• The virus• Epidemiology• Transmission• Post exposure prophylaxis• Clinical manifestations• Diagnostic tests• Hbv - coinfection (HDV/HCV)• Extrahepatic manifestations• Prognosis & survival• antiviral therapy• Vaccination

1. ‫الرحيم‬ ‫الرحمن‬ ‫هللا‬ ‫بسم‬
(‫علما‬ ‫زدنى‬ ‫رب‬ ‫وقل‬)

2. HEPATITIS B INFECTION
( HBV )
a major infectious disease
Dr.Magdy Ahmed Eldaly, MD , DTM , MSc
Consultant
Gastrointestinal, Liver Diseases & Tropical Medicine
Faculty of Medicine – Cairo University

4. • THE VIRUS
• EPIDEMIOLOGY
• TRANSMISSION
• POST EXPOSURE PROPHYLAXIS
• CLINICAL MANIFESTATIONS
• DIAGNOSTIC TESTS
• HBV - COINFECTION (HDV/HCV)
• EXTRAHEPATIC MANIFESTATIONS
• PROGNOSIS & SURVIVAL
• ANTIVIRAL THERAPY
• VACCINATION

6. THE VIRUS , AT A GLANCE
• HBV is one of the smallest viruses known to infect humans, and belongs to the Hepadnaviridae
family.
• It is a hepatotropic virus, and liver injury occurs through immune-mediated killing of infected liver
cells.
• It replicates through an RNA intermediate and can integrate into the host genome.
• The virus may retain infectivity for at least 1 month at room temperature.
• HBV is also a recognized oncogenic virus that confers a higher risk of developing Hepatocellular
Carcinoma (HCC).
• The genome encodes HBsAg, HBcAg, the viral polymerase and the HBx protein.
• The virus circulates in serum as a double-shelled particle, with an outer envelope component of
HBsAg and an inner nucleocapsid component of hepatitis B core antigen (HBcAg).
• HBV DNA can be detected in serum and is used to monitor viral replication.
• HBeAg, unlike HBsAg and HBcAg, is not particulate, but rather is detectable as a soluble protein in
serum. It has been used clinically as an index of viral replication, infectivity, severity of disease, and
response to treatment.
• HBeAg may play a role in perpetuating viral infection during perinatal transmission, often resulting
in chronic infection and eliciting HBe/HBcAg-specific T helper cell tolerance in utero.

7. EPIDEMIOLOGY
• HBV infection is one of the most important infectious diseases worldwide.(? HIV x HBV)
• Approximately one third (1/3 )of the world’s population has serological evidence of past or
present infection with the hepatitis B virus (HBV).
• 2nd Carcinogenic after Tobacco – WHO.
• An estimated 400 million people are (HBsAg) carriers. (majority in sub-Saharan Africa,
Southeast Asia, Eastern Europe, and the Middle East).
• Around one million persons die of HBV-related causes annually.
• The major complications of CHB are cirrhosis and hepatocellular carcinoma (HCC).
• The majority of people are unaware of their HBV infection, and therefore often present with
advanced disease.
• However, this figure underestimates the true HBV mortality rate due to inadequate disease
and cancer surveillance in many resource-poor countries where HBV is endemic.
• HBV-related hepatocellular carcinoma is the most common cancer among men and third
most common among women. HBV therefore represents a critical threat to health in the
African continent.

8. TRANSMISSION ( FROM MAN TO MAN) Incubation period = 30-180 days
Perinatal - vertical
( mother to her baby )
• may occur in utero, at the time of birth, or
after birth- > 90%.
• (East Asia, S.East Asia)
• related to the mother’s HBV replicative
rate
Percutaneous • IVDU-syrings,needles
• shaving razors, toothbrushes
• acupuncture, tattooing, and body piercing
Europe and the USA about 15% of newly
diagnosed HBV infections ( IVDU )
Sexual ? Saliva,Vaginal Secretions., Semen • 40% heterosexual intercourse
• 25% occurs in (MSM)- USA
Horizontal
( person to person )
• minor breaks in the skin or mucous
membranes
• close contact with other children
• contaminated toothbrushes, razors and
even toys
• infancy/childhood-Africa
• family members(living with HBVsAg +ve
person for long period) have a higher risk
of HBV transmission
Blood Transfusion HBsAg and anti-HBc (Blood test) has significantly decreased
Nosocomial • patient to patient,
• from patient to health care worker
• (& vice versa)
• including needle-stick injury
• HBV is considered the most commonly
transmitted bloodborne virus in the
healthcare settings.
Organ transplantation transplantation of extrahepatic organs from HBsAg-positive donors (e.g., kidney)

10. POSTEXPOSURE PROPHYLAXIS
In case of exposure to HBV in any of the circumstances mentioned above:
• Postexposure prophylaxis is recommended for all non-vaccinated persons.
• A passive-active immunization is recommended.
• The first dose of passive and active immunization should be given as early as possible.
• 12 hours after the exposure is usually considered the latest time point for effective postexposure
prophylaxis.
• One dose of hepatitis B-immunoglobulin (HBIG) should be administered at the same time, if the
source is known to be HBsAg-positive.
• The other two doses of vaccine should be administered after 4 and 12-24 weeks.
• Vaccinated individuals with a documented response do not need postexposure prophylaxis.
• Individuals who have had no post-vaccination testing should be tested for anti-HBs titer as soon
as possible.
• If this is not possible, or the anti-HBs titer is insufficient (<100 IU/l), they will require a second
course of vaccination.
• Individuals who are documented non-responders will require two doses of HBIG given one month
apart.

11. HBV- Clinical Outcomes of Acute Hepatitis B infections
Acute Hepatitis B
Resolution HBVsAg +ve >6 months
Resolution
Chronic
Persistent
Hepatitis Extrahepatic
Disease
PAN - GN
Asymptomatic
Carrier
Chronic
Active
Hepatitis
HCC Cirrhosis
Fulminant Hepatitis
1 %90 %
9 %
50 %

12. CLINICAL MANIFESTATIONS DEPEND ON SEVERITY AND STAGE
Acute hepatitis B
• A symptomatic in most of cases ( Flu like symptoms-subclinical or anicteric hepatitis).
• A serum sickness-like syndrome may develop in prodromal phase (Fever, skin rash, arthralgia
and arthritis).
• The most prominent clinical symptoms of acute hepatitis are: RUQ discomfort, nausea,
jaundice and other unspecific constitutional symptoms.
• Acute hepatitis B is usually a self-limiting disease marked by acute inflammation and
hepatocellular necrosis, with a case fatality rate of 0.5–1% (Fulminant Hepatitis – Fulminant
Hepatic Failure).
• In case of coinfection with other hepatitis viruses or other underlying liver disease the clinical
course may be more severe.
• The symptoms including jaundice generally disappear after one to three months, but some
patients have prolonged fatigue even after normalisation of serum aminotransferase
concentrations.
• Concentrations of (ALT and AST) may rise to 1000-2000 IU/L in the acute phase ,ALT is
typically higher than AST.
• Bilirubin concentration may be normal in a substantial portion of patients.
• In patients who recover, normalisation of serum ALT&AST usually occurs within one to four
months. Persistent elevation of serum ALT for more than six months indicates progression to
chronic hepatitis.

13. CLINICAL MANIFESTATIONS DEPEND ON SEVERITY AND STAGE
Chronic hepatitis B (CHB)
• CHB is defined as persistent HBV infection (the presence of detectable [HBsAg] in the blood or serum for
six months or more) ,with or without associated active viral replication and evidence of hepatocellular
injury and inflammation(HBVeAg/HBV DNA/ALT/AST/APRI).
• The spectrum of disease and natural history of CHB infection are diverse. In some people, CHB is inactive
and does not lead to significant liver disease.
• In others, it may cause progressive liver fibrosis, leading to cirrhosis with end-stage liver disease, and a
markedly increased risk of hepatocellular carcinoma (HCC), independent of the presence of cirrhosis –
usually many years after initial infection.
• Age is a key factor in determining the risk of chronic infection.
• Chronicity is common following acute infection in neonates (>90% of neonates born to [HBeAg]-positive
mothers) and in young children under the age of 5 years (20–60%), but occurs rarely (<5%) when
infection is acquired in adulthood.
• Worldwide, the majority of persons with CHB were infected at birth or in early childhood.
• Most patients with CHB are clinically asymptomatic. Some may have nonspecific symptoms such as
fatigue. In most instances, significant clinical symptoms will develop only if liver disease progresses to
decompensated cirrhosis.
• In addition, extrahepatic manifestations may cause symptoms.

14. CLINICAL MANIFESTATIONS- CHB
• A physical examination will be normal in most instances.
• In advanced liver disease there may be clinical signs of chronic liver disease such as:
• Abdominal distension,Hepatomegaly,Splenomegaly,Spider angioma
• Caput medusae, Palmar erythema, Testicular atrophy,Gynecomastia,etc.
• In patients with decompensated cirrhosis may be presented with:
• Jaundice, Ascites, GI bleeding, Peripheral edema, and Encephalopathy
• Laboratory testing shows mild to moderate elevation in serum AST and ALT in most
patients, whereas normal transaminases occur rarely.
• During exacerbation, serum ALT concentration may be as high as 50 times the upper
limit of normal.
• Alpha-fetoprotein (AFP) concentrations correlate with disease activity. In
exacerbations of hepatitis B, concentrations as high as 1000 ng/mL may be seen.

15. SIGNS OF CHRONIC LIVER DISEASE
Hands
 Palmar Erythema
 Clubbing
 Dupuytren’s contracture
 Leukonychia
 Flapping tremors
H&N – Upper Body
 Parotid enlargement
 Jaundice
 Fetor hepaticus
 GI Bleeding ( upper – lower)
 Spider nevi
 Gynaecomastia ( in Males )
 Scratch marks
 Loss of weight - muscle atrophy
 Breast atrophy ( in Females)
Abdomen
 Abdominal Distension
 Ascites – congested veins
 Caput medusa
Lower Limb Odema
Encephalopathy
COMA

16. DIAGNOSTIC TESTS
Acute HBV infection
• HBVsAg +ve & HBVc Ab IgM (+ve)
• HBVeAg and HBV DNA ( also present )
• Recovery is accompanied by the disappearance of HBV DNA, HBVeAg to anti-HBe
seroconversion, and subsequently HBsAg loss or seroconversion to anti-HBs.
• The differential diagnosis of HBsAg-positive acute hepatitis includes:
• acute hepatitis B exacerbations of chronic hepatitis B
• reactivation of chronic hepatitis B
• superinfection of a hepatitis B carrier with hepatitis C or D virus
• acute hepatitis due to drugs or other toxins in a hepatitis B carrier

17. DIAGNOSTIC TESTS – CHB
• All patients with CHB should be regularly monitored for progression of liver disease because
HBV DNA and ALT levels vary during the course of infection.
• In addition, patients who are not candidates for treatment at the time of presentation may
become candidates for treatment during follow-up.
• HBeAg and HBV DNA, should be performed to determine if the patient should be considered
for antiviral therapy.
• Inactive carrier state : HBeAg- ve ,normal ALT and HBV DNA (<2000 IU/mL) or
undetectable. (good prognosis-No Antivirals)
• Alanine aminotransferase (ALT), a marker of liver cell inflammation.
• Repeat periodic testing is indicated because the ALT levels can fluctuate (eg, from less than
the upper limit of normal to intermittently or consistently elevated).
• Sustained and intermittent elevations in ALT beyond the upper limit of normal are indicative
of hepatic inflammation and correlate with an increased risk of progressive liver disease.
• It must be noted that the normal ALT ranges are both age and sex dependent and,
occasionally, individuals with severe liver disease may not manifest elevated ALT.
• (Cornberg 2011, EASL 2012).

18. DIAGNOSTIC TESTS - Assessment of liver disease
• An assessment of the severity of liver disease needs to be performed.
• Not all patients with CHB have persistently elevated aminotransferases.
• Patients in the immune-tolerant phase have persistently normal ALT levels and a
proportion of patients with HBeAg-negative CHB may have intermittently normal
ALT levels.
• However AST/ALT ratio increased, when the disease progresses to cirrhosis.
• Therefore appropriate, longitudinal long-term follow-up is crucial.
• The assessment of the severity of liver disease should include:
• AST,ALT,GGT,S.Bilirubin,Prothrombin time& concentration,INR,ALP, serum albumin
• CBC, hepatic ultrasound,APRI,FIB-4, FibroTest (FibroSure), FibroScan
• A progressive decline in serum albumin concentrations and prolongation of the
prothrombin time, often accompanied by a drop in platelet counts, are
characteristically observed once cirrhosis has developed. (EASL 2012)

19. Serological Patterns of Acute & Chronic Hepatitis B
Interpretation HBsAg Anti-HBs Anti-HBc HBeAg Anti-HBe
Acute HBV Infection
HIGH INFECTIVITY + - Ig M + -
Chronic HBV Infection
HIGH INFECTIVITY + - IgG + -
Chronic / Late acute HBV
LOW INFECTIVITY + - IgG - +
Acute HBV Infection
“Window Period” - - IgM +/- +/-
False Positive
- - IgG - -
Recovery from HBV
- + IgG - +/-

20. HBV – COINFECTION
( HBV+HDV)
• Acute HBV and HDV coinfection tends
to be more severe than acute HBV
infection alone.
• It is more likely to result in fulminant
hepatitis.
• If HDV superinfection in patients with
chronic HBV infection occurs, HDV
usually predominates, and HBV
replication is suppressed.
• Severity of liver disease is worse and
progression to cirrhosis is accelerated.
(HBV+HCV)
• If HCV and HBV occurs, HCV usually
predominates.
• This may lead to lower levels of
transaminases and HBV DNA.
• The rate of HBsAg seroconversion even
appears to be increased.
• Around one third of patients coinfected lack
markers of HBV infection (ie, HBsAg)
although HBV DNA is detectable.
• Despite lower aminotransferases and HBV
DNA levels, liver damage is worse in most
instances.
• The risks of severe hepatitis and fulminant
hepatic failure seem to be elevated if both
infections occur simultaneously regardless
of whether it is an acute coinfection of HBV
and HCV or acute hepatitis C in chronic
hepatitis B.

21. EXTRAHEPATIC MANIFESTATIONS
The two major extrahepatic complications of chronic HBV that may occur are:
Polyarteritis nodosa & Glomerular disease
• They occur in 10-20% of patients with chronic hepatitis B and are thought to be mediated by
circulating immune complexes. (Han 2004)
Polyarteritis nodosa (PAN)
• The clinical manifestations are similar to those in patients with polyarteritis who are HBV-
negative.
• A typical PAN patient might present with fever, night sweats, weight loss, skin ulcerations or
tender nodules, and severe muscle and joint pains developing over weeks or months.
• There may be some clinical benefit to antiviral therapy.
Nephropathy/glomerulonephritis
• HBV can induce both membranous nephropathy and, less often, membranoproliferative
glomerulonephritis.
• Most cases occur in children.
• The clinical hallmark is proteinuria.
• In contrast to polyarteritis nodosa, there is no significant benefit of antiviral treatment.

22. PROGNOSIS & SURVIVAL
• It is very difficult to predict the individual course of hepatitis B due to the many
factors influencing disease progression.
• Several predictive models of disease progression that include clinical parameters
(eg, hepatic decompensation) and laboratory parameters (eg, bilirubin, INR) have
been evaluated, but none of these is used routinely in the clinic at present.
• In patients with cirrhosis ,these parameters can be used to assess severity, prognosis
, predict mortality, necessity of liver transplantation:
• MELD-score (Creatinine,Bilirubin,INR)
• Child-Pugh score(Bilirubin T,S.Albumin,Prothrombin Time,Ascites,Encephalopathy)
• As clinical course varies among patients, there is a wide variation in clinical
outcome and prognosis of chronic HBV infection.
• The risk of progression appears to be higher if immune activation occurs.
• The estimated five year rates of progression:
− Chronic hepatitis to cirrhosis – 10-20%
− Compensated cirrhosis to hepatic decompensation – 20-30%
− Compensated cirrhosis to hepatocellular carcinoma – 5-15%
• Accordingly, the survival rates are:
− Compensated cirrhosis – 85% at five years
− Decompensated cirrhosis - 55-70% at one year and 15-35% at five years

23. ANTIVIRAL THERAPY– ENTECAVIR,TENOFOVIR-(INTERFERON)
Acute hepatitis B
• HBV sAg + HBV cAb IgM
• A self-limited disease in 90% of adults and resolves without specific antiviral therapy
within 3 to 6 months after the onset of clinical symptoms.
• Antiviral therapy may be considered for patients with severe acute hepatitis B with
evidence of liver dysfunction such as coagulopathy or encephalopathy .
Chronic Hepatitis B (CHB)
• Not all patients are candidates for antiviral therapy.
• Only patients with detectable viremia and evidence of ongoing hepatic
necrosis.
• Typical candidates : > HBV DNA (by PCR)+ >ALT+ APRI > 2
• CHB carriers (HBsAg+ve)+normal ALT/AST,HBeAg-ve,HBV DNA low
do not require antiviral therapy, but should be monitored for evidence of
disease reactivation.
• APRI= (ALT X ALT(UL)/platelets)x100= < 2
( WHO GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION MARCH 2015 )

24. VACCINATION
• Hepatitis B vaccination is now a routine immunization worldwide.
• It insures active immunization against hepatitis B virus infection and thus can
prevent the complications of chronic active hepatitis and cirrhosis.
• In areas of both low and high prevalence, vaccination should be offered to all young
children and neonates at risk, as well as to adult high risk groups.
• In general, vaccination is recommended to who through their work or personal
lifestyle may be exposed to the hepatitis B virus.
• it is recommended for:
Health professionals
• Physicians, surgeons, dentists ,Nurses, operating room personnel, paramedical personnel
in close contact with patients
• Laboratory personnel handling blood and other clinical specimens
• Blood bank workers, Pathologists, cleaning staff who handle waste in hospitals,
emergency and first aid workers , ambulance staff
• Dental, medical and nursing students

25. VACCINATION
Patients:
Patients receiving frequent blood transfusion or clotting factor concentrates, such as
those in:
• oncology units, thalassemia, sickle-cell anemia
• cirrhosis, hemophilia, patients on hemodialysis
Personnel and residents of institutions:
• persons with frequent and/or close contacts with high-risk groups
• prisoners and prison staff, residents and staff of institutions for the developmentally
challenged.
Household contacts of the patients with acute or chronic hepatitis B infection.
Infants born of HBsAg-positive mothers
MSM & Heterosexual with multiple partners ,Persons diagnosed with STD,
Prostitutes
Injection drug users( IVDU )

26. VACCINATION
Prevaccination Serologic Testing
• Not indicated before routine vaccination of infants or children
• May be considered when vaccinating adolescents in groups with high rates of
HBV infection.
Postvaccination Serologic Testing
Not routinely recommended following vaccination of infants, children,
adolescents, or most adults
Recommended for:
• Infants born to HBsAg+ mothers
• Dialysis patients
• Immunodeficient persons
• Certain health care workers who have contact with patients or blood should
be tested for antibody after vaccination.

27. VACCINATION 3 DOSES
• Dosage and Administration
Age Recombivax HB Engerix-B Euvax B
Infants and children
<11 years of age
Dose (mcg)
0.5 ml (5)
Dose (mcg)
0.5 ml (10)
Dose (mcg)
0.5 ml (10)
Adolescents 11-19 years 0.5 ml (5) 0.5 ml (10) 0.5 ml (10)
Adults >20 years 1.0 ml (10) 1.0 ml (20) 1.0 ml (20)

28. STRATEGY TO ELIMINATE HEPATITIS B VIRUS
TRANSMISSION
• Prevent perinatal HBV transmission, HOW?
• Routine vaccination of all infants, Hope!
• Vaccination of children in high-risk groups,
• Vaccination of adolescents
• Vaccination of adults in high-risk groups

29. REFERENCES
-MAUSS, BERG, ROCKSTROH,
SARRAZIN, WEDEMEYER, HEPATOLOGY, EDITION 2015
-WHO GUIDELINES FOR THE PREVENTION, CARE
AND TREATMENT OF PERSONS WITH CHRONIC
HEPATITIS B INFECTION, MARCH 2015

30. THANK YOU