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Pharmacology of Antiviral
Agents
Tufts University School of Medicine
December 2016
Linden Hu, MD
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TREATABLE VIRAL INFECTIONS
• Influenza
• Herpes viruses
Herpes simplex
Cytomegalovirus
Varicella zoster virus
• HIV
• Hepatitis C
• Hepatitis B
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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!
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Influenza
• Hemagglutinin
– Site by which virus binds to host cell receptor
• Neuraminidase
– Degrades host cell receptor, allowing release of
virus after replication has occurred
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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
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Antiviral Agents for
Influenza
M2 Inhibitors (influenza A only)
• Amantadine
• Rimantadine
Neuraminidase inhibitors
• Oseltamavir (Tamiflu)
• Zanamivir (Relenza)
• Peramivir (Rapivab)
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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
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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
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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
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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%
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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
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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)
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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
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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
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Indications for Antiviral Treatment
for Suspected or Confirmed
Influenza
• Severe illness requiring hospitalization
• Pregnancy
• Age <2 years or >65 years
• Chronic medical condition
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Summary of Influenza Drugs
Drug
Mechanism
Virus
type
Side Effects
Amantadine
M2 inhibitor
A
CNS toxicity
Rimantadine
M2 inhibitor
A
Few side effects
Oseltamavir
Neuraminidase inhibitor A & B
GI distress
Zanamivir
Neuraminidase inhibitor A & B
Bronchospasm
Peramivir
Neuraminidase inhibitor A & B
Rash, increased
creatinine
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Herpes Viruses
•
•
•
•
•
•
•
•
Herpes simplex virus, type 1 (HSV-1)
Herpes simplex virus, type 2 (HSV-2)
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)
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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)
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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
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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
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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
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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)
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Acyclovir
• Preparations
– 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
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Acyclovir Toxicity
• Nephrotoxicity (particularly after rapid
intravenous infusion and inadequate
hydration)
• CNS
– Agitation, lethargy, tremors
– Hallucinations
– Disorientation
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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
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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
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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
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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
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Special Uses for
Intravenous Acyclovir
• Neonatal Herpes
• HSV Encephalitis
• Immunocompromised
host with chickenpox or
herpes zoster
Ganciclovir
• Active against CMV, HSV-1, HSV-2
• Not commonly used to rx HSV given
that it is more toxic than acyclovir
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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
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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
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Ganciclovir Toxicity
• Nephrotoxicity
• Bone marrow suppression (leukopenia)
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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
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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
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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
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Antiviral Therapy for CMV
Induction Dose Maintenance
Dose
Toxicity
Ganciclovir
(IV)
5mg/kg bid
5 mg/kg qd
Nephrotoxicity
Bone marrow
suppression
Foscarnet
(IV)
90 mg/kg bid
90 mg/kg qd
Renal toxicity,
Electrolyte
disturbance
Cidofovir
(IV)
5 mg/kg qwk
5 mg/kg q
2wks
Nephrotoxicity
Valganciclovir
(PO)
900 mg bid
900 mg qd
Bone marrow
suppression
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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
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