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HNNS > HNS12 Infections Of The CNS III Prion Diseases Antiviral Therapy > Flashcards

HNS12 Infections Of The CNS III Prion Diseases Antiviral Therapy Flashcards

1
Q

Prions

A
  • Infectious protein (can be transmitted / multiplied)
  • No nucleic acid —> No DNA/RNA —> ***relatively resistant to heat (121oC, 15 mins), UV light, ionising radiation, formalin
  • ***Pathogenic prion-related protein (PrPSc/PrPCJD):
    —> Misfolded “isoform” of normal cell glycoprotein (PrPc) (same amino acid sequence but different 3D conformation)
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2
Q

Pathogenesis of prion disease

A

**PrPc (protease sensitive)
—> Abnormal protein **PrPSc (protease insensitive) introduced (Genetic / Exogenous infection)
—> catalyze PrPc to abnormal shape PrPSc
—> Accumulation of PrPSc
—> Disease of CNS (Sponge-like form of brain)

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3
Q

Spongiform encephalopathies characteristics

A
  • Associated with accumulation of Prion-related protein PrPSc in brain
  • Loss of neurons
  • “Spongiform vacuolation” of brain
  • ***Lack of inflammatory reaction / immune response
  • ***Long incubation period (years)
  • ***Rapidly progressive dementia, loss of memory and intellect, personality changes, unsteadiness / clumsiness, myoclonic jerks
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4
Q

Prion diseases

A

Human:

  1. Kuru (ritual cannibalism, fore tribe in Papua New Guinea)
  2. Creutzfeldt-Jakob disease (CJD)
    - classical sporadic (85%), older patient
    - familial
    - variant CJD (after mid 1990s) —> younger patients —> transmission of BSE to man (very long incubation time)
  3. Early acute cerebral amyloid angiopathy (associated with amyloid beta)

Sheep: Scrapie

Cattle: Bovine spongiform encephalopathy (BSE), mid 1980s
- change in rendering offal (cattle brain / spinal cord) for cattle feed

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5
Q

Iatrogenic transmission of CJD through invasive procedures

A

<1% of cases

Causes:

  1. Implantation of contaminated grafts (Dura mater, Cornea)
  2. Human growth hormone
  3. Human pituitary gonadotropin (now use recombinant instead)
  4. Contaminated medical instruments (ALL pre-1980: Electrodes in brain, Neurosurgical instruments in brain)
  5. vCJD: ALL components of blood can transmit (ALL cases received non-leucoreduced RBC concentrates)
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6
Q

Transmission of prions in ward setting

A
  • NOT spread by contact (direct/indirect), droplet, airborne, fomites, environment
  • NO natural person-to-person spread
  • NO documented transmission of TSE (Transmissible spongiform encephalopathies) from patient to HCW
  • Can be nursed in open ward, general ward procedures NO different
    —> use single use / disposable instruments wherever possible
    —> label tissues / specimens as coming from CJD patient
  • Inform Infection Control Unit
  • Surgical operation / invasive procedure:
    —> inform ICN + OTS / relevant department
    —> elective procedure perform in operating theatre —> **last in list, environment should be readily cleanable
    —> use **    disposable equipment in contact with CSF / blood
    —> avoid use of high speed drill / **aerosol generating procedures in “high risk tissue” e.g. brain
    —> **    segregate tissue by decontamination requirement
    —> ***Special sterilisation procedures required for reusable items
    —> tissue biopsies: consult pathologist in advance regarding fixation
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7
Q

Disinfection and sterilisation

A
  • Cleaning: 2 log reduction in protein contamination, 4 log reduction in microbial contamination
  • NO difference between CJD and vCJD in sensitivity to disinfection / sterilisation
  • difference in the range of tissues that are infectious

Ineffective disinfectants:

  • Alcohol
  • Ammonia
  • Formaldehyde (1 log in 60 min)
  • Glutaraldehyde
  • Hydrogen peroxide (1 log in 60 min)
  • Iodine 2% (1 log in 30 min)
  • Phenolics
  • **Effective disinfectants:
    1. Chlorine >1000ppm (ideally 20,000ppm; 2%)
    2. Sodium hydroxide (1M)
    3. Proprietary enzymatic and alkaline detergents (e.g. Steris, Prionzyme)
    4. 96% formic acid (for fixing tissue for investigation)

***Effective process (>=3 log)
1. Immerse in 1M NaOH for 2 hours + Autoclave 121oC for 30min in downward displacement autoclave
—> Clean and rinse in water + Routine steam sterilisation
2. Autoclave
—> 134oC for >18 min (prevacuum)
—> 132oC for 60 min (gravity)

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8
Q

Mechanism of Viral replication

A
  1. Adsorption
  2. Penetration
  3. Uncoating
  4. Early transcription
  5. Early translation
  6. Replication of viral genome
  7. Late transcription
  8. Late translation
  9. Assembly
  10. Release
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9
Q

Problems with Antivirals

A
  1. Very few virus specific “targets”
  2. Often need to commence antiviral treatment ***early in illness in order to make a clincial impact
  3. Blocks viral replication (***Virustatic), but NOT Virucidal —> ONLY buys time for host immune response —> problematic with immunocompromised patients
  4. Cannot eliminate virus ***latency e.g. HSV
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10
Q

***Major types of antivirals

A
  1. Attachment
    - ***Maraviroc (block CCR5: chemokine receptor on T cell/macrophages): HIV
    - Sialidase: influenza, parainfluenza
  2. Penetration / fusion
    - ***Enfuvirtide: HIV
  3. Uncoating of nucleic acid
    - ***Amantadine: influenza A
  4. Protein synthesis
    - **Ribavirin: HCV, RSV
    - **    Interferon: HCV, HBV
  5. Nucleic acid replication
    - Nucleoside analogues e.g. **Acyclovir (Guanosine analogue), **Ganciclovir —> termination of growing chain
    - Other: directly block viral DNA polymerase e.g. ***Foscarnet
  6. Virus assembly and release
    - HIV protease inhibitor: **Saquinavir, Indinavir, **Ritonavir, Nelfinavir
    - HCV protease inhibitor: **Boceprevir, **Telaprevir
    - Neuraminidase inhibitor (influenza): ***Oseltamivir, Zanamivir, Lananimivir
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11
Q

Acyclovir MOA

A

ONLY work within virus infected cell:
Acyclovir (**Guanosine analogue)
—> ACV monophosphate (by **viral thymidine kinase)
—> ACV triphosphate (by cell enzymes)
—> selective inhibition of ***viral DNA polymerase
—> termination of growing chain

NO activity in healthy cell

Indication:
Oral acyclovir (low bioavailability): can effectively treat HSV1, HSV2, VZV (high dose acyclovir)
IV acyclovir: HSV1, HSV2, VZV

Clinical use:
- Immunocompromised patient with HSV / VZV infection (IV acyclovir)
- Herpes encephalitis (IV acyclovir start ASAP)
- Primary genital herpes (oral acyclovir)
- Varicella (chicken pox)
—> do NOT eradicate latency

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12
Q

Resistance to Acyclovir

A
  • Mutant viral thymidine kinase
    —> ***Cidofovir (already in monophosphate form, do not require viral thymidine kinase)
  • Mutant viral DNA polymerase
    —> ***Foscarnet (does not require any phosphorylation, act directly against viral DNA polymerase)

—> both drugs more toxic than Acyclovir —> ***Renal toxicity

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13
Q

Valaciclovir

A
  • Valine ester of acyclovir (***better absorbed in GI tract than acyclovir)
  • Pro-drug of acyclovir with better bioavailability
    —> require ***less frequent dosing
  • Broken down to acyclovir instantaneously in blood
  • Spectrum of activity similar to ACV
    —> oral therapy: Genital herpes, Herpes-zoster
    —> step down therapy after IV treatment?
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14
Q

Ganciclovir

A
  • Deoxy-Guanosine analogue
  • Phosphorylated by CMV enzyme UL97
  • NOT as specific as Acyclovir —> effect on human cell replication —> ***Myelosuppression

Clinical use:

  • Treatment and prophylaxis of ***CMV disease in immunocompromised
  • Congenital CMV (trials ongoing, limited benefit)
  • Activity against HSV, but NO advantage over Acyclovir —> no need to use Acyclovir for anti-HSV cover if patient already on GCV —> will only increase renal / CNS side effects

Major side effect:
- ***Myelosuppression

Resistance:

  • UL97
  • viral DNA polymerase

Route of administration:

  • IV
  • intra-ocular for retinitis
  • Oral (very poor bioavailability) —> Valganciclovir (Valine ester of Ganciclovir)

Valganciclovir:

  • rapidly converted to Ganciclovir in intestinal epithelial cells
  • oral bioavailability 61%
  • less IV cannula related SE but more diarrhoea
  • indication:
    1. CMV prophylaxis (OD dosing) in transplant patients
    2. Therapy of non-severe CMV in organ transplant patients
    3. Treatment of CMV retinitis in AIDS
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15
Q

Summary of spectrum of activity of anti-herpesviral agents

A

Acyclovir, Valaciclovir, Famciclovir:

  • HSV
  • VZV

Ganciclovir, Valganciclovir:

  • CMV
  • also active against HSV and VZV, but no advantage and more SE compared to Acyclovir

Foscarnet, Cidofovir:

  • CMV, HSV, VZV (no cross-resistance with Acyclovir / Ganciclovir)
  • less myelotoxic but more ***renal toxicity
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16
Q

HIV viral replication

A
  1. Adsorption
    - via CD4 receptor + CXCR4/CCR5 co-receptor protein
    —> Co-receptor antagonist
    —> ***Maraviroc
  2. Virus-cell fusion
    —> Fusion inhibitors
    —> ***Enfuvirtide
  3. Uncoating
  4. Reverse transcription
    - reverse transcriptase to produce DNA copy (cDNA) of RNA genome
    —> Reverse transcriptase inhibitors (NRTI, NNRTI)
    —> ***ZDV, 3TC, Nevirapine, Efavirenz
  5. Integration
    - cDNA copy integrated into host cell genome (proviral DNA)
    - may remain latent / direct active viral replication
    —> Integrase inhibitors
    —> ***Raltegravir
  6. Transcription
  7. Translation
  8. Proteolytic processing by viral protease
    —> Protease inhibitors
    —> ***Saquinavir, Indinavir, Ritonavir, Nelfinavir
  9. Viral protein and RNA assembly at cell membrane
  10. Budding
17
Q

Reverse transcriptase inhibitors

A

NRTI (Nucleoside/tide reverse transcriptase inhibitors / analogues)

  • ***Zidovudine (ZDV)
  • ***Lamivudine (3TC)
  • Abacavir
  • Tenofovir (Nucleotide)
  • Emtricitabine

NNRTI (Non-nucleoside reverse transcriptase inhibitors)

  • ***Nevirapine
  • ***Efavirenz
18
Q

Zidovudine (NRTI)

A 
MOA:
Zidovudine
—> ZDV monophosphate (by cell enzyme)
—> ZDV triphosphate (by cell enzyme)
—> Selective inhibition of ***Viral polymerase + ***Reverse transcriptase

**ALSO act on healthy cell (since do not require viral enzyme to be active)
—> Some non-specific inhibition of cell polymerase
—> **Bone marrow suppression

  • Effective at suppressing viral replication but has SE on rapidly multiplying cells
  • RNA virus: rapid development of resistance
  • patients will need long term therapy since HIV suppress immune system
From ERS37:
MOA:
Structurally ~ ***Thymidine
—> Compete with Thymidine in DNA synthesis
—> Stop Reverse transcription
—> Daughter chain termination

ZDV:
- Deoxythymidine derivative
—> bioactivation by cellular kinases to Triphosphate form (ZDV-TP)
—> ZDV-TP (activated) competitively inhibit HIV reverse transcriptase + act as viral DNA chain terminator
—> stop Reverse transcriptase + Reverse transcription
—> prevent HIV from replicating
—> ↓ circulating viral antigen titres
—> ↑ circulating CD4 T cells + ↓ opportunistic infections in HIV patients
—> slow disease progression + prolong survival

19
Q

Co-receptor antagonist

A

CCR5 blocker: Maraviroc
—> block CCR5 interaction with HIV glycoprotein gp120
—> prevent HIV fusion

CCR5: ***chemokine co-receptor on CD4 cells

Use:
- Multidrug-resistant CCR5-tropic HIV-1 (Salvage therapy)

20
Q

Fusion inhibitor

A

Enfuvirtide

—> prevent viral envelop fuse with cell membrane

21
Q

Integrase inhibitors

A

Raltegravir

Elvitegravir

22
Q

Protease inhibitor

A
  • Saquinavir
  • Indinavir
  • Ritonavir
  • Nelfinavir
23
Q

Highly active anti-retroviral therapy (HAART)

A

Use of multiple drugs blocking different sites of viral replication cycle
—> minimise development of drug resistance

1st line: Reverse transcriptase inhibitors + Protease inhibitors

24
Q

Existing drugs with activity against influenza virus

A

Influenza: Enveloped RNA virus

  1. Amantadine / Rimantadine (Adamantanamine derivatives)
    - block uncoating of virus
    - most viruses ***now resistant
    - ONLY effective against influenza A
    - oral
  2. **Oseltamivir / Zanamivir (inhalation) / Laninamivir (approved in Japan)
    - **    Neuraminidase inhibitors
    - effective against influenza A + B
    - rare resistance
  3. Baloxavir marboxyl / T705 (Favipiravir)
    - ***RNA polymerase inhibitor
    - Baloxavir: single dose
    - effective against influenza A + B
  4. DAS181
    - block adsorption via sialic acid
25
Q

Treating Respiratory Syncytial Virus (RSV)

A

Ribavirin:

  • licensed for use by aerosol in patients at high risk, but ***efficacy controversial
  • indicated in RSV in pre-engraftment stem cell transplant patients —> IV and aerosol Ribavirin + IVIG
26
Q

Interferons

A

Made by ***virus-infected cells
—> attach on receptor of uninfected cells
—> trigger defence mechanism in uninfected cells
—> protect other healthy cells from infection

Interferons:
Type 1: alpha, beta
Type 3: lambda
Type 2: gamma - made by immune cells, modulates immune cells

27
Q

Interferon α

A
  • produced by recombinant technology / from human leukocytes
  • **MOA:
  • Block viral ***RNA transcription
  • Block ***protein synthesis
  • Augments ***immune response

Clinical use:

  • Chronic hepatitis B (together with Lamivudine)
  • Hepatitis C (together with Ribavirin and new protease inhibitors - Boceprevir, Telaprevir)

Peginterferon-α2a / 2b: Interferon conjugated with polyethylene glycol
—> prolongs persistence of drug in blood

HNNS (58 decks)

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