Transcript Direct Link - TUSK: Tufts

Pharmacology of Antiviral
Agents
Tufts University School of Medicine
December 2016
Linden Hu, MD
1
TREATABLE VIRAL INFECTIONS
• Influenza
• Herpes viruses
Herpes simplex
Cytomegalovirus
Varicella zoster virus
• HIV
• Hepatitis C
• Hepatitis B
2
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!
3
Influenza
• Hemagglutinin
– Site by which virus binds to host cell receptor
• Neuraminidase
– Degrades host cell receptor, allowing release of
virus after replication has occurred
4
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
5
Antiviral Agents for
Influenza
M2 Inhibitors (influenza A only)
• Amantadine
• Rimantadine
Neuraminidase inhibitors
• Oseltamavir (Tamiflu)
• Zanamivir (Relenza)
• Peramivir (Rapivab)
6
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
7
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
8
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
9
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%
10
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
11
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)
12
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
13
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
14
Indications for Antiviral Treatment
for Suspected or Confirmed
Influenza
• Severe illness requiring hospitalization
• Pregnancy
• Age <2 years or >65 years
• Chronic medical condition
15
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
16
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)
17
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)
18
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
19
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
20
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
21
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)
22
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
23
Acyclovir Toxicity
• Nephrotoxicity (particularly after rapid
intravenous infusion and inadequate
hydration)
• CNS
– Agitation, lethargy, tremors
– Hallucinations
– Disorientation
24
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
25
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
26
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
27
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
28
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
30
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
31
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
32
Ganciclovir Toxicity
• Nephrotoxicity
• Bone marrow suppression (leukopenia)
33
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
34
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
35
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
36
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
37
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
38