L16. Hepatitis 2 (Chronic) Flashcards
What types of hepatitis virus cause chronic infection?
HBV, HCV and HDV
What are the sources of these chronic hepatitis viruses? How are they spread?
Source: Blood-Borne and in bodily fluids
Spread percutaneously and permucosally (sexual transmission, perinatal and IV drug use)
Does water and food sanitation have an impact on the spread of chronic hepatitis viruses?
NO
The prevention is by blood screening and modifying risk factor behaviour only.
Transmission is out of the hepatocytes into the blood (reverse to acute viruses)
What are the two forms of the Hepatitis B viral structure?
The INFECTIOUS form: double walled structure: outer envelope with surface antigen and inner capsid containing the genome
The NON-INFECTIOUS form: an incomplete filamentous form made up of the surface antigen
What is the purpose of the non-infectious filamentous form?
Because it is made up of the HBsAg (surface antigen) it is able to act as a decoy for antibodies against the virus to bind to it.
Describe the structure of the Hepatitis B genome
dsDNA
Circular - incomplete double strands
With repeated sequences called direct repeat (DR) regions
with genome has several RNA start sites and only one terminal site
Describe the replication of the Hepatitis B genome
Overlapping reading frames code for different proteins: core, surface, polymerase and other
The PRE-GENOMIC RNA is the most important and runs several loops around the DNA
Describe the pathogenesis of the hepatitis B virus
- Virus enters cells, release of core and genome
- Enters the nucleus and missing piece of DNA is repaired to a complete circle = covalently closed circular DNA (cccDNA)
- cccDNA episome is the template and undergoes reverser transcriptase (highly error prone) to produce several viral RNA including the pre-genomic RNA
- RNA and proteins leave nucleus into the cytoplasm and form the virus. This includes more reverse transcriptase to form the incomplete dsDNA loop for the next viral generation
Describe the life cycle of the hepatitis B virus
- Secreted in blood, semen and other blood exudates
- Penetrates the mucosal epithelium of new host
- Circulates in the blood and reaches the liver
- Infects and replicates in the hepatocytes
What is the Hepatitis B e-antigen an important indicator of?
Infectiousness
What is the incubation period of HBV?
60-90 days
What is the difference between ages in infection of HBV?
Young children have poorly formed immune systems and thus are more susceptible for chronic infection and spared from acute
Adults are susceptible to an acute infection (because of the immune response) and spared from chronic infection due to effective clearance
What is the difference in the serological courses of the acute vs. the chronic hepatitis B virus?
ACUTE:
HBsAg and HBeAg indicate presence of virus
HBeAg switches to anti-HBeAg
Levels of HBsAg decrease to baseline
Anti-HBc (core) levels increase and remain high (immunity)
CHRONIC:
HBsAg is present at much higher levels and stays high (no antigens against it are produced)
HBeAg doesn’t switch to Anti-HBeAg
What are some sequelae of chronic hepatitis B?
Cirrhosis
Liver failure
Primary hepatocellular carinoma (after 10-30 years)
What is the relationship between HBV and cancer?
100x higher risk of hepatocellular carcinoma if infected with HBV
About 2-10% of infected patients develop cancer
Repeated destruction and regeneration of hepatocytes increases the chance and accumulation of mutations
What are the two main classes of antiviral drugs used for HBV infections?
Interferon alpha (pegylated): for HBeAg positive carriers. Not highest effective rate and unpleasant therapy
Nucleoside and nucleotide analogs: don’t have the complete cyclic formation of the nucleotide/side and thus prevent elongation of the genome.
Is there a vaccine available for hepatitis B?
Yes
It is an inactivated virus with an alum adjuvant that protects against both HBV and HDV
What family does Hepatitis D belong to?
Deltavirus
Describe the hepatitis D virus structure and genome
ssRNA genome
Rolling circle replication (self-complementary) and only makes 1 protein (the delta antigen)
It is inside a particle that has the HBsAg
What is important about hepatitis D infection?
It only infects IN CONJUNCTION WITH HEPATITIS B because it is partly made by the HBsAg.
- Coinfection at the same time = severe acute disease (low risk of chronic infection)
- Superinfection of HDV onto HBV positive patients
= chronic HDV infection with high risk of severe chronic liver disease
What family does the HCV virus belong to?
Flavivirus
Describe the HCV virus genome and structure
+ ssRNA virus
replicates without requiring being in the nucleus (has own mechanisms)
In a lipid envelope with lipid glyoproteins and lipid droplets
Describe the replication process (intracellular pathogenesis) of the HCV virus
It enters the cell via endosomal means into hepatocytes and the endosome acidifies releasing the viral RNA. The RNA replicates in the cytoplasm through golgi for assembly before new viruses are formed
The RNA polymerase of the +ssRNA is highly error prone. What is the implication of this?
There are many mutations that can occur and hence there is a large genome diversity capable of causing disease = very difficult for vaccine makers
What is the incubation period of HCV?
6-7 weeks
What percentage of people get chronically ill with hepatitis C?
70% (30% are able to clear the acute virus)
What are the sequelae of chronic hepatitis C?
UP to 70-90% become chronic carriers
Liver fibrosis, cirrhosis, liver failure, cancer
What drugs were used for hepatitis C?
Interferon alpha
Ribavirin (nucleoside analog)
Describe the emergence of the Direct Acting Antivirals (DAA) for hepatitis C
Directly attack the specific viral enzymes and are proving to have relatively high efficacies
What are some HVC specific life cycle inhibitors?
Viral entry inhibitors HCV rna translation inhibitors Post translational protein inhibitors (NS3-4A protease inhibitors) HCV replication inhibitors Viral assembly and release inhibitors
What are the two phases of HCV treatment? (historically)
pre-2015 IFN based combination therapy
2015 onwards IFN-free combination therapy
