treatment plan

Understanding Antiviral Agents

BY WILLIAM TOWNSEND, OD
FEBRUARY 1998

Viral eye disease continues to be one of the most challenging obstacles in eye care. Herpes simplex keratitis is the most common cause of corneal blindness in developed countries. To manage this and other viral eye conditions, we must understand how antiviral drugs work.

Understanding the Enemies

Viruses are intracellular obligate parasites that are incapable of independent reproduction. They infect host cells by attaching themselves to the cell membrane. Viral DNA or RNA then directs the cell to begin producing viral particles, which are released to infect other cells. The process requires many viral and cellular enzymes, including thymidine kinase (TK), essential for phosphorylation, and DNA polymerase, required for DNA encoding. Of the herpes viruses, herpes simplex type I (HSV-1), herpes simplex type 2 (HSV-2) and varicella-zoster virus (VZV) are the most important with respect to anterior segment disease. HSV-1 causes fever blisters, cold sores and herpes simplex keratitis, conjunctivitis and uveitis. HSV-2 causes sexually transmitted genitourinary diseases and possibly ocular herpetic disease. VZV causes shingles and possibly corneal ulceration and uveitis. Adenoviruses and picornaviruses cause keratoconjunctivitis, but currently, no medications are active against these organisms.

Understanding the Drugs

All current ophthalmic antiviral agents work by interfering with viral replication. A drug's specificity for viral enzymes determines how toxic it is to host cells. The toxic effects of antivirals can cause dendritic lesions, but toxic lesions are elevated rather than ulcerated, as in HSK.

Idoxuridine (IDU), an analog of thymidine, competes with thymidine for phosphorylation by TK and is then incorporated into host and viral DNA chains. IDU is cytotoxic because it affects both viral and host cell DNA replication. Its use is limited to topical applications, either solution or ointment form (Stoxil). IDU also nonselectively interferes with viral and host cell DNA polymerase. It doesn't penetrate through the cornea, so it's used to treat superficial epithelial lesions. Up to 20 percent of herpes viruses become resistant to IDU.

Vidarabine (Vira-A), available in 3% ointment form, is an analog of adenosine. Like IDU, Vira-A is phosphorylated by both viral and cellular TK, affecting both host and viral cells. Vira-A also competitively inhibits DNA polymerase, but because it affects the virus more than host cell, it is less cytotoxic than IDU. Vira-A ointment can be instilled every three or four hours at night.

Like IDU, trifluridine (Viroptic) is an analog of thymidine and it inhibits both viral and host cell DNA. Trifluridine is available as a solution, and although it must be administered more frequently than Vira-A or IDU, it penetrates the cornea better to treat deeper corneal herpetic infections. Trifluridine is still the drug of choice for herpes simplex keratitis, but it has no activity against herpes zoster. Initial dosage is one drop in the affected eye every one to two hours up to nine drops a day.

Both acyclovir and famciclovir are analogs of guanosine and are phosphorylated by viral TK 10 to 30 times more efficiently than by host cell TK, making them less cytotoxic than other drugs. Acyclovir is available as an IV or PO medication and as a 5% dermatologic preparation. Famciclovir is available as an oral medication only. Systemic forms may be used long-term with few side effects. Herpes zoster-related eye disease is best treated systemically with acyclovir, 800mg five times a day for 10 days, or with famciclovir, 500mg three times a day for seven to 10 days.

Dr. Townsend is in private practice in Canyon. Texas, and is a consultant at the Amarillo VA Medical Center.