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Division of Digestive Diseases, Emory University School of Medicine, 2101 WMB, Atlanta, GA 30322. Fax 404-778-4715.
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Abstract |
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 Top Abstract IntroductionHBVTreatmentReferences |
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4
years of age develop chronic infection. Active vaccination is highly
efficacious.
Key Words: indexing terms: chronic disease • DNA virus • risk factors
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Introduction |
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TopAbstractIntroductionHBVTreatmentReferences |
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HBV |
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TopAbstractIntroductionHBVTreatmentReferences |
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). The latter free forms predominate. The detection of HBsAg in
serum alone does not always imply infectivity or viral replication,
since HBsAg may exist in the blood only as free forms that are
noninfectious and are not associated with viral particles. The HBsAg is
the component of the HBV vaccine that induces a protective,
neutralizing antibody with a long-term action against HBV infection.
The inner viral core of the HBV particle contains hepatitis B core
antigen (HBcAg), a double-stranded DNA molecule, and hepatitis B e
antigen (HBeAg), a soluble, nonparticulate substance that is often
present with core antigen. The detection of HBeAg is also a useful
marker of viral replication. Finally, the inner core also contains a
DNA-dependent polymerase. The inner viral core does not exist
independently in the blood; it can be detected and measured only after
digestion of the HBsAg off the circulating viral particle. The HBcAg is
a marker of the infectious viral material and it is the most accurate
index of viral replication.
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The genome of HBV consists of the S gene, which codes for HBsAg; two pre-S region genes (pre-S1, pre-S2) that code for the hepatocyte receptor binding site; the C gene, which codes for HBcAg and HBeAg; the P gene, which codes for a DNA polymerase; and an X gene that activates viral and cellular promoters (4). Although HBV is a DNA virus, it replicates in a way similar to retroviruses, making an intermediate RNA transcript. Mutations of the HBV genome have been recognized (5)(6)(7). A precore mutant strain manifests as an infection with high concentrations of HBsAg and of HBV DNA, yet an absence of HBeAg and presence of antibody to HBeAg (anti-HBe). Patients infected with this mutant often manifest with severe chronic hepatitis, early progression to cirrhosis, and a variable response to interferon therapy. It may have an association with fulminant hepatic failure.
risk factors
The major routes of transmission of HBV are intravenous drug use
(also needlesticks and tattoos), sexual transmission, and
maternal/infant transmission at birth. The maternal transmission of
HBV to her infant is almost inevitable if the mother is both HBsAg and
HBeAg positive at the time of the baby's birth. Because mandatory
blood bank screening of donor blood for HBV came into effect in 1972,
the current risk of posttransfusion transmission of HBV is extremely
low. The HBV is found in blood, saliva, breast milk, vaginal
secretions, semen, and ascitic fluid (8)(9)(10). Homosexual
transmission has been declining as a consequence of awareness and
actions taken to stem the AIDS epidemic. Heterosexual transmission
accounts for over a third of the new cases in the US. The HBV carrier
rate varies greatly in the world. The overall rate in the US is 0.3%;
in parts of Africa, the Philippines, and Asia, carrier rates are as
high as 20% (11)(12). The risk of acquiring HBV after an
accidental stick from a needle recently used on a patient with HBV
varies from 20% if the patient was only HBsAg positive to 66% if the
patient was both HBsAg and HBeAg positive.
clinical features
The incubation period for HBV ranges from 45 to 180 days. Clinical
features of the disease vary considerably. Jaundice occurs in <10% of
children <5 years of age. However, jaundice manifests in 50% of older
children and adults. No specific clinical manifestations occur with an
acute HBV infection. The presentation is no different from other causes
of acute viral hepatitis. Symptoms include anorexia, nausea, vomiting,
flu-like complaints, fatigue, and malaise. Physical findings range from
minimal nonspecific abnormalities to jaundice and hepatomegaly (often
tender), and occasionally extend to extrahepatic features
reflecting immune-complex phenomena such as vasculitis, immune complex
nephritis, arthritis, a serum-sickness-like illness, and polyarteritis
nodosa (13)(14)(15)(16)(17). The majority of adults with acute HBV
make a full and total recovery; only ~5% of adults, especially men,
develop a chronic HBV infection that is often asymptomatic. About
10–20% of these adult patients may deteriorate and progress to
cirrhosis or liver cancer (18)(19)(20). The remaining 80–90%
of patients with chronic HBV infection ultimately resolve and
totally recover from their HBV infection over 2–5 years. The risk of
developing a chronic HBV infection is as high as 90% if the acute HBV
occurs in neonates or infants <4 years of age. The fatality rate due
to fulminant hepatic failure as a consequence of acute HBV in the US is
~0.2% (1 in 2000). The outcome of acute HBV infection is determined
by the host's immune response to the HBV. Necrosis of hepatocytes
results from the host's immune attack on HBV-infected hepatocytes in
which viral replication is occurring. Immunologic activity involves
host cytotoxic T cells directed against HBcAg on the hepatocyte surface
membrane. Concurrent infection with hepatitis delta (HDV) in patients
with preexisting HBV infection can result in an accelerated
deterioration of the hepatitis and the complications of cirrhosis and
death (21).
serologic and biochemical features
The serological markers of HBV infection vary depending on whether
the infection is acute or chronic. A summary of the serologic findings
that occur in acute HBV is given in Fig. 2
(22).
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The first serologic marker of HBV infection is HBsAg, which can be detected from 2 to 12 weeks after infection with HBV. The presence of HBsAg often antedates symptoms or abnormalities of hepatic biochemistry by 6–8 weeks. In patients who recover, HBsAg disappears from the serum 12–20 weeks after the onset of symptoms or increase in concentrations of aminotransferases. The detection of IgM antibody to hepatitis B core antigen (anti-HBc IgM) usually occurs 2 weeks after the detection of HBsAg, and it remains detectable for up to 6 months after the onset of the acute hepatitis. Before the disappearance of this antibody, another antibody to the hepatitis core antigen of the IgG class (anti-HBc IgG) appears and remains detectable indefinitely. The detection of the anti-HBc IgM is of assistance in diagnosing an acute infection in patients with HBsAg concentrations that are below the sensitivity threshold of the diagnostic assay. HBeAg is detectable in acute HBV infection if the titer of the viral infection is high. The presence of HBeAg implies infectivity, and the persistence of HBeAg for >20 weeks increases the potential risk of the acute HBV progressing to chronicity.
A quantitative assay of HBV involving a molecular hybridization
technique is now available. A dot-blot or liquid hybridization
technique detects HBV DNA concentrations of 
104
genome-equivalents/mL. The HBV DNA assay is useful in determining
ongoing viral replication, even when HBeAg is not detectable. HBV DNA
assay is also useful as a prognostic index regarding response to
interferon therapy. Patients with HBV DNA concentrations <200 ng/L are
more likely to have a successful therapeutic outcome than those with
higher HBV DNA concentrations. Antibody to hepatitis B surface antigen
(anti-HBs) becomes detectable during the recovery from acute HBV
infection in patients who do not progress to a chronic infection. The
disappearance of the HBsAg occurs a few weeks before the advent of the
anti-HBs. The presence of anti-HBs after acute infection indicates
recovery from the infection and generally lifelong immunity from
reinfection. The interpretation of the above HBV markers are summarized
in Table 1
.
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Three phases of viral replication occur during the course of HBV infection, especially in patients with chronic hepatitis B.
High replicative phase.
Associated with the presence of
HBsAg, HBeAg, and HBV DNA detectable in the sera. Increases in the
aminotransferases occur, histologic evidence of moderate inflammatory
activity is evident, and the risk of evolving to cirrhosis is high.
Low replicative phase.
Associated with the loss of
HBeAg, or a fall or loss of the HBV DNA concentrations, the appearance
of anti-HBe, and histologic evidence of a decrease in inflammatory
activity. These serologic changes (loss of HBV DNA and HBeAg) are
referred to as "seroconversion."
Nonreplicative phase.
Associated with either the absence
of markers of viral replication (or they are detectable only by highly
sensitive techniques), diminished inflammation, and inactivity of the
histologic findings. However, if cirrhosis has already developed, it
persists indefinitely.
The increase in aminotransferases [especially alanine aminotransferase (ALT)] during acute hepatitis B varies from a mild/moderate increase of 3- to 10-fold to a striking increase of >100-fold. The latter does not necessarily imply a poor prognosis. The ALT concentrations are usually higher than the aspartate aminotransferase (AST) concentrations. The bilirubin concentration rises in most patients with acute HBV infection. Clinical jaundice manifests in 50% of adults with bilirubin concentrations of >51.3 µmol/L (3.0 mg/dL). Concentrations up to 513 µmol/L (30.0 mg/dL) can occur. A slight rise in alkaline phosphatase is also evident. In patients who develop fulminant hepatic failure, a rapid fall in ALT and AST may mislead one into concluding that the hepatic infection is resolving when in fact loss of hepatocytes is occurring. Sustained increases in the concentrations of the aminotransferases for >6 months is regarded as indicative of chronic hepatitis.
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Treatment |
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TopAbstractIntroductionHBVTreatmentReferences |
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. Recombivax HB is given as three intramuscular injections at 0,
1, and 6 months and Engerix-B is given as three intramuscular
injections at 0, 1 and 2 months. Both are highly effective in producing
antibodies. The seroconversion rates associated with the development of
anti-HB varies. It is in the range of 95–98% in females and 85% in
males (23). Lower rates occur if vaccination is given
after age 40 years, or in patients who are immunocompromised,
malnourished, alcoholic, obese, or who have chronic renal disease. The
current recommendation is to vaccinate all newborn infants, and all
adolescents and adults in high-risk groups. The interval for booster
vaccinations against HBV is still undecided. A 10-year booster
injection has been suggested. However, patients who initially responded
to the vaccine and subsequently lost their anti-HB titers still appear
immune to subsequent exposure to HBV (24)(25)(26). Reexposure
to HBV leads to an anamnestic response and rarely to a subclinical
infection.
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Passive immunization
is available by using pooled serum
from patients who have recovered spontaneously from acute HBV and who
have significant anti-HBs concentrations. The product, hepatitis B
immune globulin (HBIG), is given simultaneously with HBV vaccine to
newborn infants whose mothers are HBsAg positive, or postneedle stick
or after sexual exposure in adults who are not immune to HBV
(27). The vaccine and globulin are given into opposite
deltoid muscles (or for newborns, into opposite thigh muscles).
Administration of HBIG vaccine therapy is most effective if given
within 12 h of birth or exposure to HBV. Follow-up HBV vaccination
schedules must be completed at 1 and 6 months to obtain active
immunization and to provide the individual with long-term (>10 years)
immunity.
drug therapy
Acute hepatitis B does not require specific treatment because
>90% of adults will spontaneously clear their infection. Symptomatic
treatment of the nausea, anorexia, vomiting, and other symptoms may be
indicated. Many agents have been evaluated for the treatment of chronic
hepatitis B. Most have been found to be ineffective or too toxic at
effective doses. Others are still under evaluation (see Table 3
). In the US, the only approved therapeutic agents for treating
chronic hepatitis B are interferon-
-2b and interferon--2a. The
goals of therapy are the eradication of the virus, leading to a
remission of the liver disease and an improved long-term prognosis.
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Interferon.
Interferon- belongs to a family of
natural occurring proteins that have antiviral and immunomodulatory
actions (28)(29). They enhance T-cell helper
activity, cause maturation of B lymphocytes, inhibit T-cell
suppressors, and enhance HLA type 1 expression. The efficacy of
interferon for the treatment of chronic hepatitis B has been
demonstrated in a large US trial in which 37% of treated patients
receiving 5 million units per day of interferon for 16 weeks lost HBV
DNA and HBeAg, compared with 7% of untreated controls
(30). A metaanalysis of 14 studies involving >800
patients with chronic HBV treated with interferon showed a loss of HBV
DNA in 37% and HbeAg in 33% of the interferon-treated patients
compared with 17% and 13% losses, respectively, in the controls
(31). In another long-term follow-up study, 35% of
patients who lost markers of viral replication during therapy
eventually also lost HBsAg over 5 years (32).
Favorable prognostic indices for a successful outcome with interferon therapy have been evaluated and they include the following: (a) a pretreatment concentration of HBV DNA <200 ng/L, (b) being female, (c) heterosexual habits, (d) concentrations of serum ALT >100 U/L (high ALT concentrations may be indicative of a better host immune response to HBV), (e) a disease duration of <4 years, (f) absence of HIV, and (g) acquiring the HBV infection at >6 years of age (33)(34). These indices do not provide an absolute guarantee of success with interferon therapy; they suggest a higher likelihood of success and they may assist in patient selection for interferon therapy. A low concentration of HBV DNA and a raised ALT are the best indices of predicting a successful treatment outcome.
Patient inclusion and exclusion criteria for interferon therapy:
Patients with chronic hepatitis with an increased serum
aminotransferase for >6 months who have serologic evidence of active
viral replication (the presence of HBsAg, HBeAg, and an increased HBV
DNA concentration) should be considered for interferon therapy provided
they have no contraindications that exclude them from therapy. These
contraindications are summarized in Table 4
. They include the presence of hepatic decompensation as
evidenced by biochemical variables of albumin <30 g/L, bilirubin
>51.3 µmol/L (3.0 mg/dL), or a prothrombin time >3.0 s above the
control; the presence of complications of portal hypertension (ascites,
past variceal bleeding); leukopenia (<2 x 109/L),
thrombocytopenia (<7 x 107/L), or renal impairment
[creatinine >176.8 µmol/L (2.0 mg/dL)]. Pregnancy, the presence of
an autoimmune disease, a history of severe depression requiring
hospitalization, or a history of attempted suicide are also
contraindications for the use of interferon. Other contraindications
include a history of recent intravenous drug abuse, alcoholism, or a
severe major system dysfunction (cardiac failure, obstructive airways
disease, or uncontrolled diabetes).
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The recommended dose of interferon is 5 million international units, self-injected, subcutaneously daily for 16 weeks with monitoring of a complete blood count, prothrombin time, total bilirubin, ALT, AST, HBsAg, anti-HBs, HBeAg, anti-HBe, and quantitative HBV DNA at 2, 4, 8, 12, and 16 weeks. A pretreatment thyrotropin (TSH) assay is also performed. A sudden, often asymptomatic, rise in ALT associated with a fall in HBV DNA concentrations can occur 4 to 8 weeks into therapy. This is known as a "flare response" and is thought to reflect the immune-mediated clearance of HBV-infected hepatocytes. It is followed by the disappearance of serum HBV DNA, loss of HBeAg, the appearance of anti-HBe, and normalization of serum ALT, in that order (32). Loss of HBsAg occurs in 25% of patients during the 6 months after seroconversion of HBeAg to anti-HBe (32). A flare occurs in 60–70% of responders. It can also occur in 25–30% of nonresponders to interferon therapy (35)(36). The intensity of the flare seldom aggravates the underlying liver status. However, if there is a striking increase in ALT, a rise in bilirubin, or new signs or symptoms of hepatic decompensation, then the interferon therapy should be reduced or withheld and the patient should be closely followed (37)(38). Corticosteroids given as a short course concomitantly with interferon or given as a pretreatment to interferon do not improve the results over those of interferon alone and are not recommended (39).
Adverse profile of interferon therapy (see Table 5
): Several side effects have been attributed to interferon
therapy. Many are dose dependent; some resolve despite continued
therapy; some never resolve or require cessation of therapy
(37)(38). Flu-like symptoms, fevers, rigors,
fatigue, myalgia, arthralgia, and headaches are very common
immediately after injection. These symptoms respond to analgesics
(acetominophen or nonsteroidal antiinflammatory drugs). Depression of
the platelets and (or) white cells also often occurs. The interferon
dosage may have to be reduced or withheld. A granulocyte count of
<7.5 x 108/L or a platelet count <4 x
1010/L necessitates cessation of therapy. A reversible
moderate alopecia can manifest; depression with insomnia or an
inability to concentrate can also occur (40). Hypnotics
and mild antidepressants may be required. About 3% of patients
receiving interferon develop a permanent hypothyroid state requiring
lifelong thyroid replacement therapy (41)(42)(43). Weight
loss, impotence and vitreous hemorrhages have also been noted to occur.
About 50% of patients receiving interferon therapy for 16 weeks or
longer develop antinuclear antibodies, smooth muscle antibodies, and
thyroid antibodies. Autoimmune disorders such as thrombocytopenic
purpura, hemolytic anemia, vasculitis, or type 1 diabetes can
manifest
(36)(38)(44)(45).
These usually resolve (apart from the hypothyroidism) after the
cessation of interferon therapy.
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Immunomodulators.
Thymosin, containing thymic extracts,
augments T-cell function and stimulates the production of interferons
and interleukins (46)(47). Results of a large
multicenter study were, however, unfavorable in the management of
chronic hepatitis B. Likewise, prednisone, levamisole, and
interleukin-2 have not been shown to be effective.
Adoptive immune transfer.
An isolated report of a bone
marrow transplant in a patient with leukemia and HBV resulted in
clearance of HBsAg and HBV DNA (48). The limitations of
the potential therapy are obvious.
Nucleoside analogs.
Nucleoside analogs undergo
phosphorylation and then compete with substrates for incorporation into
the viral DNA sequence. The reaction is catalyzed by host cell kinases.
Fialuridine (FIAU) had a disastrous effect when used to treat chronic
HBV. After 12 weeks of therapy, study patients developed hepatic
failure, lactic acidosis, hypoglycemia, neuropathy, coagulopathy, and
renal failure (49). Death occurred because of an
irreversible effect on mitochondrial DNA in the cells of the liver,
heart, muscle, and pancreas. Liver biopsies showed microvascular
steatosis and abnormal mitochondria. The drug produced toxicity by its
incorporation into the cells' mitochondrial genome in place of
thymidine.
Lamivudine, an orally administered nucleoside analog given as a single daily dosage of 100 mg, suppresses HBV DNA in nearly all patients with chronic HBV. However, HBV DNA concentrations rebound after the cessation of short-term therapy (50). After 12 months of continuous oral therapy, some mutant HBV escape was reported; however, long suppression of HBV replication was seen in most patients (51). The drug appears to hold considerable promise; it will probably be administered in combination drug therapy with interferon. Side effects have been mild, with headache, nausea, fatigue, and slight increase of serum amylase noted. The lack of toxicity with lamivudine favors its long-term administration. Lamivudine is especially effective in treating viruses that depend on reverse transcriptase for their replication (52)(53). It was recently approved by the FDA at a higher dose range for the treatment of HIV infection. Other agents, ganciclovir and famciclovir, have shown antiviral activity against HCV (54). They are currently undergoing evaluation.
The prognosis in patients with chronic hepatitis B and the recognized
association between HBV infection and hepatocellular cancer are well
established. This latter association in part reflects the vertical
transmission of hepatitis B from mother to infant, with a high
incidence of chronic hepatitis in neonates ultimately progressing over
a few decades to cirrhosis and possibly hepatocellular cancer. An
effective universal infant vaccination program and a vigorous
therapeutic program probably involving a combination of interferon and
lamivudine may offer an effective approach to the enormous problem of
HBV infection worldwide. Studies recently published show that compared
with standard medical care, interferon--2b therapy increases the
life expectancy and the quality-adjusted life expectancy and lowers the
projected lifetime costs of the liver disease caused by the HBV
infection (55).
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Footnotes |
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References |
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TopAbstractIntroductionHBVTreatmentReferences |
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-interferon in patients with chronic hepatitis B. Gastroenterology 1988;95:1318-1325.
[Web of Science][Medline]
[Order article via Infotrieve]
-interferon therapy? A statistical analysis of predictive factors. Hepatology 1989;10:761-763.
[Web of Science][Medline]
[Order article via Infotrieve]
therapy for chronic hepatitis C. Am J Gastroenterol 1994;89:399-403.
[Web of Science][Medline]
[Order article via Infotrieve]
and levamisole. Hepatology 1992;16:1115-1119.
[Web of Science][Medline]
[Order article via Infotrieve]
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