Comparison of Herpes Antiviral Drugs

Antiviral drugs for herpes treatment

Brief history

Mechanism of action

Indications and uses

Efficacy

Side effects

Pharmacokinetics

Comparison table

Cost & generic availability

Conclusions

Antiviral drugs for herpes treatment

The major drugs developed to work against herpes simplex virus (HSV) are antiviral agents called

nucleosides and nucleotide analogues, which block viral reproduction. They include acyclovir,

valacyclovir, and famciclovir. All three oral antiviral drugs are very effective and reasonably safe. These

medications differ in their chemical structure, dosage, and price.

The antiviral medications available in pill form acyclovir, valacyclovir, famciclovir have been specifically

developed for the treatment of genital herpes. They stop the growth of the herpes simplex virus. Antiviral

medications may significantly lessen the severity of a primary outbreak and reduce the time it takes

genital herpes outbreaks to heal. The medication also decreases the number of days of painful symptoms

and for some people, the number of days you can spread the virus. Antiviral medication is most effective

if it is taken when you first notice the prodromal symptoms (tingling and pain) of a recurrent genital herpes

outbreak and if they are taken for the next 5 to 7 days or until symptoms go away. Some people with

frequent recurrent outbreaks (more than 6 recurrences a year) take antiviral medication every day

(suppressive therapy) to help reduce the frequency and duration of recurrent outbreaks. Antiviral

medication can reduce the number of outbreaks by 70% to 80%.

Brief history

Acyclovir (brand name Zovirax) is the oldest of the antiviral medications. It has been available since 1982

in a topical form (as an ointment) and sold since 1985 in pill form. Now acyclovir is available in a generic

form. Acyclovir is the only antiviral medication available for intravenous administration.

More recently, the FDA approved two other drugs to treat genital herpes: Famciclovir (brand name

Famvir) and Valacyclovir (brand name Valtrex).

Valtrex (valacyclovir) was the second antiviral medication to come to market in the United States, and it

was approved by the FDA in December 15, 1995. Valtrex is manufactured by GlaxoSmithKline. Valtrex is

a prodrug of acyclovir, meaning that the body converts it to acyclovir after it has been absorbed. This

medication delivers acyclovir more efficiently so that the body absorbs much of the drug, which has the

advantage of taking the medication fewer times during the day.

Famvir (famciclovir) is a prodrug and is manufactured by Novartis. When taken, the body converts it to the

long acting antiviral drug penciclovir. Like valacyclovir, it is well absorbed, persists for a longer time in the

body, and can be taken less frequently than acyclovir.

Mechanism of action

Antiviral agents reduce viral replication by inhibiting viral DNA synthesis, needed to reproduce itself. This

helps to keep the virus inactive, or "sleeping".

Acyclovir and penciclovir have a similar mechanism of antiviral action against HSV. Both compounds are

selectively phosphorylated only within virus-infected cells by viral thymidine kinase (TK). Further

phosphorylation by cellular enzymes leads to the production of acyclovir or penciclovir triphosphate, both

of which compete with the natural nucleotide, dGTP, resulting in the selective inhibition of viral DNA

polymerase. Incorporation of the analogue triphosphate into the growing DNA chain prevents continued

extension of the DNA chain.

However, there are several differences in the mode of acyclovir and penciclovir. Herpes virus thymidine

kinase is expressed in productively infected cells. Penciclovir has a higher affinity for HSV TK than

acyclovir (2), and consequently the levels of penciclovir triphosphate in infected cells are much higher

than the levels of acyclovir triphosphate. Penciclovir triphosphate is more stable than acyclovir

triphosphate in HSV-infected cells (3), resulting in a longer intracellular half-life. HSV DNA polymerases

have a higher affinity for acyclovir triphosphate than for penciclovir triphosphate (3). This distinction is

counterbalanced by the difference in phosphorylation favoring penciclovir: the net effect is that the two

compounds have similar antiviral potencies. Acyclovir triphosphate is an obligate DNA chain terminator,

whereas penciclovir triphosphate allows limited DNA chain elongation (short-chain terminator). (1)

Approved indications and uses

Acyclovir (Zovirax) is indicated for:

treatment of initial episodes and the management of recurrent episodes of genital herpeso treatment of initial genital herpes: 200 mg every 4 hours, 5 times daily for 10 days.

o chronic suppressive therapy for recurrent disease: 400 mg 2 times daily for up to 12 months, followed

by re-evaluation. 

Alternative regimens have included doses ranging from 200 mg 3 times daily to 200 mg 5 times daily.o intermittent therapy: 200 mg every 4 hours, 5 times daily for 5 days. 

Therapy should be initiated at the earliest sign or symptom (prodrome) of recurrence.

acute treatment of herpes zoster (shingles)

treatment of chickenpox (varicella)

Valacyclovir (Valtrex) is indicated for:

treatment or suppression of genital herpes and for the suppression of recurrent genital herpeso treatment of initial genital herpes: 1 gram twice daily for 10 days. 

Therapy was most effective when administered within 48 hours of the onset of signs and symptoms.

There are no data on the effectiveness of treatment with Valtrex when initiated more than 72 hours after

the onset of signs and symptoms.o treatment of recurrent genital herpes: 500 mg twice daily for 3 days. 

If medical management of a genital herpes recurrence is indicated, patients should be advised to initiate

therapy at the first sign or symptom of an episode. There are no data on the effectiveness of treatment

with Valtrex when initiated more than 24 hours after the onset of signs or symptoms.o chronic suppressive therapy of recurrent genital herpes: 1 gram once daily in patients with normal

immune function. In patients with a history of 9 or fewer recurrences per year, an alternative dose is 500

mg once daily. The safety and efficacy of therapy with Valtrex beyond 1 year have not been established. reduction of transmission of genital herpeso reduction of transmission of genital herpes in patients with a history of 9 or fewer recurrences per

year: 500 mg once daily for the source partner. Patients should be counseled to use safer sex practices

in combination with suppressive therapy with Valtrex. The efficacy of reducing transmission beyond 8

months in discordant couples has not been established. treatment of herpes zoster (shingles)

treatment of cold sores (herpes labialis)

Famciclovir (Famvir) is indicated for:

treatment or suppression of recurrent genital herpeso recurrent genital herpes: 125 mg twice daily for 5 days. Initiate therapy at the first sign or symptom if

medical management of a genital herpes recurrence is indicated. The efficacy of Famvir has not been

established when treatment is initiated more than 6 hours after onset of symptoms or lesions.o suppression of recurrent genital herpes: 250 mg twice daily for up to 1 year. The safety and efficacy of

Famvir therapy beyond 1 year of treatment have not been established.

treatment of acute herpes zoster (shingles)

treatment of cold sores (herpes labialis)

Efficacy

Clinical studies have not found any significant differences in effectiveness among the three medications.

All are quite safe, very rarely producing any side effects at all. All work by disrupting the virus's

reproductive ability.

All three of these oral antiviral drugs can be taken either episodically - when a person has an outbreak or

feels one coming on, or suppressively - daily to help prevent the recurrence of outbreaks.

For the treatment of first genital herpes infections, oral acyclovir or valacyclovir is preferable to

famciclovir. The efficacy of famciclovir for initial episode genital herpes infection has not been established.

For the treatment of recurrent infections, clinical trials have demonstrated that acyclovir, valacyclovir, and

famciclovir have equivalent efficacy.

Intravenous acyclovir is used to treat serious flare-ups or outbreaks that effect internal organs.

Adverse reactions and side effects

All these agents are well tolerated and have excellent safety records. Possible side effects from oral

agents include nausea, vomiting, headache, fatigue, tremor, and very rarely, seizures. They can affect the

kidney, however, and people with kidney problems should use them with caution and at lower doses.

Intravenous administration increases the risk for kidney problems and can cause blood clots at the

injection site. In rare cases, it can cause central nervous system complications.

For more detailed information about differences in side effects see Herpes antiviral drugs comparison

table.

Pharmacokinetics

Acyclovir. It has poor bioavailability of about 20% and a short half life, which necessitates frequent

dosing. Acyclovir speeds healing of lesions and suppress viral shedding if taken within 24 hours of the

first indication of a recurrent episode. Early treatment may even prevent the development of lesions in

some patients.

Valacyclovir. Valacyclovir provides a unique mechanism of enhancing the oral bioavailability of the

parent compound, acyclovir. Valacyclovir is a prodrug converted to acyclovir in the intestine and liver. It

has better bioavailability (about 55%) and has a longer duration of action than acyclovir. The main

advantage of valacyclovir is higher concentration of acyclovir in the bloodstream without added toxicity.

Thus, valacyclovir requires less frequent dosing than acyclovir. It is available in a one-day regimen for

oral herpes, a once-daily dose to suppress genital herpes, and a three-day treatment for recurrent herpes.

Valacyclovir is most effective if taken within 24 hours of the first signs of an outbreak.

When used as an episodic treatment, valacyclovir can help the sores heal faster, shorten the period of

pain during the outbreak and cut down the time during which the virus is detected on genital skin surfaces

(virus shedding). When taken as soon as the first signs of an outbreak are noticed, such as tingling,

itching or redness, valacyclovir may be able to completely prevent the development of painful blisters.

Famciclovir. Famciclovir is a prodrug for the active metabolite penciclovir. Famciclovir is converted into

its active compound within the infected cell by contact with an enzyme from the virus. It has high

bioavailability of 77%. It remains active in the body longer than acyclovir (half the dose is still active after

10 to 20 hours) and, like valacyclovir, requires less frequent dosing (usually two or three times a day). It is

most effective if taken within six hours of onset of symptoms.