Transcript Antivirals (non-HIV)

Drugs for Non-HIV
Viral Infections
Paul Lewis, PharmD
Infectious Diseases Pharmacy
Resident
Possible Sites of Action
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Viral attachment
Cell entry
Transcription
Translation
Viral assembly
Drugs for HSV and VZV
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Oral Agents
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Topical Agents
 Acyclovir
 Acyclovir
 Valacyclovir
 Docosanol
 Famciclovir
 Penciclovir
Ophthalmic
 Trifluridine
Acyclovir Mechanism of Action
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Inhibition of viral synthesis of DNA
Uptake by infected cell
 Virus-specific
thymidine kinase phosphorylates to
acyclovir monophosphate
 Cellular enzymes convert to acyclovir triphosphate
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Competes with deoxyguanosine triphosphate for
viral DNA polymerases
 Lacks
3’-hydroxyl group
 Chain termination
 Inactivates the viral DNA polymerase
Acyclovir (Zovirax®)
Guanosine analog
 Topical, oral, and intravenous formulations
 Spectrum: Herpes simplex 1 and 2,
varicella-zoster virus, possibly the EpsteinBarr Virus
 Treatment of choice for visceral,
disseminated, or central nervous system
involvement
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Acyclovir Adverse effects
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Phlebitis
Reversible renal toxicity
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Crystalization in the renal
tubules
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Neurological symptoms
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Encephalopathic changes
such as somnolence,
hallucinations, confusion
coma
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GI symptoms
Headache
TTP/HUS
Photosensitivity
Anemia
Valacyclovir (Valtrex®)
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L-valyl ester prodrug of acyclovir
 Rapidly
and almost completely converted to
acyclovir
Available orally only
 Spectrum: similar to acyclovir
 Adverse effects: headache, nausea,
weakness, dizziness, confusion
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Famciclovir (Famvir®)
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Cyclic guanine analog
 Converted
to pencyclovir in the liver and
intestines
Available orally only
 Spectrum: HSV 1 and 2, VZV, to a lesser
extent, EBV, in vitro activity to HBV
 Adverse effects: headache, GI, abnormal
LFT’s
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Acyclovir Resistance
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Defined as MIC > 2-3 mcg/mL
Mostly occurs in immunocompromised host
 4-14%
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Three basic resistance mechanisms exist:
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Reduced or absent thymidine kinase
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(compared to 0.1-0.7% in immunocompetent)
Most common
Less neurovirulent and unable to reactivate
Altered TK substrate specificity
Alterations in DNA polymerase
Cross resistance to famciclovir and valacyclovir
Famciclovir Resistance
Mutations in viral TK or DNA polymerase
 Cross resistance with acyclovir in TK
negative strains
 May still have activity in TK altered strains
 Resistance to HBV is due to the point
mutation L528M (viral DNA polymerase)
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 Also
associated with lamivudine resistance
Dosing for HSV
Acyclovir Valacyclovir Famciclovir
Primary
Genital
Recurrent
Genital
Chronic
Suppressive
Encephalitis
400 mg PO
TID X 10d
1 g PO
BID X 10d
400 mg PO
TID X 5d
500 mg PO BID 125 mg PO
X 5d
BID X 5d
200-400 mg
PO BID-TID
500-1000 mg
PO QD
10-15 mg/kg
IV Q8hrs
NA
250 mg PO
TID X 5-10d
125-250 mg
PO BID
NA
Dosing for VZV
Drug
Dosage
Varicella
Duration
Acyclovir
20 mg/kg (max 800) PO QID
5 days
Valacyclovir
Herpes Zoster
1 g PO TID
7 days
Famciclovir
500 mg PO TID
7 days
Acyclovir
800 mg PO 5X/d
7-10 days
Varicella or Zoster in Immunocompromised
Acyclovir
10 mg/kg IV Q8h
7 days
Other Topicals for HSV
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Orolabial herpes
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Penciclovir (Denavir® 1% cream)
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Topical guanine analog similar to acyclovir
Apply every 2 hours while awake
Docosanol (Abreva® OTC)
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Active against a broad range of lipid-envelop viruses
MOA: interferes with viral fusion to host cell
Apply 5X per day until healing (up to 10 days)
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Shortens healing time by 0.7 days
HSV Keratoconjuctivitis
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Trifluridine (Viroptic® 1% ophthalmic)
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1 drop q2h (max 9 drops/day)
Active against acyclovir resistant strains
Also active against vaccinia virus and smallpox
Anti-CMV Agents
Ganciclovir
 Valganciclovir
 Foscarnet
 Cidofovir
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Ganciclovir Mechanism of Action
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Competes with
deoxyguanosine
triphosphate similar to
acyclovir
However in CMV, viralencoded
phosphotransferase
converts to ganciclovir
triphosphate
Unlike acyclovir, ganciclovir
contains a 3’-hydroxyl
group, allowing for DNA to
continue
Ganciclovir (Cytovene®)
Oral, intravenous, and intraocular
 Spectrum:
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 CMV
(10X potency of acyclovir)
 EBV (10X potency of acyclovir)
 HSV/VZV (equal to acyclovir)
 Human Herpesvirus 6
Ganciclovir
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Adverse effects:
 reversible
pancytopenia (most common)
 Fever
 Rash
 Phlebitis,
 Confusion
 Renal
dysfunction
 Psychiatric disturbances
 Seizures
Vanganciclovir (Valcyte®)
L-valyl prodrug of ganciclovir
 Available orally only
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 Quickly
hydrolysed after absorption
Spectrum: similar to ganciclovir
 Adverse effects: similar to ganciclovir
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(Val)ganciclovir
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Resistance
 Mutations
in the viral protein kinase (UL97)
Responsible for monophosphorylation
 Confers resistance to ganciclovir alone
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 Mutations
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in the viral polymerase gene (UL54)
May show cross resistance to similar antivirals
Foscarnet – Mechanism of Action
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Trisodium phosphonoformate hexahydrate
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Does not require thymidine kinase
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Works on HSV strains deficient of this enzyme
Selective inhibition at the pyrophosphate binding
site on virus-specific DNA polymerase
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Inorganic pyrophosphate analog
Noncompetetive inhibitor
Does not affect cellular DNA polymerase
Resistance by alterations to viral DNA
polymerase
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Not caused by thymidine kinase alterations
Does not cause cross resistance to ganciclovir or cidofovir
Foscarnet (Foscavir®)
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Intravenous only – controlled infusions
Spectrum: CMV including ganciclovir resistant strains,
acyclovir resistant HSV or VZV, EBV, Influenza A and B,
HBV, and HIV
Adverse effects: renal dysfunction (common, can require
dialysis), NV, anemia, CNS disturbances, electrolyte
abnormalities, seizures, arrhythmias, neutropenias
Reduction of renal failure
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Saline loading (adequate hydration)
Appropriate renal dosing adjustments
Avoidance of concurrent nephrotoxic medications
Cidofovir – Mechanism of Action
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Acyclic nucleoside phosphonate derivative
Phosphorylation not dependant on viral kinases
 May
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actually enhance activity to TK deficient strains
Selective inhibition of CMV DNA
 Active
drug as cidofovir diphosphate
 DNA polymerase
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Incorporation into viral DNA chain results in
reductions of the rate of viral DNA synthesis
Cidofovir (Vistide®)
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Available intravenous only
Spectrum: CMV including acyclovir and
foscarnet resistant strains, HSV 1 and 2, VZV,
EBV, HHV-6, HHV-8
 Also
has activity against DNA viruses: papilloma
virus, polyomavirus, poxvirus, and adenovirus
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Must be avoided in preexisting renal impairment
Adverse effects: nephrotoxicity (dose-limiting),
neutropenia, metabolic acidosis
Must be given with adequate hydration and PO
probenecid---see labeled dosing directions
Cidofovir Resistance
Due to point mutations in viral DNA
polymerase in CMV, pox, and adenovirus
 Confers resistance to ganciclovir in CMV
 Foscarnet activity not affected by cidofovir
resistance
 Still active against UL97 mutation
 Not active against the UL54 mutation
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Dosing for CMV
Load
Maintenance
Ganciclovir
5mg/kg IV q12
X 14-21 days
5 mg/kg IV daily
1 g PO TID
Valganciclovir
900 mg PO BID
X 21 days
900 mg PO daily
Foscarnet
90 mg/kg IV q12
X 14-21 days
90-120 mg/kg IV
daily
Cidofovir
5 mg/kg IV qwk
X 2 doses
5 mg/kg IV every
2 weeks
Dosing for Resistant HSV/VZV
Drug
Dosage
Duration
Acyclovir-Resistant Herpes Simplex
(severe infection, immunocompromised)
Foscarnet
40 mg/kg IV q8hrs 14-21 days
Acyclovir-Resistant Zoster
(not FDA approved)
Foscarnet
40 mg/kg IV q8hrs 10 days
Hepatitis B Agents
Interferon alfa-2b/-n3/-2a
 Peginterferon alfa-2a/-2b
 Entecavir
 Adefovir
 Telbivudine
 Lamivudine/ Emtricitabine
 Tenofovir
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Interferons
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Discovered in 1957 for their antiviral effects
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Glycoproteins
Interferes with viral growth
Responsible for complex antiviral, immunomodulating, and
antiproliferative effects
Three classes (α, β, and γ)
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Each distinct
Different producer cells, inducers, and biologic effects
INF-α and –β are produced by nearly all cells in repsonse to
invasion
Only INF-α has been approved for viral treatment
INF- γ only produced by T cells and NK cells
Interferons
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Mechanism of action
 Not directly virucidal or virustatic
 Induces changes in the infected or
exposed cell to
promote resistance to the virus
 Induces several enzyme activities that promote an
antiviral state
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Proteins that inhibit synthesis of RNA
Proteins that cleave viral DNA
Proteins that inhibit mRNA
Alterations of the cell membrane that inhibit the release of
replicated virions
Interferon Alfa
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HBV
 Parenteral or subcutaneous administration
 Pegylated similar or slightly better than conventional
 Combination therapy not superior to monotherapy
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HCV
 Subcutaneous
administration preferred
 Given in combination with ribavirin
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Herpes
 Systemic
not associated with lesion reduction
 Topical may have efficacy with trifluridine in drugresistant mucocutaneous HSV
Interferon Alfa
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HIV
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Papillomavirus
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High doses have shown to induce responses Kaposi’s
May have dose-related antiretroviral effects
May benefit HIV-related thrombocytopenia and eosinophilic
folliculitis
Intralesional and systemic admin associated with regression of
anogenital warts
Respiratory Viruses
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Broad spectrum of activity in preventing respiratory viruses
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Except adenoviruses
Has been used to treat SARS coronavirus
Interferon Alfa Adverse Effects
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Flu-like syndrome
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Fevers/chills
Headache
Malaise
Myalgia/arthralgia
NVD
Local reactions
Bone marrow
suppression
Thyroid dysfunction
Neuropsychiatric
disturbances
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Depression
Anxiety
Somnolence
Behavioral disturbances
Fatigue/anorexia
Seizures
Cardiotoxicity
Pulmonary toxicity
Entecavir (Baraclude®)
Deoxyguanosine analog
 Available orally only
 More potent than lamivudine
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 Some
activity against 3TC resistant HBV at
higher doses
Should not be used to treat HBV/HIV
coinfection when HIV treatment deferred
 Adverse effects: Generally well tolerated
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 Headache,
fatigue, NVD, cough, myalgia
Adefovir Dipivoxil (Hepsera®)
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Phosphonate nucleotide analog
 Converted
to the diphosphate form
 Competes with deoxyadenosine triphosphate
Inhibits viral DNA polymerase
 Inhibits reverse transcriptase
 Chain terminator of DNA synthase
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Available orally only
 Activity includes HBV resistant to
lamivudine and entecavir, HIV, pox, HSV
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Adefovir
Should not be used to treat HBV/HIV
coinfection when HIV treatment deferred
 Adverse effects: Well tolerated
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 Asthenia,
headache, diarrhea, ab pain
 Nephrotoxicity at higher doses
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Resistance to HBV DNA polymerase by
N236T or A181V
Hepatitis C Agents
Ribavirin
 Pegylated interferon
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Ribavirin
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Purine nucleoside analog
Mechanism of action not fully understood
 Causes alterations to cellular nucleotide pools
 Inhibits viral RNA synthesis
 Lethal mutagenesis of certain RNA viral genomes
 Possibly
acts as an analog of guanosine or
xanthosine
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Possibly results in neutralizing antibody
response (RSV)
Resistance only documented in Sindbis virus
and HCV
 Point
mutation F415Y RNA polymerase identified
Ribavirin
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Available orally and via inhalation
 Intravenous
and intraventricular available
through the CDC
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Spectrum: RNA and DNA viruses including
influenza A and B, mumps, measles,
parainfluenza, HSV, togavirus, bunyavirus,
adenovirus, coxsackievirus, RSV, Hepatitis
A, B and C
 Data
also available for hemorrhagic fever,
Lassa fever, and Hantaan virus
Ribavirin Adverse Effects
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Hemolytic anemia
Respiratory
deterioration
Depression
Suicidal ideation
Bacterial infections
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Psychiatric effects
Anxiety
Fatigue
Dizziness
Influenza Agents
Oseltamivir
 Zanamivir
 Amantadine
 Rimantadine
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Oseltamivir (Tamiflu®)
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Oral neuraminidase inhibitor
 Cleaves
terminal sialic acid residues on
glycoconjugates and destroys receptors
 Newly formed virions adhere to cell surface
and limit spread
Spectrum: Infuenza A and B in both
children and adults, avian influenza, H5N1
disease
 Adverse effects: NV, headache
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Zanamivir (Relenza®)
Neuraminidase inhibitor
 Given via inhalation
 Spectrum: Uncomplicated influenza A and
B, some strains of avian influenza,
possibly effective for H5N1
 Adverse effects: nasal and throat
discomfort, bronchospasm
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Amantadine (Symmetrel®)
Rimantadine (Flumadine®)
MOA: Prevents the release of viral nucleic
acid into host cell
 Spectrum: Influenza A, however resistance
is frequent
 Adverse effects: Seizures, anticholinergic,
CNS, edema, blurry vision
 Not currently recommended in the US
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Papillomavirus Options
Imiquimod
 Podofilox
 Trichloroacetic Acid
 Podophyllin
 Cryotherapy
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Imiquimod (Aldara®)
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Imidazoquinoline compound
Immunomodulator
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Activates immune cells (monocytes, macrophages, NK cells)
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Topical treatment
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Produces antiviral cytokines (IFN-α, TNF-α, and various interleukins
Indirectly activates APC’s including Langerhan’s cells and T-helper
cells
5% cream 3X per week (for 8 hours) for 16 weeks
Can be used as adjunctive therapy with laser or surgical tx
Spectrum: External and perianal genital warts by HPV
Adverse effects:
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Site reactions (pain, erythema, scarring, and pruritis)
No systemic reactions reported
Podofilox (Condylox®)
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Also known as podophyllotoxin
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Exact mechanism not known
Topical treatment
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Main ingredient in podophyllin
0.5% solution or gel every 12 hours for 3 days then withhold for
4 days, repeat up to 4 times
Similar in efficacy to imiquimod but more adverse effects
Adverse effects
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Localized pain, burning, inflammation, and erosion
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Reported in over 50%
Systemic effects not reported
Trichloroacetic Acid (Tri-Chlor®)
Keratolytic agent
 Given topically
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 80%
Liquid
 Powder for reconstitution