Viral Hepatitis

Front 1

Two temporal "forms" of viral hepatitis:

Back 1

-Acute (A and E)

-Chronic (B, C, D can be acute OR chronic)

Front 2

Acute Hepatitis Clinical Symptoms/Signs:

how do you differentiate which type?

Back 2

-May be Asymptomatic or Symptomatic
-May lead to Fulminant Liver Failure and Death (rare)

-Symptoms (if present) are the same, regardless of cause (A, B, C, D, E, although C usually asymptomatic)
*Nausea, vomiting
*Abdominal pain (right upper quadrant)
*Loss of appetite, Fever, Fatigue
*Diarrhea, light (clay) colored stools, dark urine
*Jaundice (yellowing of skin), icterus (yellowing sclera)

-Differentiated and diagnosed using blood tests for
*Viral antigens
*Antibodies to viruses
*Viruses themselves (eg HBV DNA, HCV RNA)

Front 3

-Which has greater prevalence -- Hep B or C?

Back 3

-B is more prominent globally
-C has higher numbers in the U.S.

Front 4

HCV Overview:

Back 4

-Discovered 1989
-Most common chronic blood borne infection in U.S.
*Vast majority are undiagnosed (it's clinically silent)
-May spontaneously resolve after acute infection (20%), but most often becomes a chronic disease that can lead to cirrhosis and liver cancer
-Transmitted via contact with the blood of an infected person, primarily through sharing contaminated needles to inject drugs
-No vaccine available
-Treatment may lead to viral eradication

Front 5

HCV Viral Structure and Replication:

Back 5

-Linear, single stranded (ss) positive-sense(+) RNA virus
*ssRNA+ viruses: genomes are identical to mRNA

-Belongs to Flaviviridae family

-Enveloped, icosahedral capsid

-Replication very efficient
> 1 trillion virions/day produced

Front 6

HCV Life cycle:

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Front 7

Different strains of HCV:

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Front 8

How does genotype affect treatment of HCV?

Back 8

-Pts. with genotype 2 and 3 more likely than pts. with genotype 1 to respond to current interferon A therapies.

-Recommended duration of treatment impacted by genotype.
*Shorter course treatment for pts. with gt 2 and 3
Longer course treatment for pts. with gt 1

-Duration of therapy is also influenced by other factors
e.g. HCV viral load, on-treatment how fast HCV viral load declines

Front 9

Transmission of HCV:

Back 9

-Blood: percutaneous
*IV drugs, poor medical practices
*Needle sticks
*Sharing razors, toothbrushes (low risk)

-Permucosal
*Perinatal (low risk)
*Sex involving blood (anal)

Front 10

Risk of Needle Stick:

Back 10

-Inefficient transmission by occupational exposures

-After a needlestick or exposure to HCV-infected blood, risk HCV acquisition approximately 1.8-3%
*Associated with hollow-bore needles

-Case reports of transmission from blood splash to eye

-No post-exposure prophylaxis

[infectivity rule of thumb: 30% hbv; 3% hcv; 0.3% hiv]

Front 11

Describe risks of Perinatal Transmission of HCV:

Back 11

-Average rate perinatal infection from HCV-infected woman 5%
*Higher (15%) if woman co-infected with HIV

-No need to avoid pregnancy or breastfeeding
*No need to determine mode of delivery based on HCV status (no indication of C-Section to prevent transmission)
*Breastfeedingdoes not transmit HCV; Consider bottle feeding only if nipples cracked/bleeding

-Prophylaxis not available (no intervention to prevent perinatal transmission available)

-Test infants born to HCV-infected women
*Most infected with HCV at birth have no symptoms, do well during childhood. More research needed re long-term effects perinatal HCV.

Front 12

Why is sexual transmission of HCV unique?

Back 12

-Only occurs in sex involving blood.
~No risk with heterosexual sex.

Front 13

Serologic Pattern of Acute HCV Infection with Recovery:

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-HCV RNA detectable in blood 3-5 days after exposure with rapid rise in levels over subsequent days, followed by rise in alanine aminotransferase (ALT).

-ALT may rise > 10-fold before declining.

-Acute HCV typically subclinical and anicteric

-When symptoms develop they do so after ALT rises.

-Window period = time from exposure to detectable HCV Ab, mean 65-70 days

Front 14

Serologic Pattern of Acute HCV with Progression to Chronic Infection:

Back 14

-disease course from acute infection to chronic state is predictable, with individual variation.

-most (85%) new infections progress to chronic HCV, defined by HCV RNA persistence 6 months.

-pathogenic mechanisms leading to chronicity ill-defined.

-Ab usually detectable in 2-3 months, may take longer

*If someone has the Ab and the virus, they have CHRONIC HCV.

Front 15

Clinical Features of HCV-
Incubation period:
Acute illness:
Chronic infection:
Mortality:

Back 15

Front 16

Mechanisms of Liver Injury in HCV:
direct or indirect?
end state?

Back 16

-HCV is not directly cytopathic
- Viral replication does not directly harm cells

-Host immune response causes liver damage = fibrosis
- With hepatocyte death and impaired liver function, bilirubin accumulates in blood --> jaundice

-Role of humoral immunity is unclear
- antibody response is not protective, re-infection may occur

-Fibrosis = deposition of collagen in response to injury. Eventually liver tissue is converted into structurally abnormal nodules = cirrhosis

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Front 18

HCC and HCV?

Back 18

-Can only progress to HCC after cirrhosis.
-This is a 1˚ liver cancer.

Front 19

Describe decompensation in HCV patients:

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~25% of patients end up decompensating -->
*albumin production goes down
*ascites (scrotum, ankles, etc.)
*Variceal bleeding (esophageal varices; bleeding vv.)
*Hepatic encephalopathy --> drunken symptoms

Front 20

Back 20

-Various liver disease symptoms
-ascites
-splenomegaly
-icterus and jaundice
-Caput medusae (engorged variceals umbilical region)
-spider angioma (liver spots) on chest and back
-gynecomastia

Front 21

What factors make progression to fibrosis in HCV worse?

Back 21

Increased alcohol intake

Age > 40 years at time of infection

Immune suppression: HIV co-infection, post-liver transplant

Chronic HBV co-infection

Others: steatosis

Front 22

Problems with HIV and HCV coinfection:

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-Chronic HCV significant public health concern among HIV-infected populations
*Due to shared transmission routes, HIV/HCV coinfection common, impacting 1/3 HIV-infected persons in U.S.
*HIV accelerates HCV disease course: More rapid progression to cirrhosis, end-stage liver disease, HCC

-HCV a leading cause morbidity and mortality in the highly active antiretroviral therapy era
*HCV-related death most frequent cause non-AIDS-related death
*Lower threshold for treating HCV

Front 23

Extrahepatic Manifestations of HCV:

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-While primary site clinical infection with HCV = liver, some people develop related disease at other sites. These include:
*Mixed cryoglobulinemia
*Porphyria cutanea tarda
*Polyarteritis Nodosa
*Association with DM, B cell non-Hodgkin Lymphoma

Front 24

Back 24

left to right:
Polyarteritis nodosa, Porphyria cutanea tarda, Mixed cryoglobulinemia

Front 25

Describe HCV Treatment:
-what's the standard of care for HCV?
-how do you "cure" it (timeline of treatment)?

Back 25

-You CAN cure HCV; this is called Sustained Virologic Response (SVR).
1) IFN-α --> lots of side effects
2) Ribavirin (RBV) helped in combo with IFN-α.
3) Pegylated IFN-α led to longer t1/2 --> weekly injections

SOC: pegIFN + RBV

-Continue for a time after viral load is zero. Stop meds.
-If 24 weeks after stopping meds the pt still has no viral load, the HCV is cured = SVR
-Currently takes 6-12 months; it's a finite treatment.

Front 26

Describe RBV:
-structure
-mechanism
-guidelines for taking RBV?
-adverse effects?

Back 26

-Nucleoside analogue
-In vitro activity against some RNA and DNA viruses -Does not inhibit HCV-specific enzymes or HCV replication
-Mechanism by which it exerts its effect against HCV is unknown

*Ribavirin monotherapy of no effect in eliminating HCV or improving hepatic histology*
*When used in combination with interferons, has been shown to enhance viral clearance*
Administered orally in pill form
Excreted renally

-Adverse Effects
*Dose-dependent reversible hemolytic anemia
*Teratogenicity (even from male partners taking RBV)

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Adverse effects of pegIFN:

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-It's diffuse, systemic.
-people CAN die from it
-emotional issues are significant
-must weigh risks/benefits.

Front 28

What's the future of HCV treatment?

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-We are developing Direct Acting Antiviral (DAA) agents.
-boceprevir
-telaprevir

-Potential for shorter treatment duration
maybe 3 months in future

Front 29

HBV infects what species?

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Humans and higher apes.

Front 30

Key traits of the HBV genome:

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-Smallest genome of human viruses (except HDV)

-Encodes 4 reading frames for:
- surface antigen (HBsAg)
- core Ag (HBcAg)
- X genes
- polymerase: includes domain for reverse transcriptase enzyme, can copy RNA ->DNA, DNA -> RNA

-Encodes different proteins within same region of DNA in different reading frames

Front 31

HBV Morphology traits:

Back 31

-double-shelled spherical particle comprised of:
*outer Envelope (HBsAg) protein (with Small, Medium, Large sAg proteins)
*inner Nucleocapsid (HBcAg) protein with icosahedral symmetry

-Within nucleocapsid is the partially double stranded circular molecule of HBV DNA

Front 32

Describe HBV's replication strategy:
-why isn't HBV curable?

Back 32

-HBV gains entry into hepatocytes via receptors interacting with HBsAg
-After entry and uncoating, HBV DNA transported to nucleus. Partially double stranded DNA converted to fully double stranded, covalently closed circular DNA (cccDNA)

-cccDNA serves as template for transcription viral RNA
*5-50 copies cccDNA per hepatocyte
*cccDNA stable form of viral DNA that is the most resistant to antiviral therapy and host immunological response
*CCC stuck in our DNA permanently--once we develop chronic HBV, it is NOT CURABLE

-HBV replication through RNA intermediate produced from ccc DNA

Front 33

How does HBV escape from an infected cell?

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-In cytoplasm, nucleocapsid core particles are formed via reverse transcription.
-HBV DNA is produced within the core particle

-Nucleocapsid then assembles with HBsAg molecules in the endoplasmic reticulum to form the virion and is secreted from the cell, by vesicular transport and budding from the plasma membrane.

Front 34

HBV Nomenclature:
HBV:
HBsAg:
HBcAg
HBeAg
Anti-HBs, Anti-HBc, Anti-HBe

Back 34

Front 35

Clinical Overview of HBV:
-range of severity
-mortality
-transmission
-vaccination guidelines

Back 35

-A liver disease caused by HBV. Ranges in severity from a mild illness, lasting a few weeks (acute), to a serious long-term (chronic) illness that can lead to liver disease or liver cancer.

-Mortality 25%

-Transmitted via contact with infectious blood, semen, and other body fluids from having sex with an infected person, sharing contaminated needles to inject drugs, or from a pregnant woman who is infected to her newborn.

-Vaccination recommended for all infants, older children and adolescents who were not vaccinated previously, and adults at risk for HBV

Front 36

Modes of Transmission of HBV:

Back 36

-Sexual = STI; Through exchange
infected bodily fluids

-Perinatal; Vertically, from infected pregnant woman to infant
*Horizontally, within households; Direct contact with open sores of infected person

-Parenteral: Transfusion, blood products, sharing of injection equipment with IDU

Front 37

Should you wear gloves when treating a HBV patient?

Back 37

No.

-stigma, low risk of transmission from contact.

Front 38

[HBV] in various body fluids:
high-
moderate-
low/no-

Back 38

Front 39

Describe Acute HBV infection:

Back 39

-Most adults exposed to HBV have a transient infection which may be accompanied by symptoms (fever, nausea, right sided abdominal pain, vomiting, jaundice, icterus)
*Acute infection is symptomatic more often than HCV.

-Most acute HBV infections in adults result in complete recovery with clearance of HBsAg from the blood and the production of anti-HBs(HBsAb) designating immunity from future infection, without medication (spontaneous resolution)
*sAb is protective

Front 40

Describe Chronic HBV infection:
-Who is most at risk?
-what can it lead to?
-are you okay if you're asymptomatic?

Back 40

-In a proportion of persons with acute HBV, chronic infection develops as a result of failure of the host immune response to eliminate virus.

Up to
*90% of newborns
*30% of children
*5%-10% of adults
*90% of immune deficient adults
with acute HBV develop chronic infection.

-Chronic infection has variable course after several decades resulting in cirrhosis in up to 1/3 and liver CANCER in a proportion with AND WITHOUT cirrhosis

-Lack of symptoms does NOT mean lack of disease severity (same with chronic HCV)

Front 41

HBV Disease Progression:

Back 41

Front 42

Clinical Features of HBV:
incubation period:
clinical illness in acute phase:
mortality, from acute and chronic:

Back 42

Front 43

Typical Serologic Course of HBV acute infection:

Back 43

*IgM indicates acute
*If you fight it off, you'll retain anti-HBs and anti-HBc

Front 44

Typical Serologic Course of HBV chronic infection:

Back 44

-No antibody! IgM drops off.

Front 45

Describe HBV gentotypes:

Back 45

-Not as important in treatment as it is for HCV.

-Some of the variation in outcome of HBV may relate to genetic heterogeneity

-8 HBV genotypes of HBV thus far

-genotype A most common in U.S.

Front 46

Mechanisms of Liver Injury and Viral Clearance in HBV:

Back 46

-HBV is not cytopathic
- Viral replication in hepatocytes does not directly harm/kill cells
- Host immune response causes liver damage = fibrosis and inflammation.

-HBV viral clearance mediated by:
*Humoral immune response (anti-HBs) occurs 1-6 months later- protective immunity from reinfection
*Chronic infection due to inadequate immune responses

Front 47

What are the Goals of HBV treatment?

Back 47

#1: Reduction in the likelihood of long-term sequelae of HBV infection (cirrhosis, hepatocellular carcinoma)
*Sustained suppression of HBV replication
*Improvement in hepatic inflammation, fibrosis
*Since these endpoints arise after many years, studies of pharmacotherapy mostly use short-term surrogate outcomes

End points that can be measured:
**Virologic suppression: Undetectable or low HBV DNA level
*Correlates with clinical outcomes
*Reduction in liver injury test abnormalities (biochemical response)
*Normalization of serum ALT
*Loss of HBsAg +, appearance of HBsAb (rare but optimal)

Front 48

What is currently not possible with treatment of HBV? 2

Back 48

Cure of hepatitis B
Viral eradication

Front 49

HBV Treatment Options: 2 kinds

Back 49

-immunotherapy

-DNA polymerase inhibitors

Front 50

Describe immunotherapy therapy treatments for HBV:

Back 50

– injected, finite duration (6-12 mos)
-interferon alfa, peginterferon alfa
*same bad side effects as with HCV

Front 51

Describe the enzyme treatments for HBV:
-what enzyme is key?
-2 categories? know the names (6)
-How are they metabolized?

Back 51

**Inhibitors of viral DNA polymerase, result in chain termination of nascent HBV DNA strands**

-All taken orally (pills), renally metabolized/require renal dosing, well-tolerated. Vary in potency/ability to suppress HBV DNA. Limitation: resistance

-Nucleoside Analogues
*Lamivudine (oldest)
*Entecavir
Telbivudine

-Nucleotide Analogues
Adefovir
*Tenofovir
Other: *Emtricitabine - Antiretroviral agent for HIV with anti-HBV activity (not licensed for HBV)

*These are also active against HIV; do not use alone in HIV+ patients

Front 52

What are the concerns about resistance in HBV?

Back 52

-Pts must know to take the pills consistently, or risk of viral resistance goes up.
-Providers must keep this in mind when prescribing anti-HBV pills.

Front 53

Recommendations for Counseling in chronic HBV:

Back 53

-Counsel all patients to limit/stop alcohol use
*Tobacco too (factor in HCC development)
-Get Hep A vaccine if not immune
-HCV prevention counseling

-HBV is NOT SPREAD by breastfeeding, kissing, hugging, coughing, ingesting food or water, sharing eating utensils, or casual touching.

-HBV-infected health-care workers should follow published guidelines and applicable laws and regs regarding recommended practices to reduce the risk of HBV transmission.

Front 54

HBV Patient Education to prevent or reduce risk for transmission to others:
-household members/partners
-pregnancy

Back 54

-notify household, sex, and needle-sharing contacts to be tested for markers of HBV
*vaccinate against HBV if susceptible

-use methods (e.g., safe sex, condoms) to protect nonimmune sex partners from acquiring HBV from sexual activity until the sex partners can be vaccinated

-refrain from sharing household articles (toothbrushes, razors, personal injection equipment) that could become contaminated with blood.

Front 55

HBV pt education related to pregnancy:

Back 55

-Pregnant women with chronic HBV should be advised of the need for their newborns to receive hepatitis B vaccine and hepatitis B immune globulin beginning at birth and to complete the hepatitis B vaccine series according to the recommended immunization schedule.

-Passive-active immunoprophylaxis with HBV immunoglobulin + HBV vaccine at birth 95% efficacious in reducing risk transmission

-Offered referral to HBV expert re benefits/risks HBV antiviral therapy
*Possible antiviral meds to select women

Front 56

Describe the HBV vaccine:
-1˚ component?
-schedule?
-protection levels?
-safety?

Back 56

-HBsAg: primary component of the vaccine
Inactivated sAg induces Ab that provides long-term protection against HBV

-3 dose series, typical schedule 0, 1, 6 months

-Effective. Protective levels of Ab:
*30-50% adults after 1 dose
*75-89% after 2 doses
*96-100% after 3 doses

-Safe. Adverse effects rare. No data to link HBV vaccine with multiple sclerosis, autism

-HBIG (immune globulin) available. Preparation of concentrated Abs made from pooled human plasma. Provides protection through passive transfer of Ab
HBIG and HBV vaccination to newborns to prevent perinatal transmission

Front 57

Long term efficacy of HBV vaccine:

who should get one and when?

Back 57

-lifetime protection
-no evidence for booster doses

-everyone, right at birth.

Front 58

Describe Hepatitis Delta:

Back 58

-CANNOT exist without HBV; Needs to be encapsulated by HBsAg (doesn't make its own envelope PROs)

-Composed of a coat of HBV envelope proteins surrounding the nucleocapsid; the virus consists of a single-stranded, circular RNA genome.

-HBV vaccine protects you against HDV

Front 59

2 ways you can get infected with HDV:
-clinical consequences?

Back 59

-HDV only infects persons who are
*Simultaneously infected with HBV (= coinfection) or
*Infected with HBV already (= superinfection, suspect if clinical deterioration)

-Results in more severe liver disease than chronic infection with HBV alone

Front 60

HDV:
natural history-
transmission-
prevention-
diagnosis

Back 60

-Natural history: associated with
*increased risk fulminant hepatitis in acute phase HBV
*increased hepatitis severity during chronic phase HBV

-Transmission:
*Spread through parenteral exposure (blood)
*HDV not found at equal rates in all parts of the world where HBV is endemic. Rare in U.S.

-Prevention:
Since HDV envelope contains HBsAg, HBV vaccine also protects against HDV infection.

-Diagnosis:
Presence of detectable serum HDV-RNA, IHC staining of HDV antigen in the liver, or serum Abs (immunoglobulin M directed against HDAg)

Front 61

HDV global distro:
Genotypes:
Treatment:

Back 61

-Low prevalence in U.S., mostly clustered in high risk groups such as IDUs and immigrants from endemic areas

*In the Asia-Pacific region (e.g. Pakistan), HDV infection remains a major health problem

-8 genotypes
Genotype 1: Europe and North America
Genotypes 2 and 4: Asia
Genotype 3: South America
Genotypes 5–8: Africa

-Treatment:
*Difficult to treat, no satisfactory treatment for patients with HDV
**PegIFN has been primary therapy**

Front 62

Overview of HAV:
-disease course
-treatment
-transmission
-vaccination?
-virology

Back 62

-Causes acute liver disease, lasting days-weeks. Does not lead to chronic infection.
*Most recover with no long-term health problems
*Treatment is supportive, no antivirals

-Transmitted via ingestion FECAL matter, even in microscopic amounts, from close person-to-person contact or ingestion contaminated food.

-HAV vaccination recommended for all children starting at age 1 year, travelers to certain countries, and others at risk.

-Virology: Non-enveloped, ssRNA+
*Family Picornavirus
*Single serotype worldwide

Front 63

Who dies from HAV?

How common is it?

Back 63

-people who are already sick.

~33% of Americans have had it.

Front 64

HOW IS HAV TRANSMITTED?

Back 64

-Blood exposure (to lesser extent than fecal-oral)
-HAV released into bloodstream
*causing transient viremia prior to onset symptoms
*causing brief period in which HAV can be transmitted parentally (e.g. IDU) or by blood transfusion

-Screening of blood products for HAV has essentially eliminated the already extremely low risk associated with transfusion.

Front 65

HAV Clinical features-
incubation:
jaundice by age group:
duration of sx:
complications:
death:
sequelae:

Back 65

Front 66

Clinical Features of HAV:
how does appearance of sx coincide with Ab development?
how severe are sx by age group?

Back 66

-Symptoms usually appear coincident with the initiation of immune response
*Development IgM antibodies specific for HAV structural proteins
*IgM anti-HAV is serologic marker of acute HAV, used for diagnosis to distinguish HAV from other forms acute viral hepatitis

-Generally symptoms more severe in adults then in children.

-In endemic regions where sanitation poor, nearly all children become infected in first few years of life, most remain asymptomatic.

Front 67

Prevention of HAV:
-vaccination guidelines
-other controls
-quick protective measures

Back 67

-Vaccination (pre-exposure)
*Inactivated HAV antigen
*Standard 2-dose schedule, also combined with HBV vaccine in 3-dose schedule
*Highly immunogenic: 97%-100% have protective levels of Ab within 1 month of receiving first dose

-Good hygiene

-Clean water systems; avoidance of food contamination

-Immune globulin delivery for rapid protection

Front 68

How are we doing in the fight against HAV?

Back 68

-Rate of vaccination is being countered by contaminated food importation.

Front 69

HEV Overview:

Back 69

-A lot like A

-Like HAV, HEV is non-enveloped , single-stranded, positive-sense RNA virus
*Family Caliciviridae

-E = think pregnancy
**Symptoms more severe in pregnant women, for whom HEV infection can be life threatening.**

-Treatment supportive, no antivirals

-Transmitted via ingestion of fecal matter

Front 70

Clinical Features of HEV:
incubation period:
fatality:
severity and age:
sequelae:

Back 70

Front 71

Summary of A through E:
-source
-transmission
-chronic infection
-prevention

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