Antiviral Drugs
 Collectively,
the herpes viruses and adenoviruses are the etiologic agents
for legions of viral infections annually. We have excellent
antiherpes virus therapy, yet no specific medicine to kill
the adenoviruses, which cause epidemic keratoconjunctivitis
(EKC) and pharyngoconjunctival fever (PCF). The herpes viruses
cause herpes simplex epithelial keratitis, herpes zoster
infections, acute retinal necrosis, Epstein-Barr infections,
herpetic genital diseases, and other disease processes.
Adenoviral infections are some of the most common external
eye infections. In children, these are generally accompanied
by a mild sore throat and low-grade fever, thus the descriptive
name, pharyngoconjunctival fever. These infections
present in adults as hemorrhagic conjunctivitis with an acute,
painful red eye and, most notably, an ipsilateral, palpable
preauricular lymphadenopathy.
While we eagerly await the development of topical ophthalmic
anti-adenoviral drugs, we are able to utilize (off-label) Betadine
5% Ophthalmic Prep Solution to meet the needs of our patients
with moderate-to-severe disease. When indicated, we proceed
as:
- Anesthetize both eyes with 0.5% proparacaine (because
the Betadine stings).
- Instill 2 or 3 drops of the Betadine and have the patient
roll their eyes around to enhance distribution of the medicine.
- Using a gloved hand or a cotton swab, rub the excess Betadine
along the eyelid margin to kill any resident virus there.
- After 45 to 60 seconds of Betadine exposure, lavage the
eye to flush the Betadine.
We usually treat only the more involved eye, however, if both
eyes are markedly afflicted, we consider treating both eyes.
We then prescribe Lotemax q.i.d. for about 4 days to address
the inflammatory component of the disease - for both eyes.
Always recognize the benefit of cold compresses and artificial
tears. Nonsteroidal anti-inflammatory drugs have limited usefulness
in adenoviral keratoconjunctivitis. Perhaps in very mild cases,
such drugs could be used with artificial tears, however, a
nice article in the August, 2000 issue of Ophthalmology found
(concurred?) that artificial tear intervention was superior
to the use of ketorolac tromethamine (Acular) in the setting
of EKC.
Meanwhile, there are approximately 50,000 new cases of herpes
simplex epithelial keratitis in the United States each year.
For the most part, herpetic infections are relatively easy
to diagnose and treat with a variety of antiviral drugs.
About 20 percent of patients have concurrent or delayed stromal
inflammatory keratitis. This is where the immune system responds
to deposited viral antigenic particles during or following
epithelial infection. This can be tedious to treat, and can
occasionally be left alone to pathophysiologically slowly burn
itself out. Otherwise, steroids are judiciously used (concurrently
with antiviral therapy until the steroid dose frequency is
reduced to once daily; usually 4 to 6 weeks) over many months
to years to suppress the immune response.
Recurrence of HSK is problematic. Recurrence rates are approximately
10 percent per year for five years. Recurrent infectious or
stromal inflammatory disease is seen in 40-60 percent of patients
between 5 and 20 years. A major report of the Herpes Eye Disease
Study Group was published in the July 30, 1998 New England
Journal of Medicine. That study has shed important new light
on how we can positively influence recurrent herpetic disease.
The key finding is very straightforward: acyclovir 400mg bid
can reduce the recurrent rate of herpetic eye disease by about
50 percent! Less straightforward is which patients merit such
therapeutic intervention. Patients with high rates of recurrence,
especially of stromal inflammatory disease, appear to benefit
the most. Therapy was done for 12 months. There was no rebound
in the recurrence rate six months after cessation of therapy.
This is important information, and gives us sound guidance
in improving the quality of life in this subset of patients.
We are now keeping many of these “high risk” patients on low
dose oral antiviral therapy for 2 or 3 years without any problems.
Varicella zoster infection, or shingles, most commonly affects
the first division of the trigeminal nerve, giving the classic
presentation of herpes zoster ophthalmicus. All expressions
of varicella zoster infection are essentially treated the same.
Any one of these regimens is generally effective; however,
their maximum clinical benefit is achieved when therapy is
initiated within the first 72 hours of the onset of signs and/or
symptoms. The three available oral antivirals are:
- Acyclovir(Zovirax) 800mg of five times a day for seven
days for zoster, and 400mg five times a day for simplex.
(Acyclovir is generically available.)
- Famciclovir (Famvir) 500mg of tid for seven days for zoster,
and 250mg tid for seven days for simplex.
- Valacyclovir (Valtrex) 1,000mg of tid for seven days for
zoster, and 500mg tid for seven days for simplex.
These drugs were initially designed to treat herpes zoster
(i.e., varicella zoster) and therefore the standard, usual
dosage recommendations are for zoster disease. However, these
oral medicines are highly effective against herpes simplex
disease, both dermatologic (skin vesicles) and corneal epithelial
keratitis. Since the herpes simplex viruses are roughly twice
as easy to kill, the dosages of these oral antivirals are used
half-zoster-strength as shown above.
While it is true that epithelial herpetic disease can be treated
with these oral antivirals, such is not standard of care.
Topical Viroptic (trifluridine) remains the usual therapy for
HSV epithelial keratitis.
For herpes zoster ophthalmicus or herpes zoster dermatitis
near the eye without global involvement, use Zovirax, Famvir
or Valtrex po for seven days. The globe itself is involved
only about half of the time when the ophthalmic (1st) division
of the 5th cranial nerve is involved. Globe involvement, which
usually manifests as an inflammatory keratitis and/or anterior
uveitis, can be concurrent with the dermatological disease
or can be delayed weeks or months. In either case, aggressively
use a highly efficacious topical ophthalmic steroid to suppress
the inflammation and preserve tissue integrity.
Topical Antivirals
Trifluridine
The treatment of choice for dendritiform herpes simplex epithelial
keratopathy is topical trifluridine (Viroptic), which inhibits
DNA synthesis. The following represents a general therapeutic
approach:
- First two days: every two hours (while awake)
- Next four to seven days: every 2-4 hours
- Seven more days: four times a day
- It must be emphasized that each patient is unique and therefore
optimum therapy is always individualized.
Have patients frequently instill preservative-free artificial
tears to help promote corneal healing, especially if there
is suboptimal tear function or significant SPK along with the
epithelial herpetic lesions. Viroptic is approved for use
in patients 6 years and older.
Vidarabine
Vira-A died June 7, 2001 when its sole manufacturer, Monarch
Pharmaceuticals, pulled the plug. This is no great loss
since between the two of us, in all our combined years of
clinical practice, have prescribed it on five occasions.
Actually, its absence may improve quality of care since we
had heard of doctors prescribing trifluridine drops by day,
and vidarabine ointment at night when treating epithelial
herpes simplex keratitis; this is an unnecessary overkill
and represents overly expensive care. When treating HSV
epithelial keratitis, all that is needed is topical trifluridine
drops, as explained above. Now, for you obsessive/compulsive
over-treaters out there, you will need to replace Vira-A
with oral acyclovir at 400mg 5 times a day!
The two legitimate occasions where Vira-A was used was as
substitute therapy were when the patient was trifluridine-allergic,
and in children for whom drop instillation was problematic
and/or crying rapidly washed away the drops. The oral antivirals
are very safe in children when dosed according to their age
and weight. Acyclovir is commercially available in a ____mg
liquid for pediatric use.
Oral Antivirals
Acyclovir
Commonly known by the brand name Zovirax and available generically,
acyclovir is effective in treating both herpes simplex and
herpes zoster. The drug is non-toxic due to its unique mechanism
of action; viral thymidine kinase activates the drug, so non-infected
cells remain unaffected. The only notable side effect is mild
nausea.
The recommended treatment for HSV keratitis is 400mg five
times per day for one week if topical therapy is impractical
for some rare reason. While such oral therapy works well, topical
Viroptic is the standard of care in the U.S. A 5% dermatologic
ointment of acyclovir is available to treat genital HSV infection.
Since oral therapy is effective in both dermatological and
ophthalmic disease, how does one treat patients with both eyelid
vesicular disease and keratitis? The answer is simple. Use
oral ACV since it nicely addresses viral replication in both
tissues. We have seen the rare patient whose keratitis did
not succumb to oral dosing, and in those cases had to use trifluridine
concurrently. This is yet another example where optimum care
requires individualized therapy.
Valacyclovir
Valacyclovir (Valtrex) is a pro-drug of acyclovir. Because
it is a pro-drug, it has enhanced bioavailability and a longer
half-life than the parent compound, acyclovir. Due to the
enhanced pharmacodynamics, valacyclovir is used three times
a day rather than the five times a day of acyclovir. Valtrex
seems to be less expensive than its equally efficacious competitor,
Famvir, making it generally preferred when treating herpetic
disease. However, generic acyclovir will be the least expensive
of the three oral antivirals, although it must be used 5
times a day, as opposed to only 3 times a day for the two
newer drugs.
Famciclovir
Famciclovir (Famvir) has the same mechanisms of action as acyclovir.
It is a pro-drug of penciclovir and is a functional equivalent
to acyclovir and valacyclovir. It has a relatively long
intracellular half-life of seven to 10 hours. The main advantage
of famciclovir is that it is used only three times a day
(instead of the five times a day dosage of acyclovir), and
it has been shown to decrease the duration and severity of
post-herpetic neuralgia. It is active against herpes simplex
and varicella. It can be taken without regard to meals, and
is metabolized by the kidneys. This is true for all the
oral antivirals, therefore, in patients with kidney disease,
consultation with the patient’s kidney doctor or a pharmacist
is mandatory to prescribe the proper dosage in the setting
of compromised renal function.
In summary, we have an excellent topical medicine and three
very equivalent choices of oral anti-herpetic drugs. All of
these medications are safe, effective, and provide us with
excellent tools to rapidly normalize infected tissues.
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