HNS12 Infections Of The CNS III Prion Diseases Antiviral Therapy Flashcards
Prions
- 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)
Pathogenesis of prion disease
**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)
Spongiform encephalopathies characteristics
- 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
Prion diseases
Human:
- Kuru (ritual cannibalism, fore tribe in Papua New Guinea)
- 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) - 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
Iatrogenic transmission of CJD through invasive procedures
<1% of cases
Causes:
- Implantation of contaminated grafts (Dura mater, Cornea)
- Human growth hormone
- Human pituitary gonadotropin (now use recombinant instead)
- Contaminated medical instruments (ALL pre-1980: Electrodes in brain, Neurosurgical instruments in brain)
- vCJD: ALL components of blood can transmit (ALL cases received non-leucoreduced RBC concentrates)
Transmission of prions in ward setting
- 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
Disinfection and sterilisation
- 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)
Mechanism of Viral replication
- Adsorption
- Penetration
- Uncoating
- Early transcription
- Early translation
- Replication of viral genome
- Late transcription
- Late translation
- Assembly
- Release
Problems with Antivirals
- Very few virus specific “targets”
- Often need to commence antiviral treatment ***early in illness in order to make a clincial impact
- Blocks viral replication (***Virustatic), but NOT Virucidal —> ONLY buys time for host immune response —> problematic with immunocompromised patients
- Cannot eliminate virus ***latency e.g. HSV
***Major types of antivirals
- Attachment
- ***Maraviroc (block CCR5: chemokine receptor on T cell/macrophages): HIV
- Sialidase: influenza, parainfluenza - Penetration / fusion
- ***Enfuvirtide: HIV - Uncoating of nucleic acid
- ***Amantadine: influenza A - Protein synthesis
- **Ribavirin: HCV, RSV
- **Interferon: HCV, HBV - Nucleic acid replication
- Nucleoside analogues e.g. **Acyclovir (Guanosine analogue), **Ganciclovir —> termination of growing chain
- Other: directly block viral DNA polymerase e.g. ***Foscarnet - Virus assembly and release
- HIV protease inhibitor: **Saquinavir, Indinavir, **Ritonavir, Nelfinavir
- HCV protease inhibitor: **Boceprevir, **Telaprevir
- Neuraminidase inhibitor (influenza): ***Oseltamivir, Zanamivir, Lananimivir
Acyclovir MOA
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
Resistance to Acyclovir
- 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
Valaciclovir
- 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?
Ganciclovir
- 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
Summary of spectrum of activity of anti-herpesviral agents
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
HIV viral replication
- Adsorption
- via CD4 receptor + CXCR4/CCR5 co-receptor protein
—> Co-receptor antagonist
—> ***Maraviroc - Virus-cell fusion
—> Fusion inhibitors
—> ***Enfuvirtide - Uncoating
- Reverse transcription
- reverse transcriptase to produce DNA copy (cDNA) of RNA genome
—> Reverse transcriptase inhibitors (NRTI, NNRTI)
—> ***ZDV, 3TC, Nevirapine, Efavirenz - Integration
- cDNA copy integrated into host cell genome (proviral DNA)
- may remain latent / direct active viral replication
—> Integrase inhibitors
—> ***Raltegravir - Transcription
- Translation
- Proteolytic processing by viral protease
—> Protease inhibitors
—> ***Saquinavir, Indinavir, Ritonavir, Nelfinavir - Viral protein and RNA assembly at cell membrane
- Budding
Reverse transcriptase inhibitors
NRTI (Nucleoside/tide reverse transcriptase inhibitors / analogues)
- ***Zidovudine (ZDV)
- ***Lamivudine (3TC)
- Abacavir
- Tenofovir (Nucleotide)
- Emtricitabine
NNRTI (Non-nucleoside reverse transcriptase inhibitors)
- ***Nevirapine
- ***Efavirenz
Zidovudine (NRTI)
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
Co-receptor antagonist
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)
Fusion inhibitor
Enfuvirtide
—> prevent viral envelop fuse with cell membrane
Integrase inhibitors
Raltegravir
Elvitegravir
Protease inhibitor
- Saquinavir
- Indinavir
- Ritonavir
- Nelfinavir
Highly active anti-retroviral therapy (HAART)
Use of multiple drugs blocking different sites of viral replication cycle
—> minimise development of drug resistance
1st line: Reverse transcriptase inhibitors + Protease inhibitors
Existing drugs with activity against influenza virus
Influenza: Enveloped RNA virus
- Amantadine / Rimantadine (Adamantanamine derivatives)
- block uncoating of virus
- most viruses ***now resistant
- ONLY effective against influenza A
- oral -
**Oseltamivir / Zanamivir (inhalation) / Laninamivir (approved in Japan)
- **Neuraminidase inhibitors
- effective against influenza A + B
- rare resistance - Baloxavir marboxyl / T705 (Favipiravir)
- ***RNA polymerase inhibitor
- Baloxavir: single dose
- effective against influenza A + B - DAS181
- block adsorption via sialic acid
Treating Respiratory Syncytial Virus (RSV)
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
Interferons
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
Interferon α
- 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
