What are some general characteristics of hepatitis a virus? How is it transmitted? What is its epidemiology?
“infectious hepatitis”
- Picornavirus:
- Formal name is Enterovirus 7
- Similar to Poliovirus or Rhinoviruses
- Small, non-enveloped virion that is very environmentally stable
- Transmission:
- Fecal-oral
- Frequently found in focal, common source outbreaks (contaminated food, etc.)
•Epidemiology:
•World-wide prevalence, especially in developing
countries
• Poor sanitation is the primary risk factor
• Responsible for ~30% of primary viral hepatitis infections in the USA
What is the genome structure of the hepatitis A virus and what are some characteristics of its replication cycle?
- Genome Structure:
- Single-stranded (+) polarity RNA genome
- Replication:
- Proteins are made by cleavage of a large polyprotein
- HAV replicates with the standard cytoplasmic RNA-to-RNA mechanism employed by most single-stranded (+) polarity RNA viruses
- Released from cells primarily by cytolysis
What are some clinical features of hep A and what are some prevention and therapy techniques?
- Clinical features:
- ~80% of adult infections are asymptomatic
- Almost always asymptomatic in children
- Causes mild hepatitis: self-limiting and acute (2-3 months, slow moving)
- No chronic infection
- Elicits life-long protective antibodies
- Prevention and therapy:
- Good sanitation is most effective
- Immune seroglobin pre- or post-exposure is effective (passive immunity)
- No antiviral therapy
- Inactivated whole-virus vaccine is available
What are some general characteristics of hepatitis b virus? How is it transmitted? What is its epidemiology?
“Serum hepatitis”
•Hepadnavirus:
• (HEPAtotropic DNA VIRUS)
• Small, enveloped virion
• Produces a large excess of subviral particles
containing viral surface proteins (HBsAgs)
- Epidemiology:
- Present world-wide, especially Asia, Sub-Saharan Africa, and the Amazon
- Up to 10% of the people in high-endemic areas can be chronically infected
- Less than 1% of US population is chronically infected
- Accounts for about ~50% of primary viral hepatitis infections in the USA
- Transmission:
- Developed world: Primarily blood contact and sex
- Developing world: Primarily vertical transmission from infected mothers
What is the genome structure of the hepatitis B virus and what are some characteristics of its replication cycle?
Genome structure is partially DS DNA. It is read in two different reading frames. Thus the same DNA is used to encode two different proteins. This leads to less mutations b/c a silent mutation in one reading frame could be missense in the other. It has to work for both.
Key things to remember:
•Replication is by error-prone reverse transcription
•Overlap of the S and P ORFs slows development of
drug resistance and vaccine escape
•Viral replication and release is non-cytopathic
What are some clinical aspects of hepatitis B virus and what are some clinical outcomes? What is its pathogenesis?
•Disease:
- Hepatitis (jaundice, abdominal pain, malaise…)
- Acute infection
- Symptoms appear 50-150 days post-infection
- Recover is usually 2-3 months later
- Chronic infection causes cirrhosis, liver failure, and hepatocellular carcinoma
- Severity of disease varies widely
- HBV causes ~50% of all HCC cases world-wide
- > 90% of tumors carry random integrations of HBV DNA
- ~50% of acute infections are asymptomatic, <0.1% are fatal
- Disease usually gets worse with time during chronic infection (20+ years)
- Severity of hepatitis during chronic infection is highly variable between patients
- Recurrent “flares” of disease are common in an individual patient
- Progression to chronicity is age dependent
- ~90% of neonates will become chronically infected
- ~5% of adults will become chronically infected
- Up to 40% of male (spreads less in women) chronic carriers will die of complications of HBV infection
- Pathogenesis:
- Hepatitis B is an immune-mediated disease
- Primarily caused by cytotoxic T-cells attacking infected hepatocytes
- Cancer is caused by both chronic inflammation and viral factors
How is HBV diagnosed?
• The presence of an HBV infection and vaccination status can be characterized in a simple blood test that measures viral products and anti-
viral antibodies
- HBsAg (surface glycoproteins) in serum correlates with viremia
- anti-HBsAg antibodies without any other markers indicates vaccination
- anti-HBsAg antibodies plus anti-HBeAg or anti-HBcAg (capside proteins) indicates a cleared infection
- HBeAg (e-antigen) correlates with viremia
- anti-HBeAg antibodies correlate with effective immune control of the virus (but not necessarily clearance)
- the amount of HBV DNA in serum reveals the level of viremia
- Anti-HBsAg is protective, anti-HBcAg and anti-HBeAg are not protective
What are some ways to prevent and treat HBV?
- Protection from blood contact (safe sex)
- Vaccination (recombinant HBsAg) is highly effective and safe
- Post-exposure prophylaxis is by concurrent HBIG (HBV immune globulin), and vaccination
- Pegylated interferon A is approved, but it has serious side-effects and leads to long-term improvement for < 20% of chronic carriers
- Entecovir and Tenofovir (nucleoside analog DNA chain terminators) are approved
- They effectively suppress viral replication in most patients
- Resistance usually develops patients treated with the older drugs
- Viral replication rebounds after drug withdrawal
- Therapy cures HBV infections in only 3-6% of patients even after years of treatment
What are some general characteristics of HDV? What is its epidemiology?
Hepatitis D (Delta) Virus
- Viroid-like Defective Virus:
- Small enveloped virion
- Parasite of HBV
- Closest relative is the viroids of plants
- Epidemiology:
- World-wide prevalence
- Found only where HBV is found, but not uniformly
- Overall is much less common than HBV
What is the genome structure of HDV? How does it replicate?
- Genome structure:
- Small, single-stranded circular (-) polarity RNA genome
- Encodes 1 protein, the delta antigen
- Replication:
- RNA to RNA replication, probably by host RNA Polymerase II
- Intracellular replication is independent of HBV
- Intercellular spread needs HBsAgs for envelope formation, so HDV cannot spread from cell to cell without HBV co-infection
What are the disease and infection patterns of HDV?
- Generally increases seerity of hepatitis in HBV patients
- Superinfection of HBV asymptomatic carriers can activate hepatitis
- Chronic infection is possible
- Probably increases frequency of hepatocellular carcinoma in HBV+HDV chronically infected patients
- Disease spectrum is the same as for HBV
How do you diagnosis, prevent and treat HDV?
- Diagnosis
- Detection of anti-delta antigen antibodies
•Prevention and therapy:
- Prevent HBV infection
- Vaccination
- HBIG + vaccination for acute exposure
- HBIG + vaccination is not prophylactic in chronic HBV carriers
•No antiviral therapy
What are some general characteristics of HCV? What is its epidemiology? How is it transmitted?
- Flavivirus:
- Enveloped virus
- Primary cause of viral non-A, non-B hepatitis
- Epidemiology:
- Present world-wide
- Causes about 20% of the new viral hepatitis infections in US annually
- Establishes chronic infection in 70-80% of primary infections
- ~1.8% of US population is chronically infected •Rate is double in the African American population
- Transmission:
- Parenteral, primarily by direct blood contact
- Sexual transmission is possible but very infrequent
What is the genome structure and replication of HCV?
- Genome structure and genetics:
- Uncapped single-stranded (+) polarity RNA
- Highly genetically variable:
- Six major genotypes
- Encodes a large polyprotein
- Genotype 1 causes ~70% of the cases in the USA
•Replication:
- The viral RNA is translated independently of cap to make polyprotein
- The RNA is replicated in cytoplasm by a viral RNA RNA polymerase
- The polymerase is highly error-prone
- This causes HCV to replicate as a quasispecies
- New viruses are released without killing the cell
What are some mechanisms used by HCV to become highly persistent in their host? What is the ultimate clinical result of these factors?
- Poor immune responses:
- Slow, weak immune responses despite adequate antigen production
- Successful resolution of infection does not necessarily give lasting protection (poor memory)
- Immune Escape:
- Evolution of humoral epitopes leads to evasion of antibodies
- Evolution of CD8+ epitopes leads to escape from cell-mediated immunity
- Immune Evasion:
- Active suppression of immune system by viral proteins
Together, these problems have blocked all attempts to develop a vaccine to date
What is HCV disease like?
- Acute hepatitis is mild and usually self-limiting
- Most chronic carriers have mild liver damage
•About 20% of chronic carriers have progressive
hepatitis (very similar to HBV disease)
• Steatosis and insulin resistance are more common in HCV than HBV
•HCV-infected patients are hypersensitive to liver
damage from alcohol
•Kills 10-12,000 people per year in the USA
- Chronic carriers are at high risk of fibrosis, cirrhosis, and hepatocellular carcinoma
- HCV causes ~25% of HCC cases globally
How is HCV diagnosed and how is it prevented?
- Diagnosis:
- Primary test is an ELISA to detect anti-HCV IgGs,
- Tests for anti-HCV IgM are not available
- Causes a long window between infection and serological detection
- RT-PCR is used to measure HCV levels during therapy
- Prevention:
- Avoid blood contact
- Using safer-sex practices may help
- No vaccine is available
How is HCV treated? What is its cure rate?
- Current therapy is pegylated interferon alpha plus ribavirin plus telaprovir or boceprovir (NS3 protease inhibitors)
- Cures ~75% of patients who can take it for 6 to 12 months
- Is extremely difficult to administer due to complex dosing schedules
- Has severe side effects
- Peglylated interferon plus ribavirin plus sofosbuvir (a new NS3 inhibitor) was just approved
- Cures 75-90% of patients after 3 to 6 months
- Many other new drugs are in the pipeline
- Cure rates as high as 100% have been reported in phase I trials of interferon-free drug combinations
HCV will be a routinely curable infection within a couple of years!
