1. Pharmacology of Antiviral Agents
Tufts University School of Medicine
December 2016
Linden Hu, MD

2. TREATABLE VIRAL INFECTIONS
Influenza
Herpes viruses
Herpes simplex
Cytomegalovirus
Varicella zoster virus
HIV
Hepatitis C
Hepatitis B

3. Mechanism of Action of Antiviral Agents
Inhibit one or more of the following:
Viral nucleic acid synthesis
Viral uncoating
Binding of viral particle to host cell
Antiviral drugs must distinguish virus from host!

4. Influenza Hemagglutinin Neuraminidase
Site by which virus binds to host cell receptor
Neuraminidase
Degrades host cell receptor, allowing release of virus after replication has occurred

5. Approaches to Control of Influenza
Vaccination at start of influenza season (immunoprophylaxis)
Treatment with antiviral agents
Greatest effect when rx begun w/in 24 hrs

6. Antiviral Agents for Influenza
M2 Inhibitors (influenza A only)
Amantadine
Rimantadine
Neuraminidase inhibitors
Oseltamavir (Tamiflu)
Zanamivir (Relenza)
Peramivir (Rapivab)

7. Amantadine Inhibits M2 protein (only present on influenza A)
M2 protein is a protein channel which enhances viral uncoating and thus inhibition of M2 protein inhibits viral replication
Resistance conferred by a single amino acid mutation in the M2 protein

8. Amantadine Usual dose 100 mg po bid – rx is for 5 days
Dosed reduced in persons >65 yrs and Cr Cl <50
Toxicity
CNS side effects (insomnia, hallucinations, jitteriness, irritability, confusion, seizures) CNS side effects increase when drug given along with anticholinergics or antihistamines

9. Rimantadine
Better tolerated than amantadine, likely due to lower blood levels
Lower rate of CNS side effects compared to amantadine
Resistance results from single point mutation of M2 protein
Mutation confers cross resistance between amantadine and rimantadine

10. Neuraminidase Inhibitors
Active against influenza A and B
Blocks neuaminidase preventing release of viral particles
Reduce median duration of sx by ONE DAY and reduce odds of developing influenza by 70-90%

11. Oseltamivir (Tamiflu)
Given orally – rapidly absorbed from GI tract
Excreted by kidney
Standard dose is 75 mg po bid
Can be given for treatment and prophylaxis
Main side effect is GI upset
Few reports of neurotoxicity in children
During influenza season in US, >99% of influenza isolates were susceptible to oseltamivir
Double dose has been suggested for severely ill, immunocompromised persons
In Japan reports of delirium and self injury in children with use of oseltamivir

12. Peramivir (Rapivab) IV formulation of neuraminidase inhibitor
Recently FDA approved for treatment of uncomplicated influenza
Dosed as one time 600 mg dose IV
Potential adverse events include rash, elevated creatinine, CNS side effects (delirium, halllucinations, abnormal behavior)

13. Zanamivir (Relenza) Inhaled - not orally bioavailable
May precipitate bronchospasm
Decreases sx of influenza by 1.5 days if given w/i 48 hrs of sx onset – also reduces severity of sx
Not widely used due to lack of oral administration
IV zanamivir is being evaluated in clinical trials and is available for compassionate use

14. Neuraminidase Inhibitors - Resistance
Lower risk of resistance compared to amantadine compounds
Active against strains of influenza A resistant to amantadine and rimantadine, given different mechanism of action

15. Indications for Antiviral Treatment for Suspected or Confirmed Influenza
Severe illness requiring hospitalization
Pregnancy
Age <2 years or >65 years
Chronic medical condition
Avoid treating young otherwise healthy persons to minimize development of resistance to influenza compunds

16. Summary of Influenza Drugs
Mechanism
Virus
type
Side Effects
Amantadine
M2 inhibitor A
CNS toxicity
Rimantadine
Few side effects
Oseltamavir
Neuraminidase inhibitor
A & B
GI distress
Zanamivir
Peramivir
Bronchospasm
Rash, increased
creatinine

17. Herpes Viruses Herpes simplex virus, type 1 (HSV-1)
Varicella zoster virus (VZV)
Cytomegalovirus (CMV)
Epstein Barr virus (EBV)
Human herpesvirus 6 (HHV 6)
Human herpesvirus 7 (HHV 7)
Human herpesvirus 8 (HHV 8)

18. Acyclovir and Derivatives
Acyclovir- topical, IV and PO
Prodrugs (increase bioavailability; acyclovir ~25%)
Valacyclovir (PO pro-drug of acyclovir; ~50% bioavailable)
Famciclovir (PO prodrug of penciclovir; ~75% bioavailable)

19. Acyclovir and Derivatives
Analog of 2’ deoxyguanosine
Require phosphorylation to monophosphate form by virus-encoded thymidine kinase
Drug concentrates in herpes virus-infected cells as little phosphorylation occurs in uninfected cells
Monophosphate form is converted to a triphosphate form by host cell kinases
Triphosphate form inhibits viral DNA polymerase

20. Acyclovir, valacyclovir,
Famciclovir
Ganciclovir
CMV UL97
kinase
Herpesvirus
thymidine
kinase
Drug monophosphate
Drug monophosphate
Host cell
kinases
Host cell
kinases
Drug Triphosphate
Drug Triphosphate
Viral DNA Polymerase

21. Acyclovir Active against HSV-1, HSV-2, VZV
Generally not useful for rx of CMV
Phosphorylated sequentially by viral thymidine kinase followed by host cell kinases to active tri-phosphate form
Competitively inhibits viral DNA polymerase
Incorporated into viral DNA resulting in chain termination
Available in oral, intravenous, and topical forms

22. Clinical Use of Acyclovir
HSV infections
Genital HSV (primary, recurrent, suppression)
Oral-Labial HSV
HSV Encephalitis
Neonatal HSV
Prophylaxis (prevent reactivation of HSV in immunocompromised hosts)
VZV
Varicella (chickenpox)
Herpes zoster (shingles)

23. Acyclovir Preparations Oral bioavailability 20-30%
Topical
Oral (200, 800 mg)
Intravenous
Oral bioavailability 20-30%
Penetrates well into CSF - CSF level 50% of serum level
>60% excreted unchanged in the urine

24. Acyclovir Toxicity
Nephrotoxicity (particularly after rapid intravenous infusion and inadequate hydration)
CNS
Agitation, lethargy, tremors
Hallucinations
Disorientation

25. Mechanisms of Resistance
Thymidine kinase deficient mutant
Thymidine kinase with altered substrate and unable to phosphorylate acyclovir
Mutations in viral DNA polymerase
*Almost all clinically significant acyclovir resistance seen in immunocompromised hosts
*Commonly associated with cross resistance to famciclovir and valacyclovir

26. Herpes labialis and genitalis (HSV1 and HSV2)
Can use oral agents for treatment with modest effect in shortening length of symptoms (not usually recommended)
Topical agents can be used but needs to be applied very frequently to work
Can be used in prevention for recurrent outbreaks.
Does NOT reduce risk of transmission to uninfected partners

27. Chickenpox Treat with acyclovir (or derivatives)
Treat immunocompromised hosts with varicella
Treat pregnant women in 2nd and 3rd trimester given risk of disseminated disease
Treat perinatal varicella
Treat adults >18 yrs; reduces number of lesions and accelerates time to crusting

28. Herpes Zoster
Treated with oral agents except in immunocompromised patients with evidence of dissemination
Shortens course by one to two days
May decrease incidence of post-herpetic neuralgia
Fitzpatrick's Color Atlas & Synopsis of Clinical Dermatology Klaus Wolff, Richard Allen Johnson, Dick Suurmond Copyright 2005, 2001, 1997, 1993 by The McGraw-Hill Companies

29. Special Uses for Intravenous Acyclovir
Neonatal Herpes
HSV Encephalitis
Immunocompromised host with chickenpox or herpes zoster

30. Ganciclovir Active against CMV, HSV-1, HSV-2
Not commonly used to rx HSV given that it is more toxic than acyclovir

31. Ganciclovir Guanosine derivative
Ganciclovir triphosphate selectively inhibits CMV DNA polymerase
Resistance common among persons treated for >3 months and is usually due to mutations in CMV UL97 gene
Available in oral and intravenous forms

32. Acyclovir, valacyclovir,
Famciclovir
Ganciclovir
Herpesvirus
thymidine
kinase
CMV UL97
kinase
Drug monophosphate
Drug monophosphate
Host cell
kinases
Host cell
kinases
Drug Triphosphate
Drug Triphosphate
Viral DNA Polymerase

33. Ganciclovir Toxicity Nephrotoxicity
Bone marrow suppression (leukopenia)

34. Valganciclovir
Orally bioavailable prodrug that is rapidly metabolized to ganciclovir in the intestine and liver
60% of oral valganciclovir dose is absorbed
Used for prophylaxis of CMV disease in immunocompromised hosts and maintenance rx
IV ganciclovir used to treat severe CMV disease

35. Cidofovir Nucleotide analogue that inhibits viral DNA polymerase
Activity against CMV, smallpox, BK virus, acyclovir resistant HSV
Long intracellular half-life that allows intermittent intravenous administration
Nephrotoxic
Nucleotide analog with broad spectrum antiviral activity

36. Foscarnet Inhibits DNA polymerase – does not require phosphorylation
Effective against resistant CMV and HSV
Less well tolerated than ganciclovir and associated with considerable toxicity
Nephrotoxicity
Hypomagnesemia, hypokalemia, hypocalcaemia

37. Antiviral Therapy for CMV
Induction Dose
Maintenance Dose
Toxicity
Ganciclovir (IV)
5mg/kg bid
5 mg/kg qd
NephrotoxicityBone marrow suppression
Foscarnet
(IV)
90 mg/kg bid
90 mg/kg qd
Renal toxicity,
Electrolyte disturbance
Cidofovir
5 mg/kg qwk
5 mg/kg q 2wks
Nephrotoxicity
Valganciclovir
(PO)
900 mg bid
900 mg qd
Bone marrow suppression

38. Antiviral Take Home Points
Early initiation of therapy is a key
Impact is often minimal in immunocompetent patients; you do not always need to treat for viral infections
Toxicities can be limiting
amantadine - neurotoxicity
oseltamivir - GI toxicity
ganciclovir - bone marrow suppression
foscarnet - nephrotoxicity, electrolyte abnormalities