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Acyclovir (Zovirax)
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Acyclovir (Zovirax)

Acyclovir in Brief
  • Generic name: Acyclovir (acycloguanosine)
  • Brand names: Zovirax®
  • Therapeutic class: Antiviral
  • Pharmacologic class: Acyclic purine nucleoside analogue
  • FDA Approved:
    Ointment: March 29, 1982
    Injection: October 22, 1982
    Capsules: January 25, 1985
    Tablets: April 30, 1991
  • Pregnancy Category: B
  • Originally discovered: 1974, USA USA

History

Acyclovir was the first successful antiviral agent in the world. It was originally synthesized in 1974 by Howard Schaeffer at Wellcome Research Laboratories (now GlaxoSmithKline). After Schaeffer's discovery, Gertrude B. Elion and her team went to work, studying how it worked, why it worked, and why it was so nontoxic. They discovered that acyclovir remains inert until it meets the herpes virus.

For four years, from 1974 to 1977, more than seventy-five researchers kept acyclovir secret. The first report detailing the selective antiviral activity of acyclovir against herpes viruses was published in 1977 2.

Acyclovir got FDA approval and was released commercially in 1982. It was marked under the trade name Zovirax by the Burroughs Wellcome Company. The original formulation was a topical ointment. Acyclovir became available in oral formulation (200 mg capsules) in 1985 6.

FDA approved uses
  • Oral
    • Initial genital herpes
    • Recurrent genital herpes
    • Herpes zoster infections (shingles)
    • Chickenpox (varicella)
  • Topical
    • Recurrent herpes labialis (cold sores)
  • Parenteral
    • Herpes simplex, mucosal and cutaneous
    • Severe initial episodes of genital herpes
    • Herpes simplex encephalitis
    • Neonatal herpes simplex infection
    • Varicella-zoster (shingles) infections

Off-label & Investigational uses
  • Prevention of HSV-2 transmission 13
  • Cytomegalovirus infection and disease after organ transplantation 9
  • Herpes simplex virus infection after organ transplantation 10, 11
  • Ocular herpes simplex 15
  • Herpes zoster ophthalmicus 17
  • Varicella pneumonia16
  • Infectious mononucleosis 4
  • Reduces the need for cesarean delivery for recurrent herpes in women whose first clinical episode of genital herpes occurred during pregnancy 18.
  • Herpetic gingivostomatitis 5

Spectrum of activity

Acyclovir exhibits activity against four of the five major herpes-group viruses:

  • Herpes simplex virus type 1 (HSV-1) 7
  • Herpes simplex virus type 2 (HSV-2) 7
  • Varicella zoster virus (VZV) 7
  • Epstein-Barr virus (EBV)5, 7
  • Cytomegalovirus (CMV) (poor activity) 7, 8

Acyclovir "pros" and "cons"

Advantages:

  • High efficacy against HSV and VZV infections
  • Very effective for the suppression of recurrent genital herpes - reduces recurrence by about 90%
  • Excellent clinical safety profile 6 -- aside from drug hypersensitivity, there are no absolute contraindications to acyclovir
  • Safe during pregnancy -- although there are no large, controlled studies of acyclovir safety in pregnant women, a prospective epidemiological registry of acyclovir use during pregnancy showed no increase in the incidence of birth defects.
  • Continuous suppressive therapy with acyclovir has been shown to be safe for as long as 5-10 years.
  • Minimal toxicity - acyclovir cannot interfere with DNA synthesis in cells that are not infected with the virus
  • Well-tolerated by most patients
  • Highly effective for suppression of HSV shedding 13, 14
  • Minor risk of drug interactions
  • Inexpensive

Disadvantages:

  • A major drawback of acyclovir is its low oral bioavailability due to low water solubility -- only 15-30% of an oral dose is absorbed. Also, bioavailability decreases with increasing dose.
  • Inconvenient frequent dosing regimen (4-5 times) because the half-life is less than 4 hours.
  • Risk of renal failure and nephrotoxicity12 due to crystallization of acyclovir sodium following parenteral administration.
  • Does not eradicate latent virus

Mode of action

Acyclovir is a synthetic purine nucleoside analogue with inhibitory activity against herpes simplex virus types 1, 2, and varicella-zoster virus. In simple words, it is so similar to substance that the herpes virus needs for reproduction that the virus is deceived and commits suicide.

The inhibitory activity of Acyclovir is highly selective. It is converted to acyclovir monophosphate by virus-specific enzymes thymidine kinase then further converted to acyclovir triphosphate by other cellular enzymes.

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 thymidine kinase.

Time to clear out of the system

The half-life of acyclovir is 3 to 4 hours in people with normal kidney function and up to 20 hours in those with renal impairment.

Further reading
References
  • 1. Physicians’ Desk Reference, 54th ed; Medical Economics, Thomson Healthcare: Montvale, NJ; 2000.
  • 2. Elion, G. B., P. A. Furman, J. A. Fyfe, P. de Miranda, L. Beauchamp, and H. J. Shaeffer. 1977. Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl)guanine. Proc. Natl. Acad. Sci. USA 74:5716-5720.
  • 3. Darby, G. 1995. In search of the perfect antiviral. Antiviral Chem. Chemother. 6(Suppl. 1):54-63.
  • 4. Torre D, Tambini R. Acyclovir for treatment of infectious mononucleosis: a meta-analysis. Scand J Infect Dis. 1999;31(6):543-7.
  • 5. Nasser M, Fedorowicz Z, Khoshnevisan MH, Shahiri Tabarestani M. Acyclovir for treating primary herpetic gingivostomatitis. Cochrane Database Syst Rev. 2008 Oct 8;(4)
  • 6. Tilson HH, Engle CR, Andrews EB. Safety of acyclovir: a summary of the first 10 years experience. J Med Virol. 1993;Suppl 1:67-73. PubMed
  • 7. Collins P. The spectrum of antiviral activities of acyclovir in vitro and in vivo. J Antimicrob Chemother. 1983 Sep;12 Suppl B:19-27.
  • 8. Freitas VR, Smee DF, Chernow M, Boehme R, Matthews TR. Activity of 9-(1,3-dihydroxy-2-propoxymethyl)guanine compared with that of acyclovir against human, monkey, and rodent cytomegaloviruses. Antimicrob Agents Chemother. 1985 Aug;28(2):240-5.
  • 9. Legendre C, Ducloux D, Ferroni A, Chkoff N, Geffrier C, Rouzioux C, Kreis H. Acyclovir in preventing cytomegalovirus infection in kidney transplant recipients: a case-controlled study. J Med Virol. 1993;Suppl 1:118-22. PubMed
  • 10. Lundgren G, Wilczek H, Lönnqvist B, Lindholm A, Wahren B, Ringdén O. Acyclovir prophylaxis in bone marrow transplant recipients. Scand J Infect Dis Suppl. 1985;47:137-44. PubMed
  • 11. Pettersson E, Eklund B, Hockerstedt K, Salmela K, Ahonen J. Acyclovir and renal transplantation. Scand J Infect Dis Suppl. 1985;47:145-8. PubMed
  • 12. Lam NN, Weir MA, Yao Z, Blake PG, Beyea MM, Gomes T, Gandhi S, Mamdani M, Wald R, Parikh CR, Hackam DG, Garg AX. Risk of acute kidney injury from oral acyclovir: a population-based study. Am J Kidney Dis. 2013 May;61(5):723-9.
  • 13. Wald A, Zeh J, Barnum G, Davis LG, Corey L. Suppression of subclinical shedding of herpes simplex virus type 2 with acyclovir. Ann Intern Med. 1996 Jan 1;124(1 Pt 1):8-15. PubMed
  • 14. Sheffield JS, Hollier LM, Hill JB, Stuart GS, Wendel GD. Obstet Gynecol. 2003 Dec;102(6):1396-403. PubMed
  • 15. Oral acyclovir for herpes simplex virus eye disease: prevention of epithelial keratitis and stromal keratitis. Herpetic Eye Disease Study Group. Arch Ophthalmol. 2000 Aug;118(8):1030-6. PubMed
  • 16. El-Daher N, Magnussen R, Betts RF. Varicella pneumonitis: clinical presentation and experience with acyclovir treatment in immunocompetent adults. Int J Infect Dis. 1998 Jan-Mar;2(3):147-51. PubMed
  • 17. Hoang-Xuan T, Büchi ER, Herbort CP, Denis J, Frot P, Thénault S, Pouliquen Y. Oral acyclovir for herpes zoster ophthalmicus. Ophthalmology. 1992 Jul;99(7):1062-70 PubMed
  • 18. Scott LL, Sanchez PJ, Jackson GL, Zeray F, Wendel GD Jr. Acyclovir suppression to prevent cesarean delivery after first-episode genital herpes. Obstet Gynecol. 1996 Jan;87(1):69-73.

Published: March 31, 2008
Last updated: August 09, 2014

Interesting facts
Acyclovir facts
  • No one of the newer antivirals has been shown to be more effective for HSV than acyclovir.
  • Gertrude Elion, for her work in the discovery and development of Acyclovir, received the Nobel Prize in 1988.