Download Chronic inactive hepatitis B

Viral haepatitis
Characteristics of Hepatitis Viruses
Hepatitis
A Virus
Hepatitis
B Virus
Hepatitis
C Virus
Hepatitis
D Virus
Hepatitis
E Virus
Nucleic acid
RNA
DNA
RNA
*
RNA
Major
transmission
Fecal–
oral
Blood
Blood
Needle
Water
Incubation
period
(days)
15–50
30–180
20–120
14–60
14–60
Epidemics
Yes
No
No
No
Yes
Acute liver
failure
<0,5%
1%
<0,1%
2-20%
20%among
pregnant
Chronicity
No
5-7%
50-70%
co: 5-7%
super:100%
No
Liver cancer
No
Yes
Yes
Yes
No
*Incomplete RNA; requires presence of hepatitis B virus for replication.
THE DEVELOPMENT STAGES OF ACUTE ICTERIC VH:
 incubation period
 prejaundice period
 jaundice period
 convalescent period
COURSE OF VH INFECTION
The course is affected by two factors: the viral charge and the host response.
Acute hepatitis B, сlinical forms, in adults:
o Inapparent
o subclinical
o Symptomless infection
o Anicteric hepatitis
 ACUTE ICTERIC HEPATITIS:
o clinical manifestation of prejaundice syndromes +++,
o jaundice +++,
o hepatomegaly +++,
o biochemical modifications +++,
o presence of serum Ag, Ab +++
 ANICTERIC FORM:
o clinical manifestation of prejaundice syndromes ++,
o jaundice -,
o hepatomegaly +++,
o biochemical modifications ++,
o presence of serum Ag, Ab +++
 SLIGHT PRONOUNCED FORM:
o slight clinical manifestation of prejaundice syndromes +,
o slight jaundice +,
o hepatomegaly +,
o slight biochemical modifications ++,







o presence of serum Ag, Ab +
SUBCLINICAL FORM
o clinical manifestation of prejaundice syndromes -,
o jaundice -,
o hepatomegaly -,
o biochemical modifications +,
o presence of serum Ag, Ab +++
INAPPARENT (SYMPTOMLESS)FORM
o clinical manifestation of prejaundice syndromes -,
o jaundice -,
o hepatomegaly -,
o biochemical modifications -,
o presence of serum Ag, Ab +++
CHOLESTATIC FORM: Less common.
o Biochemical increase of cholestatic marks (phosphate alkaline, b-lipoproteins,
cholesterol)
FULMINANT HEPATITIS: 1% of acute icteric hepatitis. This complication is fatal
SUBACUTE HEPATIC NECROSIS: 3%. These patients will clinically deteriorate for a period
of 2-3 months and develop deepening of jaundice, sings of portal hypertension, worsening of
coagulation. This course is seen in patients over 40 years of age, patients with AIDS, drug
addiction.
PROLONGED: If it lasts more than 3 months.
CHRONIC HEPATITIS: If it lasts more than 6 months. At least 10% of all infected people.
Particularity of acute viral hepatitis evolution depending on etiological agent:
VHA
VHB
VHD
VHD
VHC
coinfection superinfection
Length of
0-1
0-4
0-10 days
0-10 days
0-2 weeks
prejaundice
week
weeks
period
Cause of liver Direct
Immune
VHB - immune complex
Direct
injury
cytotoxic complex
VHD - direct cytotoxic
cytotoxic
+ immune
complex
Prejaundice period
Dyspeptic
+
+
+
+
+/syndrome
(nausea,
vomiting)
Arthralgic
+
+
syndrome
Asteno+
+
+
+/vegetative
(intoxication
syndrome)
Fever
+
+/+/Hepatomegalia +
+
+
+
+
Splenomegalia +/+/+
+/Jaundice period
State after
better
same or
worse
worse
same
jaundice
worse
appearance
Length of
1-2
2-4
2-6 weeks
2-8 weeks
2-4 weeks
jaundice
weeks
weeks
period
Extrahepatic
+
+ because of HBV
+
manifestations
VHE
0-2
weeks
Direct
cytotoxic
+
+
+
+
same
1-2
weeks
-
LAB. STUDIES. ACUTE HEPATITIS :
 Cytolitic syndrome:
 high ALT, AST
 Cholestatic syndrome:
 high bilirubin level, 2/3 – conjugated,
 phosphate alkaline, b-lipoproteins, cholesterol are N.
 Haepatodepresion syndrome:
 slightly low albumin levels,
 prolongation of the prothrombin time
 Mezenchimal-inflamation syndrome:
 high  - globulines,
 low sublime test,
 high tymole test (mostly inflammation)

Hematologic abnormalities:
 leukopenia (ie, granulocytopenia)
 lymphocytosis
 increase in the sedimentation rate.
=========================================================================
VHA
Piconarvirus (RNA virus). More heat stable than most RNA viruses, for complete inactivation heat food
to > 85° C for at least 1 minute.
Virus acquired from:
 exposure to high risk source often person-person
 contaminated food/water, floods/water disasters
 most often spread among family members, child care settings or similar.
Maximum infectivity occurs during the latter half of the incubation period, extending to a few days after
onset.
The concentration of virus in the stool, and therefore the infectivity, is highest before onset of symptoms.
Cases can generally be considered non-infectious a week after onset of jaundice (if it occurs) or 2 weeks
after onset of prodromal symptoms, whichever comes first. (This period may be longer in
immunocompromised persons.)
The likelihood that symptoms will follow infection increases with age: jaundice occurs in only a small
proportion of infants and young children, but a majority of adults. Unusual to be fulminant.
Clinical manifestations
VHA
 The usual clinical presentation is acute fever, malaise, anorexia, nausea and abdominal discomfort
followed a few days later by dark urine and jaundice (pseudoflu, intoxication, dispeptic syndromes).
 Symptoms usually last several weeks.
 The likelihood that symptoms will follow infection increases with age: jaundice occurs in only a
small proportion of infants and young children, but a majority of adults.
 Unusual to be fulminant.
•
•
•
•
•
Serologic testing to detect immunoglobulin M (IgM) antibody to the capsid proteins of HAV
(IgM anti-HAV) is required to confirm a diagnosis of acute HAV infection.
In the majority of persons, serum IgM anti-HAV becomes detectable 5-10 days before onset of
symptoms.
IgG anti-HAV, which appears early in the course of infection, remains detectable for the person's
lifetime and provides lifelong protection against the disease.
In the majority of patients, IgM anti-HAV declines to undetectable levels <6 months after
infection. However, persons who test positive for IgM anti-HAV >1 year after infection have
been reported, as have likely false-positive tests in persons without evidence of recent HAV
infection.
HAV RNA can be detected in the blood and stool of the majority of persons during the acute
phase of infection by using nucleic acid amplification methods, and nucleic acid sequencing has
been used to determine the relatedness of HAV isolates for epidemiologic investigations.
However, only a limited number of research laboratories have the capacity to use these methods
Pre-Exposure Prophylaxis
• Target populations formerly children in states, communities with high rates HAV. Per 2006
recommendations, routine vaccination now recommended for all children > 1 year of age.
• For adults (recommended): at-risk international travelers, high-risk geographic populations or
individuals at risk during outbreaks/close personal contacts, MSM, frequent blood/plasma recipients,
chronic liver disease (including. Hep B and C), high risk employment, IDUs
• Active immunization: inactivated hepatitis A vaccine, given into deltoid muscle. Forms: VAQTA (for
12mos-18yrs give 25U per dose, for >18 yrs 50U per two dose schedule), HAVRIX (for 12mos-18yrs
give 720EL.U per dose, for >18 yrs 1440El.U per two dose schedule) and TWINRIX (>18yrs only,
combines hepatitis A and hepatitis B vaccines in three dose schedule (0,1, 6 months or accelerated four
dose schedule 0, 7, 21-30d followed by booster at 12 mos).
• Hepatitis A vaccine must be administered 2 weeks before expected exposure: VAQTA or HAVRIX
give 1 ml IM into deltoid muscle, with 1 ml IM booster within 6-12 months. Need for booster dose
currently unknown, but expected >10 yr duration of prophylaxis.
• Protective antibody responses seen in 94-100% of adults after 1st vaccine dose. Antibody response
~100% post second dose.
• Immunosuppressed patients may be unable to develop antibodies or may require additional boosters.
• For expected exposure risk < 2wks, use pooled human immunoglobulin. Desired duration of coverage
if 1-2 months use 0.02 mL/kg IM or long-term 3-5 months use 0.06mL/kg and repeat q 5 months for
continued exposure risk.
Post-Exposure Prophylaxis
• Passive immunization: pooled human immunoglobulin.
• Immunoglobulin prophylaxis: point source outbreaks, close contacts of index cases, daycare center
contacts, institutional contacts.
• Immunoglobulin should be administered within 2 wks of exposure. Use IG 0.02 mL/kg IM into gluteus
muscle.
===========================================================================
VHE
Transmission:
 Genotypes 1 and 2: predominantly fecal-contaminated water in developing countries worldwide.
 Genotypes 3 and 4: zoonotic transmission from unclear sources but some significant association
with undercooked meat, especially swine, in North America, Western Europe, and Japan.
 Transmission from person to person occurs less commonly than with hepatitis A virus
 Hepatitis E virus causes acute sporadic and epidemic viral hepatitis.
 Most outbreaks in developing countries have been associated with contaminated drinking water.
 Risk groups: travelers to developing countries, particularly in South Asia and North Africa
Symptomatic HEV infection is most common in young adults aged 15-40 years. Although HEV infection
is frequent in children, it is mostly asymptomatic or causes a very mild illness without jaundice (anicteric)
that goes undiagnosed.
SIGNS &
SYMPTOMS
Incubation period following exposure to HEV ranges from 2 to 10 weeks



jaundice
fatigue
abdominal pain
CAUSE

Hepatitis E virus (HEV)
LONG-TERM
EFFECTS


There is no chronic (long-term) infection
Hepatitis E is more severe among pregnant women, especially in third
trimester
TRANSMISSION

Four genotypes (all belong to one serotype) detected in humans, distinct
means transmission suspected.
Genotypes 1 and 2: predominantly fecal-contaminated water in developing
countries worldwide.
Genotypes 3 and 4: zoonotic transmission from unclear sources but some
significant association with undercooked meat, especially swine, in North
America, Western Europe, and Japan.
Transmission from person to person occurs less commonly than with
hepatitis A virus
Most outbreaks in developing countries have been associated with
contaminated drinking water.



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

RISK GROUPS

Travelers to developing
countries, particularly in
South Asia and North Africa
PREVENTION

Always wash your hands with soap and water after using the bathroom,
changing a diaper, and before preparing and eating food
Avoid drinking water (and beverages with ice) of unknown purity,
uncooked shellfish, and uncooked fruits or vegetables that are not peeled or
prepared by the traveler.




loss of appetite
nausea, vomiting
dark (tea colored) urine
Rare cases have occurred in the
United States among persons with
no history of travel to endemic
countries
In general, hepatitis E is a self-limiting viral infection followed by recovery. Prolonged viraemia or
faecal shedding are unusual and chronic infection does not occur.
Occasionally, a fulminant form of hepatitis develops, with overall patient population mortality rates
ranging between 0.5% - 4.0%.

Fulminate hepatitis occurs more frequently in pregnancy and regularly induces a mortality rate of
20% among pregnant women in the 3rd trimester.
Cause of death in pregnant women:
1. acute hepatic failure
2. haemorrhage;
3. acute renal failure, hemoglobinuria





Hepatitis E virus causes acute sporadic and epidemic viral hepatitis.
Symptomatic HEV infection is most common in young adults aged 15-40 years.
Although HEV infection is frequent in children, it is mostly asymptomatic or causes a very mild
illness without jaundice (anicteric) that goes undiagnosed.
Typical signs and symptoms of hepatitis include jaundice (yellow discoloration of the skin and sclera
of the eyes, dark urine and pale stools), anorexia (loss of appetite), an enlarged, tender liver
(hepatomegaly), abdominal pain and tenderness, nausea and vomiting, and fever, although the disease
may range in severity from subclinical to fulminant.
Hepatitis E should be suspected in outbreaks of waterborne hepatitis occurring in developing
countries, especially if the disease is more severe in pregnant women, or if hepatitis A has been
excluded..
=======================================================================
VHC
 HCV is a member of the Flaviviridae family
 The virus contains a single-stranded genome of RNA, a capsid, a matrix and an envelope
 HCV does not integrate into host DNA like Hepatitis B virus
 The nucleotide sequence of HCV is highly variable, the most divergent isolates sharing only 60%
nucleotide sequence homology. This variation accounts for resistance to antibodies.
 Isolates from all over the world have now been grouped into 6 main types, each with several
subtypes, based on sequence data.
o Types 1-3 account for almost all infections in Europe,
o type 4 is prevalent in Egypt & Zaire,
o type 5 in South Africa & type 6 in Hong Kong.
 It is not yet clear whether immunity to one type prevents subsequent infection with another, but there
is some evidence that various genome types differ in their biological properties.
 Studies conducted during natural infection in humans indicate that chronicity of hepatitis C is related
to rapid production of virus, and a lack of vigorous T-cell immune response to HCV with emergence
of HCV variants which are prone to escape immune control.
 The pathogenesis of liver damage is most likely due to a combination of direct cytopathic effects of
viral proteins and of immune mediated mechanisms including cytolytic and non-cytolytic reactions
mediated by CTLs (cytotoxic T lymphocytes) and inflammatory cytokines.

Recent data indicate that oxidative stress is an important pathogenetic factor in HCV related liver
damage. Hepatic steatosis is also a characteristic features of hepatitis C and contributes to the
progression of liver disease and fibrosis development.
Causes:
 Incubation period is 2-26 weeks (20–120 days).
 Direct percutaneous exposure is the primary means of transmission. The use of injected drugs is
the most important epidemiologic risk factor. Tattooing, body piercing, and acupuncture with
unsterile equipment are possible ways of infection.
 Blood transfusions are another means of transmission. Hemodialysis is a possible cause of HCV
infection.
 Patients who are healthcare employees may have an accidental exposure.
 With sexual transmission, the risk appears to be low, even among individuals with multiple sex
partners; however, the presence of coexisting, sexually transmitted diseases (eg, infection with
human immunodeficiency virus [HIV]) appears to increase the risk.
 Vertical transmission of HCV in utero & perinatally has also been reported, but again, appears to
be rare. Perinatal transmission affects an estimated 5% of babies born to HCV-infected mothers.
The risk is higher for babies born to mothers who are coinfected with HCV and HIV.
Breastfeeding is not contraindicated for HCV-seropositive mothers.
 Perhaps 10% of HCV-infected adults have no identified risk factor for HCV infection; this
frequency is probably higher among pediatric patients.
o
o
o
o
o
o
o
o
o
o
Infections are often inapparent or subclinical. Only 25-35% of patients have nonspecific
symptoms such as weakness, malaise, and anorexia. Fatigue is reported most often. Acute
hepatitis with jaundice is seen in no more than 20-25% of cases, whereas less than one third have
hepatomegaly.
A more severe course of acute hepatitis C can be seen in patients with excess alcohol intake, or
co-infection with HBV or HIV.
Patients with symptoms and jaundice develop chronic infection more rarely than those who
remain asymptomatic. The higher the ALT peak during acute disease, the lower the probability of
virus persistence.
A monophasic pattern of ALT profile has also been shown to predict recovery while polyphasic
ALT are often followed by chronic evolution.
It should be underlined, however, that serum ALT levels may be extremely variable in acute
hepatitis C and that ALT normalization after acute phase is not a reliable marker of recovery as
there are patients who remain viremic despite complete and persistent normalization of ALT.
Approximately half of the patients with acute hepatitis C recover spontaneously while the other
half develop chronic infection, parameters able to predict the outcome would be extremely useful
in the clinical management of these cases. Unfortunately, this has not been yet adequately
evaluated and it is clear that a single HCV-RNA negative sample or normal ALT during the late
phase of acute hepatitis C do not prove resolution of infection and prolonged follow-up with
repeated testing for at least 12 months after diagnosis is necessary to prove that the infection has
resolved.
Approximately 30% of patients with chronic HCV infection have normal ALT levels at
diagnosis, independently of age and gender and many of them do maintain normal enzyme levels
during prolonged follow-up.
15-25% will eventually show reactivation of biochemical activity during a 3 month to 10 years
follow-up.
Around 20% of HCV carriers with normal ALT have significant fibrosis or cirrhosis on liver
biopsy.
Presence of significant liver disease or the risk of future ALT reactivation cannot be predicted by
virological or biochemical testing.
VIRAL HEPATITIS B
THE VIRUS
HBV is the prototype member of the family Hepadnaviridae (from Hepa=liver, dna=DNA ). HBV is an
extremely resistant strain capable of withstanding extreme temperatures and humidity. It can survive
when stored for 15 years at -80°C, for 24 months at -20°C, for 6 months at room temperatures, and for 7
days at 44°C.
PATHOGENESIS
It appears the virus is not cytotoxic and the cytolysis is apparently produced by cytotoxic lymphocytes
sensitive to one or more viral antigens. In 1981 it was discovered that HBV-DNA in hepatocyte may exist
as an integrated (double-stranded, intranuclear) form or as an episomal (free, circular, low- molecular
weight, single- stranded, intracytoplasmic ) form. Both forms may exist in the same hepatocyte. It appears
that active viral replication is associated with predominantly episomal viral DNA while low replication is
associated with integrated viral DNA. Cases of chronic hepatitis of short duration (1-2 years) exhibit
predominantly episomal (cytoplasmic) viral DNA while cases of longer (6-8 years) duration exhibit
integrated, intranuclear viral DNA.
EPIDEMIOLOGY AND PREVENTION OF VIRAL HEPATITIS B
Internationally:The HBV carrier rate variation is 1-20% worldwide. This variation is related to
differences in the mode of transmission and age at infection. The prevalence of the disease in different
geographical areas can be characterized as follows:
 Low-prevalence areas (rate of 0.1-2%) include Canada, western Europe, Australia, and New
Zealand. In the areas of low prevalence, sexual and percutaneous transmission during adulthood
are the main modes of transmission.
 Intermediate-prevalence areas (rate of 3-5%) include eastern and northern Europe, Japan, the
Mediterranean basin, the Middle East, Latin and South America, and central Asia. In areas of
intermediate prevalence, sexual and percutaneous transmission and transmission during delivery
are the major routes.
 High-prevalence areas (rate of 10-20%) include China, Indonesia, sub-Saharan Africa, the Pacific
islands, and Southeast Asia. In areas of high prevalence, the predominant mode of transmission is
perinatal, and the disease is transmitted during early childhood vertically from the mother to the
infant. Vaccination programs implemented in highly endemic areas such as Taiwan seem to
change the prevalence of HBV infection. In Taiwan, seroprevalence declined from 10% in 1984
(before vaccination programs) to less than 1% in 1994 and the incidence of HCC declined from
0.52% to 0.13%.
COURSE IN CHILDREN
EARLY CHILDHOOD HBV INFECTION - RISK OF
CHRONICITY







Age at Infection (years)
Proportion who become carriers (%)
<1
70-90
2-3
40-70
4-6
10-40
>7
6-10
90% of infected children will develop a chronic course. More than adults.
The majority of infected children are asymptomatic. The younger the child, the more
asymptomatic.
Children however , either symptomatic or asymptomatic, grow normally.
Chronic hepatitis seldom progresses to cirrhosis. If it does superinfection with hepatitis D or C
must be suspected.
Also hepatocellular carcinoma is extremely rare but it may occur.
Asymptomatic carrier children should not be treated with alpha-interferon.
In perinatally acquired HBV infection, which is common in geographical areas of high HBV
prevalence like Asia, it appears to follow a period of immune tolerance of HBV during which
HBV DNA levels are high while ALT levels keep normal or nearly normal and liver
necroinflammtion is minimal or absent.
ACUTE RESOLVING HEPATITIS.
The incubation period is 1-6 months.
General symptoms arise 0-4 weeks before the jaundice.
The prejaundice symptomatology is more constitutional and includes the following:
 Dyspeptic syndrome : anorexia, nausea, vomiting, disordered gustatory acuity and smell
sensations (aversion to food and cigarettes),
 Arthralgic syndrome : slight arthralgia
 Asteno-vegetative syndrome : low-grade fever, myalgia, fatigability,
 Slight ache syndrome: right upper quadrant and epigastric pain (intermittent, mild to moderate).
Serum transaminases are elevated even before general symptoms and jaundice appear.
Surface antigen (HbsAg) may be detected by radioimmunoassay as early as one week after contacting the
virus by parenteral inoculation and 3-4-5 weeks before having any feeling of being sick.
ACUTE VIRAL HEPATITIS B, Extrahepatic manifestations
 ARTHRITIS-DERMATITIS: a serum sickness-like syndrome is an occasional extrahepatic
manifestation of acute hepatitis B. These patients experience urticaria, rash, petechiae, palpable,
purpura, arthralgia and arthritis of small joints. It involves mostly small joints of hands and knees
and occurs in the prodrome period, before jaundice appears and resolves within a week. Arthritis
may be accompanied by urticaria, palpable purpura, erythema multiforme, erythema nodosum ,
liken planus.
 GIANOTTI SYNDROME (Infantile papular acrodermatitis):Papular skin eruptions with
generalized lymphadenopathy in children under eight years. The hepatitis is mild and anicteric
and can be transmitted on contact to adults who may develop an icteric hepatitis.
 NERVOUS SYSTEM: Seizures (rare), Guillain-Barre' syndrome, peripheral neuropathy,
mononeuritis multiplex.These symptoms resolve at the end of the acute illness.




CARDIO-VASCULAR SYSTEM: Pericarditis, myocarditis may occur especially in the
fulminant type. Polyarteritis nodosa is seen in chronic hepatitis B.
GASTRO-INTESTINAL TRACT: Pancreatitis. The virus replicates in the pancreas.
Pancreatitis has been observed after liver transplantation for hepatitis B. HbsAg has been
demonstrated in the pancreas.
URINARY SYSTEM: resolving mild renal failure may occur in the acute phase. Membranous
glomerulonephritis occurs in chronic hepatitis B.
HEMOPOIETIC SYSTEM: aplastic anemia (rare). Cryoglobulinemia of mixed type can be
seen in hepatitis B infection. The serum contains cryoprecipitable IgG and IgM proteins with
anti-gamma globulin activity producing purpura, arthritis, glomerulonephritis and generalized
vasculitis apparently due deposits of immunoglobulin-complement complexes in the vascular
wall.
Several viral markers can be identified in the serum of the patient with acute viral hepatitis B:
IgM anti-HBc (core antibody)
 Appears early
 Persists for 6 months
HBsAg (surface antigen)
 Detectable 30-60 days after exposure
 May indicate chronic carrier status
HBsAb (antibody to surface antigen)
 Develops after resolved infection
 Indicates long term immunity
Anti-HBc/HBcAb (antibody to core antigen)
 Develops in all HBV infections
HBeAg (E antigen)
 Indicates HBV replication
 Correlates with high infectivity
 Present in acute or chronic infection
Anti-HBe (antibody to E antigen)
 Develops in most HBV infections
 Correlates with lower infectivity

HBs antigen. Hepatitis B surface antigen (HBsAg) is borne by surface viral proteins, i.e.
viral proteins anchored at the surface of viral envelopes. The presence of HBsAg is thus a
sign of HBV envelope production at the acute phase of infection or in chronic HBV carriers,
but not a marker of viral replication. The surface proteins have many functions, including
attachment and penetration of the virus into hepatocytes at the beginning of the infection
process. The target of the host’s humoral response to HBV is the hydrophilic region of the
HBsAg between amino acid residues 100 and 160. Several mutants from the S gene have
been identified worldwide. The disease they cause seems to develop earlier, and the infection
is quite often asymptomatic and has strong association with active HBV replication. In
certain cases of mutant-related hepatocellular carcinoma, only HBV-DNA positivity is
observed, HBsAg remaining seronegative.
HBe antigen. Hepatitis B e antigen (HBeAg) is borne by a nonstructural protein produced during
viral replication in hepatocytes infected by so-called "wild-type" HBV and then released into the
general circulation. When present, HBeAg is associated with HBV DNA detection. In contrast,
so-called "pre-core mutant" HBV viruses are unable to produce the HBe protein. In these patients,
HBV DNA is detected in the absence of HBeAg. Therefore, HBeAg is not a reliable marker of
HBV replication. In general, patients infected with this mutant are more likely to progress to
cirrhosis and hepatitic insufficiency, compared to those infected by the wild virus. High
prevalence rates (50-60%) have been reported in HBV-endemic areas in the Mediterranean
basin, including Italy and Greece, and Far Eastern countries, such as China and Japan. In contrast,
the mutant is less dominant (10-30%) in non-endemic areas, such as Northern Europe and North
America.
 Anti-HBs antibodies. Their appearance a few weeks after resolution of acute hepatitis B is
associated with disappearance of HBsAg (HBs seroconversion) and is considered the marker
of resolution of HBV infection. These antibodies can also rarely appear after HBsAg
disappearance in non replicative chronic HBV carriers, either spontaneously or following
successful antiviral therapy. They generally persist for life, but may become undetectable
after a few years.
 Total anti-HBc antibodies. Anti-HBc antibodies are directed against a viral capsid epitope
or core antigen. They appear early during infection and remain detectable for life, whatever
the outcome of infection. They can be present in the absence of both HBsAg and anti-HBs
antibodies, during the convalescent period following acute hepatitis B before the appearance
of anti-HBs antibodies, or in patients who resolved infection but lost detectable anti-HBs
antibodies. Anti-HBc is therefore detected in anyone who has been infected with HBV.
 Anti-HBc IgM. High titers of anti-HBc IgM are present early at the acute stage of HBV
infection. They disappear after the appearance of anti-HBs antibodies when infection
resolves. Low amounts of anti-HBc IgM can also be found with ultra-sensitive EIA
techniques in patients with chronic HBV infection, bearing witness to a strong and adapted
anti-HBV immune response.
 Anti-HBe antibodies. In patients infected with a "wild-type" HBV, anti-HBe antibodies
appear after HBeAg disappearance (HBe seroconversion) when replication ceases, either
spontaneously or following successful antiviral treatment. In patients infected with a "precore
mutant" HBV, anti-HBe antibodies are present whether or not HBV replicates. HBV DNA
detection is thus needed to distinguish between patients who have seroconverted to HBeAg
and those with pre-core mutant infections and ongoing HBV replication.
Diagnosis of HBV infections.
(i) Acute hepatitis B shows the evolution of HBV serological markers in spontaneously resolving acute
hepatitis B. The following four markers should be tested in patients suspected of having acute hepatitis B:
HBsAg, total anti-HBc antibodies, anti-HBc IgM antibodies, and anti-HBs antibodies. Interpretation of
serological profiles.
Acute hepatitis B is characterized by the simultaneous presence of HBsAg and anti-HBc IgM. During
convalescence, anti-HBc IgM is present during the window period between HBsAg disappearance and
anti-HBs antibody appearance. After resolution, both total anti-HBc antibodies and anti-HBs antibodies
are present, and these patients are protected against HBV reinfection. Anti-HBs antibodies may
sometimes become undetectable after a few years, leading to an isolated anti-HBc antibody profile.
(ii) Chronic HBV carriage. Chronic HBV carriage results of a failure of the host immune responses to
clear HBV during acute hepatitis. By definition, it is characterized by HBsAg persistence in serum for
more than 6 months. In chronic HBV carriers, total anti-HBc antibodies are present, whereas anti-HBs
antibodies are absent. HBV DNA must be sought for by means of molecular biology-based assays. A
liver biopsy must be performed in the patients with detectable HBV replication, to define the stage and
severity of the disease and to assess the need for therapy. Using these parameters, the patients can be
classified into three distinct groups, each roughly including one third of cases.
(i) Chronic HBV carriers with no detectable HBV replication. Small amounts of HBV DNA may however
be detected in these patients with recently developed highly sensitive PCR-based assays. Ongoing studies
are aimed at determining the threshold above which HBV replication should be considered clinically
relevant.
(ii) Chronic HBV carriers with HBV replication with no or mild liver lesions. The immune system of
these patients tolerates viral replication for unclear reasons, causing little damage to the liver.
(iii) Chronic HBV carriers with HBV replication with moderate to severe liver lesions (chronic hepatitis
B). In these patients, the immune response of the host directed against viral antigen-expressing cells is
responsible for liver disease. Small amounts of anti-HBc IgM may be found with ultra-sensitive EIA
techniques as a result of strong anti-HBV immunity.
The patients with no or very low levels of HBV DNA in the blood are generally HBeAg-negative/antiHBe antibody-positive. In the patients with active HBV replication, HBe/anti-HBe testing is useful to
differentiate two groups of patients : (i) those infected with a "wild-type" HBV, who are HBeAgpositive/anti-HBe antibody-negative ; (ii) those infected with a "pre-core HBV mutant", who are HBeAg-
negative/anti-HBe antibody-positive. The latter may have more severe liver disease and may respond less
well to antiviral therapy (38).
(iii) Vaccination. Individuals vaccinated against HBV have isolated anti-HBs antibodies (anti-HBc is
absent in vaccinees, who have never been infected with HBV). Anti-HBs antibodies must be titrated a
few months after vaccination in subjects frequently exposed to HBV infection, such as healthcare
workers, hemodialysis patients, frequently hospitalized patients, etc. A titer of more than 10 mIU/ml is
considered protective. Higher titers are generally observed in the responders to vaccination, who represent
more than 95% of vaccinated individuals (35, 36). If anti-HBs levels decline below 10 IU/ml, a booster
dose of vaccine may be recommended.
CHRONIC HEPATITIS B
Chronicity is characterized by persistence of viral replication with attached viral antigens for over 6
months, sometimes returning to normal in many years or advancing to induce cirrhosis and/or
hepatocellular carcinoma. The chronicity of hepatitis B may follow either a symptomatic acute icteric
hepatitis or, more commonly, an asymptomatic silent infection.
Chronic infection with HBV can be either "replicative" or "non-replicative." In non-replicative infection,
the rate of viral replication in the liver is low and serum HBV DNA concentration is generally low and
hepatitis Be antigen (HBeAg) is not detected. In "replicative" infection, the patient usually has a relatively
high serum concentration of viral DNA and detectable HBeAg. In rare strains of HBV with mutations in
the pre-core gene, "replicative" infection can occur in the absence of detectable serum HBeAg. In
chronically infected individuals, infection can switch from "non-replicative" to "replicative" and viceversa. Spontaneous reactivation may occur in 15% to 20% of previously nonreplicative patients.
The persistence of the virus produces different damage in different individuals depending on the viral
charge and the host reaction. The majority of patients, 3/4, a mild or minimal or no damage at all. They
look " healthy" and almost all become free of disease. These are asymptomatic carriers. A smaller
number of patients, 1/4, have more damage, are "sick" and most of them develop complications, namely,
cirrhosis and hepatoccellular carcinoma. These are the symptomatic carriers. All chronically infected
patients , however, either healthy looking or sick, can transmit the virus on contact.
Chronic inactive hepatitis B
 Healthy carriers have normal AST and ALT levels, and the markers of infectivity (ie, HBeAg,
HBV DNA) may be negative.
 HBsAg, HBcAb of IgG type, and HBeAb also are present in the serum.
Chronic active hepatitis B
 Patients have mild-to-moderate elevation of the aminotransferases (<5 times the upper limit of
normal). The ALT levels usually are higher than the AST levels. Extremely high levels of ALT
can be observed during exacerbation or reactivation of the disease and can be accompanied by
impaired synthetic function of the liver (ie, decreased albumin levels, increased bilirubin levels,
and prolonged prothrombin time). HBV DNA levels are high during this phase. HBsAg and
HBcAb of IgG or IgM type (in case of reactivation) are identified in the serum.
 In patients infected with a "precore mutant" HBV, anti-HBe antibodies are present whether or not
HBV replicates. HBV DNA detection is thus needed to distinguish between patients who have
seroconverted to HBeAg and those with pre-core mutant infections and ongoing HBV replication.
 Hyperglobulinemia is another finding, predominantly with an elevation of the IgG globulins.
Tissue-nonspecific antibodies, such as antismooth muscle antibodies (20-25%) or antinuclear
antibodies (10-20%), can be identified. Tissue-specific antibodies, such as antibodies against the
thyroid gland (10-20%), also can be found. Mildly elevated levels of rheumatoid factor usually
are present.
The HBeAg-positive CHB considered as the typical, prototype form of the disease, occurs in earlier
phases of chronic HBV infection than HBeAg-negative CHB, it prevails in European and North American
patients infected with HBV genotype A and is characterized by persistently high serum aminotransferases
(ALT) and hepatitis B viraemia levels. When HBeAg-positive CHB develops, serum ALT levels increase
and liver damage progresses to severe necroinflammation with advancing fibrosis.
If HBeAg-positive CHB is left untreated it may subside spontaneously terminating into loss of HBeAg,
seroconversion to anti-HBe, suppression of HBV replication to non-detectability by molecular
hybridization techniques or to <103-104 copies/ml by polymerase chain reaction, return of ALT to normal
and resolution of liver disease activity. However, the probability of spontaneous resolution of HBeAgpositive CHB is limited to approximately 10-12% per year (ranging in the various studies from 2 to 24%.
Thus, a large number of untreated patients with HBeAg-positive CHB are left with severe liver
necroinflammation which persists for several years and results in an increased likelihood of progression
of liver damage to advanced stages of fibrosis, cirrhosis and even development of hepatocellular
carcinoma (HCC), the most dire consequence in the natural history of CHB.
In a recent study, the relative risk of HCC among men positive both for HBsAg and HBeAg was 60.2
compared to 9.2 in those with only HBsAg. The need, therefore, for early and effective therapeutic
intervention in HBeAg-positive CHB is obvious, but unfortunately it has remained an unresolved issue of
clinical hepatology for more than 20 years now.
In the HBeAg-negative form of CHB, which prevails in the Mediterranean Area and Asia and is mostly
due to precore HBV mutants, serum HBV DNA levels are lower than in HBeAg-positive CHB. Both
HBV DNA and serum ALT levels are often fluctuating. However, spontaneous remissions are extremely
rare and prognosis is poor with frequent progression to cirrhosis and HCC. Therefore, similar to HBeAgpositive CHB, the need for effective therapeutic intervention is again obvious.
In anti-HBe-positive patients with elevated ALT and detectable HBV DNA (pre-core mutant) therapy is
more difficult. These patients do not respond well to interferon.
Cirrhosis
 In early stages, findings of chronic viral hepatitis can be found.
 Later on as the disease progresses, low albumin levels, hyperbilirubinemia, prolonged prothrombin
time, low platelet count and white blood cell count, and AST levels higher than ALT levels can be
identified.
 Alkaline phosphatase levels and gamm-glutamyl transpeptidase can be slightly elevated.a
Primary hepatocellular carcinoma (PHC)
 Significant risk factors for carcinogenesis include older age, liver firmness, and thrombocytopenia.
Even the presence of HBsAb in the absence of HBsAg or HBV DNA is significantly related to an
increased risk for HCC. In the Orient the incidence of carcinoma is 15% with men more affected than
whomen (6 : 1). The incidence is less in the western world. In S.E. Asia and China PHC is the most
common fatal cancer. Familiar clustering of HCC has been described among families with HBV in
Africa, the Far East, and Alaska. The cumulative probability of survival is 84% and 68% at 5 years
and 10 years, respectively.
 Delta superinfection does not appear to increase the rate of HCC. Although HDV infection has been
reported to increase the risk for HCC 3-fold and mortality rates 2-fold in patients with HBV cirrhosis.
 The prevalence of HCC among patients with HBV and hepatitis C virus (HCV) co-infection is higher
than in those with single infection alone. The rate of development of HCC per 100 person years of
follow-up is 2% in patients with cirrhosis and HBV infection, 3.7% in patients with HCV, and 6.4%
in patients with dual infection. This points to a probable synergistic effect on the risk of HCC.
 Cirrhosis appears to be a prerequisite + chronic liver damage/repair results in malignant
transformation. Approximately 9% of patients in western Europe who have cirrhosis develop HCC
due to HBV infection at a mean follow-up of 73 months. The probability of HCC developing 5 years
after the diagnosis of cirrhosis is established is 6%, and the probability of decompensation is 23%.
Further Outpatient Care:
 Healthy carriers should have routine blood tests annually to check aminotransferase levels.


Patients with chronic active hepatitis should have blood tests (ie, to evaluate aminotransferase levels,
antigen-antibody HBV profile, and viral load), liver biopsy, and treatment.
Patients with cirrhosis must be checked every 3-6 months with alpha-fetoprotein measurements and
abdominal ultrasound for HCC surveillance.
Treatment Regimens
Treatment criteria
•
•
•
•
•
•
•
•
Chronic hepatitis B (e antigen positive)
ALT > 2X ULN; confirm ALT and HBeAg in 1-3 months, then treat (below).
ALT < 1X ULN; follow ALT and HBeAg q 3-6 months.
ALT 1-2 X ULN; follow ALT and HBeAg q 3-6 months, consider biopsy if persistent or >40 yrs; treat
based on biopsy.
Chronic hepatitis B (e antigen negative)
ALT > 2X ULN and HBV DNA >20,000 IU/ml; confirm ALT in 1-3 months, then treat (below).
ALT < 1X ULN and HBV DNA <2,000 IU/ml, follow ALT and HBV DNA q 3-6 months.
ALT 1-2 X ULN and HBV DNA 2,000-20,000 IU/ml, follow ALT and HBV DNA q 3-6 months,
consider biopsy if persistent or >40 yrs; treat based on biopsy.
Treatment goals
• Reduce risk of end stage liver disease and cancer
• Sustained suppression of HBV DNA
• HBsAg clearance (transition to resolution)
• Decrease necroinflammation (transition to inactive hepatitis B)
Standard interferon alfa 2b
• Dose: 5 million U SQ q24h or 10 million U SQ thrice weekly × 16 weeks.
• Side effects: fever, myalgia, bone marrow suppression, depression, thyroid abnormalities.
Thrombocytopenia, granulocytopenia, fatigue and depression may respond to dose adjustment.
• Outcomes: sustained loss of HBeAg (33%), HBV DNA (37%), and HBsAg (~15%) . Histologic
improvement is seen more often in those with sustained HBV DNA suppression. ALT normal in ~25%.
• Response predictors (pretreatment): HBV DNA < 100,000 IU/ml, AST & ALT >100 U/L, liver biopsy
with active necrosis and active inflammation.
• Resistance notes: not affected by or a cause of HBV resistance mutations.
• Cost per course: ~$7000.
• Comments: DO NOT USE with Child-Pugh B or C cirrhosis.
Peginterferon alfa 2a
• Dose: 180 mcg subcutaneous injection per week X 48 week.
• Side effects: similar to standard interferon but lower intensit.
• Outcomes, e antigen positive (48 weeks treat, 24 weeks follow-up) : loss of HBeAg 32% (vs 19% for
LAM), HBV DNA <20,000 IU/ml 32% (vs 22% for LAM), and HBsAg clearance 3% (vs 0 for LAM).
Histologic improvement in 38% (vs 34% for LAM).
• Outcomes, e antigen negative (48 weeks treat, 24 weeks follow-up): HBV DNA <4,000 IU/ml 43% (vs
29% for LAM), and HBsAg clearance 4%(vs 0 for LAM ). Histologic improvement in 48% (vs 40%
for LAM).
• Resistance notes: not affected by or a cause of HBV resistance mutations.
• Cost per course: $16,000
• Comments: DO NOT USE with Child-Pugh B or C cirrhosis. High toxicity and cost constrain
applicability, but may have use in persons with high response likelihood and few contraindications.
Lamivudine (LAM)
• Dose: 100 mg PO daily for six months after HBeAg conversion to Anti-HBe occurs, or lifelong.
• Side effects: same as placebo. Hepatitis B flare can occur after withdrawal of therapy.
• Outcomes, e antigen positive (52 weeks treat, 16 week follow-up): loss of HBeAg 32% (vs 11%
placebo), HBV DNA <20,000 IU/ml 44% (versus 16% placebo), and HBsAg (0-3%), but may not be
sustained. Histologic improvement in 52% (vs 23% with placebo).
• Outcomes, e antigen negative (48 weeks treat, 24 weeks follow-up): HBV DNA <4,000 IU/ml 29% (vs
43% for peginterferon), and HBsAg clearance 0% (vs 4% for peginterferon). Histologic improvement
in 40% (vs 48% for peginterferon).
• Response predictors (pretreatment): HBV DNA < 100,000 IU/ml, AST & ALT >100 U/L, liver biopsy
with active necrosis and active inflammation.
• Resistance notes: mutations in polymerase occur ~15% per year with viral rebound and sometimes
disease flare. Fitness of resistant virus probably attenuated. Reversion to wild-type virus occurs with
discontinuation.
• Cost per year: ~$2200.
• Comments: proven clinical benefit with Child-Pugh B or C cirrhosis. High rate of resistance makes
some avoid. Relatively low cost and high tolerability make some use first line.
Adefovir
• Dose: 10 mg PO daily; duration unclear.
• Side effects: equal to placebo at this dose (renal toxicity seen with higher doses in phase 2).
• Outcomes, e antigen positive (48 weeks treatment): loss of HBeAg 24% (vs 11% placebo), HBV DNA
< detect 21% (vs 0 for placebo), and HBsAg clearance (0-3%). Histologic improvement in 64% (vs
33% placebo). With continued use 5 or more years, higher response rates are seen for all outcomes.
• Outcomes: e antigen negative (144 weeks of treatment): HBV DNA <1000 c/ml at 96 weeks 71% (vs
8% when ADV stopped after 48 weeks), and HBsAg clearance (<2%). Histologic improvement in 89%
(vs 50% of those who stopped ADV after 48 weeks). With continued use 5 or more years, higher
response rates are seen for all outcomes.
• Resistance notes: resistance is uncommon (~ 3.9%) at 3 yrs; novel mutation rtN236T in the D domain
of HBV RT confers resistance to adefovir in vitro and in vivo. LAM remains active, while ADV is
active against LAM resistant HBV.
• Cost per year: ~$6000.
• Comments: less potent than entecavir, telbivudine, and tenofovir but relatively high resistance
threshold. For e antigen negative, improvements were lost when use not continued beyond 48 weeks.
Entecavir
• Dose: 0.5 mg PO daily (1.0 mg daily if lamivudine experienced); duration unclea.
• Side effects: similar to lamivudine.
• Outcomes, e antigen positive (48 weeks): loss of HBeAg 22% (vs 20% for LAM ), HBV DNA < 300
c/ml 67% (vs 36% for LAM), and HBsAg clearance 2% (vs 1% for LAM). Histologic improvement in
72% (versus 62% with LAM).
• Resistance notes: little to no resistance apparent at 3 years.
• Cost per year: $7200 .
• Comments: more potent than lamivudine and much less resistance risk, but higher cost. Use 1.0 mg if
patient has ever had LAM.
Telbivudine
• Dose: 600 mg PO daily.
• Side effects: muscle pain and elevated CK in 12 pts (9%) (vs 8 (3%)for LAM) at 104 weeks in one
study.
• Outcomes: e antigen positive (104 weeks): loss of HBeAg 35% (vs 29% for LAM ), HBV DNA <
detect 56% (vs 39% for LAM), and HBsAg clearance 2% (vs 1% for LAM). Histologic improvement
in 72% (versus 62% with LAM).
• Resistance notes: key issue is early potency since resistance develops in >75% when HBV DNA >
1000 c/ml at 24 weeks; M204I resistance mutation in HBV polymerase sequence observed in all
individuals with confirmed virologic breakthrough on telbivudine.
• Cost per year: $7305
• Comments: too early to tell its role but resistance is clearly an issue; possible role in those who rapidly
respond.
Types of Interferons
Interferons are natural proteins that activate certain immune functions in the body and have anti-viral
properties.
The natural interferons being used for chronic hepatitis B, C or both are called type I interferons and
include the following:
 Interferon alpha 2b (Intron A). (Used for both hepatitis B and C.)
 Interferon alpha 2a (Roferon-A). (Mostly used for hepatitis C.)
 Interferon alfa-n1 (Wellferon). (Approved but mostly used in Canada for hepatitis C.)
 They are given by injection and need to be taken three times a week.
 Newer synthetic interferons have been developed that are showing particularly promise:
 Interferon alfacon-1 (Infergen). This agent is referred to as a consensus interferon (CIFN)
because it was genetically developed using the most commonly occurring amino acid sequences
from each of the natural type 1 alpha interferons. It is usually given three times a week when used
as initial treatment. CIFN is five to 10 times more biologically active than natural type 1
interferons.
 Pegylated interferon (PegINF). Pegylated interferons employ a small molecule called polythelene
glycol (PEG), which attaches to a protein and extends the activity of the interferon. This action
allows the drug to be taken only once a week.
 Of note, some evidence suggests that even in the absence of antiviral effects, interferon may
reduce important factors that contribute to cirrhosis, inflammation and fibrosis (scarring). It may
even have some effect on reversing liver damage. If this evidence holds up, then even patients
whose viral and liver enzyme counts remain high or steady may still benefit from long-term use
of these agents.
Common side effects of any interferon are flu-like symptoms (fever, chills, muscle aches) that usually
occur within six hours and gradually decline over a week or two. (Pegylated interferon may pose a higher
risk for these symptoms than the natural interferons.)
Chronic or more serious effects include the following:
 Emotional and mental changes. Depression can be very severe and cases of suicidal thoughts
have been reported. Other mental and emotional symptoms include anxiety, amnesia, confusion,
irritability, impaired concentration, decreased alertness, memory problems, and mental slowing.
 Changes in sensation.
 Weight loss.
 Skin rashes.
 Hair loss.
 Gastrointestinal problems, including nausea, vomiting, and diarrhea, and, in severe cases
intestinal bleeding and ulcers.
 Fatigue and general weakness.
 Back pain.
 Complications in the lungs, including exacerbation of asthma. In severe cases, interferon can
cause shortness of breath, inflammation in the lungs, and pneumonia.
 Possible negative effects on cholesterol and lipid levels.
 Heart rhythm disturbances, which, in rare cases, can be serious.
 Mild anemia.
 Interferon often causes a drop in platelet and white blood cell counts, increasing susceptibility to
bacterial infections.
 May trigger an autoimmune response, possibly causing anemia, diabetes, lupus-like symptoms,
hypothyroidism, or even autoimmune hepatitis.
 Complications in the eye, including bleeding that, in some cases, may lead to loss of vision if not
detected promptly.
 Rare reports of acute pancreatitis.
 In children, interferon therapy temporarily disrupts growth.
Patients have a difficult time with prolonged therapy. Over 20% drop out if treatment lasts longer than
two years. Depression is the most common reason for withdrawal. (New long-acting forms, such as
pegylated interferon, may improve these drop-out rates.)
Prevention
• Immunization: The vaccines presently used are composed of viral surface antigen (HbsAg) obtained
from the common baker's yeast, Saccharomyces cerevisiae, by inserting into it a gene for the synthesis
of HbsAg. These are Yeast-Recombinant vaccines. Three IM deltoid injections are given: at baseline, at
1 mo, and at 6 mo. HBV vaccine for those with increased risk (hemodialysis, HIV infected, sexual
contacts and household members, group home residents, health care workers, risky sex behaviors,
injection drug users). Check anti-HBs titer 2 months after last dose. Consider double dose for
hemodialysis, HIV infected, and those who fail initial series.
 A combined hepatitis A and B vaccine is licensed in many countries and offers the advantage
of protection against both of these diseases at the same time.
 All newborns must be vaccinated. For infants born to mothers with active HBV infection, a
passive-active (immunoglobulin and vaccination) approach is recommended.
• Postexposure prophylaxis: Specific for type of exposure, host characteristics and source characteristics.
Follow CDC guidelines for HBIG and HBV vaccination (see vaccine, drug modules).
Selected Drug Comments
• Drug: Entecavir. Recommendation: Preferred first line oral agent in lamivudine naive patient.
Potent drug with little resistance as monotherapy. Although long-term efficacy remains unclear and
more expensive than lamivudine, clearly this is an important first line alternative.
• Drug: Peginterferon alfa. Recommendation: Toxicity clearly limits use but remains an important
alternative for persons with high ALT (>2-5X ULN) and low HBV DNA (<1X106 IU/ml) before
treatment.
• Drug: Tenofovir (TDF). Recommendation: This drug is not FDA approved for treatment of chronic
hepatitis B, but is more potent than its cousin adefovir. The coformulation of tenofovir and FTC is a
preferred combination therapy for treatment naive patients. Tenofovir is also an important
consideration for treatment of lamivudine resistant chronic hepatitis B. Special use in HIV positive
patients is described below.
• Drug: Lamivudine (3TC) . Recommendation: A frequently-used comparator and inferior virologically
to entecavir and telbivudine. Nonetheless, safety and low cost makes an option especially for persons
with high baseline ALT and low HBV DNA levels. Early monitoring (and discontinuation when HBV
DNA remains detectable at 24 weeks) may, as with telbivudine, forestall resistance.
• Drug: Telbivudine (ABX). Recommendation: Too early to tell how this drug will be incorporated into
guidelines. Key issue appears to be early detection and alternative treatment of persons not responding
(HBV DNA persistently detectable) by 24 weeks.
• Drug: Interferon alpha (ABX). Recommendation: Hard to find anyone using this in 2007 in the
United States for chronic hepatitis B.
• Drug: Adefovir. Recommendation: Not as potent as tenofovir, but also active against lamivudine
resistant HBV. Less resistance than with lamivudine or telbivudine.
Other Information
• Hepatocellular carcinoma associated w/chronic HBV, especially in endemic Southeast Asia, Japan,
sub-Saharan Africa, Greece, Italy & Oceania. Found especially in perinatally acquired infection.
Higher HBV DNA levels associated with higher risk. Screening recommended.
• If HIV positive, determine if antiretroviral therapy is needed. If so, consider using tenofovir and FTC as
part of HAART (e.g., Atripla or Truvada). If antiretroviral therapy not needed, consider peginterferon,
adefovir, or starting tenofovir-based, fully HIV- suppressive antiretroviral therapy.
===========================================================================
VHD
The International Committee on Taxonomy of Viruses has proposed to classify HDV within the floating
genus Deltavirus. The virus is an enveloped, spherical particle with an average diameter of 36 to 43 nm
containing in its interior a nucleocapsid of 19 nm in diameter , which consists of an RNA genome and a
single structural protein, hepatitis delta antigen (HDAg), that are encapsidated by the hepatitis B surface
antigen (HBsAg).
 HDV can be acquired either as
o a co-infection (occurs simultaneously) with hepatitis B virus (HBV) or
o as a superinfection in persons with existing chronic HBV infection.
 HBV-HDV co-infection:
o may have more severe acute disease and a higher risk (2%-20%) of developing acute
liver failure compared with those infected with HBV alone
 HBV-HDV superinfection
o chronic HBV carriers who acquire HDV superinfection develop chronic HDV infection.
Progression to cirrhosis is believed to be more common with HBV/HDV chronic
infections
 The transmission of the Delta agent mirrors that of HBV, being primarily parenterally transmitted.
 In areas where HDV is endemic in the general population, as in Southern Europe, Africa, the Middle
East and, probably, Latin America, the inapparent parenteral route accounts for most cases of HDV
transmission.
 Most of the countries of the Far East at the moment appears to have quite a low incidence of Delta
with the exception of Taiwan. In Taiwan, it was reported that 26% of all acute hepatitis cases have
Delta antigen in the serum. Similarly in India where 14% of all acute cases are reported positive for
Delta antigen.
 In northern Europe and in the United States HDV is not endemic.





HDV has a direct cytopathic effect. Nevertheless, multiple types of autoimmune phenomena have
been reported in chronic hepatitis D.
HBV is suppressed in asymptomatic carriers of HDV.
However, a pattern characterized by decreasing levels of HDV and reactivating HBV with moderately
high ALT levels has been described during the course of chronic hepatitis D.
In triple infection, several studies have shown that HDV plays a dominant role inhibiting both HBV
and HCV.
Hepatitis D does not increase the incidence of extrahepatic disease or hepatocellular carcinoma over
hepatitis B infection.
HDV
Coinfection
 The clinical expression of acute hepatitis D acquired by coinfection with HBV may range from mild
to severe, fulminant hepatitis.
 In most cases, it resembles a typical acute self-limited hepatitis that is clinically and histologically
indistinguishable from the ordinary hepatitis B. One may see more than one rise in liver transaminase
and there may be 2 peaks of ALT, although not always.
 Delta antigen is rarely detected in the serum, though anti-Delta IgM is found in the serum and lasts 2 6 weeks. Anti-Delta IgG may be present in a low level or perhaps not detectable at all.
 Only 2.4-4.7% become chronic carriers. This course is apparently due to the fact that HDV seems to
suppress HBV replication and does not have optimal conditions for its own replication.
Superinfection
 The most common form of Delta infection is superinfection of a known HBsAg carrier and it is where
Delta infection produces its most deleterious effects. Preexisting HBsAg in the circulation captures
the Delta virus, even if it is in small amounts and intensifies its synthesis immediately.
 Delta infection of a previously healthy carrier may induce an acute hepatitic picture. Infection in a
carrier with preexisting hepatitis will aggravate the clinical picture.
 Primary Delta infection in a HBsAg carrier is often severe, with a significantly higher number of
fulminant hepatitis cases.
 Fulminant HDV hepatitis carried a mortality rate of 70%.
 100% of superinfected carriers develop chronic infection (70% of such patients develop chronic
active hepatitis).








Hepatitis D does not increase the incidence of extrahepatic disease or hepatocellular carcinoma over
hepatitis B infection.
Delta antigen appears in the serum followed by Delta IgM and Delta IgG. In contrast to acute
coinfection, Delta IgG can reach very high levels.
Acute Delta superinfection is accompanied by a drop in HBsAg in the HBV carrier, sometimes to
undetectable levels so that true diagnosis could be masked. The serum picture remains the same
whether the infection becomes chronic or not. However, in the case of the infection becoming
chronic, Delta antigen persists in the liver and can be detected by immmunoperoxidase or
immunofluorescence staining techniques.
The interaction between HBV and HDV replication has been reevaluated in recent years by using
highly sensitive PCR assays. Most patients with chronic HDV infection have antibodies to HBeAg
and low levels of HBV DNA replication.
HBV is suppressed in asymptomatic carriers of HDV.
However, a pattern characterized by decreasing levels of HDV and reactivating HBV with moderately
high ALT levels has been described during the course of chronic hepatitis D.
In intravenous drug addicts, HDV infection is most often associated with HBeAg positivity and active
HBV replication, a pattern that may increase the pathogenicity of HDV.
In triple infection, several studies have shown that HDV plays a dominant role inhibiting both HBV
and HCV.
Hepatitis D: Complications
• 10-15% develop cirrhosis within two years
• 70% eventually develop cirrhosis
• 2-20% fatality rate
• 25-50% of fulminant liver failure in hepatitis B actually due to hepatitis D co-infection
•
Hepatitis D Prevention:
 Hepatitis B vaccine
-
-
Fulminant hepatic failure
Fulminant hepatic failure is the clinical syndrome that results from massive necrosis of liver cells or
from sudden and severe impairment of hepatic function.
Typically the patient has an acute onset of severe mental changes starting with confusion and
advancing to stupor or coma. Jaundice appears and deepens, and there may be gastrointestinal
bleeding and renal failure.
Conventionally the term fulminant hepatic failure is restricted to patients in whom signs appear
within eight weeks of the onset of the illness and in whom there has been no evidence of liver disease
previously.
Ammonia is a key factor in the pathogenesis of HE.
- Ammonia is released from several tissues (kidney, muscle), but its highest levels can be found in the
portal vein. Portal ammonia is derived from both the urease activity of colonic bacteria and the
deamidation of glutamine in the small bowel, and is a key substrate for the synthesis of urea and
glutamine in the liver.
- The blood-brain barrier permeability to ammonia is increased in patients with HE; as a result, blood
levels will correlate weakly with brain values, though recent studies indicate an improvement of this
correlation by correcting the ammonia value to the blood pH
- The alterations in neurotransmission induced by ammonia also occur after the metabolism of this
toxin into astrocytes.
-
All patients with clinical or laboratory evidence of moderate to severe acute hepatitis should have
immediate measurement of prothrombin time and careful evaluation of mental status.
The Stage of encephalopathy
Stage I
PHYSICAL
prodrome
SIGN
mental status alert; slow
mentation;
euphoria,
occasional
depression,
confusion; sleep
pattern reversal
behavior
restless, irritable,
disordered speech
Stage II
impending coma
stage I signs
amplified;
lethargic, sleepy,
Stage III
stupor
arousable, but
generally asleep;
marked confusion
Stage IV
Severe coma
unarousable or
responds only to
pain
unarousable
none
none
decreased, severe
tremor
absent
none
combative, sullen, sleeping,
loss of sphincter
confusion,
control
incoherant speech
spontaneous uncoordinated with yawning,
grimacing,
motor activity tremor
blinking
Stage IV
coma
asterixis
absent
present
present
absent
absent
reflexes
normal
hyperactive
hyperactive
+ Babinski
hyperactive
+ Babinski
absent
respirations
regular or
hyperventilating
hyperventilating
hyperventilating
irregular
apnea
normal
normal
partial
dysconjugate
absent
oculocephalic normal
oculovestibul
ar
EEG
normal
normal
generalized
slowing
markedly abnormal markedly
abnormal
Glasgow
coma scale
15
15
11-13
3-9
eye opening
spontaneous = 4
spontaneous = 4
spontaneous = 4 or to pain only = 2 or never = 1
only to sound = 3 never = 1
motor
obeys commands = obeys commands = obeys commands = normal flexion = 4 extension = 2 or no
6
6
6 or localizes pain or
abnormal response = 1
=5
flexion = 3 or
extension = 2
or no response = 1
verbal
oriented = 5
Review
VIRAL
oriented = 5
confused = 4 or
inappropriate
responses = 3
3-4
inappropriate = 3, no response = 1
or
incomprehensible
= 2 or no response
=1
DIAGNOSIS
TREATMENT
A
IGM ANTI-HAV
IG WITHIN 2 WEEKS OF EXPOSURE
B
VACCINATION AND ADMINISTRATION OF
HBIG WITHIN 24 HOURS OF NEEDLE STICK,
14 DAYS AFTER SEXUAL CONTACT
CHRONIC HEPATITIS TREATED WITH
ALPHA INTERFERON AND LAMIVUDINE OR
ADEFOVIR OR ENTECAVIR OR TELBIVUDINE
C
HBSAG – INFECTIOUS
HBEAG – DEGREE OF
INFECTIVITY
IGM ANTI-HBC – ACUTE
INFECTION
ANTI-HBS – VACCINATED OR
CLEARED INFECTION
ANTI-HCV
D
ANTI-HDV
SAME AS HEPATITIS B
E
ANTI-HEV SEROLOGY
NONE
DEVELOPED BUT NOT
COMMERCIALLY AVAILABLE
IN U.S.
HEPATITIS
PEGINTERFERON ALFA-2B, PEGINTERFERON ALFA2A, RIBAVIRIN