Hepatitis B

Practice Essentials
Hepatitis B infection is a worldwide healthcare problem, especially
in developing areas. The hepatitis B virus (HBV is commonly transmitted
via body !uids such as blood, semen, and vaginal secretions.
Essential update" #$P$T% issues revised screening recommendation for
hepatitis B
The #$ Preventive $ervices Tas& %orce (#$P$T%, which had previously
recommended against screening asymptomatic persons for HBV infection,
has issued a recommendation in favor of screening of asymptomatic,
nonpregnant adolescents and adults at high ris& for HBV infection,
including the following"
Those born in countries and regions where prevalence of HBV
infection is at least '(
)ndividuals born in the #nited $tates who were not vaccinated as
infants and whose parents were born in regions with a high
prevalence of HBV infection, such as sub*$aharan +frica and
southeast and central +sia
H)V*positive individuals
)n,ection drug users
-en who have se. with men
Household contacts of individuals with HBV infection
Testing should be performed with a hepatitis B surface antigen (HBs+g
test followed by a licensed, neutrali/ing con0rmatory test for initially
reactive screening results.
$igns and symptoms
The pathogenesis and clinical manifestations of hepatitis B are due
to the interaction of the virus and the host immune system, which lead to
liver in,ury and, potentially, cirrhosis and hepatocellular carcinoma.
Patients can have either an acute symptomatic disease or an
asymptomatic disease.
)cteric hepatitis is associated with a prodromal period, during which a
serum sic&ness1li&e syndrome can occur. The symptomatology is more
constitutional and includes the following"
+nore.ia
2ausea
Vomiting
3ow*grade fever
-yalgia
%atigability
4isordered gustatory acuity and smell sensations (aversion to food
and cigarettes
5ight upper 6uadrant and epigastric pain (intermittent, mild to
moderate
Patients with fulminant and subfulminant hepatitis may present with the
following"
Hepatic encephalopathy
$omnolence
4isturbances in sleep pattern
-ental confusion
7oma
+scites
8astrointestinal bleeding
7oagulopathy
Patients with chronic hepatitis B disease can be immune tolerant or
have an inactive chronic infection without any evidence of active disease,
and they are also asymptomatic. Patients with chronic active hepatitis,
especially during the replicative state, may have symptoms similar to
those of acute hepatitis.
4iagnosis
The physical e.amination 0ndings in hepatitis B disease vary from
minimal to impressive (in patients with hepatic decompensation,
according to the stage of disease.
E.amination in patients with acute hepatitis may demonstrate the
following"
3ow*grade fever
9aundice (:; days after appearance of constitutional
symptomatology< lasts :*= mo
Hepatomegaly (mildly enlarged, soft liver
$plenomegaly (>*:>(
Palmar erythema (rarely
$pider nevi (rarely
$igns of chronic liver disease include the following"
Hepatomegaly
$plenomegaly
-uscle wasting
Palmar erythema
$pider angiomas
Vasculitis (rarely
Patients with cirrhosis may have the following 0ndings"
+scites
9aundice
History of variceal bleeding
Peripheral edema
8ynecomastia
Testicular atrophy
+bdominal collateral veins (caput medusa
Laboratory studies
The following laboratory tests may be used to assess various stages of
hepatitis B disease"
+lanine aminotransferase and?or aspartate aminotransferase levels
+l&aline phosphatase levels
8amma*glutamyl transpeptidase levels
Total and direct serum bilirubin levels
+lbumin level
Hematologic and coagulation studies (eg, platelet count, complete
blood count @7B7A, international normali/ed ratio
+mmonia levels
Erythrocyte sedimentation rate
$erologic tests
The above*mentioned serologic tests can include laboratory studies of the
following"
Hepatitis B surface antigen (HBs+g
Hepatitis B e antigen (HBe+g
Hepatitis B core antibody (anti*HBc immunoglobulin - ()g-
anti*HBc )g8
Hepatitis B e antibody (anti*HBe
hepatitis B virus (HBV deo.yribonucleic acid (42+
Imaging studies
The following radiologic studies may be used to evaluate patients with
hepatitis B disease"
+bdominal ultrasonography
+bdominal computed tomography (7T scanning
+bdominal magnetic resonance imaging (-5)
Procedures
3iver biopsy, percutaneous or laparoscopic, is the standard
procedure to assess the severity of disease in patients with features of
chronic active liver disease (ie, abnormal aminotransferase levels and
detectable levels of HBV 42+.
-anagement
The primary treatment goals for patients with hepatitis B infection
are to prevent progression of the disease, particularly to cirrhosis, liver
failure, or hepatocellular carcinoma (H77. Pegylated interferon alfa (PE8*
)%2*a, entecavir, and tenofovir disopro.il fumarate are the 0rst*line agents
in the treatment of hepatitis B disease.
Pharmacotherapy
The following medications are used in the treatment of hepatitis B"
2ucleos(tide reverse transcriptase inhibitors (eg, tenofovir
disopro.il fumarate, lamivudine
Hepatitis B?hepatitis 7 agents (eg, adefovir dipivo.il, entecavir,
telbivudine, PE8*)%2*a 'a, interferon alfa*'b
Dietary changes
%or individuals with decompensated cirrhosis (prominent signs of portal
hypertension or encephalopathy, the following dietary limitations are
indicated"
+ low*sodium diet (:.> g?day
High*protein diet (ie, white*meat protein @eg, por&, tur&ey, 0shA
%luid restriction (:.> 3?day in cases of hyponatremia
Liver transplantation
Brthotopic liver transplantation is the treatment of choice for
patients with fulminant hepatic failure who do not recover and for patients
with end*stage liver disease due to hepatitis B disease.
Background
Hepatitis B is a worldwide healthcare problem, especially in
developing areas. +n estimated one third of the global population has been
infected with the hepatitis B virus (HBV. +ppro.imately =>;*C;; million
people have lifelong chronic infection, and ;.> ( spontaneously
seroconvert annually from having the hepatitis B surface antigen (HBs+g
to having the hepatitis B surface antibody (anti*HBs.
7omplications from hepatitis B include progression to
hepatocellular carcinoma (H77 and, rarely, cirrhosis. 8lomerulonephritis
and polyarteritis nodosa are seen, as well as various dermatologic,
cardiopulmonary, ,oint, neurologic, hematologic, and gastrointestinal (8)
tract manifestations.
$ince the :DE;s, considerable progress has also been made
regarding the &nowledge of the epidemiology, virology, natural history, and
treatment of the hepatitis B virion, a hepatotropic virus particle (see the
image below. )n addition, ongoing vaccination programs have been
successful in many countries in the attempt to decrease the prevalence of
HBV disease (eg, Taiwan.
HBV is transmitted hematogenously and se.ually. The outcome of
this infection is a complicated viral*host interaction that results in either an
acute symptomatic disease or an asymptomatic disease. Patients clear
HBV and develop anti*HBs< however, as long as the individual has antibody
to hepatitis B core antigen (HBc+g, he or she is at ris& for reactivation,
because HBV infection remains an incurable disease, similar to Epstein*
Barr virus (EBV, cytomegalovirus (7-V, and Herpes simplex virus (H$V
infections. +lternatively, the patient may develop a chronic infection state
with positivity for HBs+g. 3ate conse6uences are cirrhosis and the
development of H77 in :>*=;( of individuals.
)n immunocompetent adults, less than appro.imately C( of HBV
infections become chronic, whereas up to D;( of perinatally infected
infants will have chronic disease. +mong children who ac6uire HBV
infection between ages : and > years, =;*>;( become chronically
infected. +ccording to the Forld Health Brgani/ation (FHB, by the end of
';:;, the HBV vaccine had been routinely introduced in :ED countries,
with a global coverage of E>(. 7overage in the +mericas was at GD(< in
Europe, EG(< in +frica, EH(< and in $outheast +sia, >'(. )n Taiwan, which
in :DGC launched a nationwide HBV vaccination program, the prevalence of
H77 in children younger than '; years has been reported to be ;.>( or
less.
+ntiviral treatment may be eIective in appro.imately D>( of the
patients who are treated with 0rst*line oral therapy, as de0ned by
undetectable HBV 42+. %or those who are treated with interferon, about
:E( have persistent HBV 42+ suppression. %or selected candidates, liver
transplantation currently seems to be the only viable treatment for the
latest stages of hepatitis B infection, with a posttransplantation viral
control of greater than D;*D>(.
Pathophysiology
Hepatitis B virus (HBV is a hepadnavirus (see the following
images, with the virion consisting of a C'*nm spherical, double*shelled
particle composed of small spheres and rods and with an average width of
'' nm. )t is an e.ceedingly resistant virus, capable of withstanding
e.treme temperatures and humidity. HBV can survive when stored for :>
years at 1';J7, for 'C months at 1G;J7, for H months at room temperature,
and for E days at CCJ7. )ndeed, the appro.imately C;;*year*old mummi0ed
remains of a child found on a mountain top in Korea had HBV in the liver
that could be se6uenced, and a viral genotype 7 was identi0ed.
[Hepatitis B virus (HBV) is a hepadnavirus highly resistant to
extremes o! temperature and humidity that invades liver hepatocytes" #he
viral genome is a partially double$stranded circular D%& lin'ed to a D%&
polymerase that is surrounded by an icosahedral nucleocapsid and then by
a lipid envelope" (mbedded )ithin these layers are numerous antigens
that are important in disease identi*cation and progression" +ithin the
nucleocapsid are the hepatitis B core antigen (HBc&g) and precore
hepatitis B e antigen (HBe&g) and on the envelope is the hepatitis B
sur!ace antigen (HBs&g)" #ransmission electron micrograph (#(,) courtesy
o! -raham .olm and the +i'ipedia and licensed under the .reative
.ommons &ttribution /"0 1nported license"2
Viral genome
The viral genome of hepatitis B consists of a partially double*stranded,
circular 42+ molecule of =.' &ilobase (&b pairs that encodes the following
C overlapping open reading frames"
$ (the surface, or envelope, gene" Encodes the pre*$:, pre*$', and
$ proteins
7 (the core gene" Encodes the core nucleocapsid protein and the e
antigen< an upstream region for the $ (pre*$ and 7 (pre*7 genes
has been found
L (the L gene" Encodes the L protein
P (the polymerase gene" Encodes a large protein promoting
priming ribonucleic acid (52+ M dependent and 42+*dependent
42+ polymerase and ribonuclease H (52ase H activities
3ur!ace gene
The $ gene encodes the viral envelope. There are > mainly
antigenic determinants" (: a, common to all hepatitis B surface antigen
(HBs+g, and ('*> d, y, w, and r, which are epidemiologically important
and identify serotypes.
.ore gene
The core antigen, HBc+g, is the protein that encloses the viral 42+.
)t can also be e.pressed on the surface of the hepatocytes, initiating a
cellular immune response.
The e antigen, HBe+g, which is also produced from the region in
and near the core gene, is a mar&er of active viral replication. )t serves as
an immune decoy and directly manipulates the immune system< it is thus
involved in maintaining viral persistence. HBe+g can be detected in
patients with circulating serum HBV 42+ who have Nwild typeO infection.
+s the virus evolves over time under immune pressure, core promotor and
precore mutations emerge, and HBe+g levels fall until the level is not
measurable by standard assays.
)ndividuals who are infected with the wild type virus often have mi.ed
infections, with core and precore mutants in up to >;( of individuals. They
often relapse with HBe+g*negative disease after treatment.
4 gene
The role of the L gene is to encode proteins that act as
transcriptional transactivators that aid viral replication. Evidence strongly
suggests that these transactivators may be involved in carcinogenesis.
+ntibody production
The production of antibodies against HBs+g (anti*HBs confers
protective immunity after vaccination and can be detected in patients who
have recovered from HBV infection or in those who have been vaccinated.
+ntibody to HBc+g (anti*HBc is detected in almost every patient
with previous e.posure to HBV and indicates that there is a minute level of
persistent virus, as demonstrated by the ris& of reactivation in individuals
who undergo immune suppression regardless of their anti*HBs status.
The immunoglobulin - ()g- subtype of anti*HBc is indicative of
acute infection or reactivation, whereas the )g8 subtype is indicative of
chronic infection. The activity of the disease cannot be understood using
this mar&er alone, however.
+ntibody to HBe+g may be suggestive of a nonreplicative state if there is
undetectable HBV 42+ or the emergence of the core?precore variants and
of chronic HBV HBe+g*negative disease.
Variants of HBV
Fith the newest polymerase chain reaction (P75 assay
techni6ues, scientists are able to identify variations in the HBV genome
(variants as far bac& as :DD>, even in patients who are positive for HBe+g.
-utations of various nucleotides such as the :GDH, :EHC, and :EHG
(precore?core region processing the production of the HBe+g have been
identi0ed (HBe+g*negative strain. The prevalence of the HBe+g*negative
virus varies from one region to the ne.t. Estimates indicate that among
patients with chronic HBV infection, >;*H;( of those from $outhern
Europe, the -iddle East, +sia, and +frica, as well as :;*=;( of patients in
the #nited $tates and Europe, have been infected with this strain.
)mmune response
The pathogenesis and clinical manifestations of hepatitis B
infection are due to the interaction of the virus and the host immune
system. The immune system attac&s HBV and causes liver in,ury, the result
of an immunologic reaction when activated 74C
P
and 74G
P
lymphocytes
recogni/e various HBV*derived peptides on the surface of the hepatocytes.
)mpaired immune reactions (eg, cyto&ine release, antibody production or a
relatively tolerant immune status result in chronic hepatitis. )n particular, a
restricted T*cell1mediated lymphocytic response occurs against the HBV*
infected hepatocytes.
The 0nal state of HBV disease is cirrhosis. Fith or without cirrhosis,
however, patients with HBV infection are li&ely to develop hepatocellular
carcinoma (H77. )n the #nited $tates, the most common presentation of
these patients with H77 is that they are of +sian origin and ac6uired HBV
disease as newborns (vertical transmission.
Viral life cycle
The > stages that have been identi0ed in the viral life cycle of
hepatitis B infection are brie!y discussed below. 4iIerent factors have
been postulated to in!uence the development of these stages, including
age, se., immunosuppression, and coinfection with other viruses.
3tage 56 Immune tolerance
This stage, which lasts appro.imately '*C wee&s in healthy adults,
represents the incubation period. %or newborns, the duration of this period
is often decades. +ctive viral replication is &nown to continue despite little
or no elevation in the aminotransferase levels and no symptoms of illness.
3tage 76 Immune active8immune clearance
)n the immune active stage, also &nown as the immune clearance
stage, an in!ammatory reaction with a cytopathic eIect occurs. HBe+g can
be identi0ed in the sera, and a decline in the levels of HBV 42+ is seen in
some patients who are clearing infection. The duration of this stage for
patients with acute infection is appro.imately =*C wee&s (symptomatic
period. %or patients with chronic infection, :; years or more may elapse
before cirrhosis develops, immune clearance ta&es place, H77 develops, or
the chronic HBe+g*negative variant emerges.
3tage /6 Inactive chronic in!ection
)n the third stage, the inactive chronic infection stage, the host can
target the infected hepatocytes and HBV. Viral replication is low or no
longer measurable in the serum, and anti*HBe can be detected.
+minotransferase levels are within the reference range. )t is most li&ely at
this stage that an integration of the viral genome into the hostQs
hepatocyte genome ta&es place. HBs+g still is present in the serum.
3tage 96 .hronic disease
The emergence of chronic HBe+g*negative disease can occur from
the inactive chronic infection stage (stage = or directly from the immune
active?clearance stage (stage '.
3tage:6 ;ecovery
)n the 0fth stage, the virus cannot be detected in the blood by 42+
or HBs+g assays, and antibodies to various viral antigens have been
produced. The image below depicts the serologic course of HBV infection.
$erologic course of hepatitis B virus (HBV infection. The !at bars
show the duration of seropositivity in self*limited acute HBV infection. The
pointed bars show that HBV 42+ and the e antigen (HBe+g can become
undetectable during chronic infection. Bnly immunoglobulin 8 ()g8
antibodies to the HBV core antigen (anti*HBc are predictably detectable
after resolution of acute hepatitis or during chronic infection. +ntibody to
hepatitis B surface antigen (+nti*HBs is generally detectable after
resolution of acute HBV infection but may disappear with time. )t is only
rarely found in patients with chronic infection and does not indicate that
immunologic recovery will occur or that the patient has a better prognosis.
+3T R alanine transaminase. (+dapted from 3iaw S%, 7hu 7-. Hepatitis B
virus infection. 3ancet. ';;D<=E=(DHH=">G'*D'.
-enotypes and disease progression
Ten diIerent genotypes (+ through 9, representing a divergence of
the viral 42+ of about G(, have been identi0ed. The prevalence of the
genotypes varies in diIerent countries. The progression of the disease
seems to be more accelerated and the response to treatment with antiviral
agents is less favorable for patients infected by genotype 7, compared with
those infected by genotype B. However, much of this can be e.plained by
the presence of core and precore mutations found in multivariate analysis.
)t has been con0rmed that the ris& of H77 is related to higher HBV
42+ levels in the serum, when 42+ is present for longer periodsTwith an
even higher ris& if there is an increasing level of hepatitis B viral load, the
presence of genotype 7, and the presence of mutations in the precore and
basal core promoter regions.
Hepatocellular carcinoma
Even the presence of hepatitis B surface antibody (anti*HBs in the
absence of hepatitis B surface antigen (HBs+g and hepatitis B virus (HBV
42+ is signi0cantly related to an increased ris& for H77, although
surveillance for H77 is not recommended in the aIected group unless
cirrhosis is present. )n the #nited $tates, the estimated annual incidence of
H77 in patients infected with hepatitis B is G:G cases per :;;,;;; persons.
)n Taiwan, the annual incidence of this malignancy in patients with
hepatitis B and cirrhosis is '.G(. %amilial clustering of H77 has been
described among families with hepatitis B in +frica, the %ar East, and
+las&a.
HBV and H.V coin!ection
The prevalence of H77 among patients with HBV and hepatitis 7
virus (H7V coinfection is higher than in those with a single infection. The
rate of development of H77 per :;; person years of follow*up is '( in
patients with cirrhosis and HBV infection, =.E( in patients with H7V
infection, and H.C( in patients with dual HBV and H7V infection. These
0ndings point to a probable synergistic eIect on the ris& of H77.
HBV and HDV coin!ection
)ndividuals coinfected with hepatitis 4 (delta virus (H4V are
thought to have a higher rate of H77 and cirrhosis, with the virus
reportedly increasing the ris& for H77 =*fold and mortality rates '*fold in
patients with HBV cirrhosis.
Forldwide, the prevalence of H4V coinfection among patients
infected with HBV is ;*=;(, with the highest prevalence in -ongolia,
$outheast Tur&ey, and the Brinoco 5iver in $outh +merica. The speculation
that H4V may promote hepatocarcinogenesis in these patients has been
investigated with varying results. The prevalence of anti*delta among
patients with cirrhosis with and without H77 was not signi0cantly diIerent
in one study, whereas most other investigations show the delta virus to be
more aggressive, with higher rates of cirrhosis and cancer.
Possible pathogenic mechanisms
The mechanism by which chronic hepatitis B infection predisposes
to the development of H77 is not clear. 7irrhosis is a cardinal factor in
carcinogenesis. Hepatocyte in!ammation, necrosis, mitosis, and features
of chronic hepatitis are ma,or factors in nodular regeneration, 0brosis, and
carcinoma. 3iver cell dysplasia, de0ned as cellular enlargement, nuclear
pleomorphism, and multinucleated cells aIecting groups or whole nodules,
may be an intermediate step. The high cell*proliferation rate increases the
ris& for H77.
The fact that facultative liver stem cells are capable of bipotent
diIerentiation into hepatocytes or biliary epithelium, termed oval cells,
may play an important role in the pathogenesis. These cells are small, with
oval nuclei and scant pale cytoplasm.
Bval cells are prominent in actively regenerating nodules and in
liver tissue surrounding the cancer. They appear to be the principal
producers of alpha*fetoprotein (+%P. +lthough the cellular targets of
carcinogenesis have not been identi0ed, some evidence from e.perimental
animal models suggests that oval cell proliferation is associated with an
increased ris& for the development of H77.
+lthough cirrhosis is found in the ma,ority of patients with H77, it is
not obligatory, because individuals with chronic infection may develop H77
even without the evidence of cirrhosis.
HBV has been speculated to have intrinsic hepatocarcinogenic
activity, interacting with host 42+ in diIerent ways. +fter entering the
hepatocyte, viral 42+ is integrated within the genome. The site of
integration is not constant but usually involves the terminal repeat
se6uences. 7hromosomal deletions, translocations, rearrangements,
inversions, or even duplications of normal 42+ se6uencing accompany
integration.
Transactivation of the function of genes controlling transcriptional
factors (ie, insulinli&e growth factor )) @)8%*'A, transforming growth factor*
alpha @T8%*aA, T8%*beta, cyclin*a @a protein that controls cell divisionA,
epidermal growth factor*r @E8%5A, retinoic acid receptor @5+5A, and
oncogenes such as c*myc !os ras (activating the internal signal
transduction cascade upregulating ras?mitogen1activated &inase, c*9un 2
terminal &inase, nuclear factor1&B @2%*&BA, 9a&*:*$T+T, src$ dependent
pathways in!uence normal hepatocyte diIerentiation or cell cycle
progression.
%urthermore, the integrated part of HBV controlling the production
of the HB.+g (antigen for the L gene of HBV is overe.pressed. These
observations suggest the site of viral genomic integration into the hostQs
42+ alone is not the factor.
-ost li&ely, the HB.+g produced by these se6uences is the
transactivating factor, because it has been found to bind to a variety of
transcription factors such as 75EB (cyclic adenosine monophosphate
@c+-PA1response element*binding protein and +T%*' (activating
transcription factor ', which alters their 42+*binding speci0city. Thus, the
ability of the HBV pL protein to interact with cellular factors broadens the
42+*binding speci0city of these regulatory proteins and provides a
mechanism for pL to participate in transcriptional regulation. This shifts
the pattern of host gene e.pression relevant to the development of H77.
+dditionally, HB.+g has been postulated to bind to the 7*terminus and
inactivate the product of the tumor suppressor gene #P:/, as well as to do
the following"
$e6uester #P:/ in the cytoplasm, resulting in the abrogation of
#P:/ *induced apoptosis (although controversy e.ists regarding
this concept
5educe the ability for nucleotide e.cision repair by directly acting
with proteins associated with 42+ transcription and repair such as
LPB and LP4
5educe p':F+%: e.pression, which is a cell cycle regulator
Bind to protein p>>sen, which is involved in the cell fate during
embryogenesis and is found in the liver of patients with hepatitis B,
thus altering its function
3evels of tumor necrosis factor*alpha (T2%*a, a proin!ammatory cyto&ine,
are also upregulated. The transcriptional transactivation of nitric o.ide
(2B synthetase )) by pL and the elevated levels of T2%*a are responsible
for the high levels of 2B found in these patients. 2B is a putative mutagen
through several mechanisms of functional modi0cations of #P:/ 42+
o.idation, deamination, and formation of the carcinogenic 2*nitroso
compounds. + second transactivator is encoded in the pre*$?$ region of the
HBV genome, stimulating the e.pression of the human proto*oncogenes c*
!os and c*myc< this upregulates the e.pression of T8%*a by transactivation.
Glomerulonephritis
The most common type of glomerulonephritis described in
association with hepatitis B is membranous glomerulonephritis (-82,
found mainly in children. However, membranoproliferative
glomerulonephritis (-P82 and, even more rarely, immunoglobulin ()g +
nephropathy, have also been identi0ed.
The prevalence rate of glomerulonephritis among patients with
chronic hepatitis B is not well &nown, although observations have been
made in children that suggest a range of ::*>H.'(. However, such a high
prevalence is not recogni/ed in the #nited $tates< this may be because of
the diIerences in epidemiology of HBV, which may be predominantly
perinatal in other geographic areas of the world (see Epidemiology.
+ previous history of chronic liver disease is not present in the
ma,ority of patients with chronic hepatitis B at presentation, and most of
them have no clinical or biochemical 0ndings to suggest acute or chronic
liver disease. However, liver biopsies often demonstrate features of chronic
hepatitis. )n addition, serologic mar&ers of an HBV replicative state are
often evident, and complement activation is suggested by low levels of 7=
and 7C.
8enerally, the most prominent 0nding among aIected children is
-82, primarily with capillary wall deposits of hepatitis B e antigen
(HBe+g. )n contrast, adults present with features of -P82 with mesangial
and capillary wall deposits of HBs+g. + rare overlap between membranous
nephropathy and )g+ nephropathy has also been described.
Possible pathogenic mechanisms
The mechanism by which patients with chronic hepatitis B develop
glomerulonephritis is not completely understood. Bne possible e.planation
is that HBV antigens (ie, HBs+g, HBe+g act as triggering factors, eliciting
immunoglobulins and thus forming immune comple.es, which are dense,
irregular deposits in the glomerular capillary basement membranes. HBV
42+ has been identi0ed by in situ hybridi/ation in &idney specimens,
distributed generally in the nucleus and cytoplasm of epithelial cells and
mesangial cells of glomeruli and in the epithelial cells of renal tubules.
Polyarteritis nodosa
+n association between hepatitis B and arteritis has been
described when HBs+g is present in serum and in vascular lesions.
Evidence for a cause*and*eIect relationship is further supported by a high
prevalence (=H*HD( of HBs+g in patients with polyarteritis nodosa (P+2.
This very serious complication presents early during the course of hepatitis
B, and the incidence is high among certain populations, such as +las&an
Es&imos.
The pathogenesis of P+2 is not clear. 7irculating immune
comple.es containing HBs+g, immunoglobulins ()g8 and )g-, and
complement have been demonstrated by immuno!uorescence in the walls
of the aIected vessels and may trigger the onset of P+2. However,
whether these represent the primary etiology of the disease remains
unclear.
The clinical manifestations of P+2 include the following"
7ardiovascular (eg, hypertension @sometimes severeA, pericarditis,
heart failure
5enal (eg, hematuria, proteinuria, renal insuUciency
8astrointestinal (8) (eg, abdominal pain, mesenteric vasculitis
-usculos&eletal (eg, arthralgias, arthritis
2eurologic (eg, mononeuritis
4ermatologic (eg, rashes
$igni0cant proteinuria (V: g?day, renal insuUciency (serum creatinine
V:.>G mg?d3, 8) and central nervous system involvement, and
cardiomyopathy are associated with increased mortality.
The course of P+2 is independent of the severity and progression
of the liver disease. +mong patients with P+2, ';*C>( die as a
conse6uence of vasculitis in > years, despite treatment, with the mortality
rate being similar whether patients are HBs+g seropositive or
seronegative.
Etiology
Hepatitis B infection, caused by the hepatitis B virus (HBV, is
commonly transmitted via body !uids such as blood, semen, and vaginal
secretions. 7onse6uently, se.ual contact, accidental needle stic&s or
sharing of needles, blood transfusions, and organ transplantation are
routes for HBV infection. )nfected mothers can also pass the infection to
their newborns in the delivery period.
8enetics of infection with hepatitis B
$everal genes, many having to do with the host immune response,
have been implicated in susceptibility to chronic hepatitis B infection. The
#%<3<= gene encodes the 74:=E3 protein, and its e.pression was found to
be signi0cantly higher in patients with chronic hepatitis B infection than in
healthy controls. )ts e.pression was also found to be higher in patients who
had chronic hepatitis B with cirrhosis, in contrast to those without cirrhosis.
5esearch done in Fest +frica, where D;( of the population is
infected with hepatitis B, shows that certain human leu&ocyte antigen
(H3+ class )) haplotypes in!uence the li&elihood of chronic infection. %or
reasons that are not completely clear, persons in the study who were
hetero/ygous for the HL&$D;& and HL&$D>&5 genes were found to be less
li&ely to develop a chronic infection.
I<%-;5 gene
$everal additional genes are associated with susceptibility to
hepatitis B infection. The I<%-;5 gene is located at H6'=.= and encodes
the interferon gamma ()%2*W receptor :, which has important roles in cell*
to*cell communications and can be activated in response to infection, but it
is not speci0c to hepatitis B. Patients with signi0cant dysfunction in this
gene have a particular immune de0ciency that leaves them e.tremely
susceptible to mycobacterial infections.
+ more subtle change in the promoter region at location *>H in this
gene has shown signi0cant association with the natural history of hepatitis
B infection. )ndividuals with the 7 allele at this location were found in a
study to be more li&ely to clear the virus, whereas individuals with the T
allele at this location were more li&ely to have persistent viral infections.
I<%&;7 gene
The I<%&;7 gene is located at ':6''.: and encodes the )%2*alpha,
*beta, and *omega receptor '. +lthough it presumably is li&e the previous
gene, with multiple functions in the immune system, at the present time it
is &nown only to be associated with susceptibility to hepatitis B.
+ study loo&ing at this gene found that a single nucleotide
polymorphism, resulting in a phenylalanine*to*serine substitution at
position G, was associated with an increased ris& for chronic hepatitis B
infection.
IL5?;7 gene
The same study also found that a polymorphism in the IL50;7
gene (or the .;<B9 gene, also located at ':6''.::, is associated with
increased ris& of chronic hepatitis B infection. This particular polymorphism
results in a lysine*to*glutamic acid substitution at position CE.
Variations in vaccine response
)t is also &nown that certain patients have diIerent responses to
the hepatitis B vaccine. Bne study found that :C( of patients who received
the vaccine were low responders. + greater*than*e.pected number of these
patients were homo/ygotes for the H3+*BG, *$7;:, and *45= haplotypes. )t
was hypothesi/ed that because H3+ )) binds antigens, diIerent haplotypes
may alter the way in which vaccine peptides activate the immune system.
+nother study, which loo&ed at D:C immune candidates in over
:H;; patients who were given the HBV vaccine, found numerous single*
nucleotide polymorphisms ($2Ps that were associated with inade6uate
levels of antibody after vaccination, with most found in the H3+ genes.
However, one $2P was found in the = prime (=X downstream
region of the <?4P5 gene. This gene is a transcriptional repressor that
plays a role in the diIerentiation of monocytes and the function of
macrophages.
Epidemiology
#$ statistics
+n estimated H;,;;; or less new cases of hepatitis B virus (HBV
infection occur annually in the #nited $tates, and about ' million or more
people have chronic infection. The prevalence of the disease is higher
among blac& individuals and persons of Hispanic or +sian origin.
HBV disease not only accounts for >*:;( of cases of chronic end*
stage liver disease and :;*:>( of cases of hepatocellular carcinoma (H77
in the #nited $tates, it is also the dominant cause of cirrhosis and H77
worldwide.
HBV is blamed for at least >;;; #$ deaths annually. The prevalence is
low in persons younger than :' years born in the #nited $tates, with the
subse6uent increase being associated with the initiation of se.ual contact
(the ma,or mode of transmission in adults, along with intravenous drug
abuse @)V4+A. )t is also associated with the occurrence of 0rst intercourse
at an early age. +dditional ris& factors, as identi0ed in the 2ational Health
and 2utrition E.amination $urvey (2H+2E$ ))), are as follows"
2on*Hispanic blac& ethnicity
7ocaine use
High number of se.ual partners
4ivorced or separated marital status
%oreign birth
3ow educational level
Because of the implementation of routine vaccination of infants in
:DD' and of adolescents in :DD>, the prevalence of HBV infection is
e.pected to decline further in individuals born in the #nited $tates.
)nternational statistics
8lobally, chronic HBV infection aIects =>;*C;; million people, with
disease prevalence varying among geographic regions, from :*';(. +
higher rate e.ists, for e.ample, among +las&an Es&imos, +sian Paci0c
islanders, +ustralian aborigines, and populations from the )ndian
subcontinent, sub*$aharan +frica, and 7entral +sia. )n some locations, such
as Vietnam, the rate is as high as =;(. $uch variation is related to
diIerences in the mode of transmission, including iatrogenic transmission,
and the patientQs age at infection.
The lifetime ris& of HBV infection is less than ';( in low
prevalence areas (Y '(< generally, ;.:*'(, and se.ual transmission and
percutaneous transmission during adulthood are the main modes through
which it spreads. +bout :'( of HBV*infected individuals live in low*
prevalence areas, which include the #nited $tates, 7anada, western
Europe, +ustralia, and 2ew Zealand.
$e.ual and percutaneous transmission and transmission during
delivery are the ma,or transmission routes in areas of intermediate
prevalence (rate of =*>(. These regions include Eastern and 2orthern
Europe, 9apan, the -editerranean basin, the -iddle East, 3atin and $outh
+merica, and 7entral +sia. Bne study reported appro.imately C=( of HBV*
infected individuals live in $outh 7entral and Fest +sia, Eastern Europe,
5ussia, and 7entral and $outh +merica, with a prevalence rate of '*E( and
a lifetime HBV ris& of ';*H;(.
)n areas of high prevalence ([G(, generally :;*';(, the
predominant mode of transmission is perinatal, and the disease is
transmitted vertically during early childhood from the mother to the infant.
+ppro.imately C>( of individuals infected with HBV live in high*prevalence
areas, with a lifetime infection ris& of over H;(, as demonstrated by the
presence of hepatitis B core antibodies (anti*HBc to hepatitis B core
antigen (HBc+g in serum. $uch regions include 7hina, $outheast +sia,
)ndonesia, sub*$aharan +frica, Paci0c )slands, parts of the -iddle East, and
the +ma/on Basin.
Vaccination programs implemented in highly endemic areas seem
to reduce the prevalence of HBV infection. )n Taiwan, for e.ample, HBV
seroprevalence declined from :;( in :DGC (before vaccination programs
to less than :( in :DDC after the implementation of vaccination programs,
and the incidence of H77 declined from ;.>'( to ;.:=( during the same
period.
The :; genotypes of HBV (+*9 also correspond to speci0c
geographic distributions. 8enotype + is more fre6uently found in 2orth
+merica, northwestern Europe, )ndia, and +frica, whereas genotypes B and
7 are endemic to +sia, and genotype 4 predominates in Eastern Europe
and the -editerranean. Type E is found in western +frica< type %, in $outh
+merica< and type 8, in %rance, 8ermany, 7entral +merica, -e.ico, and
the #nited $tates. Type H is prevalent in 7entral +merica< type ), in
Vietnam< and type 9, in 9apan.
5ace*, se.*, and age*related demographics
)n the #nited $tates, blac&s have a higher prevalence of HBV
disease than do Hispanics or whites. )n addition, more cases of chronic HBV
disease occur in males than in females.
The earlier the disease is ac6uired, the greater the chance a
patient has of developing chronic hepatitis B infection. )nfants (mainly
infected through vertical transmission have a D;( chance, children have a
'>*>;( chance, adults have an appro.imately >( chance, and elderly
persons have an appro.imately ';*=;( chance of developing chronic
disease.
Prognosis
+n estimated : million persons per year globally, including at least
>;;; persons annually in the #nited $tates, die from chronic hepatitis B
disease.
Positive prognostic factors
Patients who have lost the hepatitis B e antigen (HBe+g and in whom
hepatitis B virus (HBV 42+ is undetectable have an improved clinical
outcome, as characteri/ed by the following"
$lower rate of disease progression
Prolonged survival without complications
5educed rate of H77 and cirrhosis
7linical and biochemical improvement after decompensation
Hepatocellular carcinoma
7hronic hepatitis B infection is the ma,or contributor to the
development of appro.imately >;( of cases of hepatocellular carcinoma
(H77 worldwide. $tudies indicate that the level of hepatitis B virus (HBV
42+, which indicates viral replication, is a strong predictor for cirrhosis and
H77 regardless of other viral factors. +ppro.imately D( of patients in
western Europe who have cirrhosis develop H77 due to hepatitis B
infection at a mean follow*up of E= months. The probability of H77
developing > years after the diagnosis of cirrhosis has been established is
H(, and the probability of decompensation is '=(.
$igni0cant ris& factors for carcinogenesis include the following"
Blder age
E.posure to a!ato.ins
+lcohol
7oinfection
)mmune status
8enotype
7ore and precore mutations
7irrhosis
Thrombocytopenia
High serum viral load (ie, viral replication that is persistently elevated
over time is the most reliable indicator in predicting the development of
H77.
Even the presence of hepatitis B core antibody (anti*HBc in the
absence of hepatitis B surface antigen (HBs+g or HBV 42+ is signi0cantly
related to an increased ris& for H77, although there are no
recommendations for H77 surveillance in such cases unless cirrhosis is
present.
The annual incidence of H77 reported in Taiwan for patients with
hepatitis B infection and cirrhosis is '.G(. The #$ estimates for the annual
incidence of H77 in patients infected with HBV is G:G cases per :;;,;;;
persons.
4istinct mutations associated with diIerent HBV genotypes have been
lin&ed to an increased ris& of developing H77. 8enotype 7 is closely
associated with H77< this appears to be related to a higher incidence of
core and precore mutations in patients older than >; years with cirrhosis
and genotype 7, whereas genotype B is associated with H77 development
in young, noncirrhotic patients and in postsurgical relapse.
,ortality
%amilial clustering of H77 has been described among families with
hepatitis B infection in +frica, the %ar East, and +las&a. The cumulative
probability of survival is GC( at > years and HG( at :; years.
7o. regression analysis has identi0ed H variables that
independently correlate with overall survival for individuals with cirrhosis
or H77. These include age, albumin level, platelet count, splenomegaly,
bilirubin level, and positivity for hepatitis B e antigen (HBe+g at the time
of the hepatitis B diagnosis. Based on the contribution of each of these
factors to the 0nal model, a prognostic inde. has been constructed that
allows calculation of the estimated survival probability.
E.pression of in!ammatory molecules in HBV*related H77 tissues
is associated with poor prognosis.
)mbalance between intratumoral 74G\ T cells and regulatory T cells
or type : helper T cells (Th:, and type ' helper T*cell (Th' cyto&ines in
peritumoral tissues can predict the prognosis of HBV*related H77. These
molecules are also important for developing active prevention and
surveillance of HBV*infected patients.
Glomerulonephritis
The prognosis of renal disease in hepatitis B is related to several
factors, such as age and response to therapy. 7hildren with membranous
glomerulonephritis (-82 have a more favorable response than adults.
Fhite persons have a better response than +sian and blac& patients.
+ppro.imately =;*H;( of cases with -82 undergo spontaneous
remission. However, the course of HBV*related membranous nephropathy
in adults in areas in which the virus is endemic is not benign. 5egardless of
treatment, hepatitis B disease has a slow, but relentlessly progressive,
clinical course in appro.imately one third of patients, resulting in
progressive renal failure and necessitating maintenance dialysis therapy.
Patient Education
Patients with acute and chronic HBV infections should be advised
that this is a blood*borne disease that can be transmitted during se.ual
intercourse or at the time of childbirth. Prophyla.is is strongly advised.
%amily members borne by the same parents should also be chec&ed for
HBV infection. The best preventative measurement is vaccination.
Hepatitis B Clinical Presentation
History
The spectrum of the symptomatology of hepatitis B disease varies
from subclinical hepatitis to icteric hepatitis to fulminant, acute, and
subacute hepatitis during the acute phase, and from an asymptomatic
chronic infection state to chronic hepatitis, cirrhosis, and hepatocellular
carcinoma (H77 during the chronic phase.
Papular acrodermatitis, also recogni/ed as 8ianotti*7rosti
syndrome, has been associated with hepatitis B, most commonly in
children with acute infection.
The following multisystem manifestations may occur in hepatitis B virus
(HBV"
Pleural eIusion and hepatopulmonary and portopulmonary
syndrome may occur in patients with cirrhosis
4iIuse intravascular coagulation may occur in patients with
fulminant hepatitis
-yocarditis, pericarditis, and arrhythmia occur primarily in patients
with fulminant hepatitis
+rthralgias and arthritic (serum sic&ness subcutaneous nodules
may also occur, but these are rare
8uillain*Barre syndrome, encephalitis, aseptic meningitis, and
mononeuritis multiple. may occur in patients with acute hepatitis
B
Pancreatitis may develop
+plastic anemia is uncommon, and agranulocytosis is e.tremely
uncommon
+ variety of cutaneous manifestations have been recogni/ed during the
early course of viral hepatitis, including hives and a !eeting maculopapular
rash. These various lesions are episodic, palpable, and, at times, pruritic. +
discoloration of the s&in can be identi0ed after the resolution of the
e.anthem, particularly on the lower e.tremities. Fomen are more prone to
developing cutaneous manifestations.
+cute phase
The incubation period is :*H months in the acute phase of hepatitis
B infection. +nicteric hepatitis is the predominant form of e.pression for
this disease. The ma,ority of the patients are asymptomatic, but patients
with anicteric hepatitis have a greater tendency to develop chronic
hepatitis. Patients with symptomatology have the same symptoms as
patients who develop icteric hepatitis.
)cteric hepatitis is associated with a prodromal period, during which a
serum sic&ness 1li&e syndrome can occur. The symptomatology is more
constitutional and includes the following"
+nore.ia
2ausea
Vomiting
3ow*grade fever
-yalgia
%atigability
4isordered gustatory acuity and smell sensations (aversion to food
and cigarettes
5ight upper 6uadrant and epigastric pain (intermittent, mild to
moderate
Patients with fulminant and subfulminant hepatitis may present with the
following"
Hepatic encephalopathy
$omnolence
4isturbances in sleep pattern
-ental confusion
7oma
+scites
8astrointestinal (8) bleeding
7oagulopathy
7hronic phase
Patients with chronic hepatitis B disease can be immune tolerant or
have an inactive chronic infection without any evidence of active disease<
they are also asymptomatic.
Patients with chronic active hepatitis, especially during the replicative
state, may complain of symptomatology such as the following"
$ymptoms similar to those of acute hepatitis
%atigue
+nore.ia
2ausea
-ild upper 6uadrant pain or discomfort
)f progressive liver disease is present, the following symptomatology may
appear"
Hepatic decompensation
Hepatic encephalopathy
$omnolence
4isturbances in sleep pattern
-ental confusion
7oma
+scites
8) bleeding
7oagulopathy
Physical E.amination
The physical e.amination 0ndings in hepatitis B disease vary from
minimal to impressive (in patients with hepatic decompensation,
according to the stage of disease.
Patients with acute hepatitis usually do not have any clinical 0ndings,
but the physical e.amination can reveal the following"
3ow*grade fever
9aundice (:; days after appearance of constitutional
symptomatology, lasting for :*= mo
Hepatomegaly (mildly enlarged, soft liver
$plenomegaly (>*:>(
Palmar erythema (rarely
$pider nevi (rarely
The physical e.amination of patients with chronic hepatitis B virus (HBV
infection can reveal stigmata of chronic liver disease such as the following"
Hepatomegaly
$plenomegaly
-uscle wasting
Palmar erythema
$pider angioma
Vasculitis (rarely
Patients with cirrhosis may have the following 0ndings"
+scites
9aundice
History of variceal bleeding
Peripheral edema
8ynecomastia
Testicular atrophy
+bdominal collateral veins (caput medusa
Diagnostic Considerations
Fhen evaluating a patient with suspected hepatitis B virus (HBV
infection, also consider the other viral hepatitides and etiologies that can
lead to cirrhosis and liver failure, such as drug hepatoto.icity. )n addition,
because a ma,or mode of transmission of this disease is se.ual, also
consider the possibility of infection with human immunode0ciency virus
(H)V or other se.ually transmitted diseases.
Approach Considerations
3aboratory evaluation for hepatitis B disease generally consists of
liver en/yme tests, including levels of alanine aminotransferase (+3T
and?or aspartate aminotransferase (+$T, al&aline phosphatase (+3P, and
gamma*glutamyl transpeptidase (88T, as well as liver function tests (3%Ts
that include total and direct serum bilirubin, albumin, and measurement of
the international normali/ed ratio ()25. Hematologic and coagulation
studies also include a platelet count and a complete blood count (7B7.
+mmonia levels may be obtained, but the results often create diagnostic
confusion in clinicians.
$erologic tests for hepatitis B surface antigen (HBs+g and
hepatitis B core antibody (anti*HBc immunoglobulin - ()g- are re6uired
for the diagnosis of acute hepatitis B virus (HBV.
To evaluate the patientXs level of infectivity, 6uanti0cation of HBV
42+ is essential, and the presence of hepatitis B e antigen (HBe+g should
be determined. )ndeed, the best indication of active viral replication is the
presence of HBV 42+ in the serum. Hybridi/ation or more sensitive
polymerase chain reaction (P75 assay techni6ues are used to detect the
viral genome in the serum, as well as speci0c genotypes, mutants resistant
to oral nucleoside and nucleotide analogues, and core and precore
mutations.
+ positive result suggests not only the li&elihood of active hepatitis
but also that the disease is much more infectious, as the virus is actively
replicating.
HBV 42+ testing is also recommended when occult HBV is
suspected (positive anti*HBc and negative antibody to hepatitis B surface
antigen @anti*HBsA and hepatitis B surface antigen @HBs+gA or in cases in
which all of the serologic tests are negative.
Screening
HBV
The #nited $tates currently screens foreign*born residents for HBV
infection if their country of origin has an HBV prevalence of '( or greater.
+ccording to a model developed by Ec&man et al, although this threshold
for screening is cost*eIective, a broader screening program with a
threshold of :.=( or even ;.=( country*of*origin prevalence would be cost*
eIective as well, suggesting a reconsideration of current policy.
H.V
+s previously mentioned, the prevalence of hepatocellular
carcinoma (H77 among patients with HBV and hepatitis 7 virus (H7V
coinfection is higher than in those with a single infection.
$ome controversy e.ists regarding screening for H7V infections in
adults. )n +ugust ';:', the 7enters for 4isease 7ontrol and Prevention
(747 e.panded their e.isting, ris&*based testing guidelines to recommend
a :*time blood test for H7V infection in baby boomersTthe generation
born between :DC> and :DH>, who account for appro.imately three fourths
of all chronic H7V infections in the #nited $tatesTwithout prior
ascertainment of H7V ris&.
The recommendations noted that :*time H7V testing in baby boom
population could identify nearly G;G,H;; additional people with chronic
infection< thus, the 747 recommended that all individuals identi0ed with
H7V should be screened and?or managed for alcohol abuse, followed by
referral to preventative and?or treatment services, as appropriate.
However, in a systematic review for the #$ Preventive $ervices
Tas& %orce (#$P$T%, 7hou et al noted that despite the accuracy of
screening tests in identifying asymptomatic adults with chronic H7V
infection, screening strategies that target multiple ris& factors can miss
some of these patients. They recommended further investigation to
determine the eIects of diIerent H7V screening strategies on diagnostic
yield and clinical outcomes.
Diagnostic Tests
3aboratory studies will be discussed according to the stage of
disease.
Acute hepatitis B disease
High levels of alanine aminotransferase (+3T and aspartate
aminotransferase (+$T, within a range of :;;;*';;; )#?m3, is the
hallmar& of this stage of HBV disease, although values :;; times above
the upper limit of normal (#32 can be also be identi0ed. Higher values are
found in patients with icteric hepatitis. +3T levels are usually higher than
+$T levels.
8amma*glutamyl transpeptidase (88T and al&aline phosphatase
(+3P levels may be elevated, but they are usually not more than = times
the #32.
+lbumin levels can be slightly low, and serum iron levels may be
elevated as an acute phase reactant. )n the preicteric period (ie, before the
appearance of ,aundice, leu&openia (ie, granulocytopenia and
lymphocytosis are the most common hematologic abnormalities and are
accompanied by an increase in the erythrocyte sedimentation rate (E$5.
+nemia due to a shortened red blood cell survival period is an
infre6uent 0nding, although hemolysis may be noted. Thrombocytopenia is
a rare 0nding. Patients with severe hepatitis e.perience a prolongation of
the international normali/ed ratio ()25.
$everal viral mar&ers can be identi0ed in the serum and the liver.
Hepatitis B surface antigen (HBs+g and hepatitis B e antigen (HBe+g
(mar&er of infectivity are the 0rst mar&ers that can be identi0ed in the
serum in acute disease. Hepatitis B core antibody (anti*HBc
immunoglobulin - ()g- follows.
%or patients who recover, seroconversion to hepatitis B surface
antibody (anti*HBs and hepatitis B e antibody (anti*HBe is observed. The
anti*HBc is of the )g8 class. Patients with persistent HBs+g lasting more
than H months are considered to have chronic hepatitis.
nacti!e hepatitis B disease
The term Nhealthy carriersO is no longer used due to the fact that a
person who is positive for HBs+g has a high ris& of cirrhosis and
hepatocellular carcinoma (H77 and, therefore, cannot be de0ned as
healthy. $uch individuals have normal +$T and +3T levels, with mar&ers of
infectivity, such as HBe+g, being negative and HBV 42+ going undetected
are being detected at very low levels (usually below ',;;; )#?ml . HBs+g,
anti*HBc of )g8 type, and anti*HBe are present in the serum. + minimum
follow*up of these patients for : year with laboratory evaluation every = to
C months is recommended.
Chronic acti!e hepatitis B disease
7hronic active HBV disease is categori/ed into HBe+g*positive and
HBe+g*negative disease.
3ubtype @)ild typeA or HBe&g$positive disease
Patients have mild to moderate elevation of the aminotransferases
(]> times the #32. The +3T levels are usually higher than the +$T levels.
E.tremely high levels of +3T can be observed during e.acerbation or
reactivation of the disease, and they can be accompanied by impaired
synthetic function of the liver (ie, decreased albumin levels, increased
bilirubin levels, and prolonged prothrombin time @PTA.
HBV 42+ levels are high during this phase. HBs+g and anti*HBc of )g8 or
)g- type (in case of reactivation are identi0ed in the serum.
)f the +$T levels are higher than the +3T levels, the diagnosis of
cirrhosis must be considered. Hyperglobulinemia is another 0nding,
predominantly with an elevation of the )g8 globulins. Tissue*nonspeci0c
antibodies, such as anti1smooth muscle antibodies (+$-+s (';*'>( or
antinuclear antibodies (+2+s (:;*';(, can be identi0ed. Tissue*speci0c
antibodies, such as antibodies against the thyroid gland (:;*';(, can also
be found. -ildly elevated levels of rheumatoid factor (5% are usually
present, indicating the presence of cryoglobulins on further assessment.
3ubtype chronic HBV HBe&g$negative disease
2ote that although the HBe+g result is negative in this stage,
HBe+g negativity can be associated with greater HBV 42+ replication and
more rapid disease progression in patients who carry mutations in either
the precore or the basic core promoter region of the HBV genome.
Cirrhosis
)n early stages of cirrhosis, 0ndings of chronic viral hepatitis can be
found. 3ater, as the disease progresses, low albumin levels,
hyperbilirubinemia, prolonged PT, low platelet and white blood cell counts,
and +$T levels higher than +3T levels can be identi0ed. +l&aline
phosphatase (+3P and 88T levels can be slightly elevated.
"adiologic Studies
%indings on imaging studies are brie!y reviewed according to the disease
stage.
+cute and chronic hepatitis B disease
Performing abdominal ultrasonography, computed tomography
(7T scanning, or magnetic resonance imaging (-5) in patients with
hepatitis B is important to help e.clude biliary obstruction (see the
following images. 2onspeci0c 0ndings include increased echogenicity of
the liver parenchyma.
7irrhosis
)maging 0ndings in cirrhosis include coarse echogenicity of the
liver, with a nodular appearance, and 0ndings compatible with portal
hypertension (eg, varices, splenomegaly, ascites, pleural eIusion @ie,
hepatic hydrothora.A.
3esions can also be detected but may be very diUcult to evaluate
because they can be mista&en for regenerating nodules. )n such cases,
highly sophisticated techni6ues, such as -5) with superparamagnetic iron
o.ide (ferumo.ides, should be considered. %erumo.ides (negative contrast
material are phagocytosed by the reticuloendothelial cells of the normal
liver, producing predominant T' imaging on -5). Therefore, a mar&ed
decrease of the signal in the normal liver parenchyma occurs, eIectively
permitting the identi0cation of tumors.
)n a trial that compared ultrasonographic surveillance at =* or H*
month intervals to detect hepatocellular carcinoma (H77 in :'EG patients
with cirrhosis due to hepatitis B virus (:'.>(, hepatitis 7 virus (CC.:(, or
alcohol (=D.'(, investigators reported that ultrasonographic surveillance
at =*month intervals detected more small focal lesions (]:; mm than at
H*month intervals< however, the shorter interval did not improve detection
of small H77.
#i!er Biopsy and Histologic $eatures
3iver biopsy, percutaneous or laparoscopic, is the standard means
of assessing the severity of disease in patients with features of chronic
active liver disease (ie, abnormal aminotransferase levels and detectable
levels of hepatitis B virus @HBVA 42+.
+lthough liver biopsy is not indicated for patients with acute
hepatitis B disease, the 0ndings in the acute phase are predominantly
lobular, with degenerative and regenerative hepatocellular changes, as
well as accompanying in!ammation. 2ecrosis may be predominantly
centrilobular.
Acute !s chronic histologic %ndings
&cute hepatitis B
The hallmar& of acute hepatitis B is liver cell death. $cattered
within the lobule are small, individual clusters of dying hepatocytes in
apoptosis. (Fhen the nucleus is e.truded, it is an eosinophilic, or
7ouncilman, body. -any of the surviving hepatocytes show hydropic
swelling &nown as ballooning degeneration. 3ymphocytes diIusely in0ltrate
the lobule, with macrophages and neutrophils seen occasionally.
.hronic hepatitis B
The hallmar& of chronic hepatitis B infection is lymphoid
in!ammation, mostly involving the portal tracts. However, occasional
7ouncilman bodies are seen in the lobule. Hepatocytes that are distended
with viral particles may ac6uire an unusual Nground*glassO appearance on
the hemato.ylin and eosin (H^E stain (see the following image. 8round*
glass cells are seen in appro.imately >;*E>( of livers aIected by chronic
HBV infection, and they stain positive for hepatitis surface B antigen
(HBs+g. )mmunohistochemical staining of the specimen can help to
identify the presence of HBs+g or hepatitis B core antigen (HBc+g (ie,
chronic infection.
+s the severity of the histologic changes advance, interface
hepatitis (piecemeal necrosis appears, with erosion of the limiting plate by
chronic in!ammation from the portal side of the lobule. Bver time, this
ongoing type of in!ammation may lead to increasing degrees of 0brosis
that spreads out from that portal tract to connect with other portal tracts
(bridging 0brosis nearby. Fhen the 0brosis advances further in severity,
regenerating nodules of hepatocytes appear< this constitutes cirrhosis.
Staging
3iver damage is graded according to the in!ammatory component and is
described as follows"
8rade ; 1 Portal in!ammation only, no activity
8rade : 1 -inimal portal in!ammation and patchy lymphocytic
necrosis, with minimal lobular in!ammation and spotty necrosis
8rade ' 1 -ild portal in!ammation and lymphocytic necrosis
involving some or all portal tracts, with mild hepatocellular damage
8rade = 1 -oderate portal in!ammation and lymphocytic necrosis
involving all portal tracts, with noticeable lobular in!ammation and
hepatocellular change
8rade C 1 $evere portal in!ammation and severe lymphocytic
bridging necrosis, with severe lobular in!ammation and prominent,
diIuse hepatocellular damage
3iver damage staging (ie, 0brosis is described as follows"
$tage ; 1 2o 0brosis
$tage : 1 Portal 0brosis
$tage ' 1 Periportal 0brosis
$tage = 1 $eptal, bridging 0brosis
$tage C 1 7irrhosis
Hepatitis B Treatment & 'anagement
+pproach 7onsiderations
The primary treatment goals for patients with hepatitis B (HBV
infection are to prevent progression of the disease, particularly to cirrhosis,
liver failure, and hepatocellular carcinoma (H77. 5is& factors for
progression of chronic HBV include the following"
Persistently elevated levels of HBV 42+ and, in some patients,
alanine aminotransferase (+3T, as well as the presence of core and
precore mutations seen most commonly in HBV genotype 7 and 4
infections
-ale se.
Blder age
%amily history of H77
Elevated alpha*fetoprotein (+%P
7oinfection with hepatitis 4 (delta virus (H4V, hepatitis 7 virus
(H7V, or human immunode0ciency virus (H)V
+ synergistic approach of suppressing viral load and boosting the patientXs
immune response with immunotherapeutic interventions is needed for the
best prognosis. The prevention of H77 often includes the use of antiviral
treatment using pegylated interferon (PE8*)%2 or nucleos(tide analogues.
Therapy is currently recommended for patients with evidence of
chronic active hepatitis B disease (ie, abnormal aminotransferase levels,
positive HBV 42+ 0ndings, positive or negative hepatitis B e antigen
@HBe+gA. Various algorithms have been proposed, such as that by the
+merican +ssociation for the $tudy of 3iver 4iseases (++$34, the
European +ssociation for the $tudy of the 3iver (E+$3, the +sian Paci0c
+ssociation for the $tudy of the 3iver (+P+$3, the 7anadian +ssociation for
the $tudy of the 3iver (7+$3, the 2ational )nstitute for Health and 7linical
E.cellence (2)7E, Kuo and 8ish, and KeeIe et al.
The 2ational )nstitutes of Health (2)H recommends nucleos(tide
therapy for the treatment of patients with acute liver failure, as well as
cirrhotic patients who are HBV 42+ positive and those with clinical
complications, cirrhosis or advanced 0brosis with positive serum HBV 42+,
or reactivation of chronic HBV during or after chemotherapy or
immunosuppression. )n addition, immunoglobulin and vaccination should
be administered to newborns born to women positive for hepatitis B
surface antigen (HBs+g.
)n general, for HBe+g*positive patients with evidence of chronic
HBV disease, treatment is advised when the HBV 42+ level is at or above
';,;;; )#?m3 (:;
>
copies?m3 (or, per the E+$3, V',;;; )#?m3 and when
serum alanine aminotransferase (+3T is elevated for =*H months.
%or HBe+g*negative patients with chronic hepatitis B disease,
treatment can be administered when the HBV 42+ is at or above ';;;
)#?m3 (:;
C
copies?m3 and the serum +3T is elevated (+3T levels V'; #?3
for females< =; #?3 for males for =*H months.
)n patients coinfected with HBV and H)V, initiate therapy against HBV
and administer antiretroviral therapy as well.
The 2)H also indicates that immediate therapy is not routinely
indicated for patients who have the following"
7hronic hepatitis B with high levels of serum HBV 42+ but normal
serum +3T levels or little activity on liver biopsy (immune*tolerant
phase
3ow levels of or no detectable serum HBV 42+ and normal serum
+3T levels (inactive chronically infected?low replicative phase
Positive serum HBV 42+ but not HBs+g (latent HBV infection,
unless the patient is undergoing immunosuppression
)npatient care
Patients with hepatitis B disease and fulminant hepatic failure
should be hospitali/ed in the intensive care unit ()7# and be considered as
liver transplant candidates in the event that they do not recover. +ny
patient with acute HBV disease needs to be treated with 0rst*line oral
therapy, such as tenofovir disopro.il fumarate (T4% or entecavir (ETV.
Patients with acute hepatitis should be monitored with blood tests
in order to document biochemical improvement (see For&up.
4ietary limitations
Patients with acute or chronic hepatitis without cirrhosis have no
dietary restrictions. %or individuals with decompensated cirrhosis
(prominent signs of portal hypertension or encephalopathy, the following
dietary limitations are indicated"
+ low*sodium diet (:.> g?day
High*protein diet (ie, white*meat protein, such as por&, tur&ey, or
0sh
%luid restriction (:.> 3?day in cases of hyponatremia
Pharmacologic -anagement
7urrently, pegylated interferon alfa (PE8*)%2*a, entecavir (ETV,
and tenofovir disopro.il fumarate (T4% are the 0rst*line agents in the
treatment of hepatitis B disease. These are the main treatment drugs
approved globally for this disease, although ongoing trials are investigating
new types of medications, such as tenofovir disopro.il in combination with
emtricitabine (%T7. Encapsidation inhibitors, entry inhibitors, T35E
agonists, and therapeutic vaccines are all in development.
)n ';;D, international phase ))) trials with clevudine (l*%-+# for the
treatment of chronic hepatitis B virus (HBV infection were halted owing to
a very high ris& of myopathy.
3amivudine (=T7, telbivudine, and adefovir are of historical interest. These
agents are currently considered second* or third*line therapy, or
NnonpreferredO treatment.
$peci0c considerations
$pecial attention must be given to patients on liver transplantation
lists. )nitiation of treatment with entecavir or tenofovir is of cardinal
importance before and after liver transplantation to achieve viral
suppression and to prevent recurrence of the disease after the procedure.
7ombination therapy with ETV and T4% or, more rarely, T4% with %T7 or
=T7 can be considered if drug*resistant mutants are present or for patients
with failing 0rst*line therapy.
7aution must also be used with long*term and high*dose
administration of adefovir or tenofovir therapy in patients with chronic HBV
disease. )n a 2ational )nstitutes of Health (2)H study, :>( of patients on
adefovir or tenofovir for '*D years developed pro.imal renal tubular
dysfunction, de0ned as de novo incidence of = of the following > features"
Hypophosphatemia
Hypouricemia
Elevated serum creatinine level
Proteinuria
8lycosuria
$witching to other antiviral agents in the study allowed for partial
reversal of the renal tubular dysfunction.
ETV was associated with lactic acidosis in a study of > patients with
liver failure who had -odel for End*$tage 3iver 4isease (-E34 scores of
greater than ';.
)n patients with HBV who are coinfected with human immunode0ciency
virus (H)V, it may be possible to simplify treatment regimens with agents
that have dual eIectiveness against both viruses. Hepatitis 4 (delta virus
(H4V infection is best treated with PE8*)%2 therapy.
nterferon alfa
)nterferons are proteins that have antiviral, antiproliferative, and
immunomodulatory eIects. Published reports indicate that after )%2*a
treatment with > million #?day or :; million # = times per wee&
subcutaneously ($7 for C months, HBV 42+ levels and HBe+g become
undetectable in =;*C;( of patients. )n addition, :;( of patients
seroconvert from hepatitis B surface antigen (HBs+g to hepatitis B surface
antibody (anti*HBs. #nfortunately, >*:;( of patients relapse after
completion of treatment. + transient _!are,_ (ie, increased serum alanine
aminotransferase @+3TA levels during the beginning of treatment can be
identi0ed, and this represents the impact of the activated cytolytic T cells
on the infected hepatocytes.
High levels of aminotransferases, a low viral load, and infection
with the wild type virus are good prognostic factors for response to )%2*a
treatment. However, +sian patients and patients with the precore mutant
virus tend to not have a clinical response to )%2*a treatment.
3oss of HBs+g indicates resolution of the HBV infection, acute or
chronic, but it is rare in chronic infection. + study by Tseng et al that
followed Taiwanese patients with chronic hepatitis B infection who
developed spontaneous HBe+g loss (seroconversion showed that patients
with low levels of HBs+g : year after their HBe+g seroconversion had a
higher probability of loss of HBs+g.
-lomerulonephritis
)%2*a therapy has been successful in treating HBV*related
glomerulonephritis. + regimen of > million units of )%2*a subcutaneously
($7 daily for C months has achieved HBs+g seroconversion with
improvement of glomerulonephritis. )t has also been reported that )%2*a
given at a dose of = million units = times per wee& led to improvement of
proteinuria only in patients with mesangial proliferative glomerulonephritis,
not in those with membranoproliferative glomerulonephritis (-P82.
%inally, a single case report described the resolution of this
complication after liver transplantation. )n addition to interferon, antiviral
therapy with lamivudine (=T7 has not only been shown to signi0cantly
increase the incidences of proteinuria remission and of HBe+g
seroconversion but also cause a decline in levels of HBV*42+ in adult
patients with HBV*related glomerulonephritis relative to controls.
Polyarteritis nodosa
$mall and medium*si/ed arteries and arterioles are aIected in
polyarteritis nodosa (P+2. +lthough corticosteroids and
immunosuppressive agents may be bene0cial for treating vasculitis, they
may potentially have a deleterious eIect on the course of hepatitis B liver
disease due to viral reactivation, particularly after the withdrawal of
treatment.
The antiviral drug adenine arabinoside and )%2*a have been used
in con,unction with plasmapheresis and a short course of corticosteroids,
with promising results.
The combination of short*term corticosteroids accompanied by
plasmapheresis and lamivudine, as used in one study, resulted in :;;(
clinical recovery and HH( seroconversion, although the number of patients
in the trial was relatively small.
Precautions
$pecial attention must be given to patients with HBV*
decompensated cirrhosis (eg, ascites, encephalopathy who are ta&ing )%2*
a, owing to the fact that, although they occasionally may have a treatment
response, these individuals can also deteriorate further.
The adverse eIects of )%2*a treatment can sometimes be severe,
even devastating. $ome patients cannot complete treatment. + !uli&e
syndrome, myelosuppression (eg, leu&openia, thrombocytopenia, nausea,
diarrhea, fatigue, irritability, depression, thyroid dysfunction, and alopecia
are among the adverse eIects that may occur.
Pegylated $()a *a
PE8*)%2*a 'a has an enhanced half*life relative to the standard )2%*
a. Pegylation lowers the rate of absorption following subcutaneous ($7
in,ection, reduces renal clearance, and decreases the immunogenicity of
the interferon.
+ CG*wee& regimen of PE8*)%2*a 'a may induce a 'E( rate of
HBe+g seroconversion and a '>( rate of loss of HBV 42+. )n a study by
3au et al involving a CG*wee& regimen, after 'C wee&s of follow*up the
HBe+g seroconversion rate with PE8*)%2*a 'a monotherapy was ='(,
compared with 'E( in those receiving combination therapy with =T7 and
:D( in those receiving =T7 monotherapy.
)t appears that patients infected with HBV genotype + or B have a
better response to )%2 treatment than do patients infected with genotype 7
or 4. This therapy also appears to be more appealing, especially for
patients with increased +3T levels.
PE8*)%2*a 'a is also indicated for treatment of chronic hepatitis 7,
alone or in combination with ribavirin, in patients not previously treated
with )%2*a, with compensated liver disease, or with H4V infection. +t most,
:E( of patients have durable suppression of the virus as de0ned by
undetectable HBV 42+ at > years posttreatment.
#ami!udine
+ nucleoside analogue, =T7 inhibits the viral polymerase. )t
appears to be eIective in patients who do not have a treatment response
to )%2*a (eg, patients infected by the precore mutant virus. However, its
role in hepatitis B treatment is diminishing as alternate therapies become
available< thus, this agent is a third*line therapy and not preferred.
Bther agents, e.cept for adefovir, are superior to =T7 in
suppression of viral replication. +nother disadvantage to this therapy
includes its high rate of drug resistance. 5elative to other oral treatments,
however, =T7 is lower in cost.
Therapy with =T7 has been associated with a C*log reduction of viral
load. Treatment (:;; mg?day has also been associated with the following"
:H*:G( seroconversion rate from HBe+g to anti*HBe
=;*==( rate of HBe+g loss
C;*>;( normali/ation of the value of the aminotransferases
:*'( HBs+g seroconversion rate
The HBe+g seroconversion rate has been shown to possibly increase to
'E( after ' years, C;( after = years, and CE( after C years of treatment
in patients with a viral load of less than :;C pg?m3.
Histologic improvement (ie, reduction of the histologic activity
inde. by V' points has been noticed in appro.imately >;( of patients
ta&ing =T7. The adverse eIects are negligible, although a transient
elevation of aminotransferases can be noticed shortly after starting
treatment.
Treatment with =T7 has also been shown to dramatically improve
the condition of patients with decompensated disease due to HBV
reactivation. Patients with H)V infection and fulminant hepatic failure due
to active HBV infection may receive =T7*only treatment. Those with
H)V?HBV coinfection who are eligible for antiretroviral therapy and have
less severe hepatic in,ury should defer the antiretroviral treatment until
resolution of the liver in,ury.
Polyarteritis nodosa
+s previously mentioned, the combination of short*term
corticosteroids accompanied by plasmapheresis and lamivudine, as used in
one study, resulted in :;;( clinical recovery and HH( seroconversion in
patients with HBV*associated P+2, although the number of patients in the
trial was relatively small.
HBV in!ection prophylaxis in HIV
)n patients infected with H)V, antiretroviral therapy regimens
containing =T7 or T4% may be prophylactic for HBV infection. + recent
analysis e.amined stoc&ed serum samples from =>C men with H)V who had
not been vaccinated against hepatitis B and whose initial serum samples
showed no signs of HBV.
+ll of the patients in the study were men who had se. with men, a
population in which hepatitis B infection in the presence of H)V is
particularly common. +n analysis of the 0nal stoc&ed samples from these
patients found that sometime after their 0rst serum samples were
obtained, C= of the =>C men had become infected with HBV.
The investigators found that the rate of incident HBV infections was
lower during periods when antiretroviral regimens using =T7 or T4% were
used (;.HHD incident infections in :;; person*years than it was during
periods when no antiretroviral therapy was used or when antiretroviral
therapy employed neither =T7 or T4% (H.E'H and >.'H= incident infections
in :;; person*years, respectively.
.omplications
The emergence of viral variants is the ma,or complication in
hepatitis B disease. +ppro.imately :>*=;( of patients develop a mutation
of the viral polymerase gene (the S-44 variants after :' months of
treatment with =T7< appro.imately >;( develop a mutation after = years
of treatment with the drug, and as many as E;*:;;( develop a mutation
with long*term therapy. However, continued treatment after the
brea&through with the variant type has been associated with lower HBV
42+ levels, less aminotransferase activity, and histologic improvement. %or
these patients, discontinuation of treatment is accompanied by a reversion
to a wild type of HBV and a !are of the disease.
Adefo!ir dipi!o+il
+defovir is another third*line agent (not preferred that is indicated
for treatment of chronic hepatitis B disease with evidence of active viral
replication, including patients with =T7*resistant hepatitis B. This agent is a
nucleoside analogue, a potent inhibitor of the viral polymerase. The
eUcacy of adefovir dipivo.il has been tested in HBe+g*positive, HBe+g*
negative, and =T7*resistant patients with encouraging results.
The optimal dose seems to be :; mg?day< higher doses are
nephroto.ic. The estimated rate of resistance to adefovir and the
development of mutations (rt2'=HT and rt+:G:V are appro.imately C*H(
after = years and appro.imately =;( after > years of treatment.
The results of ' multicenter trials that used adefovir for CG wee&s
noted that in HBe+g*positive patients who received :; mg of adefovir
daily, there was a median =.>'*log reduction of the viral load (HBV 42+
level. )n CG( of the patients, normali/ed aminotransferase levels were
reported, and histologic improvement was seen in >=( of the patients who
received this regimen. The HBe+g seroconversion rate was :'(.
%urthermore, of the HBe+g*negative population, HC( e.perienced
histologic improvement after receiving :; mg of adefovir for CG wee&s, and
E'( had normali/ed aminotransferase levels. The serum HBV 42+ level
was decreased in >:( of sub,ects. The outcomes were maintained if
treatment was continued for :CC wee&s, but the bene0ts were lost if
treatment was discontinued at CC wee&s. The development rate for the
resistant mutations rt2'=HT and rt+:G:V has been estimated to be around
H(.
Enteca!ir
Entecavir is a 0rst*line agent in the treatment of hepatitis B. This
drug is a potent guanosine analogue inhibitor of the viral polymerase with
:.'( resistance in patients who have no history of previous treatment with
nucleos(tide analogues and almost >H( resistance in =T7*resistant
patients during a H*year treatment period.
+dvantages of therapy with this agent include potent antiviral
activity and a low drug resistance rate, although entecavir has less of a
role than other agents in the treatment of =T7*resistant hepatitis B.
+ retrospective study demonstrated that HBV 42+ responses at :'
months can potentially be used to evaluate entecavir therapy in
nucleos(tide analogue na`ve, HBV*infected patients. )nvestigators
reported = independent predictors for maintenance of viral suppression
among patients on entecavir treatment at = yearsTlower baseline HBV
42+, undetectable HBV 42+ at month :', and negative HBe+gTas well as
for the probability of HBe+g*seroconversion and the ris& of drug resistance.
HBe&g$positive patients
Fith regard to the HBe+g*positive population, administration of ;.>
mg of entecavir in patients who were na`ve to nucleoside analogues
relative to patients who received :;; mg of =T7 for a duration of CG wee&s
resulted in histologic improvement in E'( of the entecavir group
compared with H'( of the =T7 group. #ndetectable serum HBV 42+ levels
were reported in HE( of entecavir*treated patients, compared with =H( of
=T7*treated patients.
)n addition, normali/ed +3T levels were achieved in HG( of the
entecavir group, versus H;( of the =T7 group. The mean reduction in
serum HBV 42+ from baseline to wee& CG was H.D log copies?m3 (on a
base*:; scale in the entecavir*treated patients, relative to >.C log
copies?m3 in the =T7*treated patients. HBe+g seroconversion occurred in
':( of patients treated with entecavir and in :G( of patients treated with
=T7.
HBe&g$negative patients
)n an HBe+g*negative population, administration of ;.> mg of
entecavir in patients who were na`ve to nucleoside analogues compared
with patients who received :;; mg of =T7 for a duration of CG wee&s
resulted in histologic improvement in E:( of the entecavir group, versus
H:( of the =T7 group. #ndetectable serum HBV 42+ levels were found in
D;( of the entecavir*treated patients, versus E'( of the =T7*treated
patients.
2ormali/ed +3T levels were achieved in EG( of the entecavir
group, compared with E:( of the =T7 group. The mean reduction in serum
HBV 42+ levels from baseline to wee& CG was >.; log copies?m3 (on a
base*:; scale in the entecavir*treated patients, versus C.> log copies?m3
in the =T7*treated patients.
Long$term (:$ and B$y) data
+fter up to > years ('C; w& of continuous entecavir therapy (:.;
mg 64ay for HBe+g*positive patients, DC( of patients had less than =;;
copies?m3 of HBV 42+, and G;( had normal +3T levels. +n additional '=(
of patients achieved HBe+g seroconversion, and :.C( lost HBs+g. Bnly :
patient demonstrated treatment resistance with entecavir through > years.
)n another study, $chiI et al reported that long*term treatment
with entecavir (about H y of cumulative therapy @range, 'HE*'DE w&A in
nucleoside*na`ve chronic hepatitis B patients with advanced 0brosis or
cirrhosis resulted in durable virologic suppression, continued histologic
improvement, and reversal of 0brosis?cirrhosis. The patients received
entecavir for at least = years and had evaluable biopsies at baseline and
after long*term treatment.
Tel,i!udine
Telbivudine, a cytosine nucleoside analogue, is a second*line agent
(not preferred used in HBV therapy. This drug is a potent inhibitor of HBV
42+ polymerase. +lthough telbivudine appears to have slightly more
potent antiviral activity than do adefovir and lamivudine, it is more
e.pensive and plays a limited role in primary therapy.
HBe&g$positive patients
The results of the phase ))) 83BBE Trial that tested the
administration of H;; mg of telbivudine versus :;; mg of =T7 over a '*
year period showed that in the HBe+g*positive population, therapeutic
response (de0ned as HBV 42+ Y :;,;;; copies?m3, with either +3T
normali/ation or HBe+g loss was E>( for the patients treated with
telbivudine and HE( for the patients treated with =T7.
Bf the patients receiving telbivudine, 'H( lost the e antigen,
versus '=( of the patients receiving =T7. )n addition, a H.>*log reduction of
the HBV 42+ was noted for the patients receiving telbivudine versus a >.>*
log reduction for the patients receiving =T7.
HBe&g$negative patients
)n the HBe+g*negative patients in the phase ))) 83BBE Trial, the
response rates at : year were E>( for the telbivudine group and EE( in
the =T7 group, whereas GG( of the telbivudine*treated patients and E:(
of the lamivudine*treated patients had nondetectable HBV 42+. The HBV
42+ log reduction was >.' (telbivudine group, compared with C.C
(lamivudine group.
5egarding treatment resistance, a ma,or issue in hepatitis B
disease, the reported resistance rates at : year were '.H( for patients on
telbivudine and G.'( for patients on lamivudine.
Tenofo!ir
Tenofovir may be used as 0rst*line therapy for treatment*na`ve
patients. This agent is preferred as additional therapy in patients with
resistance to =T7, telbivudine, or entecavir. Tenofovir provides more potent
antiviral therapy than adefovir, and it can be used as a substitute in
patients who do not have an ade6uate response to adefovir.
Tenofovir is a nucleotide analogue (adenosine monophosphate
reverse transcriptase and HBV polymerase inhibitor.
HBe&g$positive naCve patients
)n a study that randomi/ed patients to receive either tenofovir (=;;
mg once daily or adefovir (:; mg once daily for CG wee&sTwith the
adefovir*treated patients then switched to tenofovirTED( of the patients
who received tenofovir were found to have a viral load below C;;
copies?m3, whereas EH( of patients who received adefovir before
switching to tenofovir were found to have a viral load below C;; copies?m3.
)n addition, E'( of patients in the adefovir arm who were found to
have a viral load greater than C;; copies?m3 achieved viral suppression
after they were switched to tenofovir. %or patients who achieved viral
suppression on adefovir alone, the eIect was maintained after they were
switched to tenofovir. Biochemical response was reported in EE( of
patients in the tenofovir arm at wee& E' and in H:( of those switching
from adefovir to tenofovir.
Fith regard to seroconversion, 'H( of patients who received
tenofovir seroconverted at wee& HC, while in the adefovir arm, the
observed seroconversion rate was reported as ':(. )t is noteworthy to
mention that >( of patients in the tenofovir arm e.perienced loss of the s
antigen.
HBe&g$negative patients
)n another report, involving patients who were randomi/ed to
receive either tenofovir (=;; mg once daily or adefovir (:; mg once daily,
with all eligible adefovir*treated patients being switched to tenofovir after
CG wee&s, D:( of patients receiving tenofovir at E' wee&s of treatment
were found to have a viral load below C;; copies?m3, compared with GG(
of patients in the adefovir*to*tenofovir arm. +ll of the adefovir*treated
patients who had a viral load below C;; copies?m3 at wee& CG maintained
a viral load below this level after switching to tenofovir. Bf the patients in
the adefovir arm who did not achieve optimal viral response (that is, those
with a viral load VC;; copies?m3 by the time they switched to tenofovir,
DC( had a viral load below C;; copies?m3 by wee& E'.
2ormal +3T levels at wee& E' were observed in ED( of patients
who initiated therapy with tenofovir and in EE( of patients who switched
from adefovir to tenofovir.
HBe&g$negative or $positive patients )ith chronic HBV
)n ' double*blind, phase ))) studies in which patients with HBe+g*
negative or HBe+g*positive chronic hepatitis B were randomi/ed to receive
tenofovir (=;; mg or adefovir (:; mg (ratio, '": once daily for CG wee&s,
-arcellin et al concluded that among patients with chronic hepatitis B,
tenofovir at a daily dose of =;; mg had superior antiviral eUcacy and a
similar safety pro0le to adefovir at a daily dose of :; mg through wee& CG.
+t wee& CG in both studies, a signi0cantly higher proportion of
patients receiving tenofovir than those receiving adefovir had reached the
primary end point (plasma HBV 42+ level Y C;; copies?m3 @HD )#?m3A,
and viral suppression occurred in more HBe+g*negative patients in the
tenofovir group (D=( than in the adefovir group (H=(, as well as in more
HBe+g*positive patients receiving tenofovir (EH( than in those receiving
adefovir (:=(.
%urthermore, signi0cantly more HBe+g*positive patients in the
tenofovir group (HG( not only had normali/ed +3T levels relative to those
in the adefovir group (>C(, but these individuals also had loss of HBs+g
(=( tenofovir group vs ;( adefovir group.
+t the end of CG wee&s, none the patients had developed the
amino acid substitutions within HBV 42+ polymerase that are associated
with phenotypic resistance to tenofovir or other drugs used to treat
hepatitis B. Tenofovir produced a similar HBV 42+ response in patients who
had previously received lamivudine and in those who had not. The '
treatments in both studies had similar safety pro0les.
:$Dear data
-arcellin et al reported that patients who received tenofovir
continuously for 'C; wee&s had sustained suppression of HBV 42+ levels
below C;; copies?m3 (HBe+g*negative patients" G=(< HBe+g*positive
patients" H>(. Patients who were randomi/ed to adefovir and then, at
wee& CG, rolled over to tenofovir for the subse6uent :D' wee&s also
maintained viral suppression (HBe+g*negative patients" GC(< HBe+g*
positive patients" HH(.
Bf the HBe+g*positive patients who received tenofovir through 'C;
wee&s, D( e.perienced s*antigen loss, and E( seroconverted. The HBe+g
loss rate was CH(, and the HBe+g seroconversion rate was C;(. 2o
evidence of resistance to tenofovir emerged over the treatment period.
)n addition, GE( of the =CG patients who had paired biopsies at
baseline and wee& 'C; e.perienced an improvement in overall liver
histology, as measured by an improvement of a minimum of ' points in the
Knodell necroin!ammatory score without worsening in the Knodell 0brosis
score. Bf the DH patients who had cirrhosis ()sha& 0brosis score [> at the
start of therapy, EC( e.perienced regression of cirrhosis.
HBV in!ection prophylaxis in HIV
+s previously mentioned, in patients infected with H)V,
antiretroviral therapy regimens containing =T7 or T4% may be prophylactic
for HBV infection.
Surgical nter!ention
Brthotopic liver transplantation (B3T is the treatment of choice for
patients with fulminant hepatic failure who do not recover and for patients
with end*stage liver disease due to hepatitis B disease. The
implementation of hepatitis B immunoglobulin (HB)8 during and after the
B3T period, and of lamivudine (=T7 or adefovir in the pre* and post*B3T
periods, dramatically improves the recurrence rate of hepatitis B. The
current standard is to use HB)8 and tenofovir disopro.il fumarate (T4% or
entecavir (ETV. +t some centers, HB)8 is being stopped at appro.imately
:' months or sooner< at other centers, HB)8 is no longer being used, with
the focus on 0rst*line therapy.
Hepatitis B and Pregnancy
The +merican 7ollege of Bbstetricians and 8ynecologists (+7B8
and the #$ Preventive $ervices Tas& %orce (#$P$T% recommend routine
prenatal screening for hepatitis B surface antigen (HBs+g in all pregnant
womenTduring every pregnancyTregardless of previous test results or
vaccinations. Pregnant women at ris& for hepatitis B infections should be
speci0cally targeted for vaccination. The ris& of transmission of hepatitis B
associated with amniocentesis is low.
%or newborns born to mothers with chronic hepatitis B infection,
administer combined immunoprophyla.is with hepatitis B immune globulin
(HB)8 and hepatitis B vaccine within :' hours of birth. Thereafter, these
infants should follow the hepatitis B vaccine series as part of the
recommended childhood immuni/ation schedule.
Breastfeeding is not contraindicated in women chronically infected
with hepatitis B if the infant receives HB)8 passive prophyla.is and vaccine
active prophyla.is. -others with chronic hepatitis B infection are often
treated in the third trimester if the serum hepatitis B virus (HBV 42+ level
is greater than :;
H
*:;
G
copies?m3, especially if she is positive for the
hepatitis B e antigen (HBe+g.
Vaccination
#niversal hepatitis B vaccination programs are ongoing in endemic
areas, with encouraging results. The hepatitis B vaccine consists of
recombinant hepatitis B surface antigen (HBs+g produced in yeast. +
series of = in,ections may achieve HBs+g antibody (anti*HBs levels greater
than :; million )#?m3 in appro.imately D>( of vaccinated individuals.
Vaccination with a single dose must be repeated every >*:; years.
+ll newborns must be vaccinated against hepatitis B. %or infants
born to mothers with active hepatitis B, a passive*active approach
(hepatitis B immunoglobulin @HB)8A and vaccination is recommended.
Healthcare wor&ers should be vaccinated against HBV. )ndividuals
who have had a needle*stic& accident from a patient with active hepatitis B
infection must receive active*passive immuni/ation (HB)8 and the 0rst
dose of the vaccine at the same time. These individuals must be
monitored with blood tests.
7urrent guidelines recommend that all previously unvaccinated
adults aged :D through >D years with diabetes mellitus (types : and ' be
vaccinated against hepatitis B as soon as possible after a diagnosis of
diabetes is made. 7linicians may use their discretion in determining
whether to vaccinate elderly diabetic patients (age [H; y.
The 2ew Sor& $tate 4epartment of Health recommends vaccination
with the hepatitis B vaccine series in patients infected with human
immunode0ciency virus (H)V who are negative for anti*HBs, unless they
have chronic infection.
)n a report that collected data from ' studies assessing the >* and
:;*year persistence of anti*HBs and immune response to a hepatitis B virus
(HBV vaccine challenge in children and adolescents who had received the
HBV =*dose vaccine series in infancy, 8erman investigators demonstrated
that this routine practice induced long*term anti*HBs persistence for :;
years and immune memory against HBVTeven with waning anti*HBs
levels.
3ow response rates and nonresponders
3ow vaccination response rates have been associated with obesity,
smo&ing, immunosuppression, and advanced age. +ppro.imately '>*>;(
of persons who initially do not have a vaccine response will show a
response to : additional vaccine dose, and >;*E>( of individuals will have
a response to a second =*dose series.
)t is recommended that testing for anti*HBs be obtained C*:'
wee&s following vaccination. 5evaccinate nonresponders, (HBs+b levels Y
:; )#?3 with another series of =*dose hepatitis B vaccine. 7onsider
delaying revaccination for several months after initiation of antiretroviral
therapy in patients with 74C counts below ';; cells?mm
=
or those with
symptomatic H)V disease. The delay in these individuals is an attempt to
ma.imi/e the antibody response to the vaccine.
4o not defer vaccination in pregnant patients or patients who are
unli&ely to achieve an increased 74C count. )ndividuals at increased ris& for
severe complications due to HBV infection include those unli&ely to achieve
74C counts of ';; cells?mm
=
or above after antiretroviral therapy (eg,
HBV?hepatitis 7 virus @H7VA coinfection and H)V*infected pregnant women.
+ combined hepatitis + virus (H+V?HBV vaccine is licensed in
many countries and oIers the advantage of protection against both of
these diseases at the same time. The vaccine seems to be safe, although
some 6uestions e.ist regarding neurologic complications.
#ong)Term 'onitoring
)ndividuals with inactive chronic infection with the hepatitis B virus
(HBV should have routine blood tests at least annually to chec& their
aminotransferase levels. Patients with chronic active hepatitis should also
undergo blood tests (ie, to evaluate aminotransferase levels, antigen*
antibody HBV pro0le, viral load, and alpha*fetoprotein @+%PA levels, as well
as treatment. )n rare cases, patients may be considered for liver biopsy.
7urrent guidelines recommend monitoring of HBV 42+ and alanine
aminotransferase (+3T levels at least annually< however, a study
conducted by 9uday et al suggests that adherence falls below
recommendations. E.pert opinion supports that following the
recommended guidelines reduces the ris& of disease progression.
Patients with cirrhosis must be monitored for hepatocellular
carcinoma (H77 by having their +%P levels chec&ed every H*:' months
and undergoing surveillance with abdominal ultrasonography. 2ote,
however, that +%P levels have been eliminated from the +merican
+ssociation for the $tudy of 3iver 4iseases (++$34 guidelines.
-onitoring considerations
Physicians should &eep the following in mind when managing a patient
with hepatitis B"
)dentify cases of fulminant hepatic failure, and list the patient as a
candidate for liver transplantation
-onitor individuals with inactive chronic infection for probable
disease reactivation
)nform the patientsQ spouse?se.ual partners about the infectivity of
hepatitis B and their need for screening, possible lin&age to care,
and possible need for vaccination
-onitor patients with cirrhosis and perform H77 surveillance
studies (ie, +%P levels and liver ultrasonography every H*:'
months
Place patients with cirrhosis on liver transplantation lists when
needed
)dentify hepatitis 4 (delta virus (H4V superinfection in patients
with HBV infection
$creen for human immunode0ciency virus (H)V and?or hepatitis 7
virus (H7V coinfection
+ssess for hepatitis + virus (H+V immunity< if the patient is not
immune, provide immuni/ation
Viral reacti!ation
Hepatitis B virus (HBV may persist in the blood for decades after
clinical recovery from acute hepatitis despite the presence of serum
antibodies. )mmunosuppressive conditions or drugs may allow dormant
HBV to !are or reactivate. +dditionally, genetic factors (eg, genetic
mutations may in!uence the ris& for reactivation by aIecting hepatitis B
core antibody (anti*HBc response.
7lose monitoring during and for several months after therapy with
immunosuppressive drugs is appropriate. )f reactivation of hepatitis B
occurs, stopping the agent and initiating antiviral therapy may be
warranted. Various national organi/ations including the ++$34 and the
2ational )nstitutes of Health (2)H recommend the use of prophylactic
antiviral therapy in inactive HBs+g carriers who are to undergo
antineoplastic or immunosuppressive therapy.
-edications that may increase the ris& for hepatitis B reactivation include"

+nti*74'; antibodies" Bfatumumab (+r/erra, ritu.imab (5itu.an

+ntineoplastic agents (including methotre.ate

8lucocorticoids, especially with abrupt discontinuation

)nterleu&in receptor antagonists" #ste&inumab ($telara,

ana&inra
(Kineret, tocili/umab (+ctemra

2ucleoside and nucleotide therapy, due to immune reconstitution

syndrome or discontinuation of antiviral therapy with anti*HBV
properties

T*cell regulator" +batacept (Brencia

Tumor necrosis factor (T2% inhibitors" )n!i.imab (5emicade,

etanercept (Enbrel,

adalimumab (Humira,

certoli/umab pegol
(7im/ia, golimumab ($imponi, $imponi +ria
Hepatitis B 'edication
-edication $ummary
The goals of pharmacotherapy in patients with hepatitis B disease
are to reduce the ris& of progression of disease, prevent transmission to
others, and decrease complications.
7urrently, pegylated interferon alfa (PE8*)%2*a, entecavir (ETV,
and tenofovir disopro.il fumarate (T4% are the 0rst*line agents in the
treatment of hepatitis B disease. These are the main treatment drugs
approved globally for this disease, although ongoing trials are investigating
new types of medications, such as tenofovir disopro.il in combination with
emtricitabine (%T7. Encapsidation inhibitors, entry inhibitors, T35E
agonists, and therapeutic vaccines are all in development.
HV- ("Ts
7lass $ummary
+ntiviral agents interfere with viral replication and wea&en or
abolish viral activity.
Tenofo!ir disopro+il fumarate .Viread/
Tenofovir is a nucleotide analogue (adenosine monophosphate
reverse transcriptase and hepatitis B virus (HBV polymerase inhibitor.
Tenofovir may be used as 0rst*line therapy for treatment*na`ve
patients. )t is preferred as additional therapy in patients with lamivudine,
telbivudine, or entecavir resistance. This agent has more potent antiviral
therapy than adefovir and can be used as a substitute in patients who do
not have an ade6uate response to adefovir.
#ami!udine .Epi!ir- Epi!ir)HBV/
3amivudine is a thymidine analogue that bloc&s viral replication by
competitive inhibition of viral reverse transcriptase. There is evidence that
an indirect immunomodulatory eIect can be observed.
5elative to other oral treatments, lamivudine is lower in cost. Bther
agents, however, e.cept for adefovir, are superior to lamivudine in
suppression of viral replication. +nother disadvantage to this therapy
includes its high rate of drug resistance. The role of lamivudine in hepatitis
B treatment is diminishing as alternate therapies become available.
Adefo!ir dipi!o+il .Hepsera/
+defovir is used to treat chronic hepatitis B disease. This agent is a
prodrug that is converted to the diphosphate salt. The active drug is
classi0ed as an antiviral nucleotide reverse transcriptase inhibitor. )t
inhibits hepatitis B virus (HBV 42+ polymerase (reverse transcriptase by
competing with the natural substrate deo.yadenosine triphosphate (d+TP
and by causing 42+ chain termination after its incorporation into viral
42+.
Enteca!ir .Baraclude/
Entecavir is a guanosine nucleoside analogue with activity against
hepatitis B virus (HBV polymerase. This agent competes with the natural
substrate deo.yguanosine triphosphate (d8TP to inhibit HBV polymerase
activity (ie, reverse transcriptase. Entecavir is less eIective for
lamivudine*refractory HBV infection. This drug is indicated for treatment of
chronic HBV infection and is available as a tablet and as an oral solution
(;.;> mg?m3< ;.> mg R :; m3.
Tel,i!udine .Ty0eka/
Telbivudine is a nucleoside analogue approved by the #$ %ood and
4rug +dministration (%4+ for chronic hepatitis B treatment. This drug
inhibits hepatitis B viral 42+ polymerase and is indicated for patients with
evidence of ongoing hepatitis B viral replication and either persistent
elevated aminotransferase activity or histologic evidence of active liver
disease. 7onsider telbivudine for patients whose condition did not or is
unli&ely to respond to interferon or for patients who cannot tolerate
interferon. Emergence of resistance is a ma,or drawbac& of nucleoside
analogue monotherapy.
Hepatitis B1Hepatitis C Agents
7lass $ummary
+defovir, entecavir, and telbivudine are antiretroviral agents with
reverse transcriptase*inhibiting mechanisms.
)nterferon alfa*'b and peginterferon alfa*'a are proteins with
antiviral, antitumor, and immunomodulatory actions.
Adefo!ir dipi!o+il .Hepsera/
+defovir is used to treat chronic hepatitis B disease. This agent is a
prodrug that is converted to the diphosphate salt. The active drug is
classi0ed as an antiviral nucleotide reverse transcriptase inhibitor. )t
inhibits hepatitis B virus (HBV 42+ polymerase (reverse transcriptase by
competing with the natural substrate deo.yadenosine triphosphate (d+TP
and by causing 42+*chain termination after its incorporation into viral
42+. +defovir can be used in patients with lamivudine*resistant hepatitis
B.
Enteca!ir .Baraclude/
Entecavir is a guanosine nucleoside analogue with activity against
hepatitis B virus (HBV polymerase. This agent competes with the natural
substrate deo.yguanosine triphosphate (d8TP to inhibit HBV polymerase
activity (ie, reverse transcriptase. Entecavir is less eIective for
lamivudine*refractory HBV infection. This drug is indicated for treatment of
chronic HBV infection and is available as a tablet and as an oral solution
(;.;> mg?m3< ;.> mg R :; m3.
Tel,i!udine .Ty0eka/
Telbivudine is a nucleoside analogue approved by the #$ %ood and
4rug +dministration (%4+ for chronic hepatitis B treatment. This drug
inhibits hepatitis B viral 42+ polymerase and is indicated for patients with
evidence of ongoing hepatitis B viral replication and either persistent
elevated aminotransferase activity or histologic evidence of active liver
disease.
7onsider telbivudine for patients whose condition did not or is
unli&ely to respond to interferon or for patients who cannot tolerate
interferon. Emergence of resistance is a ma,or drawbac& of nucleoside
analog monotherapy.
+lthough telbivudine appears to have slightly more potent antiviral
activity compared with adefovir and lamivudine, it is more e.pensive and
plays a limited role in primary therapy.
Peginterferon alfa *a .Pegasys/
Peginterferon alfa*'a binds to cell surface receptors in a cascade of
protein interactions, resulting in gene transcription. These stimulated
genes inhibit viral replication in infected cells, cell proliferation, and
immunomodulation. Peginterferon alfa*'a is indicated for adults with
hepatitis B e antigen (HBe+g1positive and HBe+g*negative chronic
hepatitis B disease with compensated liver disease and evidence of viral
replication and liver in!ammation.
Peginterferon alfa*'a is also %4+ approved for treatment of chronic
hepatitis 7, alone or in combination with ribavirin, in patients not
previously treated with interferon alfa, and with compensated liver disease.

nterferon alfa)*, .ntron A/
)nterferon alfa*'b is a protein product manufactured by
recombinant 42+ technology. )ts mechanism of antitumor activity is not
clearly understood< however, direct antiproliferative eIects against
malignant cells and modulation of host immune response may play
important roles.
The immunomodulatory eIects of interferon alfa*'b include
enhancement of cytolytic T*cell activity, stimulation of natural &iller cell
activity, ampli0cation of human leu&ocyte antigen (H3+ class ) protein on
infected cells, and suppression of tumor cell proliferation. The direct
antiviral activity of interferon alfa*'b activates viral ribonucleases and
inhibits viral entry into cells and viral replication. + direct anti0brotic eIect
has been postulated.
Before initiation of therapy with interferon alfa*'b, perform tests to
6uantitate peripheral blood hemoglobin, platelets, granulocytes, hairy
cells, and bone marrow hairy cells. -onitor the patient periodically (eg,
monthly during treatment to determine his?her response to therapy. )f the
patientQs condition does not respond within C months, discontinue
treatment.
)f a response occurs, continue treatment until no further
improvement is observed. Fhether continued treatment is bene0cial after
that time remains un&nown.