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Flashcards in Microbiology Antiviral therapy Deck (108):
1

Aciclovir:
Type of Drug

Nucleoside analogue of guanosine.

2

Aciclovir: MOA

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

3

Aciclovir: Process

• 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

4

Aciclovir: Safety

• Remarkedly safe antiviral

5

Aciclovir: Effective against

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

6

Aciclovir: Main indications are

• 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

7

Aciclovir: Problems

• 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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Aciclovir: Oral dosage

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

9

Aciclovir: Iv dosage

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

10

Aciclovir: Renal concern

• Safe. Dose reduction with renal dysfunction

11

Aciclovir Resistance

• 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

12

Anti-herpes Prodrugs

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

13

Anti-herpes prodrugs example

• Valaciclovir
• Famciclovir

14

Anti-cytomegalovirus drugs

Ganciclovir
Foscarnet
Cidofovir

15

Ganciclovir
Activity against

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

16

Ganciclovir dosing

I.v.

17

Cidofovir activity against

CMV
HSV/VZV
BKV
Adenovirus
Papillomavirus

18

Cidofovir dosing

Oral version in development

19

Ganciclovir and Foscarnet excretion

Renal Failure

20

Ganciclovir and Foscarnet Indications

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

21

Ganciclovir and Foscarnet used in the neonate with

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

22

Ganciclovir MOA

• 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

23

Ganciclovir Adverse effects

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

24

Valganciclovir spectrum

Similar ganciclovir

25

Valganciclovir adverse effects

Similar to ganciclovir

26

(Val) ganciclovir resistance

1. Mutations in the viral protein kinase (UL97)
2. Mutations in the viral polymerase gene (UL54)

27

Viral protein kinase (UL97) responsible for and resistance

Responsible for monophosphorylation
Confers resistance to ganciclovier alone

28

Viral polymerase gene (UL54)

May show cross resistance to similar antivirals

29

Foscarnet activity against

CMV
HSV/ VZV
HHV6

30

Foscarnet dosing

I.V only

31

Foscarnet excretion

Renally

32

Foscarnet Indications

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

33

Foscarnet used in the neonate with

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

34

Foscarnet MOA

• 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

35

Foscarnet resistance

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

36

Foscarnet adverse effects

• Renal dysfunction (common, can required dialysis)
• NV, anaemia, CNS disturbance, electrolyte abnormalities, seizures, arrhythmias, neutropenias

37

Cidofovir MOA


• 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

38

Cidofovir adverse effects

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

39

PO probenecid combination with cidofovir why

Protects against renal toxicity

40

Cidofovir resistance

• 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

41

CMV Antivirals – Recent Developments:

Maribavir
Letermovir
Brincidofovir
Leflunomide

42

Maribavir

Direct UL97 kinase gene competitive inhibitor

43

Letermovir

DNA processing gener UL56 inhibitor

44

Brincidofovir

Lipid conjugate of cidofocir – reduced toxicity , oral

45

Leflunomide

Immunosuppressive (!) – late stage viral assembly

46

Interferons → Three classes

• Alpha
• Beta
• Gamma

47

Interferons → Description

• 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

Interferons → MOA

• 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

Interferons → Pharmacology
Dosage
Excretion
Half-life
Structural changes

• 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

Interferons → Toxicities

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

51

Interferons →Antiviral indications

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

52

Interferons → Hepatitis B Agents

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

53

HBV – Who to treat

• 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

Hepatiitis B Antiviral Therapy

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

55

Antiviral therapy for Hep B resistance

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

56

Hepatitis C

Ribavirin
Pegylated interferon
Protease inhibitors
Polymerase inhibitors
NS5 gene inhibitors

57

Ribavirin I Description

Synthetic guanosine (nucleoside) analogue

58

Ribavirin I Active against

Active vs. broad range of RNA and DNA viruses
→ Flavi, paramyxo-, bunya-, arena-,retro-,herpes-,adeno-, and poxviruses

59

Ribavirin II pharmacology

Aerosol, oral, i.v. administration
Hepatically metabolizsed and renally excreted

60

Ribavirin II toxicity

Anaemia

61

MOA

Triphosphorylated by host cell enzymes

62

For influenza

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

63

For other agents

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

64

Chronic Hepatitis C

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

Influenza A antivirals

Amantidine
Rimantidine
Zanamivir
Oseltamir

66

Influenza B antivirals

Zanamivir
Oseltamivir

67

Amantidine and Rimantidine: Description

Non-nucleosides

68

Amantidine and Rimantidine: MOA

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

69

Amantidine and Rimantidine: Active against

Influenza A strains only

70

Amantidine and Rimantidine: Dosing

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

71

Amantidine and Rimantidine:Amantidine in elderly

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

72

Amantidine and Rimantidine: Side effects

Nausea, dizziness are frequent. Rimantidine has fewer side effects

73

Amantidine and Rimantidine: Resistance

Generated easily – most circulating strains resistant

74

Neuraminidase Inhibitors: Action

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

75

Neuraminidase Inhibitors: Use

Extreme conditions

76

Neuraminidase Inhibitors: Example

Relena (Zanamivir)
Tamiflu (Oseltamivir)

77

Neuraminidase Inhibitors: Relena Treatment and prevention of

Influenza A (inc avian) and B

78

Neuraminidase Inhibitors: Relena Delivery as

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

79

Neuraminidase Inhibitors: Tamiflu (Oseltamivir)

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

Neuraminidase Inhibitors: With these drugs

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

Zanamivir and Oseltamivir resistance

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

82

HAART

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

83

The aim of treatment

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

Classes of antiretroviral drugs

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

85

NNRTIs action

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

86

NNRTIs resistance

• More likely over time 1-3 years

87

NNRTIs in combination

• With an NRTI agents

88

NNRTI examples

• Nevirapine (NVP)
• Efavirenz (EFV)
• Rilpivirine (RPV)
• Etravirine (ETV)

89

Protease Inhibitors – Pis action

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

90

PI drug problems

• Drug interactions problematic

91

Dosage

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

92

Examples

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

93

Treating with HAART (HIV1)

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

94

HAART for starting therapy

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

HAART examples

Tenfovir
Emtricitabine with
Atazanavir
Ritonavir or
Efavirenz or
Raltegravir

96

HAART response

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

Maintenance of an undectable viral load requires

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

98

Treatment Failure

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

99

Signals that show development of resistance

Viral rebound and fall in CD4 count on therapy

100

HAART Adverse Effects

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

Abacavir sensitivity

Is rare (4%) but can be life threatening

102

Lamivudine (3TC)

Rare significant toxicities

103

NNRTIs are limited by

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

104

PIS were often difficult to tolerate due to a wide

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

Ribavirin for RSV

Nebulied, oral,iv
Immunocomprimised

106

Papillomavirus drug

Interferon inducer – imiquimod

107

HSV keratoconjunctivitis treatment

Trifluridine or idoxuridine

108

CMV treatment

Fomivirisen – antisense oligonucleotide, intra-ocular

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