5B: Antivirals Flashcards

1
Q

Antiviral targets

A
  • Viral replication cycle is reliant on host cellular function so limited unique targets & increased toxicity
  • Ideally unique viral targets not present in mammalian cells, & usefully therapeutic with minimal mammalian damage

Unique viral targets include:

  • Viral penetration into host cells
  • Replication of viral genome
  • Translation of viral mRNA
  • Assembly of viral components
  • Release of new viruses from host cells
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2
Q

Virology - mechanism

A
  1. Attachment
  2. Entry
  3. Replication & gene expression
  4. Assembly
  5. Release

Prevention is only with vaccination

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3
Q

Antiviral PK/PD

A
  • More (or less) complex than for bacteria or fungi
  • In vitro testing involves complex tissue culture system
  • Potency of antivirals is determined using 50% inhibitory dose (EC or IC50: Dose required to inhibit the growth of cell culture by 50%)
  • MIC is conceptually similar to an EC90
  • Limited to no studies for most drugs correlating efficacy with specific PKPD parameters
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4
Q

Herpes virus

A
  • HSV1 & 2, VSV, CMV, EBV
  • Large core containing double stranded DNA genome in a capsid, protein coat & glycoprotein structure
  • (Val)aciclovir, (val)ganciclovir, cidofovir, foscarnet
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5
Q
  1. (Val)aciclovir
A
  • Nucleotide analogue of guanine
  • Must become tri-phosphorylated to become active
    + Largely (40 – 100x more) occurs in infected cells due to viral enzyme TK for step 1
    + Cellular kinases for step 2 & 3
  • This tri-P form persists within cells at high concentrations as it cannot cross cellular membranes
  • Inhibits DNA polymerase in HSV-1, HSV-2 & VZV – cellular DNA polymerase is inhibit to a significantly lower degree
  • Inhibition of DNA polymerase occurs by stopping DNA synthesis as the chain cannot become elongated & the enzyme becomes bound
  • Aciclovir has poor (20%) bioavailability (& topical penetration) & necessitates multiple (up to 5X) daily dosing
  • Valaciclovir is a L-valyl ester that is rapidly (95%) converted to acyclovir following oral administration (BA 50%) (luminal, intestinal & hepatic esterases)
    + Has uptake via dipeptide transporter that aciclovir does not
  • Different dosing regimes for IV/PO & clinical condition
  • ADRs include nephrotoxicity (precipitation of drug in nephron) which can be prevented by a slow infusion & hydration & reversible neurotoxicity
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6
Q
  1. (Val)fanciclovir
A
  • Also a guanine analogue requiring tri-phosphorylation
  • Initial phosphorylation is achieved by a CMV UL97 gene encoded protein kinase
    + In HSV & VZV this step can be achieved by TK
  • High intracellular levels in infected cells 10-100x
  • 35-50x more selective for viral polymerase than cellular polymerase
  • Valganciclovir is also a L-valyl ester of ganciclovir with similar gains as valaciclovir
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7
Q
  1. Cidofovir
A
  • Nucleotide analogue of cytosine but already has a highly stable phosphate group
    + Still needs to be triphosphorylated to work but initial step is overcome so broad spectrum antiviral
  • As phosphonate needs active transport into cells but then has a very long intracellular t1/2 of up to 65 hours
  • Competitive inhibition of many viral DNA polymerase with high affinity compared to cellular polymerase (80x for CMV & 600x for others)
  • Poorly bioavailable so only used IV
  • ADRs – nephrotoxicity 25%: Uptake by renal proximal tubules exceeds efflux into lumen causing accumulation (probenecid reduces renal clearance of cidofovir by inhibiting tubular secretion & decreases nephrotoxicity)
    + No haematological toxicity
    + Carcinogenic – handling precautions
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8
Q
  1. Foscarnet
A
  • Analogue of inorganic pyrophosphate
  • Inhibits DNA polymerase by binding to a site where pyrophosphate has been removed in DNA chain stabilising the enzyme & chain in place blocking further production
  • Very broadly antiviral including some effect on HIV, Hep B & Influenza (not clinically useful tho)
  • Poor bioavailability (<10%)
  • ADRs – nephrotoxicity 25% (crystallisation without hydration)
    + Electrolyte changes (Ca2+, Mg2+, PO4-)
    + Rarely haematological toxicity but anaemia more common
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9
Q

Viral hepatitis

A

Hepatitis A, B, C, D & E

  • A & B vaccinated
  • A, B & C most common
  • Different kinds of viruses & clinical syndromes
  • Ideally all oral drug regimens for a chronic disease needing suppression or prolonged treatment

Hep B – DNA virus replicating with reverse transcriptase
- Treated with lamivudine, tenofovir, adefovir, entercavir

Hep C – RNA virus single stranded similar to flavivirus e.g. dengue or zika virus
- Treated with glecaprevir & pilbrentasvir, sofoxbuvir & ledipasvir

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10
Q

NRTIs (for Hep B) (Lamivudine, tenofovir, adefovir, entecavi)

A

Nucleoside or nucleotide analogies inhibiting reverse transcriptase that terminates chain when incorporated:

  • Lamivudine =cytidine
  • Tenofovir = adenosine
  • Entecavir = guanosine
  • Adefovir = adenosine
  • Entecavir only useful for Hep B, resistance rapidly develops when treating HIV
  • Adefovir IC90 doses for HIV have dose limiting nephrotoxicity

Few ADRs seen but often some GI upset & treatment specific e.g. tenofovir & chronic renal toxicity & osteopenia

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11
Q

Other direct acting antivirals (DAAs for Hep C) (Sofosbuvir, pibrentasvir, glecaprevir, ledipasvir)

A
  • Sofosbuvir & pibrentasvir inhibit RNA dependent NS5B RNA polymerase required for coping HCV genome & transcribing mRNA
  • Glecaprevir targets NS3/4A protease involved in post translational processing of HCV proteins
  • Ledipasvir inhibits NS5A which has an unclear enzymatic role but interactions with other proteins in HCV working as a regulator of host cell function
  • Relatively new treatments for Hep C with very high success rates of ‘cure’ (95%)
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12
Q

Interferon

A
  • Naturally occurring proteins with a wide variety of effects
  • Interferon has been used to treat a variety of viral infections but predominately Hep C & less Hep B
  • Gene inserted into E.coli to express interferon alpha
    + Alpha 2a & 2b are 1 amino acid different
  • Pegylated interferon (PEG-) by attaching polyethylene glycol which has low immunogenicity & toxicity & extends t1/2 through slowing degradation
    + Dosing changes from daily to weekly SC injections
  • Indirect antiviral activity by inducing/activating cytokine response pathway including up-regulated NK & T cells
  • Possible direct activity on viral proteins & DNA production
  • Almost all patients will have ADRs inc fatigue (65%), flu like illness (65%), anxiety (45%), depression (30%), neutropenia (30%)
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13
Q

Ribarvirin

A

Very broad spectrum antiviral including Hep C, RSV, Measles, Lassa virus, influenza, herpes viruses

Analogue of guanosine that is tri-phosphorylated intracellularly but has multiple proposed actions:

  • Direct inhibition of RNA polymerase
  • RNA mutagenic effect
  • Enhances T helper cell cytokine response
  • Inhibits IMPDH enzyme that synthesises guanosine triphosphate promoting inclusion of ribavirin

ADRs – LFT changes & anaemia 15-20%
- Ribavirin has an active uptake into enterocytes & accumulation due to lack of phosphatases – is reversible on cessation

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14
Q

HIV - mechanism

A
  1. Binding
  2. Fusion
  3. Reverse transcription
  4. DNA into nucleus
  5. Integration
  6. Viral DNA maintained
  7. Replication
  8. Protein production
  9. gp 120 produce on surface
  10. Assembly & budding
  11. Protease cleaving proteins
  12. Mature virus
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15
Q

HIV - HAART

A
1987 – 1993: NRTI monotherapy
1993 – 1996: Dual NRTI
1996 - : HAART = Dural NRTI + PI
1998 - : PI -> NNRTI
2006 - : Single tablet combination (Atripla)
2011 - : Treatment as prevention
2012 - : PrEP

Multiple agents are now standard of care to reduce resistance development & increased efficacy of viral suppression

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16
Q

NRTIs (for HIV) (Lamivudine, zidovudine, tenofovir, abacavir, emtricitabine)

A
  • Agents form the ‘backbone’ of treatment
  • Older agents are associated with more ADRs, hepatotoxicity & lipoatrophy (thymidine analogues) & some now discontinued e.g. stavudine & didanosine
  • Newer agents have less affinity for mitochondrial DNA & this reduced traditional ADRs
    + Newer ADRs now being identified e.g. tenofovir causing long term renal toxicity & abacavir increasing cardiovascular risk
  • Care needed when starting or stopping Hep B active agents – flares
17
Q

NNRTIs (Efavirenz, etravirine, nevirapine & rilpivirine)

A
  • Inhibit same reverse transcriptase enzyme but not as nucleotide analogues
  • Bind in a hydrophobic binding pocket near the active site forcing a conformational change which reduces the ability of RT function
  • Recommended less in clinical practice/guidelines now due to increased ADRs & chance of resistance with poor adherence
    + Single point mutations at binding pocket reduces binding
  • Efavirenz use remains high in NZ as part of a single tablet regimen
  • ADRs of efavirenz include neuropsychiatric, hepatotoxicity & rashes
18
Q

Integrase inhibitors (Raltegravir, dolutegravir, elvitegravir)

A
  • Inhibit HIV integrase which integrates HIV DNA into the host genome
  • Well tolerated newer drugs that are potent & rapid reduce viral load
  • Difficult to develop resistance esp. dolutegravir as concentrations achieved&raquo_space; IC90

Few ADRs:

  • Raltegravir – myopathies
  • Dolutegravir – 5% neuropsychiatric inc anxiety
  • Early signal of possible inc in neural tube defects seen when mother taking at conception
19
Q

Protease inhibitors (Atazanavir, darunavir, lopinavir, ritonavir)

A
  • Inhibit HIV protease enzyme which cleaves HIV proteins, activating them to form mature infectious virions
  • High barrier to resistance as require multiple mutations for resistance
  • Atazanavir requires an acidic environment for absorption so PPIs or H2 antagonists shouldn’t be used – reduce DUC by up to 75%
  • Ritonavir – has HIV activity but is used at sub-therapeutic doses to inc concentration of other PIs as a PK enhancer
    + Inhibits CYP3A4 reducing metabolism & increasing concentration allowing daily dosing
20
Q

Entry inhibitors (Maraviroc & enfuvirtide)

A
  • Not routinely used in clinical practice in NZ
  • Maraviroc is a CCR5 antagonist blocking this co-receptor that HIV binds to (gp120 associates with CCR5 or CXCR4 initiating fusion via gp41) for entry
    + Only useful if patients are CXCR4 negative & this may change over time so need to check T-cell tropism
  • Enfuvirtide is a fusion inhibitor binding to gp41 preventing conformational changes required for fusion
    + Was used as part of salvage therapy regimen only (poor bioavailability -> SC injection 2x daily)
21
Q

Influenza

A
  • Influenza A & B cause seasonal pandemics whilst C cause mild human disease
  • A infects both humans & animals whilst B causes human disease only
  • Structurally similar but different matrix proteins
22
Q

Amatadine

A
  • Inhibits/blocks hydrogen flow through M2 protein pore (Influenza A only)
  • Influenza binds via hemagglutinin & is endocytosed into cell interior
    + M2 protein allows un-coating from endosome into the cell (by changing the pH via H+ influx)
  • Amantadine enters the channel & binds to a hydrophobic residue in the channel ‘corking’ it
  • Low genetic barrier to resistance (a single point mutation) so use now has lead to >99% resistance in circulating strains but may be reducing (Australia)
  • Also used as an anti-Parkinson’s drug (& therefore has some neurotoxicity ADRs e.g. confusion, insomnia etc)
23
Q

Oseltamivir & zanamavir

A
  • Sialic acid analogues are inhibitors of neuraminidase enzyme
    + Neuraminidase cleaves sialic acid from glycoproteins allowing release of new viruses from the infected cell
  • Mutations at enzymatic cleft can prevent binding
  • Oseltamivir – oral & zanamivir – inhaled (poor BA)
  • ADRs include GI upset, possible neuropsychiatric (delirium & self-harm seen in Japanese adolescents)
  • Can be used as either prophylaxis or treatment
  • Data has been questioned – many trials not released or published to reviewer – publication bias by Roche
  • Cochrane review 2014:
    + Treatment reduces symptoms from 7 days to 6.3 days & no decrease in complications
    + Reduces risk of acquiring influenza NNTB = 33