Viral Hepatitis

By: Yilak G

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 Objectives
• Up on completion of this topic you will be able to

• Differentiate the five types of viral hepatitis by their epidemiology,

etiology, pathophysiology, clinical presentation and natural history

• Identify modes of transmission & risk factors of viral hepatitis

• Evaluate hepatic serologies to diagnose hepatitis infection

• Recommend an appropriate pharmacotherapeutic agent for prevention

and treatment of viral hepatitis

• Formulate a monitoring plan to assess side effects of agents used to treat

viral hepatitis
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 Hepatitis
• Hepatitis: inflammation of liver parenchyma or
hepatocytes.

• The are two types : duration based

• Acute hepatitis: duration for < 6 months
• Chronic hepatitis: lasting for ≥ 6 months

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Acute Viral Hepatitis
• Diffuse liver inflammation lasting less than 6 months

• Almost all cases are caused by one or more of the five

hepatitis viral agents:
• HAV, HBV/HDV, HCV, HEV

• All of which are RNA viruses except HBV

• HDV is a defective RNA virus

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Chronic Viral Hepatitis
• Chronic hepatitis (lasting longer than 6 months) is
usually associated with hepatitis B, C, and D.

• May lead to the development of cirrhosis, which may

induce end-stage liver disease (ESLD).

• Complications of ESLD include ascites, edema, hepatic

encephalopathy, SBP, Variceal bleeding, HRS,
thrombocytopenia, anemia, and HCC.
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 Acute viral hepatitis: clinical features
1. Prodromal phase: 3-9 days
• Pts experience A, N, V, alterations in taste, arthralgias, malaise, fatigue
& pruritus. Pts are often diagnosed as having gastroenteritis.
2. Icteric Phase: 2-4 wks
• Jaundice, dark urine, pale-colored stools.
• Pts become icteric & may develop RUQ pain with hepatomegaly.
3. Convalescence phase:
• Signs & symptoms gradually disappear
• Jaundice may persist for some times due to affinity of bile pigment
to elastic tissue
• Complete recovery may take up to 6 months
• Severe cases may result in Fulminant Hepatitis:
• Hepatic Encephalopathy
• Hepatorenal syndrome
• Bleeding 6
 Diagnostic approach
• Viral Markers
• LFT
• Increase serum bilirubin (total, indirect and direct)
• Increase ALT, AST
• Increase ALP, GGT
• aPTT, PT, INR: prolonged value may
• Reflect a severe hepatic synthetic defect
• Signify extensive hepatocellular necrosis
• Indicate a worse prognosis
• Albumin level (serum albumin decreases)
• Blood : Leucopenia with relative lymphocytosis, increase ESR

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 Acute hepatitis: HAV
• Common cause of acute hepatitis
• Transmission fecal-oral route; contaminated water and
food
• Generally occurs in late fall and early winter
• It almost always manifests with a self-limited clinical
course
• AST & ALT levels usually return to reference ranges
over 5-20 weeks.

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HAV: Risk Factors
• Ingestion of contaminated food substances
• Family member who is affected
• Poor personal hygiene
• Institutional resident who is affected
• Child care centers
• Neonatal intensive care units
• Use of injectable drugs
• Overcrowding
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Clinical presentation
• Incubation period
• 15 to 45 days

• Mean: ~4 weeks

• viral shedding in feces, viremia, and infectivity

diminish rapidly once jaundice becomes apparent

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Diagnostic Approach

• History: particular attention to risk factors

• Physical examination

• Diagnosis of hepatitis A is based on detection of IgM

anti-HAV during acute illness

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 Laboratory tests
• IgM anti-HAV is the diagnostic test of choice
• Appears very soon after infection
• Disappears 3–6 months later
• Incidental presence of rheumatoid factor can yield false-positive
results
• IgG anti-HAV appears later in the acute phase but persists for
decades
▪ Diagnostic tests to rule out acute hepatitis due to other viruses
▪ Liver enzymes and function
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 Complications
• Relapsing hepatitis: characterized by:
• Recurrence of symptoms
• Elevated liver enzyme levels
• Jaundice (occasionally)
• Fecal excretion of HAV
• Even when this occurs, it remains self-limited and does not
progress to CLD.
• Cholestatic hepatitis -Characterized by protracted cholestatic
jaundice and pruritus
• Fulminant hepatitis (massive hepatic necrosis)
• Rare
• Primarily in older adults and in persons with underlying
CLD
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Prognosis
• Virtually all previously healthy pts with hepatitis A
recover completely from their illness, with no clinical
sequelae.
• Complete clinical and biochemical recovery is to be
expected in 1–2 months.
• No chronic carrier state

• Fatality rate: approximately 0.1%

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Acute viral hepatitis B
• The virus particle
(virion) consists of an
outer lipid envelope
and an icosahedral
nucleocapsid core
composed of protein.
• The nucleocapsid
encloses the viral
DNA.

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Risks for infection
• Spouse of an acutely infected person
• Unprotected sex with multiple partners
• Health care workers exposed to blood
• IVDU
• Repeated blood transfusions
• Family members of chronically infected persons
• Pts on hemodialysis
• Recipients of a transplanted organ
• An infected mother for her child

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Transmission
Through infected blood or body fluids
• Percutaneous: needle sharing
• Perinatal
• Likelihood of perinatal transmission correlates with
presence of HBeAg.
• Rate of transmission to offspring
• 90% if mother is HBeAg positive
• 10–15% if mother is anti–HBe positive
• Sexual 18
 Natural history of acute infection
• Incubation period: 30–180 days, typically 3 months

• Most infections are asymptomatic

• More likely to be severe in pts co-infected with hepatitis C or D

• >90 to 95% adults self limited

• 90% neonatal infection chronicity

• 1% fulminant hepatitis

• Cirrhosis

• HCC
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 Laboratory tests
• Serum HBsAg: indicative of acute or chronic HBV infection
• Serum IgM anti-HBc: indicative of acute HBV infection
• Serum IgG anti-HBc: indicative of chronic HBV infection
• HBeAg: associated with high infectivity
• Anti-HBs
• Immunization with HBsAg (after vaccination)
• Hepatitis B in the remote past
• False-positive result
• Quantitative HBV DNA
• Typically < 0.5 pg/ mL in acute infection
• Levels > 0.5 pg/ mL associated with chronic infection
• Useful in chronic disease to assess viral activity
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Diagnosis

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Chronic hepatitis B
All forms of chronic hepatitis B are progressive

The main aims of treatment are:

• Suppress the virus to achieve HBeAg seroconversion or

undetectable viral-DNA levels, or both

• Stop or reduce hepatic necroinflammation

• Prevent the development of hepatic decompensation

• Reduce cirrhosis and HCC

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Hepatitis C virus
• Symptomatic acute hepatitis C occurs in only about
15% of pts who are infected.

• A major cause of chronic hepatitis, cirrhosis, and HCC

around the world

• Symptomatic pts are more likely to spontaneously clear

the virus than are asymptomatic pts

• Testing for HCV RNA by PCR is the only reliable test

for the diagnosis of acute infection
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Transmission
▪ Percutaneous: accounts for 90% of transmissions
▪ IVDU
▪ Accidental needle stick
▪ Hemodialysis
▪ Organ transplantation
▪ Transfusion
▪ Perinatal
▪ Accounts for ~5% of transmissions
▪ Sexual
▪ Accounts for ~5% of transmissions

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Natural history of HCV infection

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 Chronic hepatitis C
• Milder forms are nonprogressive or only slowly progressive

• More severe forms may be associated with scarring and

architectural reorganization,
• When advanced, leads to cirrhosis, liver failure, or HCC.

• Clinical presentation varies from asymptomatic infection to

ESLD.

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 Hepatitis E virus
• Transmitted by the fecal-oral route
• Has a self-limited clinical course in most cases
• Results in fulminant hepatitis in 10–20% of pregnant
women
• Primarily affects young adults: 20–40 years of age
• Risk factors for hepatitis E
• Residence or travel to endemic area
• Ingestion of contaminated water or food
• Risk factors for developing fulminant hepatitis HEV
• Pregnancy, especially third trimester

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 Transmission
• Fecal-oral route
• Eating or drinking contaminated food or water

• Transmission from person to person occurs less commonly

than with hepatitis A virus

• HEV is excreted in the stool during the late incubation period

• Pregnancy
• Can be transmitted from mother to newborn

• High mortality among infected infants

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Diagnosis

• Incubation period: 14–60 days (mean, 40 days)

• Clinically resembles hepatitis A.

• History and physical examination, with particular

attention to risk factors

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Laboratory tests
• Serologic tests
• IgG anti-HEV
• IgM anti-HEV
• Polymerase chain reaction (PCR)
• HEV RNA by reverse transcription PCR is
available in some research laboratories.

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Prognosis
• Self limited: no chronic carrier state

• Fulminant hepatitis
• 1–2% of all cases
• Occurs in 10–20% of pregnant women with HEV

• Case-fatality rate
• Similar to the rate of fulminant hepatitis

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Chronic HDV hepatitis
• Follow acute co-infection with HBV

• Increases the severity of HBV but not rate of chronicity

• Super infection

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 Prevention and Treatment of Viral Hepatitis
• General outcomes for treating hepatitis are to:
• Prevent the spread of the disease
• Prevent and treat symptoms
• Suppress viral replication
• Normalize hepatic aminotransferase
• Decrease morbidity & mortality by preventing
cirrhosis, HCC & ESLD.
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 General Approach
• Management involves both prevention and treatment.
• There is no specific pharmacologic treatment for acute
viral hepatitis A, B, C, D, or E; only supportive care is
available.
• Hospitalization is required in individuals experiencing
significant N, V, D & encephalopathy.
• Liver transplantation may be required in rare instances if
fulminant hepatitis develops.
• Pts with viral hepatitis B, C & D may develop CLD
leading to ESLD.

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 Hepatitis A Prevention

• Good personal hygiene & proper disposal of sanitary waste.

• Frequent hand washing with soap & water after using the
bathroom & prior to eating meals
• Drinking bottled water
• Avoiding fruits & vegetables harvested from sewage-
contaminated water in areas where HAV is most endemic

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Immune Globulin
• Provides passive immunization against hepatitis A.

• Intramuscular (IGIM) administration.

• IGIM does not confer lifelong immunity, but it is

effective in providing pre-exposure and post exposure
prophylaxis against HAV.

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Pre-exposure Prophylaxis
• PrEP with IGIM is indicated for individuals at high risk
of acquiring HAV who cannot receive the hepatitis A
vaccine (e.g., because of allergy to the components).
• Travelers who plan to depart for endemic areas within 2
wks and have not yet received the vaccine should
receive IGIM because active vaccine immunity takes
several weeks to develop.
• A dose of 0.02 mL/kg confers immunity against
hepatitis A for less than 3 months and doses of 0.06
mL/kg provide immunity up to 5 months.

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Post exposure Prophylaxis
• Candidates: individuals in contact with people infected
with acute HAV, including household and sexual
partners, staff and children from day care facilities, and
food handlers of restaurant
• The risk of infection may be decreased by 90% if IGIM
is given within 2 wks of being exposed to the HAV.
• IGIM may still be beneficial
• if it is given more than 2 wks after exposure to a
known case of HAV
• as it may decrease the severity of hepatic damage.

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Hepatitis A Vaccine
• Two inactivated hepatitis A vaccines, HAVRIX &
VAQTA, are effective in providing active immunization.
• HAVRIX contains 2-phenoxyethanol as a preservative but
VAQTA is preservative-free.

• May provide effective immunity for 8 years.

• Adverse effects: injection site reactions (e.g., tenderness,

pain & warmth), headaches within 5 days after
vaccination, and fatigue.
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Recommended IM Doses of HAV Vaccines

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Hepatitis B Prevention
Hepatitis B Immune Globulin

• Provides passive immunization: PEP against the HBV.

• Should only be administered intramuscularly.

• Side effects: erythema at the injection site, headaches,

myalgia, fatigue, urticaria, N & V

• Serious adverse effects are rare and may include liver

function test abnormalities, arthralgias & anaphylactic
reactions.
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Hepatitis B Prevention
Post exposure Prophylaxis
• A single dose of HBIG of 0.06 mL/kg is 75% effective in preventing
hepatitis B infections if administered within 14 days of exposure.
• Mothers who are HBsAg positive should have their newborns
immunized with both the hepatitis B vaccine and HBIG 0.5 mL
• 85% effective in preventing the hepatitis B carrier status if
administered within 24 hours of birth.
• If the mother is HBsAg negative, the newborn should be given only
the hepatitis B vaccine

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Hepatitis B Prevention
Hepatitis B Vaccine
• Two hepatitis B vaccines available: Recombivax HB
& Engerix-B.
• Should be administered IM (anterolateral thigh region
in neonates & infants; deltoid region in adults).
• S/E: local reactions at the injection site (pain,
tenderness, erythema, swelling & pruritus), fevers,
headaches, dizziness, and irritability.
• Anaphylaxis & hypersensitivity reactions (rarely and
occur within a few hours after administration).
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Recommended IM Dosing Regimens for HBV B
Vaccines

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Chronic Hepatitis B Treatment
• Pts who are hepatitis B carriers (positive HBsAg, normal ALT
levels, and negative HBeAg) should not be treated because
hepatitis B antiviral agents rarely result in HBeAg
seroconversion, and long-term treatment leads to drug
resistance.

• Pts with elevated ALT and HBV DNA levels (regardless of

the presence or absence of HBeAg) require treatment to delay
progression to cirrhosis and prevent the development of
ESLD. 45
 Indications for antivirals in chronic HBV infection
• All patients with cirrhosis (decompensated) and any detectable viral
load: Irrespective of ALT and HBeAg status
• If no liver cirrhosis, one of the following is an indication
• HBV DNA > 20,000 IU/ml a elevated ALT (above UNL): Irrespective of
HBeAg statusnd
• Detectable HBV DNA or elevated ALT (above UNL): Irrespective of
HBeAg status
• Age above 30, HBeAg-positive and HBV DNA > 2,000: Irrespective `of
ALT
• Co-infection with HIV
• Patients with chronic HBV to be started on immunosuppressives.
• Extra hepatic manifestation
• Indications for antiviral in acute HBV infection
• Presence acute liver failure or fulminant hepatitis with detectable HBV DNA.
 Interferon and Peyglated Interferon
• Interferon therapy has an advantage over other antiretroviral
treatment
• As effective in suppressing, and in some cases ceasing,
viral replication without inducing resistance.
• Approximately one-third of HBsAg-positive pts become
seronegative after 4 to 6 months of Rx.
• The HBeAg seroconversion rate is 18% greater than those
who are not treated.
• The durability (likelihood of developing and sustaining
HBeAg seroconversion) is >80% after treatment
discontinued.
• If interferon treatment duration is extended to 12 to 24 wks,
HBsAg loss is observed in about 10% of pts.
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Interferon and Peyglated Interferon
• Pts treated with unmodified interferon have undetectable
HBV DNA and normal ALT levels ranging from 60% -
70%;
• However, the rate of sustaining virologic response once
therapy discontinued is approximately 20%.
• Pts with HBeAg-negative chronic hepatitis B should be
treated with more than 12 months of therapy.
• When the duration of interferon therapy is prolonged
beyond 12 months,
• Undetectable HBV DNA may be sustained, as well as
increasing the chance of losing HBsAg.

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• Interferon alfa-2b Sc 5 million units daily or 10 million
units three times weekly in pts who are HBsAg-positive
• The dose for HBsAg-negative pts is 5 to 6 million units
three times weekly.

• Pegylated interferon alfa-2a for chronic hepatitis B 180 mcg

Sc once weekly.

• Interferon doses may need to be adjusted in pts with renal

impairment.
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Tenofovir (TDF)

• Tenofovir (Tenofovir disoproxil fumarate) (TDF)

• First line
• 300mg PO once daily
• Avoid in patients with GFR <60ml/min
Lamivudine (3TC)

• Effective in suppressing hepatitis B viral replication, normalizing

ALT levels, and improving liver histology.
• Pts with HBeAg-positive chronic hepatitis B may have a similar or
a superior response in achieving these endpoints when compared to
interferon.
• A significant loss of serum HBV DNA level was observed in 44%
of subjects receiving 3TC compared to 16% receiving placebo.
• Normalization of ALT levels and improvement in histology
occurred in approximately 50% of pts with HBeAg-positive
hepatitis B.
• 3TC resistance has been reported at 14% after 1 year of treatment
and increases to 70% at 5 years.
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• Compared with placebo, 60% to 70% of pts with
HBeAg-negative hepatitis B treated with 3CT for 52 wks
have undetectable HBV DNA and normal ALT levels.
• Rate of relapse is 80% to 90% when treatment is
discontinued.
• 3TC 100 mg po QD
• The dose must be adjusted in pts with CrCl less than 50
mL/minute.
• Adverse effects: fatigue, D, N, V and headaches.
• In rare cases, pancreatitis, hepatomegaly, and fatal lactic
acidosis

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Adefovir Dipivoxil
• A prodrug of adefovir, an adenosine nucleotide analog
that inhibits DNA polymerase.
• Adefovir dipivoxil 10 mg po QD
• Undetectable HBV DNA levels were observed in 21% of
pts treated for 48 wks and in 56% of pts when the
treatment duration was extended to 144 wks.
• Unlike 3TC, extending the duration of adefovir dipivoxil
therapy resulted in a relatively low resistance rate, 11%
after 3 years.
• The percentage of seroconversion and loss of HBeAg are
comparable to pts who received 3TC.
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• HBeAg-negative chronic hepatitis B have a significant
response, but the response is not sustained after treatment
discontinuation.
• Serum ALT levels normalized in 72% of pts treated for
48 weeks compared to 29% who received placebo.
• Additionally, 51% had undetectable HBV DNA levels
with adefovir, whereas none achieved in placebo arm
• S/E: asthenia, abdominal pain, diarrhea, dyspepsia,
headaches, nausea, and flatulence.
• Lactic acidosis, pancreatitis, and hepatomegaly rarely
• Dose-related nephrotoxicity
• dose adjustment in pts with CrCl less than 50 ml/min
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Entecavir
• A guanosine nucleoside analogue that inhibits HBV DNA
polymerase, thereby inhibiting DNA replication.
• 0.5 mg QD for 52 wks are comparable to 3TC 100 mg QD in
histologic improvement, viral load reduction, and normalization
of ALT levels.
• Resistance to 3TC have significant improvement in histology
while receiving entecavir, but higher doses (1 mg QD)
• Resistance seen in pts who had 3TC resistance.
• S/E: lactic acidosis and severe hepatomegaly with steatosis
• Dosage adjustment in pts with renal dysfunction
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Chronic Hepatitis C Treatment
Interferon or Peyglated Interferon plus Ribavirin

• Interferon alfa-2a, interferon alfa-2b

• However, they are not prescribed alone because only 12% to 16% of pts
achieve a sustained virologic response (SVR).

• Adding ribavirin, a synthetic guanosine analogue that inhibits viral

polymerase, increases SVR to 45% - 55%.

• Individuals with genotype 2 or 3 achieve an SVR of 75% to 85% compared

to 40% to 50% for pts with genotype 1.
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Antivirals for HAV in Ethiopia
• First line pangenotypic regimen
• Sofosbuvir/velpatasvir combination (400 mg of sofosbuvir and
100 mg of velpatasvir), one tablet once daily for 12 weeks.
• Alternative regimen
• Sofosbuvir 400 mg oral once daily + Daclatasvir 60mg oral once
daily for 12 weeks
• Recommended regimen for treatment-naive pts with
HCV genotype 1 who are eligible to receive IFN.
• Sofosbuvir 400 mg po daily and RBV (1000 mg [<75
kg] to 1200 mg [≥75 kg]) plus weekly PEG IFN-2a
180 mcg for 12 wks

• Sofosbuvir is a prodrug of a nucleotide analogue

inhibitor of the HCV RNA polymerase.

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• Recommended regimen for treatment-naive pts with
HCV genotype 1 who are not eligible to receive IFN
• Daily sofosbuvir (400 mg) plus simeprevir (150 mg),
with or with out RBV (1000 mg [<75 kg] to 1200 mg
[≥75 kg) for 12 weeks

• Simeprevir is a specific inhibitor of the HCV protease.

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• Recommended regimen for treatment-naive pts with
HCV genotype 2, regardless of eligibility for IFN
therapy:
• Daily sofosbuvir (400 mg) and RBV (1000 mg [<75
kg] to 1200 mg [≥75 kg]) for 12 weeks

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• Recommended regimen for treatment-naive pts with HCV
genotype 3, regardless of eligibility for IFN therapy:
• Daily sofosbuvir (400 mg) and RBV (1000 mg [<75 kg]
to 1200 mg [≥75 kg]) for 24 weeks

• Daily sofosbuvir (400 mg) and RBV (1000 mg [<75 kg] to

1200 mg [≥75 kg]) plus weekly PEG INF for 12 wks is an
acceptable regimen.

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• Recommended regimen for treatment-naive pts with HCV
genotype 4 who are eligible to receive IFN
• Daily sofosbuvir (400 mg) and RBV (1000 mg [<75 kg]
to 1200 mg [≥75 kg]) plus weekly PEG IFN for 12 wks

• Recommended regimen for treatment-naive pts with

genotype 4 who are not eligible to receive IFN
• Daily sofosbuvir (400 mg) plus RBV (1000 mg [<75 kg]
to 1200 mg [≥75 kg]) for 24 weeks
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• Recommended regimen for treatment-naive pts with HCV
genotype 5 or 6
• Daily sofosbuvir (400 mg) and RBV (1000 mg [<75 kg]
to 1200 mg [≥75 kg]) plus weekly PEG IFN for 12 wks
• Daily weight-based RBV (1000 mg [<75 kg] to 1200 mg
[≥75 kg]) plus weekly PEG IFN for 48 wks is an
acceptable regimen.

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• Most pts treated with either interferon or PEG IFN
experience flulike symptoms (fevers, chills & myalgia).

• Psychiatric (irritability, depression & suicidal ideation).

• Thrombocytopenia, neutropenia, or anemia.

• The dose should be decreased by 50% if granulocyte
or platelet counts decline to <750/mm3 and
50,000/mm3, respectively.

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• Profound thrombocytopenia (<30,000/mm3) or neutropenia
(<500/mm3); serious changes in mood or behavior and
intractable nausea, vomiting, or fatigue warrant the
immediate discontinuation of IFN-α

• Uncommon S/E: cardiac arrhythmias, DM, thyroid disorders,

amenorrhea & retinopathy (vision disturbances).

• Ribavirin: dose-related hemolytic anemia & teratogenicity

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