Mechanism Of Antiviral Action
Acyclovir is a synthetic purine nucleoside analogue with
in vitro and in vivo inhibitory activity against herpes simplex virus types 1
(HSV-1), 2 (HSV-2), and varicella-zoster virus (VZV).
The inhibitory activity of acyclovir is highly selective
due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and
VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a
nucleotide analogue. The monophosphate is further converted into diphosphate by
cellular guanylate kinase and into triphosphate by a number of cellular
enzymes. In vitro, acyclovir triphosphate stops replication of herpes viral
DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA
polymerase, 2) incorporation into and termination of the growing viral DNA chain,
and 3) inactivation of the viral DNA polymerase. The greater antiviral activity
of acyclovir against HSV compared to VZV is due to its more efficient
phosphorylation by the viral TK.
The quantitative relationship between the in vitro
susceptibility of herpes viruses to antivirals and the clinical response to
therapy has not been established in humans, and virus sensitivity testing has
not been standardized. Sensitivity testing results, expressed as the
concentration of drug required to inhibit by 50% the growth of virus in cell
culture (IC50), vary greatly depending upon a number of factors. Using
plaque-reduction assays, the IC50 against herpes simplex virus isolates ranges from
0.02 to 13.5 mcg/mL for HSV-1 and from 0.01 to 9.9 mcg/mL for HSV-2. The IC50
for acyclovir against most laboratory strains and clinical isolates of VZV
ranges from 0.12 to 10.8 mcg/mL. Acyclovir also demonstrates activity against
the Oka vaccine strain of VZV with a mean IC50 of 1.35 mcg/mL.
Resistance of HSV and VZV to acyclovir can result from
qualitative and quantitative changes in the viral TK and/or DNA polymerase.
Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have
been recovered from immunocompromised patients, especially with advanced HIV
infection. While most of the acyclovir-resistant mutants isolated thus far from
immunocompromised patients have been found to be TK-deficient mutants, other
mutants involving the viral TK gene (TK partial and TK altered) and DNA
polymerase have been isolated. TK-negative mutants may cause severe disease in
infants and immunocompromised adults. The possibility of viral resistance to
acyclovir should be considered in patients who show poor clinical response during
Two clinical pharmacology studies were performed with
ZOVIRAX Ointment 5% in immunocompromised adults at risk of developing
mucocutaneous Herpes simplex virus infections or with localized
varicella-zoster infections. These studies were designed to evaluate the dermal
tolerance, systemic toxicity, and percutaneous absorption of acyclovir.
In 1 of these studies, which included 16 inpatients, the
complete ointment or its vehicle were randomly administered in a dose of 1-cm strips
(25 mg acyclovir) 4 times a day for 7 days to an intact skin surface area of
4.5 square inches. No local intolerance, systemic toxicity, or contact
dermatitis were observed. In addition, no drug was detected in blood and urine
by radioimmunoassay (sensitivity, 0.01 mcg/mL).
The other study included 11 patients with localized
varicella-zoster infections. In this uncontrolled study, acyclovir was detected
in the blood of 9 patients and in the urine of all patients tested. Acyclovir levels
in plasma ranged from < 0.01 to 0.28 mcg/mL in 8 patients with normal renal
function, and from < 0.01 to 0.78 mcg/mL in 1 patient with impaired renal
function. Acyclovir excreted in the urine ranged from < 0.02% to 9.4% of the
daily dose. Therefore, systemic absorption of acyclovir after topical application
In clinical trials of initial genital herpes infections,
ZOVIRAX Ointment 5% has shown a decrease in healing time and, in some cases, a
decrease in duration of viral shedding and duration of pain. In studies in
immunocompromised patients mainly with herpes labialis, there was a decrease in
duration of viral shedding and a slight decrease in duration of pain.
In studies of recurrent genital herpes and of herpes
labialis in nonimmunocompromised patients, there was no evidence of clinical
benefit; there was some decrease in duration of viral shedding.