage should be reduced to four times daily for 1 more week. If there is no improvement in the appearance of the ulcer within 7 days or if re-epithelialization is incomplete after 14 days, it is recommended that other forms of therapy be considered. Continuous use of Viroptic for more than 21 days should be avoided because of ocular toxicity.

Adjunctive therapy may include gentle debridement of the affected area and/or addition of a second antiviral agent. Clinically, I have found the addition of vidarabine 3% ointment dosed three to five times daily to be helpful in providing around-the-clock antiviral coverage for larger corneal ulcers. Oral acyclovir, 400 mg five times daily, may also be beneficial. A preservative-free ocular lubricant can be added for patient comfort.

Avoid steroids

Steroids should be avoided in cases of HSV keratitis and should be used only when there is no other means to control ocular inflammation. Patients who are on topical steroid therapy for other conditions (such as after cataract surgery) should be tapered quickly, and a cycloplegic agent may be added to the treatment regimen if an anterior chamber reaction is present.

In some cases, HSV may progress from an epithelial disease to stromal involvement and/or disciform keratitis. Disciform keratitis may develop with or without a previous ulcer. The hallmark of disciform keratitis is disc-shaped areas of edema without an epithelial defect. There may be an associated granulomatous uveitis with increased intraocular pressure.

Treatment usually consists of a cycloplegic drop and long-term topical steroid therapy. Viroptic should be used prophylactically with any steroid therapy. A good rule of thumb is one drop of Viroptic for every drop of steroid used. These are extremely sight-threatening conditions that may warrant referral to an ophthalmologic corneal specialist. Stromal involvement can often result in corneal scarring, and a penetrating keratoplasty may be needed.

Side effects

The most common ocular side effect of Viroptic drops is epithelial toxicity. Minor toxic reactions can be treated with artificial tears and typically resolve quickly when Viroptic is discontinued. If a true allergic response is suspected, a switch to another form of antiviral therapy (vidarabine, idoxuridine, acyclovir) may be considered. If an epithelial defect remains after several weeks, antiviral toxicity and/or a neurotrophic ulcer should be suspected. When this occurs, antiviral therapy should be discontinued, and a nonpreserved ocular lubricant drop and/or a mild antibiotic ointment may be needed for several days.

Epithelial toxicity develops in part because Viroptic inhibits DNA synthesis in both viral infected and normal host cells. This brings up an interesting point: topical acyclovir inhibits viral DNA synthesis, but not that of healthy host cells. Therefore, topical acyclovir is less toxic to the epithelium. Topical acyclovir is not currently approved for use in the United States for treating HSV keratitis, but it is the preferred treatment in some other parts of the world. Some studies show that it is as effective as Viroptic, vidarabine or idoxuridine in treating HSV keratitis. This looks like a promising treatment alternative in the future.

There is also some indication that oral acyclovir may play a role in treating HSV keratitis. A dose of 400 mg five times daily provides a therapeutic level of acyclovir in the tears and aqueous. A long-term dosage of 400 mg to 800 mg daily may decrease recurrence rates.

Follow-up

Obviously, HSV keratitis patients require careful monitoring with frequent follow-up. If an ulcer quickly worsens or develops new infiltrates, a bacterial, fungal or Acanthamoeba secondary infection should be suspected, and appropriate cultures and treatment should be used. The most common misdiagnosis of Acanthamoeba is HSV keratitis

Viroptic can also be used for treating eyelid ulcers secondary to HSV. These small ulcers along the lid margin are common with recurrent HSV blepharoconjunctivitis and can be identified by their bright staining with fluorescein dye. They can be treated with warm compresses and Viroptic drops five times daily. Vidarabine or acyclovir ointment can be used as adjunctive therapy.

Viroptic is currently the preferred therapy for both primary and recurrent HSV keratoconjunctivitis. Clinically, I have found Viroptic to be a very effective treatment for HSV keratitis.

For Your Information:
  • John C. Smay, OD, is a 1996 graduate of Northeastern State University College of Optometry. After graduation, he completed a 1-year residency in Ocular Pathology at the Western Oklahoma Eye Center. Dr. Smay is currently in a group practice in Midwest City, Okla. He can be reached at the Heritage Park Vision Source, 6912 East Reno, Suite 101, Midwest City, OK 73110; (405) 732-2277; fax: (405) 737-4776; e-mail: jcsmay@flash.net. Dr. Smay has no direct financial interest in any of the products mentioned in this article, nor is he a paid consultant for any company mentioned.
  • Viroptic is available from Glaxo Wellcome, Five Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709-3398; (919) 248-2100.

Viroptic (trifluridine 1%, Glaxo) is an antiviral that is currently the drug of choice for treating primary keratoconjunctivitis and recurrent epithelial keratitis caused by herpes simplex virus (HSV) type 1 (oral) or type 2 (genital). It is also indicated for treating HSV keratitis that has not responded to idoxuridine or vidarabine (Vira-A, Parke-Davis). It is not indicated for other common forms of viral conjunctivitis.

Viroptic is preserved with 0.001% thimerosal and supplied as a sterile ophthalmic solution in a 7.5-mL plastic bottle. Viroptic is an analog of thymidine, which inhibits DNA synthesis and thus viral replication.

Primary/recurrent episodes

Herpes simplex infection may be either a primary or recurrent episode and usually presents as a unilateral red eye. Primary infection typically occurs before the age of 15. After this age, up to 90% of individuals will show serological evidence of exposure to HSV. Patients may complain of pain, light sensitivity, decreased vision and a skin rash.

In primary HSV, there is usually a mixed follicular and papillary conjunctivitis, which may be accompanied by vesicular eruptions on the eyelids that progress to pustules. Dendritic ulcers are rarely associated with a primary HSV infection. If keratitis is present, it is usually punctate in appearance.

There is often a tender, enlarged pre-auricular lymph node on the same side as the affected eye. If the initial presentation is a conjunctivitis with no corneal involvement, one drop of Viroptic five times a day may be sufficient treatment. However, if there is an associated keratitis, the maximum dosage of one drop every 2 hours (up to nine times daily) should be used.

Reactivation of the virus

Following resolution of a primary HSV infection, the virus becomes latent in the trigeminal ganglia. It may be reactivated by stress, immunocompromise or systemic illness. Virus produced in the trigeminal ganglion can move through the sensory nerves to infect the cornea. Corneal sensitivity may be reduced and should be evaluated before anesthetic is applied.

Secondary HSV infection usually presents in the form of a small, single, dendritic corneal ulcer or multiple ulcers. These ulcers are thin, linear, branching lesions, often with terminal end bulbs. The centers of these ulcers typically stain brightly with fluorescein, while the edges stain well with rose bengal.

The ulcers may progress from the typical dendritic pattern to a "geographic" or "ameoboid" pattern. This progression can occur with misdiagnosis and subsequent treatment with topical steroids, which are contraindicated in active HSV keratitis.

HSV keratitis should be treated with one drop of Viroptic to the affected eye every 2 hours while awake for a maximum daily dose of nine drops until the ulcer has completely re-epithelialized (usually 1 to 2 weeks).

Resolution of the ulcer

Following resolution of the ulcer, the dosage should be reduced to four times daily for 1 more week. If there is no improvement in the appearance of the ulcer within 7 days or if re-epithelialization is incomplete after 14 days, it is recommended that other forms of therapy be considered. Continuous use of Viroptic for more than 21 days should be avoided because of ocular toxicity.

Adjunctive therapy may include gentle debridement of the affected area and/or addition of a second antiviral agent. Clinically, I have found the addition of vidarabine 3% ointment dosed three to five times daily to be helpful in providing around-the-clock antiviral coverage for larger corneal ulcers. Oral acyclovir, 400 mg five times daily, may also be beneficial. A preservative-free ocular lubricant can be added for patient comfort.

Avoid steroids

Steroids should be avoided in cases of HSV keratitis and should be used only when there is no other means to control ocular inflammation. Patients who are on topical steroid therapy for other conditions (such as after cataract surgery) should be tapered quickly, and a cycloplegic agent may be added to the treatment regimen if an anterior chamber reaction is present.

In some cases, HSV may progress from an epithelial disease to stromal involvement and/or disciform keratitis. Disciform keratitis may develop with or without a previous ulcer. The hallmark of disciform keratitis is disc-shaped areas of edema without an epithelial defect. There may be an associated granulomatous uveitis with increased intraocular pressure.

Treatment usually consists of a cycloplegic drop and long-term topical steroid therapy. Viroptic should be used prophylactically with any steroid therapy. A good rule of thumb is one drop of Viroptic for every drop of steroid used. These are extremely sight-threatening conditions that may warrant referral to an ophthalmologic corneal specialist. Stromal involvement can often result in corneal scarring, and a penetrating keratoplasty may be needed.

Side effects

The most common ocular side effect of Viroptic drops is epithelial toxicity. Minor toxic reactions can be treated with artificial tears and typically resolve quickly when Viroptic is discontinued. If a true allergic response is suspected, a switch to another form of antiviral therapy (vidarabine, idoxuridine, acyclovir) may be considered. If an epithelial defect remains after several weeks, antiviral toxicity and/or a neurotrophic ulcer should be suspected. When this occurs, antiviral therapy should be discontinued, and a nonpreserved ocular lubricant drop and/or a mild antibiotic ointment may be needed for several days.

Epithelial toxicity develops in part because Viroptic inhibits DNA synthesis in both viral infected and normal host cells. This brings up an interesting point: topical acyclovir inhibits viral DNA synthesis, but not that of healthy host cells. Therefore, topical acyclovir is less toxic to the epithelium. Topical acyclovir is not currently approved for use in the United States for treating HSV keratitis, but it is the preferred treatment in some other parts of the world. Some studies show that it is as effective as Viroptic, vidarabine or idoxuridine in treating HSV keratitis. This looks like a promising treatment alternative in the future.

There is also some indication that oral acyclovir may play a role in treating HSV keratitis. A dose of 400 mg five times daily provides a therapeutic level of acyclovir in the tears and aqueous. A long-term dosage of 400 mg to 800 mg daily may decrease recurrence rates.

Follow-up

Obviously, HSV keratitis patients require careful monitoring with frequent follow-up. If an ulcer quickly worsens or develops new infiltrates, a bacterial, fungal or Acanthamoeba secondary infection should be suspected, and appropriate cultures and treatment should be used. The most common misdiagnosis of Acanthamoeba is HSV keratitis

Viroptic can also be used for treating eyelid ulcers secondary to HSV. These small ulcers along the lid margin are common with recurrent HSV blepharoconjunctivitis and can be identified by their bright staining with fluorescein dye. They can be treated with warm compresses and Viroptic drops five times daily. Vidarabine or acyclovir ointment can be used as adjunctive therapy.

Viroptic is currently the preferred therapy for both primary and recurrent HSV keratoconjunctivitis. Clinically, I have found Viroptic to be a very effective treatment for HSV keratitis.

For Your Information:
  • John C. Smay, OD, is a 1996 graduate of Northeastern State University College of Optometry. After graduation, he completed a 1-year residency in Ocular Pathology at the Western Oklahoma Eye Center. Dr. Smay is currently in a group practice in Midwest City, Okla. He can be reached at the Heritage Park Vision Source, 6912 East Reno, Suite 101, Midwest City, OK 73110; (405) 732-2277; fax: (405) 737-4776; e-mail: jcsmay@flash.net. Dr. Smay has no direct financial interest in any of the products mentioned in this article, nor is he a paid consultant for any company mentioned.
  • Viroptic is available from Glaxo Wellcome, Five Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709-3398; (919) 248-2100.