Microbiology Antiviral therapy Flashcards

1
Q

Aciclovir:

Type of Drug

A

Nucleoside analogue of guanosine.

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2
Q

Aciclovir: MOA

A

Competitive inhibitor of Viral DNA polymerase, an obligate DNA chain terminator.

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3
Q

Aciclovir: Process

A
  • Preferentially taken up by virally infected cells
  • Monophosphorylated by virally encoded thymidine kinases
  • 2nd and 3rd phosphate added by cellular kinases
  • ACV-TP is the active moiety
  • Competitive inhibitor of viral DNA polymerase
  • Cellular DNA polymerases much les susceptible to inhibition
  • Leads to viral DNA chain termination
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4
Q

Aciclovir: Safety

A

• Remarkedly safe antiviral

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5
Q

Aciclovir: Effective against

A

• HSV types 1 & 2, and VZV infections inhibitis CMV, and EBV but not clinically useful.

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6
Q

Aciclovir: Main indications are

A
  • Severe primary labial and genital herpes
  • Ophthalmic HSV and VZV
  • Eczema herpeticum
  • Herpes zoster
  • Chickenpox – adults require more aggressive
  • Herpes encephalitis
  • Prevention and treatment of disseminated herpetic disease in the immunocomprimised patient
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7
Q

Aciclovir: Problems

A
•	Limited oral bioavailability – 25%
•	Treatment needs to start within 24-72 hours
•	Intravenous
•	Topical therapy (creams) of limited value with exception of eye drops used in ophthalmic herpes ad ophthalmic zoster.
•	Toxicities
→ Headache, nausea
→Renal
→ Neurological (encephalopathic)
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8
Q

Aciclovir: Oral dosage

A

• Requires to be given 5x daily for 5-7 days.

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9
Q

Aciclovir: Iv dosage

A

• Intravenous therapy substantially better at disease control in all compartments. Given 8 hourly

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10
Q

Aciclovir: Renal concern

A

• Safe. Dose reduction with renal dysfunction

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11
Q

Aciclovir Resistance

A

• Can be problematic in continuous use or in immunocomprimised
• Mediated by mutations in viral thymidine kinae and/or viral DNA polymerase genes
→TK-deficienct and TK altered virus can be produced

• Clinically significant infections can be caused by drug resistant HSV and VZV

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12
Q

Anti-herpes Prodrugs

A

• Better absorption – both drugs improve bioavailability by 55% and 77% respectively for oral abministration

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13
Q

Anti-herpes prodrugs example

A
  • Valaciclovir

* Famciclovir

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14
Q

Anti-cytomegalovirus drugs

A

Ganciclovir
Foscarnet
Cidofovir

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15
Q

Ganciclovir

Activity against

A

CMV (10x better than acyclovir)
HSV/VZV (similar acyclovir)
HHV6

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16
Q

Ganciclovir dosing

A

I.v.

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17
Q

Cidofovir activity against

A
CMV
HSV/VZV
BKV
Adenovirus
Papillomavirus
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18
Q

Cidofovir dosing

A

Oral version in development

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19
Q

Ganciclovir and Foscarnet excretion

A

Renal Failure

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20
Q

Ganciclovir and Foscarnet Indications

A

CMV infection and disease in the immunocomprimised-haematology-oncology and HIV patient
CMV pneumonitis retinitis, colitis, hepatitis and encephalitis

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21
Q

Ganciclovir and Foscarnet used in the neonate with

A

Congenital infection to stop progression of hearing loss and other associated neurology

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22
Q

Ganciclovir MOA

A
  • Competes with deoxyguanosine triphosphate similar to acyclovir
  • Howevere in CMV, viral-encoded phosphotransferase converts to ganciclovir triphosphate
  • Competitive inhibitor of DNA polymerase, unlike acyclovir, ganciclovir contains a 3’-hydroxyl group, allowing for DNA to continue – short chain terminator
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23
Q

Ganciclovir Adverse effects

A
  • Reversible pancytopaenia (most common)
  • Fever
  • Rash
  • Phlebitis
  • Confusion
  • Renal dysfunction
  • Psychiatric disturbances
  • Seizures
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24
Q

Valganciclovir spectrum

A

Similar ganciclovir

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25
Q

Valganciclovir adverse effects

A

Similar to ganciclovir

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26
Q

(Val) ganciclovir resistance

A
  1. Mutations in the viral protein kinase (UL97)

2. Mutations in the viral polymerase gene (UL54)

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27
Q

Viral protein kinase (UL97) responsible for and resistance

A

Responsible for monophosphorylation

Confers resistance to ganciclovier alone

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28
Q

Viral polymerase gene (UL54)

A

May show cross resistance to similar antivirals

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29
Q

Foscarnet activity against

A

CMV
HSV/ VZV
HHV6

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30
Q

Foscarnet dosing

A

I.V only

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31
Q

Foscarnet excretion

A

Renally

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32
Q

Foscarnet Indications

A

CMV infection and disease in the immunocomprimised-haematology-oncology and HIV patient
CMV pneumonitis retinitis, colitis, hepatitis and encephalitis

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33
Q

Foscarnet used in the neonate with

A

Congenital infection to stop progression of hearing loss and other associated neurology

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34
Q

Foscarnet MOA

A

• Inorganic pyrophosphate analogue – trisodium phosphonoformate hexahydrate
• Does not require thymidine kinase – works on HSV strains deficient of this enzyme
Selective inhibition at the pyrophosphate binding site on virus-specific DNA polymerase (100x cellular) – non-competitive inhibitor

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35
Q

Foscarnet resistance

A

• By alterations to viral DNA polymerase
→ Not caused by thymidine kinase alterations
→ Does not cause cross resistance to ganciclovir or cidofovir

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36
Q

Foscarnet adverse effects

A
  • Renal dysfunction (common, can required dialysis)

* NV, anaemia, CNS disturbance, electrolyte abnormalities, seizures, arrhythmias, neutropenias

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37
Q

Cidofovir MOA

A

• Acyclic nucleoside phosphate derivative (nucleotide analogue)
• Phosphorylation not dependent on viral kinases (TK)
• Selective inhibition of CMV DNA pol
→ Active drug as cidofovir diphosphate
• Incorporation into viral DNA chain results in reduction of the rate of viral DNA synthesis

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38
Q

Cidofovir adverse effects

A
  • Nephrotoxicity: nephrotoxicity (dose-limiting), neutropenia, metabolic acidosis
  • Must be given with adequate hydration and PO probenecid (protects against
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39
Q

PO probenecid combination with cidofovir why

A

Protects against renal toxicity

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40
Q

Cidofovir resistance

A
  • Due to point mutations in viral DNA polymerase
  • Can confer resistance to ganciclovir in CMV
  • Foscarnet activity not affected by cidofovir resistance
  • Still active against UL97 mutations induced by ganciclovir
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41
Q

CMV Antivirals – Recent Developments:

A

Maribavir
Letermovir
Brincidofovir
Leflunomide

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42
Q

Maribavir

A

Direct UL97 kinase gene competitive inhibitor

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43
Q

Letermovir

A

DNA processing gener UL56 inhibitor

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44
Q

Brincidofovir

A

Lipid conjugate of cidofocir – reduced toxicity , oral

45
Q

Leflunomide

A

Immunosuppressive (!) – late stage viral assembly

46
Q

Interferons → Three classes

A
  • Alpha
  • Beta
  • Gamma
47
Q

Interferons → Description

A
  • INF – alpha and beta are produced by nearly all cells in response to infection
  • INF – gamma only produced by T cells and NK cells
48
Q

Interferons → MOA

A

• Not directly virucidal or virustic
• Induces changes in the infected or exposed cell to promote resistance to the virus
• Induces several enzyme activities that promote an antiviral state
→ Proteins that inhibit synthesis of RNA
→ Proteins that cleave viral DNA
→ Protein that inhibit mRNA
→ Alterations of the clel membrane that inhibit the release of replicated virions.

49
Q
Interferons → Pharmacology
Dosage
Excretion
Half-life
Structural changes
A
  • Injected IM or SC
  • Renal excretion and inactivation in body fluids/issues
  • Pegylated – a linear or branched polyethylene glycol (PEG) moiety is attached to covalently to interferon
  • Increased half-life and steady drug concentrations
50
Q

Interferons → Toxicities

A
  • Flu-like symptoms
  • Haematological effects 0leukopaenia and thrombocytopaenia
  • Neuropsychiatric effects
51
Q

Interferons →Antiviral indications

A
  • HBV
  • HCV
  • Papillomavirus (intalesional), respiraoty viruses? (SARS)
52
Q

Interferons → Hepatitis B Agents

A
  • Interferon alfa-2b/2a
  • Peginterferon alfa-2a/2b
  • Entecavir
  • Adefovir
  • Telbivudine
  • Lamivudine/Emtricitabine
  • Tenofovir
53
Q

HBV – Who to treat

A
  • All HBV carriers are potential treatment candidates

* Based on risk of developing cirrhosis and liver cancer – active inflammation evidence by raised ALT or high viral load

54
Q

Hepatiitis B Antiviral Therapy

A
Nucleosides (nucleotides)
•	Lamivudine
•	Adefovir
•	Entecavir
•	Tenofovir
Effective rapid reduction in HBV DNA
55
Q

Antiviral therapy for Hep B resistance

A
May develop
•	Especially to lamivudine
•	20% at one yr, 60% at 5 yrs
•	Consider combination therapy/sequential therapy
Prolonged or life long therapy
56
Q

Hepatitis C

A
Ribavirin
Pegylated interferon
Protease inhibitors
Polymerase inhibitors
NS5 gene inhibitors
57
Q

Ribavirin I Description

A

Synthetic guanosine (nucleoside) analogue

58
Q

Ribavirin I Active against

A

Active vs. broad range of RNA and DNA viruses

→ Flavi, paramyxo-, bunya-, arena-,retro-,herpes-,adeno-, and poxviruses

59
Q

Ribavirin II pharmacology

A

Aerosol, oral, i.v. administration

Hepatically metabolizsed and renally excreted

60
Q

Ribavirin II toxicity

A

Anaemia

61
Q

MOA

A

Triphosphorylated by host cell enzymes

62
Q

For influenza

A

Ribavirin – TP interferes with capping and elongation of mRNA and may inhibit viral RNA polymerase

63
Q

For other agents

A

Ribavirin-MP inhibits inosine-5’- monophosphate dehydrogenase depleting intracellular nucleotide pools, particularly GTP

64
Q

Chronic Hepatitis C

A

Goal is to clear HCV RNA
A sustained virological response (SVR) is associated with greatly rediced progression to cirrhosis
Combination antiviral therapy
• Standard therapy
• Interferon alpha and ribavirin
• Pegyylated interferon and ribavirin can clear virus in up to 80% genotype 2,3 and 50% genotype 1
• New agents highly effective

65
Q

Influenza A antivirals

A

Amantidine
Rimantidine
Zanamivir
Oseltamir

66
Q

Influenza B antivirals

A

Zanamivir

Oseltamivir

67
Q

Amantidine and Rimantidine: Description

A

Non-nucleosides

68
Q

Amantidine and Rimantidine: MOA

A

Act on the early phase of virus un-coating by blocking the function of the matrix protein.
Ion channel blockers

69
Q

Amantidine and Rimantidine: Active against

A

Influenza A strains only

70
Q

Amantidine and Rimantidine: Dosing

A

Taken as 100 or 200mg o.d. for up to 2 weeks

71
Q

Amantidine and Rimantidine:Amantidine in elderly

A

Not well tolerated in the elderly. Parkinsonian and extra-pyramidal signs are occasionally seen

72
Q

Amantidine and Rimantidine: Side effects

A

Nausea, dizziness are frequent. Rimantidine has fewer side effects

73
Q

Amantidine and Rimantidine: Resistance

A

Generated easily – most circulating strains resistant

74
Q

Neuraminidase Inhibitors: Action

A

Inhibition of virues maturation and release at the level of the cell membrane

75
Q

Neuraminidase Inhibitors: Use

A

Extreme conditions

76
Q

Neuraminidase Inhibitors: Example

A

Relena (Zanamivir)

Tamiflu (Oseltamivir)

77
Q

Neuraminidase Inhibitors: Relena Treatment and prevention of

A

Influenza A (inc avian) and B

78
Q

Neuraminidase Inhibitors: Relena Delivery as

A

An aerosol of powder from blister pack inhaled as 10mg x b.d. for 5 days

79
Q

Neuraminidase Inhibitors: Tamiflu (Oseltamivir)

A

Oral formulation (75 mg capsule) b.dd for 5 days and oral suspension for the treatment of influenza A and B (and prevention-o.d. regimen)

80
Q

Neuraminidase Inhibitors: With these drugs

A

Needs to be taken within 48 hours of first symptoms for maximum benefit but should be given later if severely unwell/ high risk group

81
Q

Zanamivir and Oseltamivir resistance

A

Oseltamivir
• H275Y in neuraminidase gene
• Rare de novo but can be induced, esp immunocomprimised
Zanamivir – occurs but rare, not cross-resistant

82
Q

HAART

A

Highly active anti-retroviral therapy. Combination therapy made up of 2-5 classes of antiviral drug

83
Q

The aim of treatment

A

Is not to cure but to suppress HIV VL and improve CD4 count, giving a longerCD4 count, giving a longer and better quality of life while reducing the incidence of opportunistic disease and lowering transmission potential (functional cure not eradication).

84
Q

Classes of antiretroviral drugs

A
  • NRTI-pNRTI – zidovudine/tenofovir
  • NNRTI-nevirapine
  • Protease inhibitors – Iopinavir
  • Fusion Inhibitor-enfuvirtide
  • Co-receptor (CCR5) – maraviroc
  • Integrase inhibitor-raltegravir
85
Q

NNRTIs action

A
  • Acts as reverse transcriptase blocking agents not as competitors
  • Less poten than NRTIs
86
Q

NNRTIs resistance

A

• More likely over time 1-3 years

87
Q

NNRTIs in combination

A

• With an NRTI agents

88
Q

NNRTI examples

A
  • Nevirapine (NVP)
  • Efavirenz (EFV)
  • Rilpivirine (RPV)
  • Etravirine (ETV)
89
Q

Protease Inhibitors – Pis action

A
  • Act as protease blockers disabling maturation of the HIV virion on release from the cell
  • Potent
90
Q

PI drug problems

A

• Drug interactions problematic

91
Q

Dosage

A

• Dual Pi’s utilised low dose ritonavir to inhibit cutochroe P450 allowing high levels of the main PI in the dual formulation

92
Q

Examples

A
  • Ritonavir (RTV)
  • Nelfinavir (NFV)
  • Tipranavir (TPV)
  • Lopinavir (LPV)
  • Darunavir (DRv)
  • Atazanavir (ATV)
93
Q

Treating with HAART (HIV1)

A

• Combination therapy is used for potency and prevention of drug resistance.

94
Q

HAART for starting therapy

A

Two nucelo (t)ide reverse transcriptase inhibitor (NRTIs) plus one of the following: a ritonavir – boosted protease inhibitor (Pl/r), an NNRTI or an integrase inhibitor (INI)

95
Q

HAART examples

A
Tenfovir
Emtricitabine with
Atazanavir
Ritonavir or
Efavirenz or 
Raltegravir
96
Q

HAART response

A

Most patients with a naïve wild-type HIV infection respond to HAART with a reduction in HIV viral load (V), >500,000 copies to undetectable (<50 copies), with a significant rise in CD4 count within 6 weeks of treatment initiation.

97
Q

Maintenance of an undectable viral load requires

A

Good adherence >80% of the dose, >80% of the time.

98
Q

Treatment Failure

A

Is defined as persistent detectable viral as persistent detectable viral load >50 copies/mL blood

99
Q

Signals that show development of resistance

A

Viral rebound and fall in CD4 count on therapy

100
Q

HAART Adverse Effects

A

Modern combinations very good
Early NRTIs limited by serious toxicities including anaemia and neutropenia (ZDV) and peripheral neuropathies (d4T), lipodystrophy, mitochondrial toxicity and lactic acidosis are serious consequences of NRTI therapy

101
Q

Abacavir sensitivity

A

Is rare (4%) but can be life threatening

102
Q

Lamivudine (3TC)

A

Rare significant toxicities

103
Q

NNRTIs are limited by

A

Tendency to cause rash, fever, myalgia, hepatitis and diarrhoea (NVP) and Depression (EFV)

104
Q

PIS were often difficult to tolerate due to a wide

A

Range of GI symptoms. Lipid changes can significantly increase risk of heart disease and stroke, as well as altering body shape (buffalo hump, midriff deposition, facial and thigh fat pad loss).

105
Q

Ribavirin for RSV

A

Nebulied, oral,iv

Immunocomprimised

106
Q

Papillomavirus drug

A

Interferon inducer – imiquimod

107
Q

HSV keratoconjunctivitis treatment

A

Trifluridine or idoxuridine

108
Q

CMV treatment

A

Fomivirisen – antisense oligonucleotide, intra-ocular