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Comparison of Herpes Antiviral Drugs

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 herpes
    • treatment of initial genital herpes: 200 mg every 4 hours, 5 times daily for 10 days.
    • 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.
    • 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 herpes
    • 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.
    • 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.
    • 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 herpes
    • 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 herpes
    • 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.
    • 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.

Brief comparison table
 
  Acyclovir (Zovirax®) Valacyclovir (Valtrex®) Famciclovir (Famvir®)
FDA approval date January 25, 1985 December 15, 1995 June 29, 1994
Pharmaceutical Forms 200 mg, 400 mg, 800 mg tablets
oral, injected, and topical
500 mg, 1000 mg caplets 125 mg, 250 mg, 500 mg tablets
Activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2)
varicella-zoster virus (VZV)
herpes simplex virus types 1 (HSV-1) and 2 (HSV-2)
varicella-zoster virus (VZV)
herpes simplex virus types 1 (HSV-1) and 2 (HSV-2)
varicella-zoster virus (VZV)
FDA approved indications for genital herpes - treatment of initial genital herpes
- treatment of recurrent genital herpes
- chronic suppressive therapy for recurrent genital herpes
- treatment of initial genital herpes
- treatment of recurrent genital herpes
- chronic suppressive therapy for recurrent genital herpes
- reduction of transmission of genital herpes
- treatment of recurrent genital herpes
- chronic suppressive therapy for recurrent genital herpes
Most common side effects nausea
vomiting
diarrhea
headache
nausea
vomiting
dizziness
abdominal pain
headache
nausea
diarrhea
fatigue
abdominal pain
Less common side effects headache
malaise
renal failure
dysmenorrhea
arthralgia
renal failure
vomiting
dysmenorrhea
flatulence
migraine
renal failure
Bioavailability 10% - 20% 55% 77%
Major route of elimination Mainly renally excreted unchanged Renal Renally excreted
Pregnancy Category B B B
Generic availability Yes Yes Yes

Cost

Acyclovir is available in a generic form, which is less expensive. Valacyclovir is sold only in brand name form Valtrex®. Famciclovir is also sold only in brand name form Famvir®.

Conclusions

Generic acyclovir is usually less expensive than the other two drugs and therefore preferable. If the costs of the drugs are equivalent, however, the choice is between the safety record of acyclovir and having to take fewer daily doses of valacyclovir or famciclovir.

References
  • 1. Teresa H. Bacon, Myron J. Levin, Jeffry J. Leary, Robert T. Sarisky, David Sutton. Herpes Simplex Virus Resistance to Acyclovir and Penciclovir after Two Decades of Antiviral Therapy. Clinical Microbiology Reviews, January 2003, p. 114-128, Vol. 16, No. 1. Full Text
  • 2. Datema, R., A.-C. Ericson, H. J. Field, A. Larsson, and K. Stenberg. Critical determinants of antiherpes efficacy of buciclovir and related acyclovir guanosine analogs. Antiviral Res. 1987. 7:303-316.
  • 3. Earnshaw, D. L., T. H. Bacon, S. J. Darlison, K. Edmonds, R. M. Perkins, and R. A. Vere Hodge. 1992. Mode of antiviral action of penciclovir in MRC-5 cells infected with herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus. Antimicrob. Agents Chemother. 36:2747-2757.

Published: May 05, 2007
Last updated: September 01, 2014