Hepatitis Flashcards
What is Hepatitis B?
Small DNA virus
Infects hepatocytes
What can hepatitis B cause?
Acute infection
Chronic infection
Predisposes to hepatocellular carcinoma
Extrahepatic disease
Describe hepatitis B in the UK
96% of new chronic hepatitis B in UK found in migrants
Intermediate prevalence in large urban centres in low endemic countries
How is hepatitis B spread?
Parentally via blood and bodily fluids
Not spread by saliva, insect bites or casual contact
Sexual contact, drug use, blood transfusion, haemodialysis
How are chronic hepatitis B infections transmitted?
Mostly vertical (mother to baby) or early horizontal (among individuals of the same generation) globally
How much blood is sufficient for transmission of hepatitis B?
0.00004ml - highly infectious
Is hepatitis B more or less infectious than HIV?
50-100x more infectious than HIV
What are risk factors of hepatitis B?
Age at acquisition determines outcome - 95% or neonates develop chronic infection, 95% of immunocompetent adults spontaneously clear HBV (sAG loss)
Chronicity higher in immunosuppressed (more chronic)
When does vertical transmission occur?
Usually at delivery
Depends on viral load and Hepatitis B e-antigen (HBeAg) status of mother - transmission occurs in 90% of HBeAg+ where HBV > 10^7 IU/ml)
Describe hepatitis B structure
Small surface proteins
Icosahedral core
Polymerase
DNA
Large surface proteins
Medium surface proteins
Describe the genome of HBV
Partially double stranded
Inner strand shorter than outer strand
Enters hepatocytes
In nucleus, inner strand completed by cellular polymerases
Forms covalently closed circular DNA (cccDNA)
How is cccDNA formed?
Mutistep process converting relaxed circular DNA of HBV to cccDNA
What happens once cccDNA formed?
Incorporated to host genome as an episome
Template for HBV replication
Remains in infected cells for the life of the cell
Implications for reactivation of HBV even after long-term quiescence
What does a HBsAg serology test for?
Ongoing HBV infection
What is an anti-HB serology?
Tests immunity - natural or vaccine
What is an anti-HBc (IgG) serology for?
Current or resolved HBV infection
What is an anti-HBc (IgM) serology for?
Acute HBV infection or flare of chronic HBV
What is a HBeAg serology for?
Active viral replication (tolaragen - helps evade host immunity)
What is an anti-HBe serology for?
May indicate immune control but active replication may occur
What is a HBV DNA serology for?
Direct measure of viral particles
Describe the immunopathology of hepatitis B
Injury to HSC, fibrocytes, Kpuffer cells and portal fibroblasts cause oxidative stress, TLR4 signalling/innate immunity and NFkB/JNK signalling
Inflammation due to chemokine and cytokine prod
Injury to hepatocytes and cholangiocytes leads to epithelial mesenchymal transition (EMT) and hepatocellular EMT
Fibrogenesis and cancer
What are the stages of infection of HBV?
Immune tolerant - high HBV DNA, low ALT (alanine transaminase)
Immune clearance (HBeAg+ chronic hepatitis) - decreased HBV DNA, high ALT
Inactive carrier phase - low HBV and ALT
Reactivation (HBeAg- chronic hepatitis) - low HBV and ALT
Describe post-exposure prophylaxis for HBV
For unvaccinated individuals - Hepatitis B immunoglobulin (HBIG) within 48hrs and HBV vaccination
For vaccinated individuals - Anti-HBs titres assessed, if < 10 IU/ml treat as unvaccinated, if > 10 IU/ml no action required
How is prophylaxis done for infants of HBsAg+ mothers?
HBIG at birth
HBV vaccination schedule
Not 100% effective
Describe prophylaxis in pregnancy
Antivirals in third trimester
Infant vaccine only if mother has unkown HBsAg and father HBsAg+ve
Test infants at 9-12 months
Describe prophylaxis in pregnancy
Antivirals in third trimester
Infant vaccine only if mother has unkown HBsAg and father HBsAg+ve
Test infants at 9-12 months
Describe HBV therapy
Direct-acting antivirals - nucleoside/nucleotide analogues
Immune stimulation - interferon
Important indications for treatment
Reactivation
Extrahepatic manifestations
What do nucleotide/nucleoside analogues do?
Inhibit reverse transcriptase activity of HBV polymerase
NAs incorporated to virions, leading to chain termination and non-functional viral DNA
Well tolerated oral treatment
What does interferon do?
Activates antiviral genes in infected cells and adaptive immune systems
PEG-IFN once weekly
No resistance
Poor tolerability - flu-like symptoms, BM suppression, depression, can trigger latent autoimmunity, avoid in cirrhotics with synthetic failure
What happens in reactivation of HBV?
Sudden reappearance/increase HBV replication in patient with prior evidence of resolved or inactive infection
Describe a typical clinical scenario in which the risk of reactivation if very high
HBsAg +ve and receiving anti-CD20 (e.g. rituximab) and/or stem cell transplantation
Describe a typical clinical scenario in which the risk of reactivation is high
HBsAg +ve and will receive high dose steroids (>20mg/d for >4 weeks) or anti-cytokine agents (e.g. Campath)
Describe a typical clinical scenario in which the risk of reactivation is moderate
HBsAg +ve and chemotherapy without steroids or anti-TNFa treatment or anti-rejection therapy for solid organ transplants
Describe a typical clinical scenario in which the risk of reactivation is low
HBsAg +ve methotrexate/azathioprine
HBsAg -ve high dose steroids or anti-cytokine agents
Describe a typical clinical scenario in which the risk of reactivation is very low
HBsAg -ve chemotherapy without steroids or anti-TNFa treatment or anti-rejection therapy for solid organ transplants or methotrexate/azathioprine
Describe reactivation
Occurs in HBsAg +ve usually
Can occur for HBsAg -ve HBsAb +ve
Always check HBsAg/HBcAb/HBV DNA for any immunomodulation
Especially rituximab and steroids
How is reactivation managed?
Stop cytotxics/immunosuppressants
Tenofovir/entacavir
+/- liver transplantation
Describe the incidence of hepatocellular carcinoma
0.3-0.6% incidence in non-cirrhotics
2.2-3.7% incidence in compensated cirrhotics
What is hepatocellular carcinoma?
Most common type of primary liver cancer
Occurs most often in people with chronic liver diseases e.g. cirrhosis caused by HBV
What can cause HBV to be carcinogenic?
BCP mutations
Genotype C
Male
Older age
Heavy EtOH
Family Hx HCC
Metabolic syndrome
Describe future therapy options for HBV
Entry inhibitors (e.g. Bulevirtide)
Core protein binders
RNA interference (e.g. siRNA)
Inhibitors of HBsAg release
HBsAg neutralisation
Inhibitors of cccDNA
TLR agonists (immune modulation)
Immune checkpoint inhibitors
Engineered T cells
Therapeutic vaccines
Multi-targeted immunotherapy
Describe delta virus
Small enveloped RNA virus
Requires co-infection with HBV (uses HBsAg as its own envelope)
Systematically screen patients with HBVsAg +ve for HDV
Check HDV RNA in anti-HDV Ab
Co-infection or superinfection
Synergistic fibrosis
Describe treatment of HDV
Traditional = 48 weeks of PEG-IFNa
Poor efficacy and tolerability
Combination IFN and nucleoside/nucleotide not effective
Novel therapies - bulevirtide (HDV entry inhibitor) - approved by EMA, awaiting NICE, lonafarnib in evaluation, other drugs (silencing RNA), combinations
Describe the structure and genome of HCV
E1 and E2 surface envelope glycoproteins
Core forms nucleocapsid
Non-structural proteins
How is HCV diagnosed?
History - risk factors
HCV Ab EIA - if negative then immunocompetent and no chronic HCV, if positive then patient has had contact with the virus
Positive HCV Ab means HCV RNA present
Presence of Abs 2 weeks after exposure but can be longer
HCV RNA present early as 1 week
Babies tested after 18months
Check genotype
How is HCV treated?
Traditionally PEG-IFN and ribavarin but this had poor tolerability and cannot be used in advanced cirrhosis/fibrosis so searching for new drugs
What do direct-acting antivirals (DAAs) target?
Viral replication
What are combinations of DAAs based on?
HCV genotype
Presence of cirrhosis
Treatment history
Severity of cirrhosis
Blood counts
Renal impairment
How do DAAs work?
Inhibit specific non-structural proteins that are vital for HCV replication
What DAAs target translation of the virus?
NS3/4A protease inhibitors:
- Telaprevir
- Boceprevir
- Simeprevir
- Faldaprevir
- Paritaprevir
- Ritonavir
What DAAs target the replication stage of the virus?
NS5B polymerase inhibitors:
- Sofosbuvir
- Dasabuvir
What other type of DAA is there?
NS5A inhibitors (MOA not known):
- Daclatasvir
- Ledipasvir
- Ombitasvir
How do resistance mutations occur?
Due to high replication rate of virus, leading to novel strains and quasi-species of HCV
Mutations in NS3, NS5A and NS5B genes
Resistance testing may be of less value given the multitude of retreatment options
What is extrahepatic disease?
Disease located or occurring outside the liver as a result of HCV
Give examples of extrahepatic disease
Cardiovascular disease
Chronic kidney disease
Insulin resistance and T2D
B cell lymphoma
Cryoglobulinaemic vasculitis - immune complex-mediated inflammation of blood vessels
What are the challenges of HCV treatment?
Resistance mutations
Cost of DAA regimens and retreatment esp in LMICs
Screening and access to treatment in vulnerable groups
What type of virus is hepatitis A?
Single stranded RNA
How is hepatitis A transmitted?
Faeco-oral route
Describe effects of hepatitis A
Acute self-limiting episode of hepatitis
Asymptomatic/symptomatic
Can survive in dried faeces for 4 weeks
Self-limiting jaundice/cholestasis > 10wks
Acute hepatic failure possible (1%)
How long does it take to recover from hepatitis A?
Full recovery in almost by 6 months
Relapsing over 2-3 months
What kind of virus is hepatitis E?
Small RNA virus
How is hepatitis E transmitted?
Faeco-oral transmission via water or pork products
Where is hepatitis E found?
North Africa and Middle East
What are the effects of hepatitis E?
Self-limited acute hepatitis or chronic hepatitis in immunocompromised
Anorexia, nausea, abdominal pain and transaminitis +/- diarrhoea, arthralgia, rash
60% prolonged cholestasis for months
Fulminant hepatic failure (FHF) possible - liver begins to fail very quickly
When does FHF occur more frequently?
In pregnant women
15-25% mortality and worse fetal outcomes
What is used to treat hepatitis E?
Ribavarin may be used to treat in certain circumstances
