Antivirals for Herpes Virus

Antiviral agents against human herpesviruses (HHVs) include acyclovir, cidofovir, and foscarnet. Human herpesviruses are DNA viruses in the Herpesviridae family. Herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and HHV-8 belong to the Herpesviridae family. Antivirals against the group generally act via inhibition of DNA polymerase. Acyclovir (the prototypical nucleoside analog) requires viral kinase for phosphorylation to become a triphosphate, which is incorporated in viral DNA. Cidofovir requires phosphorylation by host cellular kinase, which allows cidofovir to have activity against mutated viruses and become deficient in viral kinase. Foscarnet (a pyrophosphate analog) does not require phosphorylation. Nephrotoxicity is a shared adverse effect in the agents. Acyclovir can also cause obstructive crystalline nephropathy and foscarnet carries a risk of electrolyte abnormalities and seizures. The nephrotoxic effect of cidofovir can be reduced with IV saline and probenecid.

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Overview

Human herpesviruses (HHVs)

  • DNA viruses (a similar infection process):
    • Viruses enter the nucleus of the host cell.
    • Viral DNA is transcribed into mRNA via host-cell polymerase.
    • Subsequently, the mRNA is translated into virus-specific proteins. 
  • Herpesviridae family:
    • Subfamily: Alphaherpesvirinae:
      • Herpes simplex virus (HSV)-1 and HSV-2 (mucocutaneous and genital lesions)
      • Varicella-zoster virus (VZV) (chickenpox)
    • Subfamily: Betaherpesvirinae:
      • Cytomegalovirus (CMV)
      • HHV-6 and HHV-7 (roseola)
    • Subfamily: Gammaherpesvirinae:
      • Epstein-Barr virus (EBV) (Burkitt lymphoma and infectious mononucleosis)
      • HHV-4
      • HHV-8 (Kaposi sarcoma)

Antiherpes agents

  • Target viral nucleic acid synthesis by inhibiting DNA polymerase
  • Groups of drugs:
    • Nucleoside analogs:
      • Acyclovir
      • Valacyclovir
      • Famciclovir
      • Ganciclovir
      • Penciclovir
    • Cytidine nucleotide analog: cidofovir
    • Pyrophosphate analog: foscarnet
Antivirals for Herpesviruses

Antiviral drug mechanism:
Antivirals for herpesviruses (right side) generally inhibit nucleic acid synthesis.

Image by Lecturio.

Nucleoside Analogs

Chemical structure

  • Acyclovir: an acyclic guanosine nucleoside analog (the prototypical drug of the group)
  • ​​Valacyclovir: the L-valyl ester prodrug of acyclovir
  • Penciclovir, famciclovir, and ganciclovir are related agents.

Pharmacodynamics

Acyclovir:

  • Sequential phosphorylation of viral kinase (e.g., dependent on thymidine kinase (TK)) and host kinase convert the drug to a monophosphate and then to a triphosphate moiety.
  • Since the initial step requires viral kinase, only infected cells are affected.
  • The steps allow the drug to become triphosphate inhibitors of DNA polymerase.
  • Inhibits viral DNA synthesis:
    • The triphosphate competes with deoxyguanosine triphosphate (dGTP) for viral DNA polymerase.
    • The triphosphate incorporates into the viral DNA. 
    • Chain termination occurs due to the lack of a 3’-hydroxyl group and prevents attachment of nucleosides. 
  • Mechanism of resistance: 
    • Change in viral DNA polymerase 
    • Absence or impairment of TK (caused by viral mutations)
Mechanism of action of acyclovir

Mechanism of action of acyclovir:
The drug undergoes sequential phosphorylation, which is facilitated by thymidine kinase (TK) of the herpesvirus and host kinases. Since viral TK is required for phosphorylation of acyclovir, only cells infected with the virus are affected by the drug. Host enzymes convert the monophosphate to acyclovir triphosphate, which subsequently competes with deoxyguanosine triphosphate (dGTP) for the viral DNA polymerase. The triphosphate gets incorporated into the template of the viral DNA. Chain termination follows because a 3′-hydroxyl group is lacking.

Image: “OSC Microbio 14 03 Acyclovir” by CNX OpenStax. License: CC BY 4.0

Pharmacokinetics

  • Absorption: 
    • Acyclovir:
      • Available as oral, IV, and topical 
      • Poor oral bioavailability (10%–30%)
    • Valacyclovir: higher bioavailability 
    • Penciclovir: topical
  • Distribution: 
    • High distribution rate (including CSF)
    • Good tissue and fluid penetration 
    • Multiple doses per day are required because of the short half-life
  • Metabolism: minimally metabolized (> 80% excreted unchanged)
  • Excretion: 
    • Renal via glomerular filtration rate and tubular secretion 
    • Dose modification is required in renal impairment. 
    • Elimination half-life varies between 2–4 hours.

Indications

Acyclovir (and other related agents): 

  • HSV
  • VZV
  • Prevention of herpes viruses in immunocompromised individuals 
  • Off-label: Bell palsy and CMV prevention in individuals with low-risk hematopoietic stem cell transplant

Adverse events and contraindications

Acyclovir:

  • Notable adverse events:
    • Acute kidney injury:
      • Obstructive uropathy (formation of acyclovir crystals)
      • Interstitial nephritis
      • Rental tubular acidosis
    • Neurotoxicity:
      • Confusion, agitation, and hallucination
      • Myoclonus and tremor
    • Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS)
  • Contraindications: hypersensitivity to acyclovir

Comparison of nucleoside analogs

Table: Comparison of nucleoside analogs against herpesviruses
AgentCharacteristics and mechanism of actionPharmacokineticsApproved indicationAdverse drug effects
Acyclovir
  • Nucleoside analog
  • Polymerase inhibitor
Poor oral bioavailability
  • Herpes simplex virus (HSV)-1
  • HSV-2
  • Varicella zoster virus (VZV)
  • Acute renal injury
  • Neurotoxicity
  • Thrombotic microangiopathy
Valacyclovir
  • Nucleoside analog
  • Prodrug of acyclovir
  • Polymerase inhibitor
Good oral bioavailability
Penciclovir
  • Nucleoside analog
  • Polymerase inhibitor with a 3’-hydroxyl group (not an obligate chain terminator)
TopicalHSV (herpes labialis)Mild side effects
Famciclovir
  • Nucleoside analog
  • Prodrug of penciclovir
  • Polymerase inhibitor
Better oral bioavailability than penciclovir
  • HSV
  • Shingles
  • Headache
  • Nausea, diarrhea
Ganciclovir
  • Nucleoside analog
  • Phosphorylation catalyzed by the virus protein kinase phosphotransferase UL97
  • Polymerase inhibitor
  • IV
  • Poor oral bioavailability
Cytomegalovirus (CMV) infections
  • Hematological toxicity (↓ platelets, leukopenia)
  • Nephrotoxicity
  • In animal studies, associated with birth defects, ↓ spermatogenesis, and carcinogenesis
Valganciclovir
  • Nucleoside analog
  • Phosphorylation catalyzed by the virus protein kinase phosphotransferase UL97
  • Prodrug of ganciclovir
  • Polymerase inhibitor
Better oral bioavailability than ganciclovir

Cidofovir

Chemical structure

Cidofovir is a cytidine nucleotide analog.

Pharmacodynamics

  • Targets viral replication by inhibiting viral DNA polymerase: 
    • Unlike nucleoside analogs, cidofovir is phosphorylated by cellular (host kinase), not viral, enzymes.
    • Competes with deoxycytidine triphosphate (dCTP) for incorporation into viral DNA by viral DNA polymerase.
    • Disruption of further chain elongation occurs when the drug is incorporated.
  • Cidofovir has activity against TK-deficient or TK-altered viruses because viral enzymes are not required.
  • Mechanism of resistance: mutation in viral DNA polymerase

Pharmacokinetics

  • Absorption:
    • IV administration
    • Low oral bioavailability
  • Distribution:
    • Poor CSF penetration
    • The active metabolite (cidofovir diphosphate) is slowly eliminated → long intracellular half-life
  • Metabolism: Most of the drug is excreted unchanged in the urine.
  • Excretion:
    • Renal 
    • Glomerular filtration and tubular secretion

Indications

  • CMV retinitis (in AIDS)
  • Activity against:
    • Herpesviruses
    • Adenovirus
    • Polyomavirus (BK virus nephropathy)
    • Papillomavirus (e.g., warts, molluscum contagiosum)
    • Poxvirus 
  • Active against mutant viruses resistant to acyclovir and ganciclovir:
    • TK-negative HSV
    • UL97 phosphotransferase-negative CMV 

Adverse effects and contraindications

  • Adverse effects:
    • Nephrotoxicity: 
      • Most important adverse effect
      • Decreased when administered with IV saline and probenecid (blocks active renal tubular secretion)
    • Nausea, vomiting
    • Neutropenia
    • Acute iritis and ocular hypotony
    • In animal studies: hypospermia, carcinogenesis, and teratogenesis
  • Contraindications:
    • Proteinuria ≥ 2+ or urine protein ≥ 100 mg/dL
    • Baseline serum creatinine > 1.5 mg/dL

Foscarnet

Chemical structure

Foscarnet is a pyrophosphate analog.

Pharmacodynamics

  • Inhibits viral nucleic acid synthesis: 
    • No intracellular phosphorylation required for antiviral activity
    • Reversibly binds to the pyrophosphate-binding site of viral DNA polymerase (or reverse transcriptase)
    • Inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates → stops DNA chain elongation 
  • Mechanism of resistance: point mutations in the viral DNA polymerase

Pharmacokinetics

  • Absorption: 
    • Poor oral bioavailability
    • IV form
  • Distribution: 
    • Vitreous levels similar to plasma
    • CSF levels approach 66% of plasma.
  • Metabolism: minimally metabolized
  • Excretion:
    • Tubular secretion and glomerular filtration 
    • Approximately 20% of foscarnet may be taken up in bone.
    • Decreased excretion in individuals with kidney disease

Indications

  • Ganciclovir-resistant CMV infections (AIDS or transplant recipients)
  • Mucocutaneous acyclovir-resistant HSV infections

Adverse effects and contraindications

  • Adverse effects:
    • Nephrotoxicity (reduced by IV saline)
    • Hypocalcemia, hypomagnesemia, and hypokalemia
    • Ulcer formation in the genitals
    • Neurologic:
      • Seizures
      • Paresthesia
      • Irritability
      • Headache
      • Hallucinations
    • QT prolongation
  • Contraindications: hypersensitivity to foscarnet

Nonsystemic Agents

Docosanol

  • A saturated 22-carbon aliphatic alcohol
  • Inhibits fusion between the host-cell plasma membrane and the HSV envelope → prevents viral entry into cells 
  • Topical docosanol 10% cream:
    • Over the counter
    • Reduces healing time if applied within 12 hours of prodromal symptom onset 

Trifluridine

  • Trifluorothymidine
  • Mechanism of action: 
    • Inhibition of viral DNA synthesis (HSV-1, HSV-2, CMV)
    • Undergoes intracellular phosphorylation by host cell enzymes → competes with thymidine triphosphate for incorporation by the viral DNA polymerase 
  • 1% solution:
    • Treatment for keratoconjunctivitis and recurrent epithelial keratitis due to HSV-1 or HSV-2
    • Off-label: topical application for acyclovir-resistant HSV infections

Comparison of Medications

Table: Comparison of medications
Antiviral agentMechanism of actionIndicationsMajor adverse effects
Acyclovir (nucleoside analog)Polymerase inhibitor requiring phosphorylation by viral kinase
  • HSV-1
  • HSV-2
  • VZV
Acute kidney injury (obstructive nephropathy)
Cidofovir (nucleotide analog)Polymerase inhibitor requiring phosphorylation by host kinase (not viral kinase)Approved for CMV retinitis with activity against other viruses*Nephrotoxicity (risk decreased by IV saline and probenecid)
Foscarnet (pyrophosphate analog)Polymerase inhibitor not requiring phosphorylationResistant CMV and HSV
  • Nephrotoxicity
  • Electrolyte abnormalities
  • Seizures
*Herpesviruses, adenovirus, polyomavirus, papillomavirus, poxvirus, TK-negative HSV, UL97 phosphotransferase-negative CMV

References

  1. Acosta, E.P. (2017). Antiviral agents (nonretroviral). In Brunton L.L., & Hilal-Dandan R., & Knollmann B.C.(Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=172486085
  2. Klatte, J. (2019). Herpes Simplex Virus Infection Medication. Medscape. Retrieved August 14, 2021, from https://emedicine.medscape.com/article/964866-medication#2
  3. National Institute of Diabetes and Digestive and Kidney Diseases. (2016). Acyclovir. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. https://www.ncbi.nlm.nih.gov/books/NBK548548/
  4. Rodriguez, M., Zachary, K.C. (2021). Foscarnet: An Overview. UpToDate. Retrieved Aug 14, 2021, from https://www.uptodate.com/contents/foscarnet-an-overview
  5. Rodriguez, M., Zachary, K. (2021). Cidofovir: an overview. UpToDate. Retrieved Sep 1, 2021, from https://www.uptodate.com/contents/cidofovir-an-overview
  6. Ryan, K. J., (Ed.). (2017). Sherris Medical Microbiology. Seventh edition, McGraw-Hill.
  7. Safrin, S. (2021). Antiviral agents. In Katzung B.G., & Vanderah T.W.(Eds.), Basic & Clinical Pharmacology, 15e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2988&sectionid=250602382
  8. Salvaggio, M., Gnann, J. (2017). Drugs for Herpesvirus Infections. In Cohen, J., Powderly, W., Opal, S.(Eds), Infectious Diseases (Fourth Edition, pp.1309-1317), Elsevier. https://doi.org/10.1016/B978-0-7020-6285-8.00153-2
  9. Zachary, K. (2021) Famciclovir: an overview. UpToDate. Retrieved Sept 1, 2021, from https://www.uptodate.com/contents/famciclovir-an-overview
  10. Zachary, K. (2021) Ganciclovir and valganciclovir: an overview. UpToDate. Retrieved Sept 1, 2021, from https://www.uptodate.com/contents/ganciclovir-and-valganciclovir-an-overview

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