Академический Документы
Профессиональный Документы
Культура Документы
Under Supervision of
Faculty of Medicine
Cairo University
2005
ACKNOWLEDGEMENT
I would like to start by thanking "God" for
his help during this work as a part of his generous
help through out my life.
I am deeply indebted to Professor. Dr. LAILA
AHMAD MOHAMMAD (Professor of Tropical
Medicine, Faculty of Medicine, Cairo University) for
suggesting, planning and supervising this work and
for her continuous guidance and encouragement .
I would like to express my deepest thanks
and gratitude to DR. AHMAD NABIL LOTFY
HASSAN (Lecturer of Tropical Medicine, Faculty of
Medicine, Cairo University) for his wise guidance,
criticism and valuable suggestions throughout the
present study.
Last, but not least, to all patients who are
suffering, hoping that this work will give them hope
for a better future.
II
Table of Contents
Title
Introduction and Aim of the Work
Page No.
1-3
Review of Literature
1
Historical Note.
5-20
Epidemiology of HBV.
21-34
35-44
45-54
55-76
77-112
Prevention of HBV.
113-124
125-126
Recommendations
References
Arabic Summary
127
128-159
III
List of Figures
Title
Fig. (1): Schematic diagram of hepadnavirus particles.
Fig. (2): Electron microscopic presentation of HBV particles.
Fig. (3): Genome organization of HBV.
Fig. (4): A group of hepatitis B virions (right) and enlargements of the
two exposed cores.
Fig. (5): Hepatitis B Surface Proteins.
Fig. (6): Largest HBs proteins.
Fig. (7): Middle Hepatitis B proteins (MHBs).
Fig. (8): Schematic diagram of two loops of the "a" determinant of HBs
protein.
Fig. (9): Small Hepatitis B proteins (SHBs).
Fig. (10): HBV outer envelope contains high amounts of hepatitis B
surface proteins.
Fig. (11): Diagram showing Purified virions possess the HBc protein.
Fig. (12): HBV has evolved a unique life cycle.
Fig. (13): HBsAg Endemicity.
Fig. (14): Countries with areas with moderate to high risk of infection.
Fig. (15): Geographic pattern of Hepatitis B prevalence.
Fig. (16): Geographic distribution of HBV Genotype.
Fig. (17): Analysis of 1860 acute hepatitis cases.
Fig. (18): Evolution of HBV markers in acute infection.
Fig. (19): Characteristics of progression to chronic HBV infection.
Fig. (20): Mode of action of interferon alpha (INF-).
Fig. (21): Global status of countries using HepB vaccine in their
national infant immunization system.
Page
No.
6
7
9
10
12
13
14
15
16
16
18
20
21
22
23
47
49
61
62
80
118
IV
List of Tables
Title
Table (1): Characteristics of endemic patterns of hepatitis B
virus infection.
Table (2): Geographic Distribution of HBV Genotypes.
Table (3): Prevalence of HCV, HBV and HBsAg in Egypt 1996.
Table (4): Etiology of acute viral hepatitis among 200 patients.
Table (5): The frequency of acute hepatitis B in different age
groups in year 2002 in comparison to year 1983.
Table (6): HBeAg.
Table (7): Interpretations of available serologic test results
for HBV.
Table (8): Serological test findings at different stages of HBV
infection and in convalescence.
Table (9): Hepatitis B tests.
Table (10): Antibody to Hepatitis B Surface Antigen (HBsAg
Assay).
Table (11): Hepatitis B Surface Antigen (Anti-HBs Assay).
Table (12): Hepatitis B Virus Core Antigen (Anti-HBc Assay).
Table (13): Histological Activity Index.
Table (14): Modified HAI grading: necroinflammatory scores.
Table (15): Glossary set by Keeffe et al., 2004 to correlate
clinical terms with laboratory results.
Table (16): The stages of HBV in correlation with the
laboratory results.
Table (17): Interpretation of serological markers.
Table (18): Hepatitis B Therapies and Treatment.
Table (19): Types and Properties of Interferon
Table (20): Determinant of responsive factors to interferon.
Table (21): Comparison of Three Approved Treatments of
Chronic Hepatitis B.
Table (22): Goals of Therapy and Definitions of Response to
Therapy in Chronic Hepatitis B.
Table (23): Available Agents for Treatment of Chronic Hepatitis
B.
Table (24): Recommendations for Treatment of Chronic
Hepatitis B.
Table (25): Post Exposure Prophylaxis and Post Liver
Transplant Therapies & Preventive Vaccines for HBV.
Table (26): Results of Lamivudine Monotherapy Prior to OLT.
Table (27): Effect of Combination Therapy with HBIG and
Lamivudine to Prevent HBV Reinfection after OLT.
Page
No.
27
47
48
48
49
64
65
66
66
67
67
68
72
73
74
75
76
79
81
83
104
105
106
112
119
123
124
List of Graphs
Title
Graph (1): Virological response of chronic hepatitis C patients
with and without past history of HBV.
Graph (2): Age distribution of patients with acute HBV.
Graph (3): Lamivudine: Histologic Improvement at week 52 in
HBeAg-positive patients.
Graph (4): Effect of Lamivudine on HBV DNA Levels.
Graph (5): Response to Lamivudine in HBeAg-negative CHB.
Graph (6): Treatment of Lamivudine Resistance: Prospective
study of Adefovir vs Lamivudine vs Combination Therapy.
Graph (7): HBeAg Seroconversion with Lamivudine: Effect of
treatment Duration and Baseline ALT.
Graph (8): HBeAg-positive patients: Adefovir vs placebo for 48
weeks.
Graph (9): Long-term Adefovir in HBeAg-negative Patients:
Serum ALT.
Graph (10): Long-term Adefovir in HBeAg-negative Patients:
Median Serum HBV DNA.
Graph (11): Adefovir vs Placebo: Change from Baseline in HBV
DNA.
Graph (12): Entecavir Treatment of Lamivudine-resistant
Hepatitis B.
Page
No.
42
50
86
87
88
90
91
94
95
96
96
97
VI
List of Abbreviations
Abbreviation
ADV
Anti-HBc
Anti-HBe
Anti-HBs
ALT
AST
CHB
cccDNA
CTL
ETV
FHF
GMCSF
HBV
HBIG
HBcAg
HBeAg
HBsAg
INF-
LAM
LHBs
MHBs
ORFs
OLT
PCR
Pre-S1, pre-S2
SHBs
ULN
WHO
WT
Term
Adefovir depevoxil
Antibody to HBcAg
Antibody to HBeAg
Antibody to HBsAg
Alanine aminotransferase
Aspartate aminotransferase
Chronic hepatitis B
covalently closed circle DNA
cytotoxic T lymphocyte
Entecavir
Fulminant hepatic failure
granulocyte macrophage colony stimulating factor
Hepatitis B virus
Hepatitis B immune globulin
Hepatitis B core antigen
Hepatitis B e antigen" Envelope "
Hepatitis B surface antigen
Interferon Alfa
Lamivudine
Large HBs protein
Middle HBs protein
Open reading frames
Orthotopic liver transplantation
Polymerase chain reaction
Envelope protein epitopes
Small HBs protein
Upper limit of normal
World health organization
Wild Type
Under Supervision of
Faculty of Medicine
Cairo University
2004
global
health
concern.
Despite
recommendations
and
REFERENCES:
1. Alter M.J. (2003): Epidemiology of hepatitis B in Europe and
worldwide.J Hepatol; 39 Suppl 1:S64-9.
2. Attia M.A. (1998): prevalence of hepatitis B and C in Egypt and
Africa.Antiver ther; 3(supl 3):1-9.
3. Keeffe E. B., Dieterich D.T.,Han S.H., Jacobson I.M. et. al.
(2004): A Treatment Algorithm for the Management of Chronic
Hepatitis B Virus Infection in the United States. Clinical
Gastroenterology and Hepatology; 2: 87-106.
4. Lavanchy D. (2004): Hepatitis B virus epidemiology, disease
burden, treatment, and current and emerging prevention and
control measures. J Viral Hepat ; 11(2):97-107.
5. Lin, K.W. and Kirchner JT. (2004): Hepatitis B. Am Fam
Physician; 69(8):1863.
6. Orfi M. (2002): The role of hepatitis B virus as a cause of acute
viral hepatitis after the wide use of hepatitis B vaccine in Egypt.
M.Sc. Thesis: Tropical Medicine, Cairo University: 63-71.
7. Russo M. W. (2004): Care and Management of Chronic Hepatitis
B: An Overview for Patients and Family Caregivers Hepatitis B.
Emergency Medicine.
8. Sherif M.M., Abou-Atia M.A., Pazzagalia G. et.al. (1985):
Hepatitis B Virus infection in Upper and Lower Egypt. J. Med.
Virol; 15(2); 129-35.
9. Tran, T.T. and Martin, P. (2004): Hepatitis B: epidemiology and
natural history. Clin Liver Dis.; 8(2):255-66.
10.Zakaria S.; Zakaria M. and Fouad R. (2000): Sero-prevalence
of viral hepatitis markers in a rural and semi-rurual Egyptian
district.Antiviral therapy; 5(suppl 1):12.
/
-
2004
-1-
Historical Note
HISTORICAL NOTE
The HBV was discovered in 1966 (Blumberg et al., 1967). HBV,
the causative agent of B-type hepatitis in humans, is a Hepatotrophic
DNA-containing virus that replicates via reverse transcription (Shen et
al., 2004). HBV is the only known DNA virus that has hepatocytes
specificity (Lu et al., 2004a).
Hepatitis B virus (HBV) was the first human hepatitis virus from
which the proteins and genome were identified and characterized. Before
discovery of the hepatitis viruses, two types of hepatitis transmission
were differentiated based on epidemiological observations. Type A was
considered to be predominantly transmitted by the fecal-oral route,
whereas type B was transmitted parenterally (Seo et al., 2004).
In 1966, Blumberg, in a research for polymorphic serum proteins,
discovered a previously unknown antigen in the blood of an Australian
Aborigine (Australia antigen). Four years later, it was recognized that the
appearance of this antigen was related to type B hepatitis (Mao et al.,
2004). Using immune electron microscopy, Dane eventually discovered
virus-like particles that carried this antigen on their surface, in the serum
of hepatitis B patients, and these particles were considered the hepatitis B
virus (Lee et al., 2004).
In 1973, the viral nature of the particles discovered by Dane was
confirmed by the detection of an endogenous DNA polymerase activity
within their core (Schiefke et al., 2004).
This enzyme allowed Shen et al. (2004) to detect and characterize
the HBV genome as a small, circular, partially double-stranded DNA
molecule.
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Review of Literature
CHAPTER I
MORPHOLOGY OF HEPATITIS B VIRUS
The virion of hepatitis B (Dane particle) consists of surface and
core. The core is formed in hepatocyte nucleus and the surface particles
are made in the cytoplasm. The core contains a DNA polymerase. The
structure is double-stranded and circular. It is approximately 3200
nucleotides in length and has a single-stranded gap of 600-2100
nucleotides (Sherlock and Dooley 2002). The DNA-polymerase reaction
appears to repair the gap. The core contains a core antigen and another
antigen called e is a protein subunit of the core (Shindo et al., 2004).
Hepatitis B virus is spherical with a diameter of 42nm. Using
negative staining of virions adsorbed to the electron microscopic grids, a
double-shelled structure of the virions becomes apparent. The outer
protein shell (or envelop) is formed by the HBs proteins (Kumar and
Agrawal, 2004). Surface structure details such as knobs or spikes as
observed on many other enveloped viruses are found on HBV (Sugauchi
et al., 2004).
The inner protein shell is referred to as the core particle or capsid,
having a diameter of 34nm in cryoelectron microscopy (Hanazaki,
2004). It is composed of HBc protein and encloses the viral DNA, which
is often positively stained (Tsitsilonis et al., 2004).
-4-
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-5-
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HBV Genome:
The complete virus comprises a lipoprotein coat, the HBsAg,
enveloping a nucleocapsid core that contains a small, circular DNA
molecule. Four open reading frames (ORFs) have been identified on the
HBV DNA genome. They encode seven proteins, including a HBV DNA
polymerase molecule with reverse transcriptase activity. The replication
of the virus resembles that of retroviruses and occurs predominantly but
not exclusively in hepatocytes. Virus variants involving genomic
mutations have been identified (Michael et al., 2002).
-6-
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-7-
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Fig. (3): Genome organization of HBV. The outer lines represent the different
classes of transcripts; the bold inner circles the DNA genome as present in the
virion. The four major ORFs (preC/C, preS1/preS2/S, P and X) are indicated
in the center (Kawaguchi et al., 2003).
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Fig. (4): A group of hepatitis B virions (right) and enlargements of the two
exposed cores (Tong and Tu, 2004).
-9-
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(ii)
(iii)
- 10 -
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The other 50% remain on the cytosolic side. The significance of this dual
topology of LHBs is obvious; most studies on the attachment of HBV to
the target cells showed the necessity of the pre-S domain for binding to
the cellular receptors, implying that externally localized pre-S is essential
for the viral life cycle. The pre-S domain is one of the most variable
regions of the HBV genome (Duseja et al., 2002).
Review of Literature
domain (amino acid 7-20), which also forms the major epitope, binds a
modified form of serum albumin (Li et al., 2003). HBV carriers with
more than 10mg HBsAg/ml have usually free albumin binding sites on
their particles, whereas at lower HbsAg concentrations all binding sites
are occupied (Tang et al., 2003).
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Review of Literature
Fig. (8): Schematic diagram of two loops of the "a" determinant of HBs
protein. The major epitope is located in the second loop between amino acids
139 and 147 (Hwang et al., 2003).
- 14 -
Review of Literature
Fig. (9): Small Hepatitis B proteins (SHBs) (Hayashi and Furusyo, 2004).
Fig. (10): HBV outer envelope contains high amounts of hepatitis B surface
proteins. The envelope surrounds the inner nucelocapsid which is comprised
of 180 hepatitis B core proteins arranged in an icosahedral arrangement with
T=3 and T=4 symmetry. The nucleocapsid also contains at least one hepatitis
B polymerase protein as well as the HBV genome (Lacarnini, 2004).
- 15 -
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Fig. (11): a diagram showing Purified virions possess the HBc protein, which
aggregates to form the core particle (Ding et al., 2004).
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- 18 -
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Fig. (12): HBV has evolved a unique life cycle that results in the production of
enormous viral loads during active replication without actually killing the infected
cell directly (Lacarnini, 2004).
- 19 -
Review of Literature
Epidemiology of HBV
CHAPTER II
EPIDEMIOLOGY OF HBV
The world health organization (WHO) estimated that 2 billion
people have been infected by HBV worldwide of these more than 300
millions are chronically infected carriers of whom 25% are at risk of
serious illness and eventually death from cirrhosis or hepatocellular
carcinoma (WHO, 2004). Three quarters of the world population lives in
areas where there are significant levels of infection (Tsai, 2004).
Review of Literature
Epidemiology of HBV
anti-HBs (HBsAb) is much higher than those of chronic carriers (HBsAgpositives) in all populations (Deng et al., 2004).
The annual incidence rate of acute hepatitis B is estimated to be
approximately 7.4 per 100.000 in Western Europe and approximately 3.7
per 100.000 in the U.S.A. (Hahne et al., 2004).
Fig. (14): Countries with areas with moderate to high risk of infection (WHO,
2003).
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Epidemiology of HBV
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Epidemiology of HBV
in adolescents and adults; however, the high rates of chronic infection are
maintained mostly by infections occurring in infants and children
(Suskind and Rosenthal, 2004). In these areas, mixed patterns of
transmission exist, including infant, early childhood and adult
transmission (Lu et al., 2004b).
The endemicity of HBV is low in most developed areas, such as
North America, Northern and Western Europe and Australia (Song et al.,
2004). In these regions, HBV infects 57% of the population, and only
0.52% of the population is chronic carriers (Flisiak et al., 2004). In
these areas, most HBV infections occur in adolescents and young adults
in relatively well-defined high-risk groups, including injection drug user,
homosexual males, health care workers and patients who require regular
blood transfusion or hemodialysis (Wang et al., 2004b).
Most countries in Africa have high HBV endemicity, with the
exceptions of Tunisia and Morocco, which have intermediate endemicity
(Lada et al., 2004). Zambia has borderline intermediate/high endemicity.
In the Middle East, Bahrain, Iran, Israel and Kuwait are areas of low
endemicity, Egypt, Saudi Arabia, Cyprus, Iraq and the United Arab
Emirates have intermediate endemicity, and Jordan, Oman, Palestine and
Yemen have high endemicity (Zhu et al., 2004).
The outcome of HBV infection is the result of complicated viralhost interactions. As in other infections with non cytopathic viruses, the
immune response is thought to play a crucial role in disease pathogenesis
but there is increasing evidence that a variety of viral mechanisms, some
depending on the function of virally encoded proteins, have a profound
impact on the infected hepatocytes, the liver microenvironment and host
anti-viral responses (Brunetto and Bonino, 2004).
Park et al. (2004) found that chronic hepatitis B is often a silent
disease. The patient may be virtually symptom-free with only
- 23 -
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Epidemiology of HBV
(ii)
(iii)
(iv)
(v)
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(vi)
Epidemiology of HBV
- 25 -
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Characteristic
Chronic infection prevalence
Past infection prevalence
Prenatal infection
Early childhood infection
Adolescent/adult infection
Epidemiology of HBV
Endemicity of infection
Low (%)
Intermediate
(%)
0.5-2
2-7
5-7
10-60
Rare
Uncommon
(<10)
(10-60)
Rare
Common
(<10)
(10-60)
Very
Common
common
(70-90)
(20-50)
High (%)
8
70-95
Common
(>20)
Very common
(>60)
Uncommon
(10-20)
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Epidemiology of HBV
- 27 -
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Epidemiology of HBV
- 28 -
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Epidemiology of HBV
Transmission of HBV
Percutanous exposure to blood, sexual transmission and peri-natal
transmission account for the majority of cases of HBV infections in
humans (Wang et al., 2002c).
Infection by faeces; urine, tears breast milk, bile or pancreatic juice
has never been demonstrated even though HBsAg or HBV particles been
detected in such fluids (Shang et al., 2002).
1- Peri-natal transmission:
Transmission from mother to neonate may occur through contact
with maternal blood and other infectious fluids during labour, colostrums
and rarely through breast milk or placental transmission (Thakur et al.,
2002b). Between 90-100% of the neonates infected by this route will
themselves go on to become carriers and in turn infect their offsprings
(Saudy et al., 2003). Almost all (HBeAg) positive mothers transmit HBV
to their infants who usually become chronic HBsAg/HBeAg carriers. This
probably because of a tolerogenic effect of HBeAg, this crosses the
placenta inducing immunologic tolerance in utero (Saab et al., 2003).
In high-carriage rate areas, HBV infection is acquired by passage
from the mother to the baby. The infection is usually not via the umbilical
vein, but from the mother at the time of the birth and during close contact
afterward. The risk of transmission increases as term approaches and is
greater in acute than in chronic carriers (Villamil, 2003). The mother is
HBsAg positive, and also, but not always, hepatitis B "e" antigen
(HBeAg) positive.
Antigenaemia develops in the baby within 2 months of birth and
tends to persist (Tamori et al., 2003). There is an inverse relationship
between the risk of chronicity and the age of infection, the risks being
- 29 -
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Epidemiology of HBV
80% to 90% for infections before the age of 1 year and 20% to 50% for
infections in early childhood (Tang et al., 2003).
A curious, but yet not fully explained observation is that peri-natal
transmission is much more common in Asia than in Africa (Song et al.,
2004). This finding may be because HBsAg positive women in Asia are
much more likely to be HBeAg positive and to have higher levels of
circulating HBV DNA than women in Africa. However, even when
mothers in Africa are HBeAg positive, their babies do not become
HBsAg positive until 6 moths to one year of age, whereas in Asia,
exposed babies tend to become HBsAg positive by 3 months after birth
(Zhang, 2004).
2- Sexual contact:
HBV-DNA has been detected in seminal fluid, vaginal secretions
and saliva suggesting that these fluids are likely to be infectious. Studies
in patients attending clinics for sexually transmitted diseases have
demonstrated a link between promiscuous sexual activity and the risk of
hepatitis B infection and in terms of population risk, sexual transmission
represents the most important route of transmission in the developed
world (Ferraro et al., 2003). Hepatitis B was previously considered a
sexually transmitted disease predominantly related to homosexual
activity. In recent years, however, changes in sexual practice among the
homosexual community, prompted by health concerns over human
immune deficiency virus, have slowed the spread of HBV among this
population (Giannini et al., 2003).
This decrease of homosexual transmission has high lighted the
relative importance of heterosexual transmission and led to the increased
recognition of HBV infection through heterosexual activity (Trifan and
Stanciu, 2003).
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Epidemiology of HBV
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Epidemiology of HBV
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Epidemiology of HBV
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CHAPTER III
CLINICAL PRESENTATION AND SEQUELAE
(a) Acute HBV Infection:
The incubation period ranges from 2 to 20 weeks (average 8-12
weeks). The onset is usually insidious beginning with non-specific
prodromal constitutional and gastrointestinal symptoms including;
malaise, anorexia, nausea and vomiting, and flu-like symptoms of
pharyngitis, cough, coryza, photophobia, headache and myalgias.
Prodromal symptoms abate or disappear with onset of jaundice, although
anorexia, malaise and weakness may persist. These events can be related
to circulating immune complexes (Livezey et al., 2002).
The usual clinical attack diagnosed in the adult tends to be more
severe than for hepatitis A or C, however, the overall picture is similar.
The self-limited, benign icteric disease usually lasts less than 16 weeks,
jaundice rarely exceeds 4 weeks. Occasionally, a prolonged benign
course is marked by increased serum transaminase value for more than 16
weeks, relapses are rare. Cholestatic hepatitis with prolonged deep
jaundice and pruritus is unusual (Craxi and Cooksley, 2003). Physical
examination reveals mild tender hepatomegaly in over 70% of cases.
Mild splenomegaly and posterior cervical lymphadenopathy is found in
15-20% of cases (D. Valla, 2003).
Nevertheless, the clinical course of acute HBV infection may be
anicteric. The high carriage rate of serum markers in those who give no
history of acute HBV infection suggests that subclinical episodes must be
extremely frequent. The non-icteric cases are more liable to become
chronic than the icteric ones (Akarca et al., 2004).
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aseptic
meningitis,
mononeuritis
multiplex,
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(iv)
(v)
Cardiopulmonary
hepatopulmonary,
manifestations:
portopulmonary
Pleural
syndrome,
effusion,
myocarditis,
Hematologic
and
Pancreatitis,
aplastic
gastrointestinal
anemia,
tract
manifestations:
agranulocytosis
- 38 -
and
diffuse
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- 40 -
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40
20
0
At week 24
At week 48
(EVR)
At week 72
(SVR)
than
in
women,
in
neonates
than
in
adults,
and
in
Review of Literature
prognosis for these subjects was excellent, with a low risk of developing
cirrhosis or HCC over 10 years (Ohshiro et al., 2002).
Conversely, HBeAg-seropsitive patients with replicating HBV
display various degrees of liver damage, from benign forms of chronic
lobular hepatitis to more severe forms of active cirrhosis and HCC
(Rodriguez et al., 2003). Persistent HBV replication is instrumental in
the progression of the disease to cirrhosis and HCC. Virus heterogenecity
is another important factor in the natural history of HBV infection
(Stephen, 2004).
Hepatocellular carcinoma (HCC) is a frequent sequela of chronic
HBV infection. In endemic areas, the risk of developing HCC among
individuals chronically infected with HBV is up to 100 times that of nonHBV carriers (Tanaka et al., 2004). The risk to carriers, however, varies
substantially from region to region because of factors not clearly
understood (Tsai, 2004).
The classic work of Beasley, 1988 in adult Taiwanese civil service
workers reported an incidence rate of 495 per 100.000 person-years in
HBsAg-positive subjects McMahon et al., 1990 studying a populationbased cohort of Alaskan natives, have found an HCC incidence of 387
per 100.000 person-years in HBV carrier males of all ages. Wright
(2004) have reported HCC incidence rates for a cohort of 1.069 HBV
carriers in Toronto with an average follow up length of 26 months. He
found HCC incidence rates of 657 per 100.000 person-years in males and
122 per 100.000 person-years in females (Zhang, 2004).
In a multicenter European study of 349 patients with compensated
cirrhosis, secondary to chronic HBV infection, HCC developed in 9%
during a mean follow up period of 6 years. The yearly incidence of
cirrhosis among chronic HBV patients is 2.4% to 7%, with approximately
1.5% of cirrhotic developing HCC every year (Yang et al., 2004).
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CHAPTER IV
HBV STATUS IN EGYPT
Hepatitis B is and will for some time be a major health problem in
Egypt (Marzaban, 2003). It is recommended to consolidate the Egyptian
program of infant hepatitis B vaccination, and to extend it to older
children and high-risk adult groups (Sallam, 2000). The prevalence of
HBsAg carriers in Egypt varies widely with age, sex, community (urban
or rural), schistosomiasis and/or chronic liver disease, exposure to certain
risk factor (Marzaban, 2003).
Egypt was reported by Andre (2000) to be an area of high
prevalence for HBV; however, Poynard (2002) reported it to be an
intermediate area. It was also reported that the carrier rate to be 8%
among primary school children (Esmat, 2005).
In the early 90s, carrier rate of 3.25% and 3.6% were reported in
Alexandria and Cairo by Marzaban (2003); and Hasseb (2000) found
that, among school children 5-15 years from a rural village in Dakahlia,
the exposure rate for HBV infection was 22% with frequency of HBsAg
of 4% by counter immune electrophoresis, 16% by reversed passive
haemagglutination and 18% by other tests. The frequency of HBsAb was
4.5%.
Labib et al., 2002 stated that the maximum HBsAg percentage
13.37% was found in the age group 2-5 years, decreasing afterwards to
reach 12.85% in the age group 5-12 years.
In the mild 80s, Abdelaziz (2004) reported higher prevalence as
follows; 8.8% in Lower Egypt and 11.7% in Upper Egypt with more
prevalence in young adults and in males than females in both
communities.
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HCV
14.5
18.9
9.1
16.4
12.7
HBcAb
22.5
24.9
19.5
23.9
21
HBsAg
4.5
5.2
3.7
5.0
4.0
Total
N
68
25
63
34
%
34
12.5
31.5
17
Single infection
N
%
34
17
15
7.5
29
14.5
10
5
HAV
HEV
HBV**
HCV
Non A-E hepatitis
CMV
12
6
1
EBV
7
3.5
1
HGV
23
11.5
1
TTV
46
23
9
Undiagnosed
13
6.5
* Infection by more than one virus: 82 (41%)
** HDV in 8 patients (3 co-infection and 5 super infections)
0.5
0.5
0.5
4.5
- 46 -
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21%
25%
16%
HCV
HBV
All-ve
Mixed
HEV
HAV
24%
1%
13%
Fig. (17): Analysis of 1860 acute hepatitis cases (Mohamed and Aoun, 2002).
1983
Total
(235)
< 5ys
6-8ys
9-11ys
12-20ys
21-40ys
41-60ys
>60ys
(36)
(22)
(12)
(48)
(73)
(28)
(16)
Acute HBV
N
%
7
19.4
9
40.9
5
41.7
28
58.3
38
52.1
11
39.3
4
25
2002
Total
(200)
(23)
(35)
(22)
(26)
(73)
(19)
(2)
- 47 -
P
Acute HBV
N
%
0
0
0
0
6
27.3
10
38.5
41
56.2
6
31.6
0
0
NS
NS
NS
NS
Review of Literature
30
20
10
0
< 14 ys
14-30 ys
31-50 ys
> 50 ys
Graph (2): Age distribution of patients with acute hepatitis B (Zakaria et al.,
2004).
Review of Literature
age groups (except neonates and infants in their first year of life), thus
permitting a mass evaluation of HBV in Egypt. Serum from each
participant was tested for HBsAg, HBcAb and HBsAb. They found that
the prevalence of HBsAg in the whole population was 6.35% and HBcAb
was 38.68% of those studied (Marzaban, 2003).
Sallam (2000) measured the exposure rate of hepatitis B in Egypt.
Exposure rate depends on both HBsAg and HBcAb where:
No. of cases positive for HBcAb + No. of cases positive for
Exposure rate =
HBsAg alone
Total number of cases studied
Review of Literature
converts
uncomplicated
intestinal
schistosomiasis
to
Review of Literature
Review of Literature
The carrier rate among blood donors was 3.9% for villagers
(Annual report Agouza center, 1982) whereas Abdelaziz (2004) and
Marzaban (2003) in Alexandria and Cairo reported a carrier rate of
3.25% and 3.6% respectively. A more recent study El-Zayadi (2005) on
90 blood donors showed 4.4% HBsAg positivity.
(8) Among the immunocompromised:
Several workers reported an increased susceptibility to hepatitis B
virus in immuncompromised patients. A study done by Sallam (2000) on
137 patients with an immuncomprimising illness (Leprosy, Bronchial
asthma and diabetes mellitus) along with 25 healthy individuals serving
as controls indicated that HBsAg carrier rate was 4% for the control
healthy group, 7% for bronchial asthma, 10% for diabetes and 24% for
leprosy.
(9) Dental field:
The exposure rate of HBV among dentists working or studying at
the Faculty of Oral and Dental Medicine, Cairo University was found to
be 27.1% with a carrier rate of 7.1% (Abdelhamed et al., 2002).
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Diagnosis of HBV
CHAPTER V
DIAGNOSIS OF ACUTE AND CHRONIC
HEPATITIS B
(1) Acute Hepatitis:
Newly infected subjects have an incubation period averaging 8-12
weeks after exposure and before clinical symptoms, and the length of
time depends on size of inoculum and host factors (Akahane et al.,
2002). HBsAg appearance accompanies the prodromal phase, the
arthralgia and skin rash that sometimes appear are thought to be related to
formation of HBsAg anti-HBs complexes. All of this occurs before ALT
elevations and other manifestations of liver involvement (Akcam et al.,
2002).
HBsAg concentrations peak at or shortly after an increase in serum
ALT. The duration of HBsAg positivity can be highly variable and
usually has little relationship to recovery, but the ALT and HBsAg
decline and disappear together. HBsAg is cleared from serum early in
10% of patients by the time they present to physicians (Aoki et al., 2002).
Such a serological event can cause diagnosis problems, but in such cases,
the detection of IgM anti-HBc can help to confirm the diagnosis. The
presence of a strong IgM anti-HBc is indicative of acute phase infection
(Arase et al., 2002).
HBeAg and HBV-DNA is detected in sera of patients before
symptoms develop and at about the same time that HBsAg is detected.
Both are considered markers of viral replication. The disappearance of
these markers and the seroconversion to anti-HBe precede clearance of
HBsAg, and such events predict recovery. The best serological indicator
of recovery is the appearance of anti-HBs, but in many cases, it is not
74
Review of Literature
Diagnosis of HBV
remain
detectable, with
anti-HBe
and
anti-HBs
usually
Review of Literature
Diagnosis of HBV
the
clinical
symptoms
of
HBV
infection
are
as
agar-gel
diffusion
(AGD)
or
counter
Review of Literature
Diagnosis of HBV
during the prodromal phase and is not usually cleared from the serum
until convalescence (Chan et al., 2002).
Hepatitis B surface antigen (HBsAg) subtyping method based on
a commercial enzyme immunoassay (EIA) for detection of HBsAg in
which the procedure was modified to include the use of monoclonal
antibodies with restricted anti-HBs specificities. This method, which was
able to classify HBsAg as: ayw1, ayw2, ayw3, ayw3* (intermediate
between ayw3 and ayw4), ayw4, ayr, adw2, adw4 and adr. This reliable
procedure, derived from commercially available reagents, can be easily
used in several applications such as large epidemiologic studies and as a
substitute for nucleotide sequencing genotyping which is not adapted for
large-scale screening and not applicable on samples from nonviremic
hepatitis B virus (HBV) carriers (Cerenzia et al., 2002).
It was subsequently found that most of the remaining patients with
hepatitis B also had serum HBsAg, but that tests with significantly greater
sensitivity were necessary to detect those (Chan et al., 2002). Ferraro et
al. (2003) develop a modified "sandwich" radio immunoassay (RIA) to
detect HBsAg this diagnostic method has a dilution sensitivity more than
100 times that of AGD and can detect less than 0.5ng HBsAg/ml serum
(Craxi and Cooksley, 2003). In the last decade, enzyme sandwich
immunoassays (EIAs) have largely replaced RIAs. Recent modified EIAs
that use micro-particles, computerized instrumentation produce very rapid
and completely automated micro-particle enzyme immunoassay
(MEIAs) for HBsAg (Conjeevaram and Lok, 2003).
HBsAg is often used as the serological marker to screen for HBV
infection in the investigation of liver cirrhosis (Chang, 2003). HBsAg is
the most important serological marker of acute and chronic hepatitis B
infection. Therefore, sensitivity of the currently used detection system for
74
Review of Literature
Diagnosis of HBV
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Diagnosis of HBV
74
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Diagnosis of HBV
Fig. (18): Evolution of HBV markers in acute infection (Guillevin et al., 2004).
74
Review of Literature
Diagnosis of HBV
(III) HBcAg:
Hepatitis B core antigen (HBcAg) is not directly detectable in
serum because of the HBsAg envelope that surrounds it. Furthermore,
any exposed HBcAg reacts with circulating antibody, thus blocking its
detection. However, HBcAg can be identified in liver biopsies by
immunofluorescent techniques, and the histochemical detection of this
antigen is occasionally used as a marker of viral replication (Gheit et al.,
2002). HBcAg does not circulate in serum (Hbscher and Potmann,
2002).
(IV) HBcAb:
Detection of IgM HBcAb is a useful marker for HBV acute
infection (Goldstein et al., 2002). IgA HBcAb is a sensitive marker for
HBV replication, and its absence may exclude HBV replication (Kao et
al., 2002b).
Anti-HBc (antibody to HBcAg), is perhaps the most serological
prominent marker of HBV exposure. HBcAg is very immunogenic and
consequently high anti-HBc titers early in an infection suggest a period of
active viral replication. The antibody is detectable in serum shortly after
the appearance of HBcAg, but usually before elevations in ALT, and it
persists in serum throughout disease and recovery (Kao and Clsen,
2002). The earliest anti-HBc in acute disease is predominantly. IgM antibody, with lower activities of IgG and IgA anti-HBc also present
concurrently. There is no evidence; however, that serum anti-HBc offers
any immune protection (Mao et al., 2004).
(V) HBeAg / Anti-HBe:
HBeAg in serum can be detected by a sandwich immunoassay
format similar to that for HBsAg. The antigen is captured by antibody
affixed to a solid phase and is then detected with a second labeled
antibody (Gotsman et al., 2002). The HBeAg positive chronic hepatitis
74
Review of Literature
Diagnosis of HBV
Review of Literature
Diagnosis of HBV
74
Review of Literature
Diagnosis of HBV
TOTAL
ANTIHBC
-
ANTIHBS
INTERPRETATION
-or +
HBsAg AntiHBs
Late incubation period
+
Acute hepatitis B or +
persistent carrier state
HBsAg
ve
acute hepatitis
Recovery with loss of anti-HBs
Healthy HBsAg carrier
++
+
Chronic
hepatitis
B, +
persistent carrier state
HBV infection in recent ++
past, convalescence
HBV infection in distant + or past, recovery
Recent HBV vaccination, ++
repeated
exposure
to
antigen without infection,
74
ANTI-HBC
IGG IGM
HBeAg
AntiHbe
+ or +
++
+
++
+
++
+ or -
+ or
+ or -
+ or -
Review of Literature
Diagnosis of HBV
Approval
Date
Serum /
Donor
Abbott Laboratories 4/1/1985
Plasma
Screen & Abbott Park, IL
Conf. Kit US License 0043
Serum /
Donor
Bio-Rad
12/28/1999
Plasma /
Screen & Laboratories Blood
Cadaveric Conf. Kit Virus Division
Serum
Redmond, WA
US License 1109
Serum /
Donor
Ortho-Clinical
7/23/1971
Plasma
Screen & Diagnostics, Inc.
Conf. Kit Raritan, NJ
US License 1236
Auszyme
Monoclonal
EIA
Genetic
Systems
HBsAg
EIA 2.0
EIA
Ortho
Antibody to
HBsAg
ELISA Test
System 2
AUK-3
EIA
RIA
Serum /
Plasma
ETI-MAK-2
EIA
Serum /
Plasma
Use
Manufacturer
Donor
Screen &
Conf. Kit
Donor
Screen &
Conf. Kit
DiaSorin s.r.l.
Saluggia, Italy
US License 1257
DiaSorin s.r.l.
74
5/9/1986
4/18/1995
Review of Literature
Diagnosis of HBV
Manufacturer
Ausab
RIA
Serum / Anti-HBs
Plasma
Ausab EIA
EIA
AB-AUK-3
RIA
Serum / Anti-HBs
Plasma
Serum / Anti-HBs
Plasma
ETI-AB-AUK
EIA
Serum / Anti-HBs
Plasma
Approval
Date
Abbott Laboratories 2/5/1975
Abbott Park, IL
US License 0043
Abbott Laboratories 11/18/1982
DiaSorin s.r.l.
Saluggia, Italy
US License 1257
DiaSorin s.r.l.
6/27/1989
4/18/1995
Format
Sample Use
Manufacturer
EIA
ABCOREK
RIA
ETI-ABCOREK
EIA
Approval
Date
Abbott Laboratories 3/19/1991
Abbott
Park,
IL
US License 0043
Ortho-Clinical
4/18/1991
Diagnostics,
Inc.
Raritan,
NJ
US License 1236
DiaSorin
s.r.l. 3/19/1991
Saluggia,
Italy
US License 1257
DiaSorin s.r.l.
3/19/1991
74
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Diagnosis of HBV
Review of Literature
Diagnosis of HBV
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Diagnosis of HBV
Review of Literature
Diagnosis of HBV
74
Review of Literature
Diagnosis of HBV
0
1
2
3
4
0
1
2
3
4
5
6
0
1
2
3
4
0
1
2
3
4
18
Review of Literature
Diagnosis of HBV
Definitions:
- Chronic hepatitis B:
Chronic necroinflammatory disease of the liver caused by persistent infection
with HBV.
Chronic hepatitis B can be subdivided into HBeAg-positive and HBeAg-negative
chronic hepatitis B.
- Inactive HBsAg carriers state:
Persistent HBV infection of the liver without significant, ongoing
necroinflamamtory disease.
- Resolved hepatitis B:
Previous HBV infection without further virolgoic, biochemical, or histologic
evidence of active virus infection or disease.
- Acute exacerbation or flare of hepatitis B:
Intermittent elevations of aminotransferase activity to more than 10 times the
upper limit of normal and more than twice the baseline value.
- Reactivation of hepatitis B:
Reappearance of active necroinflammatory disease of the liver in a person known
to have the inactive HBsAg carrier state or resolved hepatitis B.
- HBeAg clearance:
Loss of HBeAg in a person who was previously HBeAg positive.
- HBeAg seroconversion:
Loss of HBeAg and detection of HBeAb in a person who was previously HBeAg
positive and HBeAb negative, associated with decrease in serum HBV DNA to <
10 copies/mL.
- HBeAg reversion :
Reappearance of HBeAg in a person who was previously HBeAg negative and
HBeAb positive.
Diagnostic criteria :
a) Chronic hepatitis B:
1. HBsAg positive > 6 months.
2. Serum HBV DNA > 10 copies/ml.
3. Persistent or intermittent elevation in ALT/AST levels.
4. Liver biopsy showing chronic hepatitis (necroinflammatory score 4)
b) Inactive HBsAg carrier state :
1. HBsAg positive > 6 months.
2. HBeAg negative, HBeAb positive.
3. Serum HBV DNA < 10 copies/ml.
4 Persistently normal ALT/ AST levels.
5. Liver biopsy confirms absence of significant hepatitis (necroinflammatory
score <4).
c) Resolved hepatitis :
1. Previous known history of acute or chronic hepatitis B or the presence of
HBcAb HBsAb.
2. HBsAg negative.
3. Undetectable serum HBV DNA.
4. Normal ALT level.
74
Review of Literature
Diagnosis of HBV
REPLICATIVE PHASE
INTEGARATIVE PHASE
Stage 1
+
+(strongly)
+
+
Normal
Stage 3
+
+
Normal
Stage 2
+
+
+
+
elevated
74
Stage 4
+
+
+
Normal
Diagnosis of HBV
Review of Literature
Diagnosis of HBV
Table (17): Interpretation of serological markers according to symptoms, transaminases and histological features
(Poynard, 2002).
Acute
+/-
+/-
-/+
+/-
+/-
'Healthy carrier"
"Immune tolerance"
++
Recovery/Immunity
from -
+/-
+/-
+/-
+/-
+/-
+/-
Review of Literature
Immunity
vaccination
Occult infection
74
Review of Literature
CHAPTER VI
TREATMENT OF CHRONIC HEPATITIS B
Effective treatment of chronic hepatitis B is defined as sustained
clearance of circulating HBeAg and HBV-DNA with production of
HBeAb and improvement in liver disease as determined by normalization
of serum ALT level and reduction of necro-inflammation on liver
biopsies. The most widely available agents for the treatment of chronic
hepatitis B are interferon and Lamivudine (Pramoolsinsup, 2002).
Definitive treatment:
The kinetics of HBV clearance during anti-viral therapy is slow
requiring long-term therapy to control viral replication. Emergence of
resistant mutants is accelerated by high HBV replication and hepatocyte
turnover, which are common features in patients with chronic HBV
infection. These mutants have a decreased priming and elongation
activity, and remain sensitive to novel nucleoside analogues (Kiss et al.,
2002).
Decision to treat: it must be taken individually, based on
precisely weighted parameters. Elevated ALT activity, a liver biopsy
showing chronic hepatitis with or without cirrhosis and the presence of
significant levels of HBV DNA are strong arguments about initiating
antiviral therapy. The precise HBV DNA cutoff that discriminates
between low and high pretreatment replication needs to be determined,
using standardized quantification units (De Gottardi and Negro, 2004).
Treatment monitoring: HBV DNA quantification with repeated
ALT determinations and HBeAg/HBeAb assessment in HBeAg positive
patients are critical in monitoring treatment (Kirschberg et al., 2004).
Aims of treatment: are to achieve sustained suppression of HBV
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Review of Literature
replication and remission of liver disease. The end points used to assess
treatment response include normalization in serum ALT level,
undetectable serum HBV, loss of HBeAg with or without detection of
HBeAb and improvement in liver histology (Kobak et al., 2004).
Inconsistencies
in
the
definition
of
response,
lack
of
- 76 -
Review of Literature
Drug Class
Manufacturer
interferon
Schering-Plough
Baraclude
(entecavir)
nucleoside
analogue
Bristol-Myers Squibb
interferon
Roche Labs
Pegasys
(peginterferon alfa-2a)
Emtricitabine
(FTC)
Telbivudine
(LdT)
Clevudine
(L-FMAU)
Elvucitabine
(ACH 126, 443)
Valtorcitabine
Racivir
BAM 205
HepX-B
nucleotide
analogue
nucleoside
analogue
Gilead Sciences
GlaxoSmithKline
nucleoside
analogue
nucleoside
analogue
nucleoside
analogue
nucleoside
analogue
nucleoside
analogue
nucleoside
analogue
small molecule
monoclonal
antibody
Gilead Sciences
FDA Status
FDAapproved
FDAapproved
FDAapproved
about to
got FDAapproval
FDAapproved
Phase III
NDA filed
Idenix
Phase III
Gilead Sciences
Phase II
Achillon Pharmaceuticals
Phase II
Idenix
PhaseII
Pharmasset
Phase II
Novelos
Phase II/III
XTLBiopharm
Phase II
Phase II
Phase II in combo
with Epivir-HBV
AND Orphan drug
for liver cancer in
US
Phase II
Phase II
Phase I
Phase I
Phase I
Phase I
HE 2000
immune stimulant
Hollis-Eden
Zadaxin
(thymosin-alpha)
immune stimulant
SciClone
Theradigm
EHT 899
MCC 478
MIV 210
Hepavir B
HBV DNA vaccine
immune stimulant
viral protein
nucleoside analogue
nucleoside analogue
nucleoside analogue
immune stimulant
Epimmune
Enzo Biochem
Eli Lily
Medivir
Ribapharm
PowderJect
Prednisone priming:
The rationale for administering a tapering course of steroids prior
to antiviral therapy (prednisone priming) is that recovery of immune
function following steroid withdrawal may be beneficial particularly if
- 77 -
Review of Literature
this is timed with the initiation of IFN- therapy (Lada et al., 2004).
Although a small subset of patients may benefit from prednisone
priming, there is a risk of fatal exacerbations in patients with underlying
cirrhosis. Therefore, prednisone priming is not recommended as a
primary treatment of chronic hepatitis B (Lai, 2004).
- 78 -
Review of Literature
Principal source
Alpha
Leukocyte IFN
Type I
>20
Stable
Viruses
(RNA>DNA)
dsRNA
Leukocytes,
Epithelium
Interferon
Beta
Fibroblast IFN
Type I
1
Stable
Viruses(RNA>DNA)
dsRNA
Gamma
Immune IFN
Type II
1
Labile
Antigens,
Mitogens
Fibroblasts
Lymphocytes
Review of Literature
Dosage regimen:
The recommended regimen of interferon alfa-2b 5 MU or 10 MU
- 80 -
Review of Literature
Favorable outcome
HBeAg positive
Low serum HBV-DNA level
High serum ALT
Active liver histology
Female-western adult
Acquired or recent HBV infection
Unfavorable outcome
HBeAg negative
High serum HBV-DNA level
Normal serum ALT
Inactive liver histology
Male Asian
Long standing HBV infection
Non-cirrhotic
Anti-HIV negative
HDV negative
Cirrhotic patients
Anti-HIV positive
HDV positive
Review of Literature
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al., 2003).
Treatment of patients with lamivudine results in loss of detectable
levels of HBV DNA from serum; however, the relapse rate, with regard
to both reappearance of virus in the bloodstream and hepatic
inflammation, is high when therapy is terminated (Abdelhamed et al.,
2002).
Samuel (2004) concluded the following results; 1) Lamivudine
resistant mutants are likely to be cross resistant to other L-cytidine
analogues; 2) antiviral therapy using a single reverse transcriptase (RT)
inhibitor is likely to fail to eradicate viral DNA and 3) new nucleoside
analogues with unique mode of action (inhibition of priming or
elongation of RT, or DNA polymerase activity) and activity against
lamivudine resistant strains are emerging. Combination of these new anti
HBV agents with DNA based immunization may prove useful to
eradicate viral infection.
- 87 -
Review of Literature
Review of Literature
Lamivudine Resistance:
The likelihood of developing drug resistance increases with
duration of therapy. After 1 year of lamivudine therapy, 14 to 32% of
individuals have genotypic resistant mutations. This figure increases with
each year of extended Lamivudine therapy (Selimo et al., 2002).
Lamivudine resistance is more likely to develop in individuals with
high baseline HBV DNA and/or high baseline ALT (Seo et al., 2004),
high HAI score, and high body mass index (31) (Wright, 2004).
patients
with
mild
disease.
However,
in
Review of Literature
lamivudine-resistant
mutations
(Yano
et al.,
2002),
Adefovir Dipivoxil
Adefovir dipivoxil is a nucleotide analogue of adenosine
- 90 -
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Review of Literature
Entecavir:
On March 29, 2005, FDA approved Baraclude (entecavir) for the
treatment of chronic hepatitis B virus infection in adults with evidence of
active viral replication, and either evidence of persistent elevations in
serum aminotransferases (ALT or AST), or histologically active disease
(Gish et al., 2005a).
Entecavir is a guanosine nucleoside analogue, which is a potent
selective inhibitor of hepatitis B virus, and is undergoing phase III
development worldwide (Gish et al., 2005b). In the woodchuck model,
it is highly active, and importantly has shown reduction in CCC DNA
(covalently closed circular DNA) levels and reduction in development of
HCC with prolonged survival (Brown, 2005).
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Review of Literature
Famciclovir:
It is the oral pro-drug of penciclovir, an acyclic deoxyguanosine
analogue. Penciclovir triphosphate competes with dGTP for incorporation
into the nascent HBV DNA chains and for the priming of reverse
transcription. Given the low virological response rates, potential risk of
drug resistance and the need for thrice daily administration, the role of
famciclovir in the management of chronic HBC is limited (Kao, 2002).
Emtricitabine/ coviracil:
It is a cytosine nucleoside analogue with potent anti viral activity
against HBV. Because of the structural similarity with lamivudine, longterm therapy with emtricitabine may select the same resistant mutants
(Kim et al., 2004).
Others:
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Review of Literature
Three simple related nucleosides -L-2 deoxycytidine, -Lthymidine and -L 2 deoxyadenosine; have been discovered to be
potent, specific and selective inhibitors of the replication of HBV. The
nucleosides are efficiently converted intracellularly into active
triphosphate metabolites that have a long half-life. These compounds
have the potential for use in combination therapy with goal of achieving
superior viral suppression and diminishing the onset of resistance (Lohr
et al., 2002).
BAY 41-4109 is a member of a class of heteroaiyl-pyimidines that
was identified as potent inhibitors of human HBV replication and antiHBV drug candidate (Manesis et al., 2002). Pharmacokinetic studies in
mice have shown rapid absorption, a bioavailability of 30% and dose
proportional plasma concentrations (Manesis et al., 2002).
Oligodeoxynucleotide TGO20 can be transfected into cells by
packing with liposme and can be combined with HBV DNA. TGO20 can
effectively inhibit replication of HBV (Moola et al., 2002).
Novel 2-amino-6 arylthio-9-2 {(phosphonomethoxy) ethyl}
purine bis (2, 2, 2-trifluoroethyl) esters (PMEA) showed considerably
high anti- HBV activity, and exhibited low cytotoxicity (Gotsman et al.,
2002). It is a lipophilic prodrug of 9-(2-phosphonylmethOxyethyl)
adenine (PMEA), designated PMEALO, and incorporated it into
reconstituted lactosylated high-density lipoprotein (LacNeoHDL) was
internalized by the asialogycoprotein receptor on parenchymal liver cells
and converted into its active diphosphorylated metabolite. Asialofetuin,
an established ligand for the asialoglycoprotein receptor, inhibited the
association by > 75%, which confirms the role of the asialoglycoprotein
receptor. Association of the prodrug-loaded particles to HepG2 cells was
coupled to degradation. LacNeoHDL-associated PMEALO effectively
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Review of Literature
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Furusyo, 2004).
Combination or sequential therapy of nucleoside analogues may
help to better achieve the goals of treatment for chronic hepatitis B in the
new century (Hm et al., 2004).
Review of Literature
(6) Immunotherapy:
Administration of monoclonal antibodies against HBsAg to HBVTrimera mice, a system that provides a mouse model for human hepatitis
B infection, reduced the viral load and the percentage of HBV-DNA
positive mice in a dose dependent manner. They were more effective than
a polyclonal antibody preparation in both inhibitions of HBV liver
infection and reduction of viral load (Hunter, 2002).
CTL (cytotoxic T lymphocyte) reactivity is stimulated following
treatment with certain cytokines, but is dependent on the time of
administration (Rapicetta et al., 2002). IL-12 plays a central role in
mounting an effective cellular immune response directed towards
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Therefore,
transcriptional
interference
mediated
by
Review of Literature
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Review of Literature
IFN-
Not indicated
HBeAg+ chronic
Indicated
hepatitis
HBeAg- chronic hepatitis
Indicated
Duration of Treatment
HBeAg+ chronic
4-6 months
hepatitis
HBeAg- chronic hepatitis
1 year
Route
Subcutaneous
Side Effects
Drug Resistance
Lamivudine
Not
indicated
Not indicated
Indicated
Indicated
Indicated
Indicated
1 year
1 year
>1 year
Oral
>1 year
Oral
Potential
nephrotoxicity
None, year 1
3%, year 2
Intermediate
Many
Negligible
0%, year 1
70%, year 5
Low
Cost*
High
*
Based on treatment duration of 1 year.
Adefovir
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Review of Literature
High and low serum HBV-DNA levels are considered as >/= and < 105 copies/ml.
Lamivudine
Adefovir
dipivoxil
Anti-viral activity
++
++
Immunomodulatory activity
++
Frequent and
potentially severe
Minimal
Minimal
High
Low
High
None
25%, 40%,
>50%
at 1, 2 and 3
years
Minimal
(< 2% at 2
years)
17-32%
(controls: 611%)
24%
(controls:
11%)
Side-effects
Cost
Efficacy of courses of finite
duration*
In HBeAg-positive CHB
HBeAg loss
HBeAg seroconversion
33%
(controls: 12%)
18%
(more than controls)
16-17%
12%
(controls: 4(controls: 6%)
6%)
In HBeAg-negative CHB
End-of-therapy response
46-54%
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65-90%
70-75%
Review of Literature
22-30%
< 10-15%
Unknown
Unknown
27%
21%
HBeAg seroconversion at 36
months
Unknown
33%
Unknown
HBeAg seroconversion at 48
months
Unknown
47%
Unknown
In HBeAg-negative CHB
On-therapy 24-month response
46%
55-65%
71-73%
Unknown
40-50%
Unknown
Unknown
35-40%
Unknown
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without
cirrhosis,
the
following
strategies
are
recommended:
A 12-24 month course of interferon alpha, 5-6 MIU thrice weekly
may be considered as an initial therapy. If interferon is contraindicated,
ineffective or poorly tolerated, lamivudine or Adefovir should be
considered. Because HBeAg is already undetectable, the end point of
treatment is not established. Sustained suppression of HBV replication is
associated with histological improvement and therefore appears a realistic
goal of treatment. The optimal duration of treatment is not known. Most
patients will require more than one year of therapy, decision to continue
treatment should weigh the likelihood of a sustained response against the
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Review of Literature
Review of Literature
(V) Post transplant patients with recurrent hepatitis B who have not
previously received lamivudine should be treated with lamivudine or
adefovir. Breakthrough during lamivudine therapy should be treated with
adefovir and careful monitoring of the renal function is required (Hm et
al., 2004).
(VI) In HBV infected patients requiring immunosuppressive therapy
Lamivudine is generally preferable to interferon as antiviral therapy.
Treatment can be started 2-4 weeks before immunosuppression or at the
first sign of an exacerbation of the hepatitis. (Yao et al. 2004).
Table (24): Recommendations for treatment of Chronic Hepatitis B
(Lok et al., 2004):
HBeAg
+
HBV
DNA*
+
ALT
Treatment Strategy
2
ULN
>2
ULN
>2
ULN
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ULN
Cirrhosis Compensated: LAM or ADV
Decompensated: LAM (or ADV); coordinate
treatment with transplant center. Refer for liver
transplant. IFN- contraindicated
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Prevention of HBV
CHAPTER VII
PREVENTION OF HBV
Risk personnel:
Persons who should be screened for HBV infection: persons born
in hyperendemic areas, men who have sex with men, injecting drug users,
dialysis patients, HIV-infected individuals, pregnant women, family
members, household members, and sexual contacts of HBV infected
persons (Chang et al., 2002).
Review of Literature
Prevention of HBV
Review of Literature
Prevention of HBV
HBV
vaccination
program
among
students
before
Review of Literature
Prevention of HBV
Review of Literature
Prevention of HBV
Types of vaccines:
1- Human plasma derived vaccines:
The first active protective vaccines were introduced in 1981 (Schiff
et al., 2003a).
2- Recombinant DNA vaccine:
The first human vaccine produced with molecular biologic
techniques (Kakimi et al., 2002b).
3- Hybrid virus vaccine:
Potential live vaccines using recombinant vaccine viruses to HB,
rabies and herpes simplex (Chen et al., 2002b).
Immune response to HB vaccines in special groups:
Vaccination of special groups who are at increased risk of infection
shows lower immune response to the vaccines. For example, only 60% of
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Review of Literature
Prevention of HBV
Fig. (21): Global status of countries using HepB vaccine in their national
infant immunization system (WHO, 2003).
I.D. administration of recombinant HB vaccine in repeated small
injections is absolutely effective in Haemodialysis patients (gave higher
antibody titers in at least 50% of the follow-up measurements) (Zhou
and Wu, 2004).
Zhu et al. (2004) investigated the immune response of liver
transplantation to HB vaccines they stated that the total response rate to
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Review of Literature
Prevention of HBV
Activity
Manufacturer
FDA Status
FDAapproved
FDAapproved
BLA filed with
FDA
Brand Name
Activity
Manufacturer
FDA Status
Recombivax HB
Hepatitis B
BayHepB
FDAapproved
Hepatitis B
GlaxoSmithKline
Energix-B
FDAapproved
Hepatitis
A GlaxoSmithKline
Twinrix
FDAand B
approved
Hepatitis
B GlaxoSmithKline
Pediarix*
FDAand other
approved
Pediarix: a new combination vaccine that protects infants against diphtheria, tetanus,
pertussis (whooping cough), polio, and disease due to the hepatitis B virus.
Review of Literature
Prevention of HBV
et
al.,
2002).
Indefinite
administration
of
passive
Review of Literature
Prevention of HBV
Review of Literature
Prevention of HBV
N=
Grellier et al.,
Markowitz et al.,
Villeneuve et al.,
Lo et al.,
Perrillo et al.,
Yao et al.,
Seehofer et al.,
Rosenau et al.,
Marzano et al.,
Fontana et al.,
Andreone et al.,
Fontana et al.,
17
10
35
31
30
23
17
19
33
162
25
154
Duration of
Therapy*(months)
>1
2.7
19
3.2
29
13
7.2
12
16
16
4.5
5.7
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Negative HBV
DNA (%)
100
100
100
63
74
100
88
NR
73
67
92
>80
Resistant
Mutants (%)
NR
NR
25
NR
22
10
18
10.5
3
11
8
27
Review of Literature
Prevention of HBV
N=
HBV
DNANegative
at OLT (%)
HBIGRoute of
Administration
HBV
Reinfection
(%)
14
Pre-OLT
Duration*
of
LAM(mos)
3
Markowitz et
al.,
Yao et al.,
Yoshida et al.,
Angus, et al.
Marzano et
al.,
McCaughan et
al.,
Rosenau et al.,
Roche et al.,
Han et al.,
Seehofer et al.,
93
IV
10
7
37
33
8.6
NR
3.2
4.6
80
100
NR
100
IV then IM
IM
IM
IV
10
0
3
4
NR
IM
21
15
59
17
4.6
4.6
NR
10.6
77
73
NR
71
IV
IV
IV
IV
10
7
0
18
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Prevention of HBV
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Summary
Summary
- 122 -
Recommendations
RECOMMENDATIONS
Hepatitis B vaccination is the best protection as it provides protection
against hepatitis B for 15 years and possibly much longer. It is
recommended that all infants, health care workers and persons at risk
of exposure e.g. sexual partners of chronically infected persons;
should be vaccinated.
Hepatitis B Immune globulin is recommended for accidentally
exposed persons, ideally within 24 hours of exposure and no later than
7 days. A repeated dose is necessary 28 - 30 days later.
Newborns of HBV infected mother should receive HBIG plus the
hepatitis B vaccine within l2 hours of birth and two additional doses
of vaccine at one and six to twelve months of age.
Strict governmental instructions for hygiene and sterilization should
be followed particularly in risky procedures e.g. surgical intervention,
dental procedures, endoscopies and blood or body fluids sampling.
Strict observation of blood donors, the presence of normal ALT, AST
are not sufficient. Evaluation for occult HBV infection by
determination of HBV DNA in serum or tissues should be considered
in the context of the prevalence of HBV infection in this geographical
area and the type of population.
In order to prevent HBV reinfection after liver transplantation, it is
recommended to combine Lamivudine therapy pre- and posttransplantation with HBIG post-transplantation. This regimen has
become the standard of care for most liver transplant programs.
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References
REFERENCES
Abdelaziz, M.S. (2004): Interrelation between HCV related chronic
liver disease and various serelogical status of HBV infection. M.D.
thesis, Tropical Medicine, Cairo University; 73-99.
Abdelaziz, F., Habib, M., Mohamed, M.K. et al. (2000): Hepatitis C
virus (HCV) infection in a community in the Nile Delta: Population
description and HCV prevalence. Hepatology, 32: 111-115.
Abdelhamed, A.M., Kelley, C.M., Miller, T.G. et al. (2002):
Rebound of hepatitis B virus replication in HepG2 cells after cessation
of antiviral treatment. J Virol; 76 (16): 8148-60.
Abdelhamed et al. (2004): sited by Esmat, G. (2005): Hepatitis B
virus (HBV): the Egyptian situation. The first Egyptian HBV day;
Sheraton Heliopolis, Cairo-Egypt; Jan.13.2005 (Conference Book):
17-25.
Agarwal, N., Naik, S., Aggarwal, R. et al. (2003): Occult hepatitis B
virus infection as a cause of cirrhosis of liver in a region with
intermediate endemicity. Indian J Gastroenterol. Jul-Aug; 22 (44):
127-31.
Akahane, Y., Okada, S., Sakamoto, M. et al. (2002): Persistence of
hepatitis B viraemia after recovery from acute hepatitis B: correlation
between anti HBc titer and HBV DNA in serum. Hepatol Res; 24 (1):
8.
Akarca, U.S., Ersoz, G., Gunsar, F. et al. (2004): Interferonlamivudine combination is no better than lamivudine alone in antiHBe-positive chronic hepatitis B. Antivir Ther. June; 9 (3): 325-34.
Akbar, S.M., Furukawa, S., Horiike, N. and Onji, M. (2004):
Vaccine therapy for hepatitis B virus carrier. Curr. Drug Targets Infect
Disord. Jun; 4 (2): 93-101.
Akcam, Z., Sunbul, M., Durupinar, B. et al. (2002): Tissue types as
prognostic risk factor in hepatitis B virus infection. Indian J
Gastroenterology; 21 (4): 139-41.
Aliyu, S.H., Aliyu, M.H., Salihu, H.M. et al. (2004): Rapid detection
and quantitation of hepatitis B virus DNA by real-time PCR using a
new fluorescent (FRET) detection system. J. Clin Virol. Jun; 30 (2):
191-5.
Allain, J.P. (2004): Occult hepatitis B virus infection. Transfus Clin
Biol. Feb; 11 (1): 18-25.
Alter, M.J. (2003): Epidemiology and prevention of hepatitis B.
Seminars in Liver Disease. Hepatitis B. Editors: Paul D Berk and
Anna SF Lok. Thieme Medical Publishers; 23 (1): 39-46.
Andre, F. (2000): HBV epidemiology in Asia, the Middle East and
Africa. Vaccine; 18 Suppl 1: S 20-2.
- 124 -
References
References
References
- 127 -
References
References
References
Han, L., Sun, W., Ma, C. et al. (2002): The influence of HBV
infection on a TRAIL induced apoptosis and its mechanism.
Zhonghua Yi Xue Za Zhi; 82 (9): 597-600.
Hanazaki, K. (2004): Antiviral therapy for chronic hepatitis B: a
review. Curr Drug Targets inflamm. Allergy J. Mar; 3 (1): 63-70.
Hasseb, A.F. (2000): A study on the relation between hepatocellular
carcinoma, HBV, HCV and aflatoxins among Egyptian. M.Sc. thesis,
Tropical Medicine, Cairo University; 70-75.
Haushofer, A.C., Hauer, R., Brunner, H. et al. (2002): HCV, HBV
genotypes and age distribution in patients of Vienna and surrounding
areas. J Clin Virol Dec: 25 Suppl 3: s99-102.
Haushofer, A.C., Hauer, R., Brunner, H. et al. (2004): No evidence
of hepatitis B virus activity in patients with anti-HBc antibody
positivity with or without anti-hepatitis C virus antibody positivity.
Journal of Clinical Virology 29; 221-223.
Hayashi, J. and Furusyo, N. (2004): The epidemiology of HBV: the
trend from 1970 to present. Nippon Rinsho. Aug; 62 Suppl 8: 180-5.
He, M.L., Wu, J., Chen, Y. et al. (2002): Quantification of HBV ccc
DNA by real-time PCR. Biochem Biophys Res Commun; 295 (5):
1102-7.
Heikal, O. (2005): Chronic Hepatitis B virus (HBV): Update points
and management. The first Egyptian HBV day; Sheraton Heliopolis,
Cairo-Egypt; Jan.13.2005 (Conference Book): 53-55.
Hm, X., Little, N.R., Gardner, S.D. and Jonas, M.M. (2004):
Predictors of virologic response to Lamivudine treatment in children
with chronic hepatitis B infection. Pediatr. Infect Dis. J. May; 23 (5):
441-5.
Honkoop, P. and de Man, R.A. (2003): Entecavir: a potent new
antiviral drug for hepatitis B. Expert Opin Investig Drugs. 12 (4):683688.
Hou, J., Liu, Z. and Gu, F. (2005): Epidemiology and Prevention of
Hepatitis B Virus Infection. Int. J. Med. Sci; 2:50-57.
Hu, K.Q. (2002): Occult hepatitis B virus infection and its clinical
implications. J Viral Hepatol. Jul; 9 (4) 243-57.
Hbscher, S.G. and Potmann, B.C. (2002): Transplantation
pathology. In: MacSween RNM, Burt AD, Portman BC, Ishak KG,
Scheuer PJ, Anthony PP, eds. Pathology of the Liver. 4 th ed. London:
Churchill Livingstone; 228-941.
Humphries, J.C. and Dixon, J.S. (2003): Antiviral for the treatment
of chronic hepatitis B: current and future options. Intervirology. 2003;
46 (6): 413-20.
- 130 -
References
References
- 132 -
References
References
References
References
References
References
References
References
References
References
References
- 143 -
1966 42
) HBc HBe
2004
300 %25
-1-
D C
-2-
/
-
/
-
2005