Vivek Raj, MD, MRCP (UK),
Assistant Professor, Division of Gastroenterology and Hepatology, University of
Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System,
Little Rock, Arkansas
Hepatitis B virus (HBV) is a major world health problem and a common cause of
cirrhosis and hepatocellular carcinoma. The natural history of HBV varies with
many factors, including age of acquisition. Persistent elevation of alanine aminotransferase
(ALT) levels and presence of hepatitis B surface antigen for >6 months after
infection suggest chronic HBV. Presence of hepatitis B e antigen (HBeAg) and HBV
DNA in serum indicate active disease. Treatment is indicated for chronic active
HBV. The aim of treatment is to suppress viral replication and eliminate the virus.
Endpoints of treatment are normalization of ALT levels and elimination of HBeAg
and HBV DNA from the blood. Available treatments are interferon alfa and lamivudine.
Interferon is effective in 25% to 40% of patients, but has serious side effects.
Lamivudine is effective in a similar percentage of patients and has fewer side
effects; however, it is associated with the emergence of viral mutations and drug-resistant
Chronic hepatitis B virus (HBV) affects >5% of
the world's population -- it is the primary cause of cirrhosis and
hepatocellular carcinoma and the ninth leading cause of death worldwide. In the
United States, ~1 million persons are chronically infected with HBV. The HBV
carrier rate in the United States, Western Europe, and Australia is 0.1% to
0.2%, but is as high as 10% to 20% in China, Southeast Asia, and sub-Saharan
Africa. An effective vaccine has been available since 1982, but its use has been
primarily restricted to high-risk groups. Since 1991 the vaccine has been given
to all newborns in the United States. Because treatment of chronic active HBV
can prevent cirrhosis and liver cancer, effective therapy and universal
immunization are highly desirable goals. To treat HBV, it is important to
understand the epidemiology, natural history, and serologic markers of the
The clinical presentation of acute HBV ranges from
subclinical hepatitis (70%) to icteric hepatitis (30%) with rare cases of
fulminant hepatitis (0.1% to 0.5%). Elevation of liver enzyme levels, primarily
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) with levels
typically up to 1000 to 2000 IU/L (ALT > AST), is a hallmark of acute HBV.
Elevation of bilirubin levels occurs after an increase in liver enzymes. In
acute HBV the best indicators of prognosis are parameters of hemostasis
(prothrombin time). In patients who recover, ALT levels normalize within 1 to 4
months. Persistent elevation (>6 months) of serum ALT levels usually
indicates progression to chronic HBV.
The outcome of acute HBV depends on age of acquisition, immune status of the
host, and rate of replication of the virus. In the perinatal period or
childhood, infection is usually associated with mild or no symptoms but a high
risk of chronicity. In adults, infection is usually symptomatic with a low risk
of chronicity. With perinatal infection, the initial phase is characterized by
high levels of HBV replication, hepatitis B e antigen (HBeAg) in serum, and high
levels of HBV DNA, but no evidence of active liver disease. The patient is
asymptomatic, has normal ALT levels, and minimal changes on liver biopsy.
Minimal liver disease, despite high levels of HBV replication, may be caused by
immune tolerance in infants and children. These patients usually experience an
immune-clearance phase during the second and third decade when spontaneous HBeAg
seroconversion to antibody to HBeAg (anti-HBe) increases to an annual rate of
10% to 20%.
Chronic HBV ranges from the asymptomatic carrier, to chronic active HBV, to
cirrhosis and hepatocellular carcinoma. The rate of progression from acute to
chronic HBV is ~90% for perinatal infection, 20% to 50% for infection acquired
between the ages of 1 to 5 years, and <5% for adult-acquired infection. Of
these adults, some develop chronic active HBV while others are asymptomatic
In healthy hepatitis B surface antigen (HBsAg) carriers, prognosis is very
good with a low rate of progression to cirrhosis. However, in HBV patients from
endemic areas and in patients with chronic HBV, the risk of progression over 5
years from chronic hepatitis to cirrhosis is 12% to 20%, from cirrhosis to
decompensation 20% to 23%, and from compensated cirrhosis to hepatocellular
carcinoma 6% to 15%.
Serologic tests used to diagnose HBV infection are
shown in the Table.
HBsAg and Anti-HBs
HBsAg is the serologic hallmark of HBV infection.
HBsAg appears 1 to 10 weeks after acute infection and before the onset of
symptoms or elevation of ALT levels. In patients who recover, HBsAg becomes
negative 4 to 6 months later. Persistence of HBsAg beyond 6 months suggests
progression to chronic HBV. Antibody to HBsAg (anti-HBs) appears as HBsAg
disappears, and in most cases anti-HBs persists and confers lifelong immunity.
In 25% of cases the titers of anti-HBs are not sufficient to neutralize
circulating virions, and HBsAg and anti-HBs coexist. Individuals with this
combination are considered carriers.
HBcAg and Anti-HBc
Hepatitis B core antigen (HBcAg) is an intracellular antigen in infected
hepatocytes and is not detectable in serum. Antibody to HBcAg (anti-HBc) appears
early in the infection and is then detected throughout the course of infection.
In the acute phase, it is primarily an immunoglobulin (Ig) M antibody. In
patients who recover, the anti-HBc changes to IgG and remains detectable with
anti-HBs. It is also detectable in patients with chronic active HBV with HBsAg.
IgM anti-HBc may be detectable during HBV exacerbations.
HBeAg and Anti-HBe
HBeAg is a marker of active HBV replication and
infectivity. HBeAg is usually associated with high titers of HBV DNA in the
serum, active liver disease, and high rates of infectivity; however, patients
with perinatal HBV infection can be HBeAg positive but have minimal liver
inflammation and normal ALT levels. Seroconversion from HBeAg to anti-HBe is
associated with recovery and the disappearance of serum HBV DNA. Although rare,
some patients have a viral mutation in the precore region that prevents
expression of HBeAg; these patients have active liver disease and HBV DNA in the
serum but are HBeAg negative.
Serum HBV DNA
The presence of serum HBV DNA is sensitive and specific
for viral replication. Hybridization or signal amplification (branched DNA)
assays detect 105 to 106 viral equivalents/mL, while the more sensitive
polymerase chain reaction (PCR)-based assays detect 102 to 103 viral
equivalents/mL. Recovery from acute HBV and HBeAg seroconversion in chronic HBV
is associated with the disappearance of HBV DNA by non-PCR-based assays.
PCR-based assays may remain positive for many years, which suggests the
persistence of small numbers of virions that are contained by the host immune
system. The main use of HBV DNA assays is to assess chronic active HBV patients
for treatment and to evaluate their response.
Patterns of Serologic Tests for HBV
Acute HBV is diagnosed by the
presence of elevated ALT, HBsAg, and IgM anti-HBc levels. Similar changes may be
seen with exacerbation of chronic HBV, reactivation of HBV, superinfection of an
HBV carrier with hepatitis C virus (HCV) or hepatitis D virus (HDV), and acute
drug- or toxin-induced hepatitis (eg, alcohol) in an HBV carrier.
HBV infection with spontaneous recovery is characterized by the presence of
anti-HBs and IgG anti-HBc. Following successful HBV vaccination, the only
serologic marker detected is anti-HBs.
Chronic HBV is characterized by the persistence of HBsAg for >6 months.
During active viral replication, HBeAg and HBV DNA (by non-PCR-based assay) are
positive, and ALT levels are usually elevated. These tests are necessary to
decide if therapy is warranted. A carrier state is characterized by positive
HBsAg and anti-HBs, negative HBeAg, normal ALT levels, and undetectable HBV DNA
(by non-PCR-based assays).
Liver biopsy is helpful in assessing the severity of liver damage, predicting
prognosis, determining treatment, and monitoring response. Liver biopsy is
generally indicated if any of the parameters for chronic active HBV are present
-- HBsAg along with either elevated ALT levels, HBeAg, or HBV DNA, or all 3 of
them. In most cases all 3 parameters are present but in some the ALT levels may
be normal or HBeAg may be negative.
Treatment of HBV
In compensated patients with chronic HBV, antiviral therapy is indicated for active
viral replication, elevated ALT levels, and histologic evidence of chronic liver
injury. Two agents are FDA-approved for treatment of chronic HBV -- interferon
alfa (IFN-) and lamivudine (a nucleoside analogue). The
mechanism of action of the 2 drugs is different as is patient selection for treatment.
Mechanism of action. IFNs are proteins produced by host cells in response
to viral infection. Three different types have been identified -- IFN- produced by B lymphocytes and monocytes, IFN-b by fibroblasts,
and IFN- by helper T and natural killer cells. Of these,
only IFN- is effective against HBV. HBV is a noncytopathic
virus. Liver injury is caused by the host immune response. IFN- has both immunoregulatory and antiviral activity and therefore
is effective in suppressing viral replication and augmenting the host immune response.
IFN- responders have a rapid increase in ALT levels
during the second or third month of therapy (Figure 1). This increase is commonly
associated with seroconversion from HBeAg to anti-HBe and is thought to reflect
immune stimulating properties of IFN. IFN- also has an antifibrogenic
effect that may decrease the progression to fibrosis and cirrhosis.
Patient selection and indications for IFN therapy. Patients suitable
for treatment with IFN have: (1) active viral replication by presence of HBeAg
or HBV DNA (non-PCR-based assay) for >6 months; (2) elevated ALT
levels; and (3) active HBV on biopsy. Because 5% to 10% of patients who are
HBeAg positive will convert spontaneously to anti-HBe, patients should be
screened for >6 months before initiating therapy. IFN is
contraindicated in patients with decompensated cirrhosis because there is a risk
of a hepatitis flare with seroconversion from HBeAg to anti-HBe (seen in 60% of
patients treated with IFN) that can precipitate liver failure.
Predictors of response to IFN therapy. Clinical and serologic
parameters associated with a good response to IFN include high pretreatment ALT
levels (>3 to 4 x normal), low HBV DNA (<200 pg/mL by solution
hybridization), and active disease on liver biopsy. Other variables associated
with a better response include adult infection, female sex, short duration of
infection, and heterosexuality. Because the precore/core region of the virus is
the major target for the host immune response, mutations in this region are
associated with a poor response to IFN therapy and a higher relapse rate. These
factors help to assess prognosis, but "poor response" factors should not deter
treatment with alternative strategies, such as lamivudine.
Efficacy of IFN therapy. The goal of IFN therapy is permanent
suppression of viral replication or elimination of infection. In most trials of
antiviral therapy, the endpoint of successful therapy was the disappearance of
HBeAg and HBV DNA and normalization of ALT levels for >6 months after
therapy. This result was seen in 25% to 40% of patients treated with IFN for 4
to 6 months. In a meta-analysis of 15 clinical trials, the overall response rate
(disappearance of HBeAg) was 33% with IFN compared with 12% in controls.
In patients who become HBeAg negative at the end of therapy, remission is
usually sustained and results in an inactive HBsAg carrier state. About one
third of these patients eventually lose HBsAg. In about 80% of patients who
become HBsAg negative, serum HBV DNA is not detectable even by PCR. Virologic
response after IFN treatment has been maintained for 3 to 11 years. Patients who
respond to IFN have improvement in symptoms and liver histology. Long-term IFN
treatment results in a decreased risk of mortality, liver transplantation, and
complications of cirrhosis. Few patients undergo HBV reactivation within the
first year of completion of therapy.
Dose and side effects. IFN is given as 5 million units daily or as 10
million units 3 times a week subcutaneously for 4 months. Therapy should be
monitored closely. Patients should be seen at 2- to 4-week intervals and ALT and
AST levels monitored and a complete blood cell count taken. HBsAg, HBeAg, and
HBV DNA should be tested at initiation, end of therapy, and 6 months later.
Figure 1 shows typical courses of responders and nonresponders. Treatment with
IFN is associated with frequent side effects. Most patients experience
influenza-like illness with fever, chills, myalgia, and headache after IFN
injection. These symptoms, however, tend to improve after the first few days of
therapy. Psychiatric side effects, especially depression, occur in 15% of
patients. Although rare, suicidal ideation and delirium can occur. IFN
frequently causes a 30% to 50% reduction in platelet count, 20% to 40% reduction
in white blood cell count, and a slight fall (3% to 5%) in hematocrit. IFN can
also induce an autoimmune diathesis and can unmask or worsen preexistent
autoimmune conditions. Both hypothyroidism and hyperthyroidism have been
reported, but in most cases there is no clinically significant change. If
adverse effects are not very severe, then dose reduction by 50% is advised and
should be adjusted back to the original dose once any side effects disappear.
Dose reduction is necessary in ~20% of patients. Discontinuation of treatment
due to severe adverse events is necessary in <5% of patients.
HDV and HBV coinfection. Patients who are coinfected with HDV tend to
have rapidly progressive disease and earlier decompensation compared with
patients who have HBV alone. Unfortunately, results with IFN therapy in these
patients are disappointing. IFN has been shown to decrease ALT levels and
suppress HBV replication but the virus is not eradicated, and when treatment is
stopped, almost all patients relapse.
HIV and HBV coinfection. Improved survival in HIV patients has led to
increased interest in the treatment of HBV in these patients. HIV coinfection
may result in a poor response to IFN because of high levels of HBV DNA,
relatively low serum ALT levels, and depressed immune function. Data on the
treatment of these patients with IFN are limited. A better response with fewer
side effects may be seen with lamivudine.
HCV and HBV coinfection. Coinfection with HCV and HBV is associated
with severe liver injury and poor response to IFN. In one study, loss of HBV DNA
and HBeAg was seen in only 6.7% of patients.
Nucleoside Analogue Therapy
Mechanism of action. Nucleoside
analogues block HBV replication by inhibiting HBV DNA polymerase; therefore,
unlike IFN, the activity of these drugs is independent of host immune responses.
These agents are highly bioavailable by oral administration and are well
tolerated. Of these, lamivudine is the most extensively studied, most effective,
and the only one that is FDA-approved.
Efficacy of lamivudine. Lamivudine is associated with a 4-log
suppression of HBV DNA. Lamivudine treatment, 100 mg PO daily for 1 year,
results in HBeAg seroconversion in 17% of patients; HBeAg loss in 32%; sustained
normalization of ALT levels in 41%; and histologic improvement in 52% (Figure
2). Moreover, lamivudine is effective in patients not usually responsive to IFN
and in those who have failed IFN. Prolonging lamivudine therapy increases the
likelihood of a sustained response. Of patients who lost HBeAg after treatment
with lamivudine, 80% maintained their response for ฃ2 years. However, patients
without an HBeAg response invariably returned to pretreatment levels of HBV DNA
Dose, duration of treatment, and side effects. The standard dose of
lamivudine is 100 mg PO daily for 1 year. It is recommended that lamivudine be
stopped after a sustained period (>2 months) of HBeAg loss or seroconversion.
Patients are then monitored closely to identify reactivation, which is an
indication for retreatment. Lamivudine is remarkably free of side effects and
discontinuation of therapy due to side effects is rarely necessary.
Lamivudine in patients with predictors of poor response to IFN.
Patients who respond poorly to IFN, including those with perinatal acquisition
of HBV, normal ALT levels, precore-mutant strains of HBV, and immunosuppression
by HIV or organ transplantation, tend to respond well to lamivudine. Lamivudine
has been used safely in some patients with hepatic decompensation and also may
be effective in patients who fail IFN therapy.
Resistance to lamivudine. Emergence of resistance, commonly associated
with a mutation in the YMDD motif of the polymerase gene, is a major limitation
of lamivudine therapy. The frequency ranges from 15% to 30% after 1 year of
therapy to 50% after 3 years. In immunocompetent patients, continued treatment
with lamivudine has maintained improvement, but in immunosuppressed liver
transplant patients, YMDD mutation has resulted in hepatic decompensation in 50%
IFN or Lamivudine as First-Line Therapy?
IFN requires only 4 months of
therapy, achieves a 30% to 40% HBeAg loss, about a 10% HBsAg loss, and long-term
improvement in histology and natural history. However, IFN requires
uncomfortable injections, is associated with many side effects, and is of
limited value in the subgroups discussed earlier.
On the other hand, lamivudine is safe, convenient to administer, achieves a
>30% HBeAg loss, shows histologic improvement in the majority of patients,
and is effective in treating patients with poor response indicators to IFN
treatment such as precore mutants or normal ALT levels. However, lamivudine
requires a long duration of treatment and is associated with the emergence of
viral variants and resistance. These factors also can hamper consideration for
The choice of drug, therefore, should be tailored to the patient, taking into
account factors such as the likelihood of response to therapy, compliance, cost,
and follow-up. The algorithm shown in Figure 3 indicates a reasonable approach
to stratification for therapy. As shown in the figure, elevated ALT levels
(>3 to 4 x normal), HBeAg positive, and HBV DNA positive are all indicators
of good response to IFN treatment, while patients with normal ALT levels or
absence of HBeAg do not respond well to treatment with IFN. However, the
efficacy of lamivudine is similar in both groups of patients. For patients who
have good predictors of response to IFN, the author's preference is to use IFN
if the patient can tolerate it since it has a 30% to 40% sustained response rate
and is not associated with the emergence of drug-resistant mutations.
Combination Therapy with IFN and Lamivudine
Data on combination therapy
are limited. In a randomized controlled trial of 230 patients, HBeAg
seroconversion rates were higher with combination therapy (29%) than with IFN
(19%) or lamivudine (18%) monotherapy. However, the difference was not
statistically significant by intention-to-treat analysis (P = .12 and
.10, respectively). More studies are needed to define the role of combination
HBV and Liver Transplantation
For patients with acute fulminant liver
failure or liver failure caused by chronic HBV, liver transplantation is
necessary. Early experience with liver transplantation in HBV-related liver
failure was disappointing. The recurrence rates of HBV and progression of liver
damage in the graft were high, leading to early rejection, high mortality, and
reluctance to perform liver transplant in HBV-related liver failure. However,
with the advent of options such as the use of HBV Ig, lamivudine, and
famciclovir, in most centers HBV is no longer a contraindication for liver
Hepatocellular Carcinoma Screening
There are no clear guidelines for
screening patients for hepatocellular cancer who are HBsAg carriers or have
chronic active HBV. Most of the recommendations for screening are for patients
with cirrhosis or severe chronic active HBV. In these patients, annual or
semi-annual serum alpha fetoprotein and ultrasound of the liver are recommended.
It is hoped that screening will detect tumors at an earlier stage, resulting in
better cure rates. Even in this group, reduction in mortality from
hepatocellular cancer has not been well demonstrated. There are some data that
favor a similar screening strategy for patients with chronic active HBV and for
HBsAg carriers in high endemic areas like Japan.
Since HBV is one of the leading causes of liver cancer in
the world, vaccination prevents not only hepatitis and cirrhosis due to HBV but
also liver cancer. Universal vaccination for HBV has been adopted in 80
countries in the world. In the United States, universal vaccination for HBV with
recombinant vaccine that consists of HBsAg particles was introduced in 1991.
In adults, the vaccine is given as three 10-mg doses at 0, 1 to 2 months, and
6 months. Seroprotective levels (>10 mIU/mL) are achieved in 95% of people
who complete the schedule. Efficacy in individuals who develop anti-HBs
approaches 100%. Immunity lasts >10 years and may be lifelong, even
though anti-HBs levels disappear in a large number of individuals after 10
The vaccine is indicated for all infants, children, and adolescents through
18 years of age. Among adults, it is indicated for high-risk groups (high-risk
occupation, sexually active adults with multiple partners, homosexual men, IV
drug users, patients attending sexually transmitted disease clinics, and
patients needing clotting factor preparations). Neonates born to HBsAg-positive
mothers also should be vaccinated.
Postexposure Prophylaxis of Health Care Workers
health care workers who are exposed to infection by needle stick or splash and
the source is HBsAg-positive should be given HBV Ig (0.06 mL/kg) and the first
of 3 doses of the HBV vaccine as soon as possible. The second and third doses of
the vaccine should be given at 1 and 6 months. If the health care worker has
been previously vaccinated for HBV and is a responder, no further treatment is
Progression to cirrhosis and liver cancer occurs in patients
with chronic HBV who have active viral replication characterized by presence in
the serum of HBeAg and HBV DNA. Depending on the likelihood of response,
compliance, cost, and other factors, these patients should be treated with
either IFN or lamivudine. In the future, universal HBV vaccination is likely to
decrease the burden of cirrhosis and liver cancer from this disease.
The rate of progression from acute to chronic HBV is ~90% for perinatal
infection, but <5% for adult infection.
Serologic markers that indicate active viral replication and suggest the
need for therapy are elevated ALT levels, HBeAg, and HBV DNA (non-PCR-based
assay). Liver biopsy assesses degree of inflammation and fibrosis.
The goal of IFN therapy is suppression of viral replication or elimination
of infection. Serologic markers suggesting therapeutic response are
normalization of ALT levels, HBeAg loss, HBV DNA loss, seroconversion to
anti-HBe, and in some cases loss of HBsAg. IFN therapy is successful in 25% to
40% of cases.
Lamivudine is effective in patients who respond poorly to IFN. It is well
tolerated; however, it is associated with a high incidence of resistance and
mutations in the virus.
Since HBV is one of the leading causes of liver cancer, vaccination
prevents not only hepatitis and cirrhosis due to HBV but also liver cancer.
Sidebar: Dialogue Box
ADVISORY BOARD Please elaborate on the relationship between
HBsAg and HBV DNA. For example, if the HBsAg is positive, can the HBV DNA be
RAJ HBsAg arises from excess surface particles produced by
virions multiplying in liver cells. Since HBV DNA arises from hepatitis
virions replicating in the liver, one would expect it to be positive in
patients with positive HBsAg. Having said that, the less sensitive
non-PCR-based HBV DNA assays can be negative in such a patient, but the more
sensitive PCR-based assay will always be positive. The PCR assays are so
sensitive that they can remain positive for years after the virus is cleared
from the blood.
ADVISORY BOARD Do patients infected with HBV ever completely
eliminate the virus?
RAJ Probably not. Even in patients with positive antibody to
HBsAg and negative HBsAg and DNA in the blood, the PCR-based assays in liver
cells will still likely be positive. In the vast majority of patients, HBV
infection is best viewed as a continuum, which at any given time reflects
the degree of viral replication, the immune response mounted by the patient,
and our ability to detect or measure it. For example, the HBsAg carrier is a
patient who at that moment is mounting sufficient immune response to suppress
active replication but not enough to completely eliminate the production of
surface antigen. However, this is a dynamic situation; thus, it is possible
that if the immune response were to change, the carrier state could reactivate
and result in a state of chronic active hepatitis.
ADVISORY BOARD Why not simply use quantitative PCR DNA
measurements as the metric to follow chronic HBV patients as opposed to
relying on a composite of ALT levels and various viral replication
RAJ Primarily because of the great fluctuations seen in this
measurement. For example, a patient may one day have a high number of virions,
such as 6 million viral equivalents/mL; 5 days later have only 3 million; and
a few days later have up to 5 million. Second, the number of circulating
virions measured doesn't consistently correlate well with the histologic
picture of the liver. Unlike HIV where viral replication and the number of
virions correlate well with CD-4 counts and prognosis, in HBV it has not been
as good. As a result, it is necessary to put 4 or 5 pieces of the puzzle
together to arrive at an accurate picture.
It is important to appreciate that any single piece of the puzzle is not
likely to give you a complete, accurate picture. For example, with respect to
HBeAg, recognize that there are some patients with viral mutations in the
precore region of the virus in whom this antigen is negative, yet these
patients can have a lot of virus replicating and inflicting damage. Similarly,
if you rely solely on ALT levels, you'll find there are some patients who have
normal ALT levels and viral replication going on and others who have higher
ALT levels and relatively low viral replication.
ADVISORY BOARD What is the recommended follow-up in the HBsAg
RAJ Normally we follow patients who are carriers on a 6- to
12-month basis. In addition to ordering a full panel of liver tests that
includes an ALT value, we check HBeAg as well.
ADVISORY BOARD What about the patient who has a positive
HBsAg with an elevated ALT level but negative viral replication markers (ie,
HBeAg and hybridization DNA assay)?
RAJ Typically we would recommend a liver biopsy and offer medical
therapy. If the patient declines, then close follow-up is indicated since the
patient has not been able to suppress the infection enough to achieve a
ADVISORY BOARD What screening protocol for hepatocellular
carcinoma do you follow in patients with chronic HBV infections?
RAJ Let me begin by stating there are no definitive studies to
guide you in this regard. Having said that, for patients who are carriers --
that is HBsAg positive and surface antibody positive, HBeAg negative, with no
DNA detected by hybridization assay -- I probably wouldn't screen. For
patients with chronic active hepatitis -- regardless if mild, moderate, or
severe -- I would screen every 2 to 3 years with an ultrasound of the liver
and a serum alpha fetoprotein. For the patient with evidence of cirrhosis, I
would screen with these studies on an annual basis.
ADVISORY BOARD Why is screening for hepatocellular carcinoma
more aggressive in Southeast Asia?
RAJ Since HBV DNA lives within cells, patients with HBV do not
have to progress in a sequential fashion from chronic active hepatitis to
cirrhosis to liver cancer. This seems to be the case in high endemic areas in
Southeast Asia where patients who have chronic active hepatitis with mild
activity have developed liver cancer without first having cirrhosis. That is
why health practitioners in China and Japan are very aggressive about
screening and recommend screening every 6 months in all patients with chronic
HBV. For reasons not entirely clear, the incidence of such a rapid progression
is much lower in Western Europe and the United States. As a result, in the
United States we screen less aggressively in patients with mild disease or who
are carriers and reserve frequent screening for those patients who have more
active liver disease and cirrhosis or for those patients who have failed
ADVISORY BOARD Why do you favor IFN therapy only in those
patients with elevated ALT levels and positive HBeAg and hybridization DNA
assays and lamivudine if even 1 of these 3 parameters is negative?
RAJ The answer lies in the observation that the best response to
IFN is seen in patients who have 3- to 4-fold elevations in ALT levels and are
both HBV DNA and HBeAg positive. For such patients the main reason I favor IFN
over lamivudine is that IFN avoids the risk of viral resistance emerging and
the risk that if these patients were to require a liver transplant 2 or 3
years down the line they would have a mutated virus that might cause them to
get turned down for the transplant. IFN is a more toxic treatment than
lamivudine, but it represents a sure-shot treatment since there are more data
and experience to support its use. However, for patients who don't have all of
these positive markers, the response rate for IFN falls from 30% to 40% to 10%
to 20%, which seems to me to be a very low response rate for such a toxic
treatment. In those cases, I prefer lamivudine.
ADVISORY BOARD Do you have difficulty convincing people with
normal ALT levels to undergo a liver biopsy?
RAJ It's usually not a problem. I tell them that although having
a normal ALT level is an indicator of inactive disease, it by no means
guarantees it. I then inform them that a liver biopsy is the only sure way
of determining the degree of liver damage and whether medical therapy is
ADVISORY BOARD Should patients with chronic HBV infections,
including carriers, be vaccinated against hepatitis A (HAV)?
RAJ Yes, vaccination against HAV is recommended even in carriers.
The bottom line is that coinfection with another hepatitis virus is bad news.
Consequently, for HCV patients we vaccinate against HAV and HBV. For HBV, we
recommend vaccinating only against HAV simply because there's no vaccine
available for HCV.
ADVISORY BOARD What are your thoughts with regard to the need
for an interval booster for HBV for people who have been vaccinated in the
RAJ Although by no means definitive, most of the vaccination data
up to this point show that at 10 years antibody levels may fall off but you
continue to be protected.
ADVISORY BOARD In health professionals who have been
vaccinated, should we test their B surface antibody at some point, say after
RAJ I would not routinely check it since I really wouldn't know
how to interpret it. However, if significant time has elapsed since the
vaccination series and the patient then has significant exposure to HBV, I
would probably check the serology to see if the antibody titer is low. If it
is, I would give a booster. It should be noted, though, that the general
opinion is that if someone has already been vaccinated and has developed a
good antibody response, then you don't need to do any testing even if the
person is exposed to HBV.
ADVISORY BOARD For health care professionals who have
completed the vaccination series, do you routinely check titers to make sure
RAJ Yes, I do, because they are a group at high risk of exposure.
But once seroconversion is demonstrated, routine follow-up titers are not
needed regardless of the elapsed interval.
ADVISORY BOARD What do you do in the 5% of patients who don't
form an antibody to HBsAg following the immunization?
RAJ I do 2 things. First, I repeat the entire immunization
series. Second, I switch to a different vaccine product. If they don't
seroconvert after this, I advise them to take extra precautions and inform
them that in the event of a significant exposure, HBV immunoglobulin should be
administered immediately after exposure.
ADVISORY BOARD How well has it been demonstrated that current
medical therapy can favorably impact the development of cirrhosis, the
development of hepatocellular cancer, and/or mortality due to liver failure in
a patient with chronic HBV?
RAJ A lot of prospective data have been collected on treated
patients on rates of progression to cirrhosis, the need for liver
transplantation, and death from hepatocellular cancer. Long-term follow-up of
patients treated for hepatitis B has shown that responders have improved
overall survival as well as survival free of hepatic decompensation and/or
hepatocellular carcinoma. (See Niederau C, Heintges T, Lang S, et al.
Long-term follow-up of HBeAg-positive patients treated with interferon alfa
for chronic hepatitis B. N Engl J Med. 1996;334:1422-1427 and
Papatheodoridis GV, Manesis E, Hadziyannis SJ. The long-term outcome of
interferon-alpha treated and untreated patients with HBeAg-negative chronic
Table. Serologic Tests for Hepatitis B Virus
HBsAg = hepatitis B surface antigen; anti-HBs = antibody to HBsAg; anti-HBc
= antibody to hepatitis B core antigen; HBeAg = hepatitis B e antigen; anti-HBe
= antibody to HBeAg; HBV = hepatitis B virus; IgM = immunoglobulin M; IgG =
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