Hepatology - Virology Flashcards
What kind of genome does HBV have?
DNA-virus
What is the transmission route of HBV? What the ways in which this happens? (5)
Blood-to-blood
1. Sexual contact
2. Blood transfusion
3. Contaminated needles
4. Vertical transmission
5. Profession
There is a vaccine for [only HBV/only HCV/both]
Only HBV
There is curative treatment for [only HBV/only HCV/both]
Only HCV
Which cell type is targeted by HBV?
Hepatocytes
HBV is usually [symptomatic/asymptomatic] in children, and [symptomatic/asymptomatic] in adults
Children = asymptomatic
Adults = symptomatic
What is the chance of HBV infection becoming chronic in newborns, children & adults?
Newborns: 90% becomes chronic
Children (<5): 30% becomes chronic
Adults: 10% becomes chronic
What is the disease pathogenesis of chronic HBV/HCV?
Inflammation -> fibrosis -> cirrhosis -> liver failure and/or HCC
What kind of genome does HCV have?
RNA-virus
What is the transmission route of HCV? What the ways in which this happens? (5)
Blood-to-blood
1. Sexual contact
2. Blood transfusion
3. Contaminated needles
4. Vertical/perinatal transmission
5. Profession
What is the most important way(s) that HBV and HCV are transmitted?
HBV: vertical transmission & sexual contact
HCV: sexual contact & contaminated needles
Which cell type does HCV target?
Hepatocytes
HCV is [largely symptomatic/largely asymptomatic]
HCV = asymptomatic
What is the chance of HCV infection being acute vs. becoming chronic?
20-40% = acute
60-80% = chronic
What is the difference between HBV & HCV when it comes to type I IFN responses?
HBV = stealth virus -> avoids triggering IFN response
HCV = suppressive –> does trigger IFN response, but suppresses it
By which mechanisms does HBV lower transcription of type I IFNs? (4)
- HBV sub-viral particles suppress TLR9 signalling in DCs
- HBeAg suppresses TLR2/TLR4 signalling in hepatocytes -> no NF-κB and IRF-genes
- HBV polymerase impairs nuclear translocation of STAT -> no interferon-stimulated genes
- HBx prevents RIG-I to MAVS signalling
What are the characteristics of HBV-directed T-cell responses?
- Lack of an innate resposne -> insufficient antigen presentation
- Lack of CD4+ T-cell help
- Exhaustion by prolonged antigen exposure
What determines the chance of viral clearance in HCV infections?
Magnitude & breadth (=amount of epitopes covered) of the T-cell response
Through which mechanisms can HBV and HCV lead to HCC? (4)
- Integration of viral DNA into host DNA
- Inflammation/fibrosis
- Cellular/mitochondrial stress -> ROS -> DNA damage
- Lower CD8+ T-cell activity
How many people are chronically infected with HBV? How many deaths does this virus cause each year?
296 million chronically infected
~820.000 deaths/year
How many people are chronically infected with HCV? How many deaths does this virus cause each year?
58 million chronically infected
~290.000 deaths/year
What was the treatment of HCV prior to the introduction of viral inhibitors?
PEG-IFN-α + ribavirin
What is the benefit of pegylating IFN-α for the treatment of viruses?
Increases the half-life of IFN-α
What is the benefit of adding ribavirin to IFN-α treatment?
Increases potency of IFN-α
How many % of PEG-IFN-α recipients are cured?
61%
What is the cause for the relatively low response rate of IFN-α treatment?
Specific genotypes are not sensitive
What is the main drawback of IFN-α + ribavirin treatment for HCV?
Long treatment duration (48 weeks) with severe side effects
What are the side effects of IFN-α treatment? (5)
- Mild sickness
- Headache
- Fatigue
- Heart & kidney failure
- (Severe) depression & mood swings
What are the side effects of ribavirin treatment? (3)
- Nausea
- Itching
- Anaemia
Why did many people not complete the complete course of IFN-α treatment?
They were mostly asymptomatic prior to treatment -> treatment caused severe decrease in QoL
Which types of interferons are there?
Type I, II & III
Which interferons belong to type I?
IFN-α, -β, -δ, -ε, -κ, -ω
Which interferon belongs to type II?
IFN-γ
Which interferons belong to type III?
IFN-λ1 (IL-29), -λ2 (IL-28A), -λ3 (IL-28B)
What is the difference between type I and type III interferon signalling? What could make it more suitable for treatment of chronic viral disease?
Receptor distribution -> type I IFN receptor can be found throughout the body, while type III receptor is present on a more limited amount of cell types
Result: fewer side effects
True or false: type III IFNs show a weaker antiviral response than type I IFNs
False: the antiviral response is clinically similar
Type III IFNs are clinically effective & have fewer side effects than IFN-α. Why were they never introduced for treatment of chronic HCV?
Introduction of viral polymerase/protease inhibitors with higher efficacy
Which important condition had to be met before viral inhibitors for HCV could be introduced?
Enabling of HCV viral culture -> allows for discovery of targets & testing
What is the curation rate of polymerase/protease inhibitors for chronic HCV?
99%
What is seen as curation of chronic HCV?
Elimination of HCV RNA
True or false: there is growing resistance against viral inhibitors for HCV
False: no resistance has been identified
What are the remaining challenges in the field of HCV?
- Identifying all HCV patients
- Distributing available treatments across the world
In which regions do most HBV infections occur?
- Asia
- Africa
What are the effects of HBV vaccine on a population level? (4)
- Lower % of population infected with chronic HBV
- Decrease of liver cirrhosis/chronic liver disease
- Decrease of HCC mortality
- Decease of HCC incidence
What is the most common way of HBV diagnostics? What are its advantages? (2)
HBsAg ELISA
- Cheap & widely available
- Reliable
Which biomarkers are used for HBV monitoring during treatment? (3)
- HBV DNA
- HBeAg/HBeAb
- Liver transaminases (ALAT/ASAT)
Which group of chronic HBV patients is treated with viral replication inhibitors?
Only patients with elevated HBV DNA & ALAT/ASAT
What is the main treatment of chronic HBV?
Nucleoside analogues (NA)
What is the effect of nucleoside analogues on HBV replication?
Cause chain termination -> suppresses replication
What makes nucleoside analogues for HBV treatment HBV specific?
They specifically inhibit the reverse transcription on HBV -> no off-target effects in human cell replication
What is the disadvantage of the use of nucleoside analogues for HBV treatment?
Life-long treatment required
What are the currently used nucleoside analogues for HBV? (3)
- Tenofovir
- Entecavir
- Tenofovir alafenamide (TAF)
What is the most important side effect of nucleoside analogues for HBV?
Decrease of kidney function when used for a long time in a small subset of patients
True or false: nucleoside analogues cannot prevent vertical transmission of HBV
False; nucleoside analogues effectively prevent vertical transmission
What are the options to prevent vertical transmission of HBV from mother to child? (2)
- Use of nucleoside analogues
- Use of anti-HBsAg during delivery
What is an alternative of nucleoside analogue for HBV? What is its advantage? What is its disadvantage?
PEG-IFN
Advantage: has a 20-30 chance to fully clear the virus by targeting cccDNA
Disadvantage: severe side effects
What is the main problem for HBV curation?
cccDNA
Where is cccDNA located in the cell?
Nucleus
What is the function of cccDNA
Can form a transcriptional template for all HBV RNAs -> allows for the production of new virus
What is the most important difference between cccDNA and HBV DNA integrated into the host genome?
cccDNA is able to produce pre-genomic RNA (pgRNA), which can be used for the production of new HBV virus particles
HBV DNA in the host genome cannot do this
What is the main disadvantage of HBV integration into the genome?
Can cause oncogenic mutations
What are the effects of nucleoside analogues against HBV on a patient level? (4)
- Improves survival
- Delays the progression of cirrhosis
- Reduces (but does not eliminate) HCC risk
- Reduces the need for liver transplantation
Which aspects of current HBV therapy need to be improved to enable curation? (3)
- Eradication of cccDNA
- Stimulate HBsAg seroconverson
- Get full immune control over the virus
What is the current aim for an HBV cure?
Functional cure = sustained HBsAg-loss (s-loss) with or without seroconversion, with cccDNA still present
Which three ‘levels of cure’ for HBV can be distinguished?
- Sterilizing cure
- Functional cure
- Partial cure
What is meant with ‘sterilizing cure’ for HBV?
Complete elimination of all traces of HBV
What is meant by ‘functional cure’ for HBV?
Sustained HBsAg-loss with or without seroconversion, cccDNA still present
What is meant by ‘partial cure’ for HBV?
HBeAg & HBV DNA negative without treatment, but still HBsAg+
What are the common targets of compounds that are currently investigated for the curation of HBV?
- Replication inhibition
- Antigen reduction
- Immune stabilization
Which compounds aimed at replication inhibition of HBV are currently being tested? (3)
- Viral entry inhibitors
- Nucleoside analogues
- Capsid assembly modulators
Which compounds aimed at antigen reduction for HBV are currently being tested? (3)
- Small interfering RNA (siRNA)
- Antisense oligonucleotides (ASO)
- RNA destabilizers
What is the rationale of using antigen reduction to stimulate HBV curation?
Decreases antigen exposure, thus decreasing immune exhaustion
Which compounds aimed at immune stabilization in HBV are currently being tested? (5)
- Cytokines
- TLR stimulation
- Vaccines
- Anti-HBsAg
- Immune checkpoint inhibitors
What is the mechanism of action of capsid assembly modulators?
Disrupt HBV life cycle by destabilizing nucleocapsid/blocking DNA packaging -> production of particles without genetic information
Are capsid assembly modulators for HBV being investigated for standalone use, or in concert with other compounds?
In combination with nucleoside analogues
What are the side effects of capsid assembly modulators? (2)
- Rash
- ALAT flares
What are the results of treatment with capsid assembly modulators + nucleoside analogues?
- Deeper viral load decline than NA alone
- No/modest HBsAg/HBeAg decline
What is the function of siRNA in the clearance of HBV?
Can knock down production of all HBV genes & significantly decrease viral particles/antigens
What is the mechanism of action of antisense oligonucleotides in the clearance of HBV?
Similar to siRNA: knock down production of HBV genes
What is ‘s-loss’?
No HBsAg detectable in serum
Which immune mechanisms promote HBV persistence in the liver? (8)
- Tregs
- IL-10 & TGF-β
- Regulatory B-cells
- Active elimination of T-cells
- Impaired NK-cells
- T-cell exhaustion
- Myeloid-derived suppressor cells
- Mitochondrial dysfunction
What is the aim of the use of immunological compounds in the clearance of HBV?
Restore immune reactions to the levels of acute reaction -> enables viral clearance
Which immune stimulatory compound are currently being used/tested for HBV curation?
- PEG-IFN
- TLR8 agonists
- Immune checkpoint inhibitors
- Therapeutic vaccination
What are the advantages of using PEG-IFN in an HBV cure? (4)
- Well-characterized
- Dual mode of action: antiviral + immunomodulatory
- Proven to target cccDNA
- Higher s-loss than nucleoside analogues
What are the disadvantages of using PEG-IFN in an HBV cure? (3)
- Toxicity
- Difficult to administer
- Low response rate
What is the rationale behind using immune checkpoint inhibitors for an HBV cure?
Reverts T-cell exhaustion -> proliferation & activation of HBV-specific T-cells
What is an overarching problem in the development of an HBV cure?
No HBV animal model available -> in vivo studies only possible in patients
