Hepatitis Viruses Flashcards
1
Q
Viral Hepatitis
Overview
A
-
Hepatitis A-E, which are all antigenically and genetically unrelated
- 3 most common: Hep A, Hep B, and Hep C
-
HAV and Hep E Virus (HEV) ⇒ acute infections only
- Acquired from the environment by oral ingestion
- Both reside in the liver, where replication takes place
- Infected hosts mount an effective immune response that clears virus from liver and blood
- Generates long-lasting immunity
- Infections can be severe but fatalities are infrequent
- Resolution occurs in most cases
-
Hep B and Hep C ⇒ acute & chronic infections
- Extensive viral replication in the liver
- Acute infection w/ ± disease sx
- Immune response is not always effective at clearing infection ⇒ persistent infection
-
Persistent infection: continued virus replication in the liver and release of infectious virus into the blood
- 5-10% of HBV infections
- 80% of HCV infections
- Hep D Virus (HDV) intrinsically linked to HBV
2
Q
Hep A
Properties
A
-
Picornavirus in genus Heparnavirus
- 27nm naked, icosahedral capsid
- Linear ⊕-sense, ssRNA genome
- Only one serotype
- Interacts specifically w/ HAV cell receptor 1 glycoprotein (HAVCR-1) aka “T-cell immunoglobulin and mucin domain protein (TIM-1)”
- HAVCR-1 expressed on liver cells and T-cells
- Specific forms correlated w/ severity of disease
- HAVCR-1 expressed on liver cells and T-cells
- Unlike other picornaviruses, HAV is not cytolytic ⇒ released by exocytosis
- Spread via fecal-oral route
- Consumption of contaminated water, shellfish, or other foods
- Resistant to detergents, acid (pH of 1) and temperatures as high as 60°C
- Survives for several months in fresh and salt water
3
Q
Hep A
Pathogenesis
A
- Incubation period 15-40 days
- Ingested → bloodstream through epithelial lining of OP or intestines
-
Replicates in hepatocytes and Kupffer cells
- Replicates slowly ⇒ no apparent cytopathic effects
-
Virions → bile → stool
- Present in feces for up to 2 wks prior to sx onset or Ab detection
-
Immune response:
- Interferon shown to limit viral replication
- NK cells and cytotoxic T cells required to eliminate infection
- Ab, complement, and ADCC also facilitate clearance of the virus
- Liver damage likely caused by immunopathology
- HAV damage indistinguishable from HBV
- Cannot initiate chronic infection
- Not ass. w/ hepatic cancer
4
Q
Hep A
Epidemiology
A
-
Leading cause of acute viral hepatitis worldwide (> 40%)
- In some developing areas, HAV seropositivity close to 100%
-
Virus is spread readily
- Pts contagious for up to 2 wks prior to sx
- 90% of infected children and 25-50% of infected adults have inapparent but productive infections
- HAV outbreaks usually originate from a common source
5
Q
Hep A
Transmission and Risk Factors
A
- 1° transmitted via fecal-oral route
- Most commonly acquired via ingestion of contaminated food or during sexual activity
-
In the US, 3 leading risk factors for Hep A infection are:
- Sexual or household contact
- International travel
- Male-male sexual activity
6
Q
Hep A
Clinical Syndromes
A
- Incubation phase 2-7 wks (mean 28-30 days)
-
Prodromal sx are non-specific:
- Anorexia, fever, nausea, and malaise
-
Jaundice typically appears within 1 wk after sx onset & resolves within 2 wks
- Occurs in 70-80% of adults
- < 10% of children < 6 y/o
- ± Bilirubinuria several days before jaundice ⇒ dark urine
- Jaundice and hepatomegaly are the most commonly observed PE abnl
-
± Extra-hepatic manifestations
- Less frequent than w/ HBV or HCV
- After onset of jaundice, most constitutional sx abate quickly
- Some pts c/o residual fatigue for several wks
- Most cases of hep A are self-limited
- 85% show complete resolution of sx by 3 months
- Hep A carries no risk for chronic hepatitis
- < 100 HAV-related deaths/yr reported
7
Q
Hep A
Serology
A
-
Serum IgM anti-HAV almost always detectable @ onset of sx
- Peak before 3 months, gradually decline until they become undetectable
-
IgG anti-HAV levels rise soon after
- IgG levels remain elevated and confer lifelong immunity
-
Acute HAV Infection
-
[Serum IgM anti-HAV] ⇒ diagnostic test of choice
- Sensitivity ~100%, specificity 99%, positive predictive value 88%
- Completed by standard ELISA or radioimmunoassay
-
[Serum IgM anti-HAV] ⇒ diagnostic test of choice
8
Q
Hep A
Treatment and Prevention
A
- No specific antiviral therapy for acute hep A infection
- Most pts tx symptomatically as an outpatient w/ lab and clinical f/u
- Pts w/ acute HAV infection who do not develop acute liver failure will have complete recovery w/o any permanent sequelae
- Interrupt fecal-oral spread by avoiding contaminated food and water, proper hand-washing, and chlorine treatment of drinking water
- Killed HAV vaccines available for all children and adults at high risk
9
Q
Hep B
Properties
A
- Member of hepadnavirus family
- Enveloped, icosahedral nucleocapsid
- Nicked, circular, partially dsDNA genome
- Pt’s serum may contain:
- Complete infectious virus (42 nm)
- Non-infectious spheres and filaments (composed of HBsAg)
-
Viral antigens and antibodies:
- HBsAg = hepatitis B envelope surface antigen
- HBcAg = hepatitis B core antigen
- HBeAg = hepatitis B e antigen
- anti-HBs = Ab against hepatitis B surface antigen
- anti-HBc = Ab against hepatitis B core antigen
- anti-HBe = Ab against hepatitis B e antigen
- Carry DNA-dependent DNA polymerase
- One major serotype (based on HBsAg)
- Humans are the only natural reservoir
- Highly hepatotropic
- Very complicated lifecycle
- One of a few known pararetroviruses ⇒ non-retroviruses that still use reverse transcriptase
10
Q
Hep B
Entry and Replication
A
- Viral entry via endocytosis by binding to NTCP (sodium/bile acid cotransporter)
-
Virus multiplies via RNA made by a host enzyme:
- Viral genomic DNA → cell nucleus
-
Viral partially dsDNA → fully dsDNA → covalently closed circular DNA (cccDNA) ⇒ template for transcription of 4 viral mRNAs
- Largest mRNA ⇒ new copies of genome, capsid core protein, viral DNA polymerase
- 4 viral transcripts undergo additional processing
- Form progeny virions ⇒ released from the cell or returned to the nucleus and re-cycled to produce even more copies
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Long pre-genomic mRNA → cytoplasm ⇒ virion P protein (DNA polymerase) synthesizes DNA by its RT activity
- 3 basic functions of HBV polymerase:
- Priming ⇒ initiates ⊖ strand synthesis
- Reverse transcriptase ⇒ generates ⊖ strand of DNA
- DNA synthesis ⇒ generates ⊕ strand of DNA
- 3 basic functions of HBV polymerase:
- Virus released by exocytosis w/o killing cell
11
Q
Hep B
Pathogenesis
A
- Incubation period 10-12 wks
- Viremia
- Entry via HBsAg ↔︎ NTCP on hepatocyte cell surface
- Penetration and uncoating
- Virus replication
-
Effective immune response ⇒ inflammation → elimination of infected hepatocytes → resolution
- ↑ NK cell activity & INF-α production
- Early sx such as arthralgia caused by Ag-Ab reactions ⇒ Type III hypersensitivity
-
Cytotoxic T cells attack and destroy infected hepatocytes
- Inflammation and necrosis
-
Lifelong immunity after resolution of infection
- Mediated by anti-HBs Ab
-
~9-10% become chronic carriers
- More common in newborn and immunocompromised adults
- Jaundice and other sx occur less often than in older children and adults
12
Q
Hep B
Epidemiology
A
-
HBV is found throughout the world
- Endemic areas: majority of infections acquired at birth
-
Non-endemic areas: infection is usually acquired venereally or through IV drug abuse
- In the US: 50% of infections are sexually transmitted
-
Chronic carriers are the major reservoir of HBV
- Many are asymptomatic
- Usually identified only when they become ill or routine serologic screen done
- In the US: about 1/250k individuals are chronically infected
13
Q
Hep B
Transmission and Risk Factors
A
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4 recognized modes of transmission:
- Mother to child at birth (perinatal)
- Contact w/ an infected person (horizontal)
- Sexual contact (venereal)
- Parenteral (blood-to-blood) exposure to blood or other infected fluids
- Can be carriers w/ or w/o hepatitis
- Transmission occurs by percutaneous and permucosal exposure to infective body fluids
-
Percutaneous exposures:
- Transfusion of unscreened blood/blood products
- Sharing unsterilized needles for IV drug use
- Hemodialysis
- Acupuncture
- Tattoos
- Injuries from contaminated sharp instruments sustained by hospital personnel
- Sexual and perinatal HBV transmission usually result from mucous membrane exposures to infectious blood and body fluids
-
Perinatal transmission is common in hyperendemic areas of south-east Asia and the far East
- Esp. when HBsAg carrier mothers are also HBeAg ⊕
-
Percutaneous exposures:
- Infectious HBV can be present in blood w/o detectable HBsAg
- Failure to detect Ag does not exclude the presence of infectious virus
- Natural reservoir for HBV is man
14
Q
Hep B
Clinical Syndromes
A
- Many 1° infections are asymptomatic
- Effective immune response ⇒ inflammation → elimination of infected hepatocytes → resolution
-
Ineffective immune response ⇒ ↑ likelihood of chronic HBV infection
- Definition: persistence of HBsAg for ≥ 6 mos
- Hepatocytes remain infected instead of being destroyed by cytotoxic T cells
- Most chronic carriers are asymptomatic
- Detected by routine screening
- Characterized by replicating virus (HBV-DNA), persistence of HBeAg and HBsAg
- When replication ends: HBV-DNA levels ↓ and anti-HBe levels ↑
- Detection of HBeAg is a measure of virus replication, infectivity and transmissibility
-
Chronic Hep B presentations:
- Asymptomatic: pt appears healthy, no liver damage, hepatocytes contain HBsAg
- Chronic persistent hepatitis: mild hepatitis w/ minimal or mild histologic changes
-
Chronic active hepatitis: marked hepatic inflammation
- Can lead to cirrhosis and death
-
Outcomes:
- Acute Hep B Infection
- 5-10% ⇒ chronic carriers
- ~ 25% ⇒ chronic hepatitis
- Chronic carriers
- 80-85% ⇒ complete resolution
- 15-20% ⇒ complications
- Acute Hep B Infection
- Definition: persistence of HBsAg for ≥ 6 mos
-
Remission
- Can occur after yrs/decades of persistent illness
- ~ 10% of pts who go into remission have subsequent reactivation
- Some go thru cycles of remission then reactivation
- Each reactivation results in more severe disease
-
Hepatocellular Carcinoma occurs at a relatively high rate in chronic carriers
- HBV has no oncogenes
- ? D/t persistent cell regeneration to replace dead hepatocytes
- ? D/t insertion of viral DNA into hepatocyte DNA ⇒ activation of cellular oncogene
15
Q
Hep B
Serology
A
-
HBsAg
- Detectable several wks before sx onset to months after onset
- ⊕ during acute infections and persists in chronic infections
- ⊕ HBsAg ⇒ person is potentially infectious
-
HBeAg
- Detectable shortly after HBsAg
- ⊕ HBeAg ⇒ high infectivity and severity of disease
-
Anti-HBc Ab
- 1st Ab to appear
- ⊕ anti-HBc Ab ⇒ current or past HBV infection
-
IgM anti-HBc
- High titers during acute infection
- Usually disappears within 6 months
- Can persist in some cases of chronic hepatitis
-
IgG anti-HBc
- Remains detectable for a lifetime
-
Anti-HBe Ab
- Appears after anti-HBc Ab
-
⊕ anti-HBe Ab ⇒ ↓ infectivity
- Anti-HBe Ab replaces HBeAg w/ resolution
-
Anti-HBs Ab
- Anti-HBs replaces HBsAg as acute infection resolves
- Persists for a lifetime in > 80% of pts
- ⊕ anti-HBs Ab ⇒ immunity
-
Constant [HBsAg] or persistent [HBeAg] 8-10 wks after sx have resolved
- ↑ likelihood of being carriers
- ↑ risk of chronic liver disease
16
Q
Hep B
Treatment and Prevention
A
-
Chronic HBV infection
- INF-alpha
-
Lamivudine, telbividune, entecavir, adfovir, and tenofovir
- Nucleoside analogs
- Inhibits reverse transcriptase
- Appears to be no advantage to combined therapy of nucleoside/nucleotide analogue and interferon
-
HBsAg vaccine
- Produced in yeast
- Required in most states before children can attend school
-
Passive-active immunization
- Used when immediate and long-term protection is needed
- E.g. newborn whose mother is HBsAg ⊕
- Used when immediate and long-term protection is needed
17
Q
Nucleoside/Nucleotide Analogues
Drugs & MOA
A
-
⊗ HBV polymerase at one or all of steps
- Priming, reverse transcriptase, DNA synthesis
-
Drugs:
- Entecavir, Tenofovir ⇒ currently used in primary tx
-
Lamivudine, telbivudine, and adefovir ⇒ now considered 2nd and 3rd line therapy
- Lamivudine: competes w/ CTP
- Telbivudine: competes w/ TTP
- Adefovir: competes w/ ATP
18
Q
Entecavir
A
- Nucleoside analogue used in primary treatment
- ⊗ All three functions of the HBV polymerase
- Low rate of drug resistance
-
Excellent choice for pts not exposed to lamivudine
- Resistance may develop in pts resistant to lamivudine
22
Q
Hep D
Properties
A
- Envelope containing HBsAg
- Circular ⊖-sense ssRNA genome
-
Defective virus
- Lacks genetic info for envelope proteins
- Does code for an internal protein ⇒ delta antigen
- No virion polymerase
- HDV RNA has no sequence homology to HBV RNA
- 1 serotype
- No animal reservoir
23
Q
Hep D
Pathogenesis
A
-
HDV can only replicate in cells infected w/ HBV
- HBsAg in HBV envelope also in HDV envelope
- Genomic RNA replicated and transcribed in the nucleus by host cell DNA-dependent RNA polymerase
- HDV RNA’s are RNA catalysts or ribozymes
- Capacity to self-cleave and self-ligate
- Involved in genome replication
- Causes production of mRNA for delta-Ag
- Capacity to self-cleave and self-ligate
- delta-Ag ⇒ ⊕ association of HDV genome and HBsAg ⇒ forms HDV⇒ ⊕ association of HDV genome and HBsAg ⇒ forms HDV
24
Q
Hep D
Epidemiology & Transmission
A
- HDV infections are found worldwide
- > 10 million people infected
- Prevalence varies in different geographical areas
- Anti-HDV Ab found in 20-40% of HBsAg carriers in Africa, the Middle East, and Southern Italy
-
Transmission of HDV is similar to HBV:
- Sexual
- Vertical
- Parenteral
- HDV infection in the US is relatively uncommon
-
High-risk groups:
- IV drug users and hemophiliacs ⇒ prevalence rates of 1-10%
- Hemodialysis pts
- Sex contacts of infected individuals
- Infants born to infected mothers (rare)
- HDV occurs most often in IV drug users who share needles and only in a person who is also infected w/ HBV
-
High-risk groups:
26
Q
Hep D
Serology
A
-
Acute HDV infection:
- Total anti-HDV Ab detected by RIA/EIA kits
- Markers of HDV infection (IgM and IgG Ab)
- Disappears within months after recovery
- To monitor ongoing HDV infection, RT-PCR should be used
- In chronic HDV infection: HDV RNA, HDAg, IgM anti-HD Ab, and IgG anti-HD Ab persist
28
Q
Hep C
Properties
A
- Enveloped, linear ⊕-sense, ss RNA-containing flavivirus
- Humans are the reservoir
- Multiple serotypes exist
- More likely to cause persistent chronic infection than HBV
- No vaccine
-
Transmission:
- Blood-containing virus (1° method)
- Venereal
- Mother to child during delivery
29
Q
Hep C
Replication & Diversity
A
- Single open reading frame
- Encodes a large polyprotein
- Posttranslational processing by host and viral enzymes ⇒ structural and non-structural proteins and enzymes of HCV
- Highly conserved 5’ and 3’ UTRs
- 5’ UTR essential for replication
- Contains elements that coordinate viral protein synthesis
- Region is highly conserved
-
HCV lacks proofreading ability ⇒ tremendous viral diversity
-
Heterogeneity important in:
- Dx of infection
- Pathogenesis of disease
- Allows virus to escape eradication by host’s immune system
- Response to treatment / completeness of response to antiviral therapies such as interferon
- Prevents development of conventional vaccines
-
Heterogeneity important in:
30
Q
Hep C
Pathogenesis
A
-
Acute infection:
- Transmission → viremia → hepatocytes, lymphocytes, others
- Replication ⇒ virus becomes cell-associated
- 1° infection commonly asymptomatic
- Infections frequently become chronic and persistent
- HCV inhibits apoptosis and INF-alpha ⇒ prevents death of host cell
- Cell injury d/t cell-mediated immunologic mechanisms, not to virus- induced lysis
- Multiple serotypes of HCV ⇒ reinfection possible
-
Chronic infection:
- May occur despite the presence of Ab
- Relatively common (~70-80%)
- Of those chronically infected, ~10% become diseased
-
Factors:
- Viral load or genotypes do not influence disease severity or progression
-
Size of viral inoculum may determine course of disease
- Posttransfusion cases may proceed more aggressively than infections ass. w/ IV drug use
-
Disease expression is related to viral expression
- Low levels of circulating HCV RNA usu. found in asymptomatic pts w/ normal ALT levels
- HCC may occur as a result of frequent cell repair and new cell growth
31
Q
Hep C
Epidemiology
A
- Worldwide distribution
- Major cause of transfusion-associated hepatitis b4 screening started
- transmission by blood products ↓ to almost zero
- New HCV infections ↓ by over 80% since 1990 in the US
- Most new infections d/t high-risk drug behavior (60%) or unsafe injection practices
-
Acute infection is generally asymptomatic ⇒ incidence unclear
- > 70% HCV seropositivity in IV drug users and hemophiliacs
- 20-30% HCV seropositivity in pts receiving hemodialysis
-
New cases annually: ~150k in US and Western Europe, ~350k in Japan
- 25% are symptomatic
- 60-80% progress to chronic liver disease
- 20% of these develop cirrhosis
- 5-7% of pts ultimately die of the consequences of infection
-
Chronic infections: > 170 million chronic carriers
- Risk of developing liver cirrhosis and/or liver cancer
32
Q
Hep C
Transmission and Risk Factors
A
-
↑ Risk for HCV infection:
- Current or former injection drug users, including those who injected only once many yrs ago
- Recipients of clotting factor concentrates before 1987
- Recipients of blood transfusions or solid organ transplants before July 1992
- Chronic hemodialysis pts
- Persons w/ known exposures to HCV
- Ex. health care workers after needlesticks involving HCV ⊕
- Blood recipients of blood or organs from a donor who tested HCV ⊕
- Persons w/ HIV infection
- Children from HCV ⊕ mothers
- Most common modes of transmission: IV drug use, hemophilia, and tattoos
34
Q
Hep C
Serology
A
-
Dx of acute HCV infection difficult due to:
- # of asymptomatic cases
- No reliable and specific IgM-based serologic test
- Potential overlap of labs for acute and chronic hep C infection
-
Criteria for definitive acute HCV diagnosis:
- Pt reports recent risk factors for acquiring HCV
- Current ⊕ HCV RNA, ⊕ HCV Ab, ↑ ALT
- Labs within the past 12 months: ⊖ HCV RNA, ⊖ HCV Ab, nl AST/ALT
- Most pts will not have recent retrospective labs for comparison
35
Q
Hep C
Serology
A
- Possible HCV exposure within past 6 mos ⇒ test for HCV RNA or f/u testing for HCV Ab
- Immunocompromised pts ⇒ testing for HCV RNA can be considered
- Differentiate past/resolved HCV infection vs false ⊕ for HCV Ab ⇒ testing w/ another HCV Ab assay can be considered
-
Repeat HCV RNA testing in 16-24 wks if:
- Pt had previous ⊖ qualitative results
- Pt had a ⊖ anti-HAV test result at 4-6 wks after suspected exposure
- HCV exposure within 6 mos suspected
- Clinical evidence of HCV disease
- Concern regarding handling or storage of test specimen
- Consider treatment if pt tests ⊕ for HCV RNA 8-12 wks after infection
36
Q
Hep C
Testing Algorithm
A
37
Q
Hep C
Treatment and Prevention
A
Goal: undetectable HCV RNA at least 6 months after cessation of therapy.
-
Historical tx:
- Interferon monotherapy ⇒ combined interferon & ribavirin ⇒ combined pegylated interferon & ribavirin
- Response rates 40–80%
- ≤ 50% for genotype 1 (most common genotype in the US)
- ≤ 80% for genotypes 2 or 3
- Approved for use in adults & children ages 3-17 yrs
- Ribavirin: severe ADRs, major drug interactions, resistance issues
- Peg-interferon: numerous ADR, no resistance issues
- Response rates 40–80%
- Interferon monotherapy ⇒ combined interferon & ribavirin ⇒ combined pegylated interferon & ribavirin
-
Direct Acting Antiviral Agents
- Target enzymes and proteins involved in hep C replication
- ↑ Tx success rates
- Expensive ⇒ priority to pts w/ most urgent need
-
3 classes of drugs:
- NS3/4A Protease Inhibitors
- NS5B RNA Polymerase Inhibitors
- NS5A Inhibitors
- Many new agents on the market
- Tx will vary depending on the genotype
- Different classes used in combo to ⊗ HCV replication @ multiple steps
- Length of treatment for acute hep C ranges 4 wks to 1 yr
38
Q
NS3/4A Protease Inhibitors
A
-
NS3/4A serine protease
- Responsible for cleavage at 4 sites of HCV polyprotein
- NS3 protein ⇒ catalytic subunit
- NS4A protein ⇒ activating cofactor
- Essential for viral replication
- Responsible for cleavage at 4 sites of HCV polyprotein
-
Drugs:
-
Simeprevir [Olysio]
- Resistance a significant issue
- No longer a recommended tx for HCV
-
Voxilaprevir
- Now preferred tx
- Usu. given in combo w/ sofosbuvir and velpatasvir ⇒ combo pill “Vosevi”
-
Simeprevir [Olysio]
39
Q
NS5B RNA Polymerase Inhibitors
A
-
NS5B RNA-dependent RNA polymerase
- Essential for HCV viral replication
-
Sofosbuvir
- Nucleotide analogue
- ⊗ NS5B
40
Q
NS5A Inhibitors
A
NS5A protein ⇒ important role in RNA replication
Drugs in this class include Ledipasvir and Velpatasvir
43
Q
Hep E Virus
Properties
A
- Non-enveloped
- Linear ⊕-sense ssRNA genome
- Caliciviridae family
- Genus within Norovirus group
44
Q
Hep E Virus
Epidemiology & Transmission
A
- Cause of water-borne epidemics throughout world
- Mostly in developing countries
- Transmitted mainly via fecal-oral route
- Fecal contamination of drinking water
- Sporadically ingestion of raw shellfish
- Humans are natural host
- Risk factors for HEV related to poor sanitation
45
Q
Hep E
Clinical Syndromes
A
- HEV causes acute sporadic and epidemic viral hepatitis
- Symptomatic infection most common in young adults aged 15-40 yrs
-
Frequent infection in children, disease mostly asymptomatic or very mild w/o jaundice
- Usu. undiagnosed
- No chronic or carrier state
- HEV mortality rate higher vs HAV, esp. in pregnant women
46
Q
Hep E
Serology
A
