This
report was written by the CASL consensus conference rapporteur group
See
end of article for conference participants and rapporteurs
INTRODUCTION
This
report is the proceedings of a consensus conference on the management of
viral hepatitis sponsored by the Canadian Association for Study of the
Liver and Health Canada. This meeting was open to the public.Experts
in various aspects of viral hepatitis were asked to present a review the
medical literature on assigned topics.Three
expert panels were convened, consisting of the speakers and other invited
experts from the fields of hepatology, infectious disease, epidemiology,
virology, medical microbiology and public health.The
expert panels debated assigned topics, which corresponded to the reviews
presented earlier.Audience participation
was sought.Attempts were made to
reach consensus, on a number of recommendations about the management of
viral hepatitis.A "rapporteur" group
then synthesized the content of the literature reviews, and the debates
and consensus statements into a preliminary document.This
was presented to the audience, and additional comments sought to determine
how well the document reflected the views expressed in the earlier discussions.The
draft document was amended as necessary, and edited to produce this report.All
participants were obliged to publicly declare any potential conflicts of
interest.The report gives some background
and offers recommendations aimed at both the general practitioner and the
specialist.The recommendations and
other important statements are highlighted in the text.The
recommendations are also summarized at the end of the document.
HEPATITIS
B
1.
Epidemiology of Hepatitis B in Canada
The
prevalence of hepatitis B (HBV) infection varies considerably across Canada
because of the heterogeneity of the Canadian population.If
the Canadian population can be described by three groups - Native/Inuit,
Immigrant and Non-immigrant then the estimated prevalence and number of
cases in Canada are shown in Table 1 (1-6).Immigrants
constitute the largest group of HBV carriers, particularly those from regions
with high endemic rates of HBV, such as Asia.The
proportion of HBV infected patients who are HBeAg-positive also varies
amongst the different groups (1).HBeAg-positivity
ranges from <9% in the Inuit population, to <15% for non-immigrants,
to 46% for Asian immigrants and 55% for Indochinese immigrants.The
majority of HBeAg-positive cases occur in the young immigrant population.
Following
acute HBV infection, the percentage of infected patients who become carriers
varies with age.The risk is greatest
in the very young and in the elderly (see later). Although acute hepatitis
B continues to be an important clinical problem in Canada the majority
of acute cases will resolve and clear HBsAg spontaneously.Chronic
HBV infection, established when HBsAg is detectable for longer than 6 months
with or without continuing liver enzyme abnormalities, accounts for the
greatest burden of disease.
2.
Natural History of Chronic Hepatitis B
The
course of chronic hepatitis B is highly variable, characterized in some
patients by exacerbations and remissions of inflammatory activity in the
liver, in others by continuous active hepatitis of varying degrees of severity,
and in yet others by trivial inflammation.The
disease can be described by three phases (7).The
first phase, the so-called immuno-tolerant phase, is characterized by high
levels of virus in serum, and no or minimal hepatic inflammation (8).These
patients are HBeAg-positive.This
is followed by the "active" phase, during which there is intermittent or
continuous hepatitis of varying degrees of severity (8-11).Seroconversion
to anti-HBe-positive may occur during this phase (12), but cessation of
inflammatory activity does not always follow.The
third phase is the inactive phase during which viral concentrations are
low, and there is minimal inflammatory activity in the liver (3).In
general, patients who clear HBeAg have a better prognosis than patients
who remain HBeAg-positive for prolonged periods of time do (14).About
1%/year of anti-HBe-positive patients will clear HBsAg (15).However
these patients remain at risk for hepatocellular carcinoma.
One
of the major mechanisms by which seroconversion occurs (possibly the only
mechanism) is by the development of the so-called "pre-core mutant" (16).This
is a mutation which arises during the course of infection, and which results
in inability of the virus to produce HBeAg.The
virulence of this mutant is uncertain.Patients
who are anti-HBe-positive with elevated ALT concentrations and detectable
HBV DNA almost all carry the pre-core mutant.However,
anti-HBe-positive patients with normal ALT levels and undetectable HBV
DNA also frequently carry the mutant.It
may be that virulence is determined by another related mutation in pre-core
mutants.
Patients
with hepatitis B-induced cirrhosis who are anti-HBe-positive have a 97%
5-year survival, compared to a 72% survival for those who are HBeAg-positive
(17).Once hepatic decompensation
occurs in anti-HBe-positive patients, the survival at 5 years is only 28%,
whereas in HBeAg-positive patients the 4-year survival is zero (18).Factors
predicting an adverse outcome include active hepatitis, bridging necrosis
on biopsy, older age, and persistent HBV DNA in serum (19).
Patients
with chronic hepatitis B are at risk for the development of hepatocellular
carcinoma (20).The relative risk
has been prospectively determined to be about 100, but that is highly dependent
on the population being studied.Studies
in Asian populations describe a much higher risk than Caucasian populations.However,
even in a Caucasian population the 10 year incidence of HCC may be as high
as 15% (17).
3.
Evaluation of the HBsAg-Positive Patient
Who
should be tested?
Any
patient with clinical or laboratory evidence for either acute or chronic
liver disease should be considered as possibly infected with HBV.Individuals
engaged in high-risk activities such as intravenous drug use or high-risk
sexual activity are at risk, as well as individuals exposed to blood by
reason of their occupation.In addition
being a member of a population with a high endemic rate of HBV is a risk
factor for infection.The diagnosis
of HBV infection is based on the detection of HBsAg in serum.All
HBsAg-positive individuals require further detailed assessment.The
objectives are to characterize the nature of the infection and the extent
and severity of any underlying liver disease.Other
objectives include identifying patients who may benefit from anti-viral
treatment, early diagnosis and management of cirrhosis and its complications,
timely detection of HBV-associated hepatocellular carcinoma, and immunization
of contacts at risk.
Chronic
hepatitis B - Initial Investigations
The
laboratory tests needed in the initial assessment in all cases of chronic
HBV infection are listed in table 2.Measurement
of the aminotransferases provide a measure of ongoing inflammation, whereas
the bilirubin, albumin and INR estimate liver function.Anemia,
leukopenia or thrombocytopenia may indicate cirrhosis with portal hypertension.A
positive HBeAg is associated with the continued presence of actively replicating
HBV in the liver and detectable HBV DNA in the blood.Such
patients are at risk for ongoing liver injury.Their
blood and body fluids are highly infectious.Anti-HBe-positive
patients may have much lower viral loads, which may be undetectable in
blood by standard assays.These patients
usually have little ongoing liver damage.Anti-HBe-positive
patients may be infected with the so-called "pre-core" mutant, which does
not produce HBeAg.These patients
may have detectable HBV DNA and may develop progressive liver disease leading
to cirrhosis, and therefore merit life-long observation.In
selected cases additional tests are needed.Anti-HCV
should be requested in patients at high risk (IVDU, high risk sexual exposures,
origin in countries of high HCV prevalence).For
those at risk for hepatocellular carcinoma (long term and childhood infections,
positive family history), and those in whom cirrhosis is suspected an ultrasound
is strongly advised.
Chronic
hepatitis B - Special Investigations
HBV
DNA Assays
HBV
DNA can be detected in serum by several commercially available methods
(see later).Table 3 lists the current
tests, their limits and ranges. There
is poor inter-assay standardization so that quantification of HBV DNA when
tested on different assays can vary by approximately 10 fold or more when
testing the same specimen.There
is also considerable intra-assay variation so that repeat testing of the
same sample will result in a significant difference in results (coefficient
of variation for bDNA assay is 10-20%, and for PCR assays is 20-40%).It
is therefore important for the clinician to understand the type of assay
methodology used, and its limitations, and that a consistent methodology
be used for all assays.HBV DNA testing
should be limited to those patients being considered for treatment and
to evaluate response to treatment.It
is not indicated routinely in the evaluation of all HBsAg-positive patients.HBV
DNA testing should be readily available to qualified practitioners regularly
involved in the treatment of HBV.
Liver
Biopsy
Biochemical
or serological tests, including HBV DNA, cannot predict histopathology
with adequate precision.Therefore
liver biopsy may be required to determine the severity of permanent liver
injury (fibrosis or cirrhosis).The
biopsy appearances may help in choosing appropriate therapy.
Ancillary
tests
The
detection of IgM anti-HBc in the serum is not a reliable surrogate for
HBV DNA testing.Its use is not recommended
for this purpose.Positive immunostaining
of hepatocyte nuclei and cytoplasm for HBcAg reliably predicts the presence
of HBV DNA in serum.
4.
Treatment of the Hepatitis B Patient
The
licensing of the nucleoside analogue, lamivudine, has significantly increased
the therapeutic options available for the management of HBV-infected patients.Clinical
trials indicate that the response rates, as measured by HBeAg seroconversion
to anti-HBe-positive, after lamivudine therapy in HBeAg-positive patients
with elevated liver enzymes range from 17-33%, and are comparable to seroconversion
rates documented with interferon therapy (21-23).Loss
of HBsAg with lamivudine therapy occurs in less than 5% of patients, compared
to 8-33% with interferon (23).Response
to lamivudine therapy is associated with improved liver histology.Preliminary
results suggest that combined therapy with interferon and lamivudine has
no advantage over the use of interferon or lamivudine alone.Lamivudine
is well tolerated with minimal side effects.It
use is associated with the development of viral mutants, the so-called
YMDD mutants (24), which may develop in 16-32% of treated patients after
one year of therapy (21,22).Although
these mutants often appear to be less virulent than the wild-type HBV,
they have been associated with rapidly progressive liver disease in some
patients.There are no data on the
long-term benefits of lamivudine therapy.The
initial trigger for consideration of treatment is an abnormal ALT level.This
is defined as an elevated ALT on at least three consecutive occasions over
a three-month period.For interferon
therapy the cut-off is twice the upper limit of normal, and for lamivudine
therapy the cut off is 1.3 times the upper limit of normal.A
response to therapy is defined as loss of HBeAg, development of anti-HBe,
clearance of HBV DNA from serum (by the bDNA, solution hybridization or
hybrid capture assays), and normalization of the aminotransferases.This
response is seen at the end or within 3-6 months of the end of interferon
therapy, whereas on lamivudine therapy this response is usually seen while
still on treatment.
The
recommendations below apply only to patients > 18 years of age (see later
for recommendations for children).
In
the HBeAg-positive patient with abnormal ALT levels liver biopsy is strongly
recommended, but not mandatory.Treatment
is recommended regardless of the stage of fibrosis.However,
the degree of fibrosis may influence the choice of therapy.Therapy
may be with either interferon or lamivudine.Interferon
is given at a dose of 27-35 mu weekly (5-6mu daily or 9-10 mu TIW) for
16 weeks (25-32).Lamivudine is
given at a dose of 100 mg daily for 52 weeks (21).Factors
which should be considered in choosing an appropriate regimen include age,
pre-treatment liver histology (amount of fibrosis), HBV viral load, and
the potential side effects of the drugs (33).Other
important considerations are the risk of development of mutant viruses,
and its implications for future antiviral therapy, and the likelihood of
pregnancy.Interferon therapy results
in a delayed but enhanced clearance of HBsAg compared to untreated patients.Treated
patients have a 5-year rate of clearance of HBsAg of 16% vs. 4% in the
untreated group (15).The data on
the efficacy of lamivudine on clearance of HBsAg are not yet available.
In
patients treated with interferon development of anti-HBe with normalization
of ALT is a good surrogate marker for clearance of HBV DNA.Therefore
monitoring with HBV DNA is not essential.In
patients treated with lamivudine clearance of HBV DNA is a marker of efficacy
of treatment.The ALT response may
be delayed or incomplete.Therefore
HBV DNA testing is essential to evaluate the response to therapy.In
addition, an increase in ALT levels while on treatment may be a marker
of the development of viral resistance to lamivudine, and should be followed
by quantitative assessment of hepatitis B viral DNA levels.In
anti-HBe-positive patients with elevated ALT and detectable HBV DNA (pre-core
mutant) therapy is more difficult.These
patients do not respond well to interferon (33,34).There
are reports of extended treatment (6-12 months) interferon with sustained
viral clearance.However, this remains
controversial.Lamivudine treatment
will suppress viral replication in these patients with improvement in ALT
(35).However, the relapse rate
is high once treatment is stopped.The
consensus was that these patients should be treated in expert centers.Lamivudine
therapy for patients who are anti-HBe-positive and HBV DNA-positive is
still considered experimental.The
use of prednisone withdrawal prior to interferon therapy is contraindicated
in the management of HBV-associated disease.Interferon
use in the immunosuppressed patient is not effective.In
the setting of organ transplant up-regulation of HLA display may also enhance
rejection.The optimal management
of HBV-infected patients who are immunosuppressed has not yet been defined.These
include patients who have been transplanted with an organ other than the
liver, or who are being treated for autoimmune disease, or malignancy.Routine
screening of patients undergoing organ transplantation is standard practice.At
the present time there is insufficient information to support routine screening
of other immunosuppressed patients for HBV infection.However,
patients with risk factors should be screened.There
is also insufficient information to recommend lamivudine anti-viral prophylaxis
for immunosuppressed patients who are known to be hepatitis B carriers.There
are several case reports of the use of lamivudine in patients following
renal transplantation and bone marrow transplantation, indicating that
suppression of virus is possible, with resolution of the hepatitis (36,37).However,
there are no reports of long term outcome, and therefore no recommendations
could be made for or against the use of lamivudine in immunosuppressed
patients.
5.
SPECIAL CASES
Hepatitis
D Virus
Hepatitis
D virus (HDV) is a small, defective RNA virus that requires the presence
of a coating of hepatitis B surface antigen (HBsAg) for entry into and
exit from the hepatocyte.HDV therefore
may be acquired as a co-infection simultaneously with hepatitis B or as
a super-infection in a patient who already is a carrier of HBV.Infection
with hepatitis D usually causes an aggressive hepatitis (38).Interferon
at a dose of 9 Mu three times a week for a year can induce a virological
response but this is only sustained in 21% of cases when assessed six months
after completing therapy (39).Whether
or not interferon therapy alters outcome in terms of morbidity or mortality
is unknown. Patients with active hepatitis D should be treated in expert
centres.
Decompensated
Hepatitis B Cirrhosis:
Patients
with decompensated HBV-associated liver disease have a poor prognosis,
particularly those with active viral replication.Low-dose
interferon therapy in such patients (HBeAg-positive) may result in one-third
responding with seroconversion and improvement in liver function, but some
20 to 70% of patients have significant complications from the treatment
(40).Lamivudine appears to yield
a better response rate, approaching 80%, without significant side effects
(JP Villeneuve, personal communication).Whether
or not this changes the overall outcome remains to be determined.
Patients
with decompensated chronic hepatitis B are candidates for liver transplantation.Prior
to the availability of anti-viral therapy re-infection of the graft was
common.Chronic hepatitis B post-liver
transplant causes aggressive disease and a rapid evolution to cirrhosis
and liver failure.Many liver transplant
centres are currently treating these patients with lamivudine before transplantation.Some
patients may improve sufficiently to avoid or delay the need for transplantation.Timing
of the introduction of lamivudine is important.Waiting
times for liver transplantation are long.Prolonged
use of lamivudine pre-transplant may allow the appearance of the YMDD-variant.These
patients develop HBV DNA in serum once more, and may lose their opportunity
for transplantation.Therefore the
possibility of improved liver function must be balanced by the risk of
emergence of viral resistance.Furthermore
some patients in transplant studies experience a return of active hepatitis
after developing YMDD-variant HBV; and may progress to liver failure and
death.Loss or partial loss of lamivudine
virologic efficiency in patients with advanced disease and/or immunosuppression
may also be associated with more frequent or more severe disease progression
than is observed in non-decompensated patients. Low dose interferon is
not recommended in decompensated hepatitis B cirrhosis.Patients
with decompensated chronic hepatitis B should be referred to a liver transplant
center, and treatment with lamivudine coordinated with the transplant center.
Extra
Hepatic Manifestations of Hepatitis B:
Glomerulonephritis
Both
acute and chronic HBV infections have been associated with membranoproliferative
glomerulonephritis, in which immune complexes are deposited in the basement
membrane of the glomerulus.Interferon
therapy is very effective for hepatitis B-induced membranous glomerulonephritis,
but response is poor in those with membranoproliferative glomerulonephritis
(41,42).In membranoproliferative
glomerulonephritis HBeAg clearance occurs in the same proportion of patients
as with standard indications for chronic liver hepatitis B.Corticosteroid
therapy is contraindicated.There
are no reports on the use of lamivudine in these patients.The
indications for interferon therapy in patients with hepatitis B-induced
membranproliferative glomerulonephritis are the same as for hepatitis B
patients without glomerulonephritis, i.e., the indication for treatment
is the liver disease.In membranous
glomerulonephritis, the renal disease per se is an indication for interferon
therapy (because the response rate is so good).No
recommendations for or against the use of lamivudine could be made.
Chronic
Hepatitis B in Children
The
risk of chronicity in hepatitis B infections in newborns and early childhood
is high (see table 4).In addition,
most infants and young children infected with hepatitis B have normal aminotransferases
and are not candidates for therapy (8,43).Children
who are first infected at ages over 7 years of age have a low risk of developing
chronic disease.The prognosis of
hepatitis B in children is generally good, cirrhosis and hepatocellular
carcinoma are only rarely seen in the childhood years.Spontaneous
seroconversion from HBeAg to anti-HBe antibody occurs in between 6-12%
of infected children per year.In
randomized controlled trials treatment with alpha-interferon in children
resulted in 35% clearance of HBV DNA and HBeAg(11%
in controls) and 7% clearance of HBsAg (1% in controls) (44).Optimal
treatment is between 3-6 Mu/m2 of interferon TIW for 6 months.The
indications for treatment are similar to those in adults.There
is no information on the use of lamivudine in children.Normally
treatment should not begin before two years of age, because of the side
effects of alpha-interferon.In older
children the side effects of interferon appear to be well-tolerated.Weight
loss can be offset by dietary interventions.
4.
COMMENT
The
treatment of chronic hepatitis B is complex, and is evolving rapidly.Only
physicians who are familiar with the disease and its management should
undertake to treat chronic hepatitis B.Appropriate
therapy may require consultation with experts, because inappropriate therapy
may limit future therapeutic options.
HEPATITIS
C VIRUS
Hepatitis
C virus (HCV) is a heterogeneous, single-stranded, positive-sense RNA virus
belonging to the Flaviviridae family.Like
many other RNA viruses, HCV has an inherently high mutation rate, resulting
in considerable genetic heterogeneity throughout the genome.This
genetic heterogeneity subdivides the hepatitis C virus into six major genotypes
that vary in distribution worldwide (47).Genotype
1 appears to be the predominant type in Canada (46-49).Quasispecies
are closely related variants of a single genotype within a single individual,
which arise from mutations that occur during viral replication.Quasispecies
diversity may increase with time and contribute to interferon resistance
and viral persistence. Information on the rates of development of chronicity
after an initial HCV infection comes largely from studies of post-transfusion
hepatitis.In these studies viral
clearance from serum occurred in about 20-30% of patients initially infected
with hepatitis C.It is not known
whether this is also true for hepatitis C acquired through other routes.To
be confident that viral clearance has been achieved PCR-based assays must
be used.Negative HCV RNA by PCR
assays indicate viral clearance from serum, but give no information about
the state of HCV in the liver or in other privileged niches (e.g., lymphocytes).Thus,
given the current state of knowledge complete viral clearance cannot be
ascertained with certainty.Therefore,
patients who are anti-HCV-positive who have spontaneously developed negative
HCV RNA by PCR should continue to be monitored at intervals for the presence
of liver disease.
The
outcome of chronic hepatitis C virus infection is not well defined.A
proportion of patients will ultimately develop cirrhosis and hepatocellular
carcinoma (50-52).However, the
proportion of patients at risk for this outcome has not been accurately
determined.Various reports have
suggested that the lifetime risk of cirrhosis in HCV carriers is between
20-50%.Although several factors
have been identified which increase this risk, e.g., alcohol consumption
(53-55), the magnitude of increase in risk has not been well defined.Furthermore,
the rate at which disease progresses has also not been completely defined
(56-58).Some studies have indicated
that after 17 years of infection the prevalence of cirrhosis is no more
than 2% (60).Other studies have
indicated that the mean duration between infection and the first diagnosis
of cirrhosis is about 20 years (50).The
differences in these studies are accounted for by referral bias.As
a result there is considerable uncertainty about the rate of disease progression.Factors
that increase the risk of progression to cirrhosis include age over 40,
consumption of even moderate amounts of alcohol (53-55), and increased
age of acquisition of infection.Patients
infected by transfusion are also thought to have more aggressive disease,
but in this cohort having a transfusion may be a surrogate marker for increased
age at acquisition of disease, since the transfused population is considerably
older than the average population. The risk of progression to cirrhosis
also appears related to the degree of liver inflammation and fibrosis seen
at the time of a biopsy.Patients
with persistently normal ALT have a lower likelihood of progression to
cirrhosis (56,60,61).There is no
clear association of disease progression with genotype or viral load.Co-infection
with HIV is associated with higher viral loads, and a more rapid progression
to cirrhosis (see later).Co-infection
with hepatitis B is associated with a greater risk of HCC than either disease
alone (see later).Predictions of
disease progression depend on the assumption that the rate of disease progression
is linear, and that it takes an equal amount of time to progress from e.g.,
stage 1 fibrosis to stage 2 fibrosis as from stage 3 to stage 4 fibrosis.This
assumption may not be correct.
Once
cirrhosis has developed the 10 year survival is about 80%.However,
the rate of development of complications of cirrhosis over the same time
period is about 40% (62).Over the
next 10-20 years chronic hepatitis C is predicted to be come a major burden
on the health care system in Canada as patients who are currently asymptomatic
with relatively mild disease progress to end-stage liver disease and develop
hepatocellular carcinoma.Predictions
in the USA indicate that there will be a 60% increase in the incidence
of cirrhosis, a 68% increase in hepatoma incidence, a 279% increment in
incidence of hepatic decompensation, a 528% increase in the need for transplantation,
and a 223% increase in liver death rate.There
are no comparable studies to assess the future health burden in Canada,
but since the demographics in the US and Canada are similar, we can expect
a similar increase in these disease states in Canada.1.
Hepatitis
C RNA testing
As
with HBV DNA testing, there is a large inter-assay and intra-assay variation
with HCV RNA testing.Once more the
requesting physician should be familiar with the characteristics of the
assay being used (table 5), and the use of a particular assay should be
consistent.This variability must
be considered when adapting results from the published literature to local
practice.
There
are two types of assay for hepatitis C viral RNA.Qualitative
tests give a positive or negative result.Quantitative
tests give the viral concentration or viral load.The
only qualitative assay available is the Roche AMPLICOR(tm) assay (lower
limit of sensitivity 100 copies/ml).Quantitative
assays available include the Chiron bDNA assay and the Roche Monitor(tm)
assay, which measures down to 1000 particles/ml.The
most recent studies on therapy using interferon and ribavirin or PEGylated
interferon use the National Genetics assay, which although commercially
available requires the sample to be sent to the NGI lab.There
is approximately a 10-fold difference between the Monitor and the NGI assay,
so that 2x106 copies/ml in the NGI assay is equivalent to about
2x105 copies/ml in the Monitor assay.This
becomes important when comparing viral load data between published studies
and individual patients.
2.
Use of HCV RNA testing
Qualitative
HCV-RNA testing is not essential to make the diagnosis of hepatitis C in
typical patients who are anti-HCV positive.HCV
RNA testing is indicated in patients who are anti-HCV-positive with normal
ALT levels.Interpretation of the
results of such testing is given in table 6.HCV
RNA testing is also sometimes necessary in patients who are immunosuppressed,
and who have unexplained elevations of the aminotransferases.In
these patients there may be a false-negative anti-HCV assay.Qualitative
HCV RNA may also be used to determine whether infants of infected mothers
are also infected (see later), and in resolution of indeterminate serological
testing.Qualitative HCV RNA monitoring
is also useful in assessing the response to therapy.Quantitative
HCV RNA testing is not routinely required for all patients.There
was no consensus as to the requirement for quantitative HCV-RNA testing
prior to treatment.Viral load is
a predictor of response to therapy, but the panel felt that viral load
should not be used to assess duration of therapy (see later).High
viral loads should not be a deterrent to initiating treatment.
3.
Sexual transmission of the hepatitis C virus
Direct
percutaneous inoculation is the most efficient mode of transmitting HCV,
although sexual, household occupational and vertical transmission of HCV
may also occur (63-67).HCV intra-spousal
transmission appears to be rare in the absence of a parenteral risk in
the partner.In case-control studies
sexual co-habitation with an anti-HCV-positive person was not identified
as a risk for infection.Therefore
HCV is not considered to be a sexually transmitted disease.Some
factors, however, such as sexual promiscuity, HIV and HSV2 co-infections
are associated with sexual transmission of hepatitis C (66,67).It
is not clear whether the probability of transmission between partners increases
with decades of marriage and/or age (68,69).This
does not necessarily represent sexual transmission.The
infected person should inform sexual partners.Testing
should be offered to the sexual partner.Patients
should be advised to avoid sharing items of personal hygiene.In
short-term sexual relationships condom use is advised.Unprotected
sex during menstruation should be avoided.Couples
should be given information about the risks of transmission, and about
precautions which may reduce the risk of transmission.The
committee neither recommends nor recommends against the use of condoms
in stable monogamous relationships.It
is up to the couple to make a decision, based upon the best information
that can be provided to them.
4.
Mother-to-Infant Transmission of the Hepatitis C Virus
Rates
of transmission of hepatitis C from mother to newborn infant vary between
0 and 3% according to different reports (70-73).Two
risk factors have been identified, HIV infection in the mother, and high
maternal viral load (70,73).It
is controversial whether caesarian section prevents transmission of HCV.Results
of testing breast milk for HCV RNA are conflicting.However,
transmission from breast milk has not been documented.Breast
feeding is considered safe and is not contraindicated.
Anti-HCV
testing in the neonate is not helpful, because there is passive transfer
of antibody across the placenta.This
may take 12-18 months to clear.Testing
for hepatitis C infection within the first 18 months of life should be
by PCR assays.There is very limited
information in the literature concerning the rate of chronicity after neonatal
transmission.Clearance of the virus
may occur more frequently than in adult infection.
5.
Therapy for Chronic Hepatitis C
The
prime indication for treatment in chronic hepatitis C is an ALT level more
than 1.5 times the upper limit of normal on three consecutive occasions
over more than three months. Patients with ALT levels below 1.5 times the
upper limit usually have mild disease and an excellent prognosis (60).Treatment
may not be required.Interferon
monotherapy treatment in this group is largely ineffective.There
are no data on the use of interferon and ribavirin combination therapy
in this group.Although the ALT is
the trigger for considering treatment, other factors may also influence
the decision whether to treat or not.A
liver biopsy is recommended for grading and staging of the liver disease.When
treating immunosuppressed patients such as renal or bone marrow transplant
recipients, a biopsy is mandatory to confirm the diagnosis.If
the biopsy is normal or shows minimal disease then treatment may not be
necessary.An adequate biopsy consisting
of at least 3-5 portal zones is necessary for assessment.Many
other factors have to be taken into consideration before deciding to treat
a particular patient.Most important
is to try to make an assessment of whether the patient will ever develop
cirrhosis and liver failure, or particularly in patients over age 50, whether
completing causes of mortality are more or less likely to cause death.Liver
biopsy may also be required in patients in whom treatment is not being
considered, in order to assess the extent of liver injury.It
is recommended that response to treatment be defined in virologic terms.The
use of ALT levels to define response to treatment is no longer recommended.Successful
treatment is indicated by clearance of hepatitis C virus RNA from serum
(by sensitive PCR-based assays) 6 months after the completion of therapy
(sustained response).There is now
evidence showing that this response is durable, in that serum HCV RNA remains
negative for years (74).ALT levels
return to normal, and the incidence of complications of cirrhosis and hepatocellular
carcinoma are reduced.Survival is
improved.
Dose
and Duration of Treatment
The
recommended treatment for chronic hepatitis C is with a combination of
interferon alpha 2b and ribavirin. The dose of interferon is 3 mu TIW,
and the dose of ribavirin is 1000 mg for patients weighing less that 75
kg, and 1200 mg daily for patients weighing more than 75 kg (75-77).The
use of interferon alpha 2a or other interferons in combination with ribavirin
has not been reported. Overall,
about 40% of patients treated with this combination will have a sustained
response.Patients with genotype
2 or 3 have about a 65% response rate (76,77).Patients
with genotype 1 have about a 30% response rate.The
response rates in other genotypes are not as well defined.Response
rates are also improved with lower viral loads (<2 x106 copies/ml
by the NGI assay), age less than 40 years, absence of fibrosis and female
gender (77).Treatment duration with
interferon and ribavirin is determined by the viral genotype.Patients
who carry genotypes 2 or 3 may be treated for 24 weeks.Patients
carrying any other genotype should be treated for 48 weeks (53,54).Viral
load may be used to predict response to therapy, but the data on viral
load as an indicator of duration of treatment were weaker than for genotype,
and viral load should not at this stage be used to determine duration of
therapy.An algorithm has been developed
using several of the favourable response factors listed above (77).However,
the algorithm has not been prospectively validated, and should not be used
to determine treatment duration. Unlike interferon monotherapy, a small
number of patients treated with interferon and ribavirin who ultimately
become long term responders first clear HCV RNA between 12 and 24 weeks
of therapy.There is as yet insufficient
data to recommend whether the 12 week stop rule described for interferon
monotherapy (see below) also applies to combination therapy.Approximately
14% of patients with positive HCV RNA assays at 12 weeks will become sustained
responders.However, it is clear
that patients who fail to clear HCV RNA by 24 weeks of treatment will not
become sustained responders.Therefore,
a positive HCV RNA assay after 24 weeks of therapy is an indication to
stop treatment.Interferon monotherapy
should now be reserved for patients who cannot tolerate ribavirin (e.g.,
patients with anemia).The intended
treatment duration of interferon monotherapy is 48 weeks.Response
is assessed at three months using the qualitative HCV RNA test.Failure
to clear HCV RNA after three months of therapy predicts inability to develop
a sustained response.Treatment should
be stopped if the HCV RNA is positive at three months.
Monitoring
During Therapy
The
addition of ribavirin to the therapy increases the likelihood of side effects.Ribavirin
predictably causes hemolysis.The
hemoglobin level falls within the first 2-4 weeks, then stabilizes in most
patients.Ribavirin dose reduction
is recommended if the hemoglobin falls below 100 gm/l.Routine
monitoring for adverse effects includes a CBC weekly for the first month
then CBC monthly and TSH every 3 months (there is a increased incidence
of thryroiditis on interferon therapy, particularly in patients with chronic
hepatitis C).Symptoms should be
monitored monthly during treatment. Treatment response is monitored by
the ALT and the HCV RNA concentration.ALT
is an imperfect surrogate marker for viral clearance, so that HCV RNA testing
is mandatory at the appropriate time points (12 or 24 weeks of therapy,
and 24 weeks after completion of therapy).Qualitative
HCV RNA testing is adequate to determine response.Quantitative
HCV RNA is not required.
Contraindications
to therapy
In
assessing whether a patient is a good candidate for therapy with interferon
and ribavirin, it is essential to consider the benefits and risks for that
individual.Factors that may decrease
the likelihood of long term benefit from treatment include shorter life
expectancy e.g. older age, co-morbid conditions, decompensated liver disease,
and active alcohol abuse (abuse within previous 6 months).Ideally
patients should abstain from alcohol completely while on treatment.Factors
that may predispose to a higher risk of adverse events include major psychiatric
disorders, cardiovascular diseases such as significant arrhythmias, major
congestive heart failure, uncontrolled hypertension or ischemic heart disease,
active autoimmune diseases, poorly controlled seizure disorders, diabetic
retinopathy (interferon can exacerbate diabetic retinopathy), thyroid disease
(relative contraindication).Interferon
can cause an autoimmune thyroiditis.However,
patients who are hypothyroid cannot suffer any further harm.Other
factors increasing the risk of adverse events include myelosuppression,
such as thrombocytopenia and neutropenia.Therapy
should not be instituted if the platelet count is less than 80x109/l or
the neutrophil count is less than 1.0x109/l.Renal
failure and anemia increase the risk of adverse effects from the ribavirin.Ribavirin
is teratogenic.Patients on combination
therapy and their partners must use adequate contraception.Patients
in whom poor compliance is expected, or in whom there is a significant
risk of re-infection e.g. active substance abuse may not be suitable candidates
for treatment.Other conditions,
which are relative contraindications, include severe asthma, psoriasis
and past history of autoimmune diseases or psychiatric disorders.
Absolute
contraindications to therapy with interferon and ribavirin are decompensated
liver disease, active alcohol abuse, pregnancy or lack of appropriate contraception
and expected non-compliance.
Special
Cases
Thalassemia
Patients
with thalessemia can be offered therapy with the understanding that during
treatment there is likely to be a 40 to 90% increase in their transfusion
requirements. It may be possible to reduce the ribavirin dose.Data
on the need to aggressively reduce hepatic iron by chelation to optimize
response to treatment is controversial. Alternatively these patients may
be better off waiting for the long acting interferons to become available.
Hemophilia
Patients
with hemophilia can be offered therapy (78,79).Pre-treatment
assessment should include a liver biopsy that may be performed by the transjugular
or by plugged percutaneous route with clotting factor coverage.
Methadone
maintenance
Patients
on methadone maintenance should not be excluded from treatment.
Prisoners
Therapy
for incarcerated patients should be individualized based on their expected
compliance and risk of re-infection.
Treatment
Failures
Relapse
after interferon monotherapy: - these are patients in whom the ALT normalized
or in whom viral clearance occurred transiently during interferon monotherapy,
but who relapsed after completion of therapy.These
patients should be offered treatment with interferon and ribavirin (80).The
expected response rate is similar to naïve patients.Non-responder
to interferon monotherapy: - These are patients in whom the ALT did not
return to normal during therapy, or in whom viral clearance from serum
was not achieved. There are several treatment options for these patients,
each with a response rate of 10-15%.These
include re-treatment with interferon and ribavirin, treatment with consensus
interferon (81), or induction therapy with interferon.There
is insufficient information to make a recommendation on the effectiveness
of any of the therapeutic options for patients who were non-responders
to interferon monotherapy.
Failure
of combination therapy
Patients
who fail to respond or who relapse after combination therapy should be
managed in consultation with a centre with expertise in this area.There
are no proven treatment options for these patients at present, but they
may be candidates for experimental therapies.
Hepatitis
C Infection in Children
In
past years, hepatitis C was found with high prevalence in children who
received multiple transfusions of blood derived products before testing
for hepatitis C was introduced.Currently,
age-related distribution of infection is likely related to different patterns
of exposure.Vertical transmission
in infants and body piercing, tattooing and drug abuse in adolescents are
the most common routes of infection.The
rate at which the initial infection becomes chronic in infants is still
unknown.Up to 30% of these children
appear to have spontaneous resolution of their infection.Although
progression of the disease seems to be more benign in children than in
adults, some children do develop significant fibrosis.Uncontrolled
trials suggest that the response rate to interferon may be as high as 33-50%(82-84).The
response to combination therapy (interferon and ribavirin) is unknown.The
indications for treatment in children with hepatitis C have not been adequately
defined.Chronic hepatitis C in children
should not be treated except in controlled trials.
Acute
hepatitis C
Since
1991, the routine screening of blood products has decreased the prevalence
of acute HCV following transfusion to negligible levels.Therefore,
acute HCV infection is now seen mainly in individuals who have received
an accidental needle stick injury.Although
a risk for infection is relatively low at <5%, because the majority
of these individuals are health care workers, every effort should be made
to make an early diagnosis, and thereby minimize the risk of nosocomial
transmission.There are no data to
indicate which testing algorithms, using serological tests or PCR assays,
are more cost effective.HCV RNA
may become positive as early as 2 weeks after exposure.Anti-HCV
usually becomes positive 10 weeks after exposure.There
has been a suggestion that early treatment of acute hepatitis C with interferon
monotherapy C may enhance the likelihood of response compared to chronic
hepatitis C (85-87).There is no
information as to whether this is true for interferon and ribavirin.The
possibility of an enhanced response to early therapy has to be balanced
against the theoretical 20% chance of spontaneous clearance of the virus.No
recommendations can be made about the timing of therapy of acute hepatitis
C.The following recommendation is
therefore based on expert opinion, rather than evidence from the medical
literature.Healthcare workers or
others subjected to needle-stick injury or equivalent exposure should be
tested by anti-HCV at the time of the injury and at 12 weeks or later to
detect infection. Treatment should be with standard combination therapy
of interferon and ribavirin for the standard duration despite the lack
of prospective studies proving efficacy.Given
the urgent need to gather data on such cases it is strongly recommended
that patients with acute hepatitis C be treated in the setting of a clinical
trial or a registry.
COMBINED
INFECTIONS
1.
Hepatitis B and Hepatitis C
The
prevalence of combined infections with these two organisms in Canada is
unknown.Elsewhere the prevalence
ranges between 3.4-18.3% in series of patients with hepatitis C (88-90).Various
studies have demonstrated that the outcome of combined infection is more
severe than infection with either virus alone (91,92).In
most patients one infection predominates, while the other is dormant.Thus
in HBV-dominant disease the HBV DNA is detectable, while the HCV RNA is
not, and vice versa.Occasionally
both diseases may be active.The
risk of HCC is also increased compared to the risk with hepatitis B or
hepatitis C alone (93-96).There
are few reports of treatment (97).In
patients with one infection dominant, and the other dormant the indications
for treatment and the dose and duration of treatment are identical to when
the dominant disease exists on its own.For
example, in patients who are HBeAg-positive with detectable HBV DNA, undetectable
HCV RNA and elevated aminotransferases, treatment is with interferon 27-36
mu weekly for 4 months.Conversely,
if the HBV DNA is undetectable, and HCV RNA is present, the treatment is
with interferon and ribavirin for 24 or 48 weeks, as dictated by the hepatitis
C genotype.
2.
Hepatitis B and HIV
Since
hepatitis B and HIV are spread via similar routes patients often have evidence
of infection with both agents.However,
only about 10% of HIV-positive subjects are chronic carriers of hepatitis
B.In the presence of HIV infection
hepatitis B replication is increased, liver disease is more common, and
tends to be more rapidly progressive.However,
until the advent of highly active anti-retroviral therapy most patients
who were co-infected with hepatitis B and HIV died of AIDS, rather than
complications of hepatitis B.This
may no longer be true now that more effective anti-HIV therapy is available.Interferon
treatment of hepatitis B in HIV-positive patients has been largely unsuccessful
(31,32,98).Lamivudine therapy is
effective in suppressing viral replication, but at present there are no
reports of long term outcome after lamivudine therapy in this population.Since
lamivudine is a component of highly active anti-retroviral therapy, patients
co-infected with both viruses may receive appropriate treatment for the
hepatitis B as a fortunate, but not necessarily intended, result of HIV
therapy.Chronic hepatitis B in
HIV-infected patients must not be treated with lamivudine monotherapy.Lamivudine
monotherapy will result in the rapid emergence of resistant HIV virus.
3.
Hepatitis C and HIV
Hepatitis
C infection occurs in HIV-positive patients with a frequency between 50-90%.Co-infection
results in hepatitis C viral loads that are higher than in the absence
of HIV (99,100).Progression to cirrhosis
is also more rapid (100).Treatment
with interferon monotherapy has a success rate not much different than
for hepatitis C in the absence of HIV (about15%)(101-104).There
are no data on the use of combination therapy with interferon and ribavirin
in these patients.There are no recommendations
about therapy in patients co-infected with hepatitis C and HIV.
SCREENING
PATIENTS WITH CHRONIC HEPATITIS B AND HEPATITIS C FOR HEPATOCELLULAR CARCINOMA
Hepatocellular
carcinoma (HCC) is a well known complication of chronic hepatitis B (HBV)
infection. The risk appears to be related to the duration of infection.
Thus Asian patients who acquire the disease in childhood, by virtue of
the long duration of the disease, are at a significantly higher risk of
developing HCC than, Alaskan natives or Caucasians (20,105-107).The
cumulative probability of developing HCC in patients who are HBsAg-positive
has been estimated to be 6% at 5 years and 15% at 10 years. Once HCC develops,
the prognosis is very poor.Survival
of patients with symptomatic untreated tumours beyond 3 years is rare (108).The
enthusiasm to screen patients with HBV for HCC is based on the premise
that earlier detection can offer these patients a chance for potential
cure.There are 2 large North American
studies of screening in hepatitis B carriers (107,109). One suggests that
screening is very effective at finding curable tumours, whereas the other
suggests otherwise.The risk of developing
HCC in a non-cirrhotic patient with hepatitis C (HCV) is trivial. Once
cirrhosis is present, the cumulative probability of developing HCC is estimated
to be 1.4 to 3.3% per year (50,62). Apart from cirrhosis, other factors
that increase the patient's risk for developing HCC include long duration
of infection, male gender, greater than 55 years, continued alcohol consumption
and co-infection with HBV. Response to interferon treatment appears to
confer a protective effect against the development of HCC.Although routine
screening for HCC in patients with HCV is not as widespread as for patients
with HBV, this is still practiced in certain community groups. Much of
what is known about screening for HCC in patients with HBV also applies
to patients with HCV.There have been no studies to determine whether screening
for HCC decreases the disease-specific mortality.Thus
the most important piece of information about whether the potential effectiveness
of screening is missing.The decision
to screen or not screen therefore must rest on other factors.One
of the reasons why screening may not be effective is the poor sensitivity
of our screening tests. The currently employed screening tests, which include
alpha-fetoprotein and ultrasound, have sensitivities of 50% and 70% respectively
(107). Furthermore, HCC tends to occur in patients with cirrhosis, many
of whom cannot tolerate a curative surgical resection. Thus the other treatment
options left are liver transplantation or alcohol injection of the lesions.
The former is only limited to patients who are HBV DNA negative either
spontaneously or induced by therapy. The lack of suitable organ donors
makes this option available to a limited few. Alcohol injection can be
an effective treatment for HCC, but its efficacy is markedly reduced in
patients with large tumours (> 5 cm).It
is technically difficult to perform in patients with ascites and coagulopathy.
Screening should only be performed when effective curative therapy is possible,
and in patient groups where the relative risk of HCC development is high.Screening
is also appropriate in patients who have undergone a curative resection
for HCC. In the absence of documented benefit of mass screening, the committee
makes no recommendations for or against screening for HCC in HBsAg-positive
patients, nor for patients with chronic hepatitis C.Screening
may be justified in high risk cases (presence of cirrhosis, long duration
of infection, HBV/HCV co-infection, past curative resection for HCC, family
history of HCC [HBV only]).
HEPATITIS
B VACCINATION
At
present B vaccination policies vary by province across Canada.All
provinces include some form of universal vaccination, offered either to
all newborns, or to adolescents, as well as vaccination of individuals
at high risk of acquiring hepatitis B. Since high risk situations are not
always adequately identified, there is a risk that some susceptible individuals
will not receive vaccination.Strategies
aimed at pre-teens fail to protect against horizontal transmission in children
who reside in communities where hepatitis B is endemic.Recent
data indicate that in endemic countries horizontal transmission is more
common than previously recognized.Horizontal
transmission has also been shown to occur at a high rate in South East
Asian and other immigrant communities in North America (110-112).The
objectives of a universal hepatitis B vaccination policy should be to eliminate
vertical (mother to child) transmission, as well as horizontal transmission
in early childhood.The policies
should also protect against hepatitis B risks imposed by environment, behaviours,
or occupation.The vaccination strategy
for Canada should be universal vaccination of all neonates, combined with
screening of all pregnant women.Newborns
of infected mothers should be given hepatitis B immunoglobulin in addition
to the vaccine.A catch up program
should be instituted for all children and young adults who have not yet
been vaccinated. There should be a standardized national policy, so that
vaccination is assured for all children when their families move between
provinces. The seroconversion rate after hepatitis B vaccination in healthy
young adults is >90% and children >98%.Therefore,
serologic testing post-immunization is not recommended routinely.It
is recommended, however, for those with continual or repeated exposures.This
would apply to infants of infected mothers, sexual partners of chronic
carriers and those with occupational exposure.For
further details see the Canadian Immunization Guide, Fifth edition, 1998
(113).
HEPATITIS
A VACCINATION
The
age distribution and number of hepatitis A-susceptible individuals in Canada
has changed over the last twenty years. An increasing percentage of adults
have never been exposed to hepatitis A and remain at risk of infection.Hepatitis
A in childhood is usually a trivial disease.However,
in adults hepatitis A can be severe with considerable morbidity, and even
mortality.In addition, some studies
have suggested that acute hepatitis A infection in patients with chronic
liver disease may also cause severe disease, including death (114).However,
it is not clear whether the risk of severe hepatitis A is related to the
severity of the underlying liver disease or to other factors.Hepatitis
A vaccines are safe and effective.Patients
with compensated cirrhosis appear to respond adequately to the hepatitis
A vaccine (115).Current recommendations
by NACI with regard to populations in whom vaccination is appropriate remain
pertinent (116).These are listed
in table 7. The cost effectiveness of a universal strategy of hepatitis
A vaccination in Canada is not known.There
is limited information on the long-term benefit of hepatitis A vaccination
in patients with chronic liver disease.Although
universal vaccination for hepatitis A is a worthy goal its role in any
unified strategy for disease prevention remains to be determined.
HEPATITIS
G VIRUS
Hepatitis
G (HGV) is a flavivirus, which shares about 27 - 40% sequence homology
with HCV (117).HGV is identical
to the "GB-C" agent, originally found in a surgeon with hepatitis and later
identified in animals to be different from hepatitis viruses A, B, C, D
and E, respectively. Studies on post transfusion hepatitis in HGV RNA-positive
blood donors, and in community acquired acute hepatitis have suggested
that HGV is not an important cause of chronic liver disease (118,119).Some
patients who acquired hepatitis G from transfusion have developed a mild
transient aminotransferase elevation that resolves spontaneously (120).Although
the virus may persist, it appears that chronic liver disease do not ensue.Further,
the liver is not the primary site of HGV replication (121).There
is a high prevalence of HGV in blood donors, perhaps in the order of 1-2%.Fulminant
hepatitis is rare.HGV is transmitted
by intravenous and sexual routes and perhaps also via perinatal transmission.Its
presence in liver transplant recipients does not affect the outcome of
the disease (122).Routine screening
of blood donors or wide spread testing for HGV is not recommended.Diagnosis
requires virologic methods based on PCR or serologic assays using the E2
antibody.Neither of these is readily
available.
TRANSFUSION
TRANSMITTED VIRUS
Transfusion
transmitted virus is a recently described virus (123,124).Its
epidemiology and disease associations are unknown.Viremia
is common (125), but there is no known association with liver disease.
There are no commercially available kits to assay for this virus.Therefore,
no active attempt at diagnosing this infection is required.
THE
CANADIAN ASSOCIATION FOR STUDY OF THE LIVER CONSENSUS CONFERENCE ON VIRAL
HEPATITIS
This
report was written by a committee consisting of:-
Chairman
- Eldon Shaffer, University of Calgary; Florence Wong, Susan King, Morris
Sherman, University of Toronto; Fernando Alvarez, University of Montreal;
William Depew, Queens University; Jutta Preiksaitis, University of Alberta.
The
consensus panel participants were:-
Eric
Yoshida, Christopher Sherlock, Richard Schreiber - University of British
Columbia
Mel
Krajden - BC Centers for Disease Control
Mark
Joffe, Winnie Wong, Klaus Gutfreund - University of Alberta
Sam
Lee - University of Calgary
Gerry
Minuk, Barry Rosser, Kelly Kaita - University of Manitoba
Cameron
Ghent - University of Western Ontario
Helga
Witt-Sullivan, McMaster University
Jenny
Heathcote, Morris Sherman (Chairman), Victor Feinman, Eve Roberts - University
of Toronto, Linda Scully - University of Ottawa
Bernard
Willems, Jean Pierre Villeneuve, Steven Martin - University of Montreal
Averell
Sherker, Marc Deschenes - McGill University
Kevork
Peltekian - Dalhousie University
Pierre
Pare - Laval University.
SUMMARY
OF RECOMMENDATIONS
CHRONIC
HEPATITIS B
Although
acute hepatitis B continues to be an important clinical problem in Canada
the majority of acute cases will resolve and clear HBsAg spontaneously.Chronic
HBV infection, established when HBsAg is detectable for longer than 6 months
with or without continuing liver enzyme abnormalities accounts for the
greatest burden of disease.
Who
should be tested?
Any
patient with clinical or laboratory evidence for either acute or chronic
liver disease should be considered as possibly infected with HBV.
HBV
DNA Assays
It
is important for the clinician to understand the type of assay methodology
used, and its limitations, and that a consistent methodology be used for
all assays..
HBV
DNA testing should be limited to those patients being considered for treatment
and to evaluate response to treatment.It
is not indicated routinely in the evaluation of all HBsAg-positive patients.HBV
DNA testing should be readily available to qualified practitioners regularly
involved in the treatment of HBV.
Treatment
of the Hepatitis B Carrier
In
the HBeAg-positive patient with abnormal ALT levels liver biopsy is strongly
recommended, but not mandatory.
Therapy
may be with either interferon or lamivudine.Interferon
is given at a dose of 27-35 mu weekly (5-6mu daily or 9-10 mu TIW) for
16 weeks.Lamivudine is given at
a dose of 100 mg daily for 52 weeks. Lamivudine therapy for patients who
are anti-HBe-positive and HBV DNA-positive is still considered experimental.The
use of prednisone withdrawal prior to interferon therapy is contraindicated
in the management of HBV-associated disease.There
is insufficient information to recommend routine screening of immunosuppressed
patients for HBV infection. There is also insufficient information to recommend
lamivudine anti-viral prophylaxis for immunosuppressed patients who are
known to be hepatitis B carriers.
Hepatitis
D Virus
Patients
with active hepatitis D should be treated in expert centres.
Decompensated
Hepatitis B Cirrhosis
Low
dose interferon is not recommended in decompensated hepatitis B cirrhosis.Patients
with decompensated chronic hepatitis B should be referred to a liver transplant
center, and treatment with lamivudine coordinated with the transplant center.
Glomerulonephritis
The
indications for interferon therapy in patients with hepatitis B-induced
membranproliferative glomerulonephritis are the same as for hepatitis B
patients without glomerulonephritis.In
membranous glomerulonephritis, the renal disease per se is an indication
for interferon therapy.No recommendations
for or against the use of lamivudine could be made.
Chronic
Hepatitis B in Children
Optimal
treatment is between 3-6 Mu/m2 interferon thrice weekly for 6 months.The
indications for treatment are similar to those in adults.
HEPATITIS
C VIRUS
Patients
who are anti-HCV-positive who have spontaneously developed negative HCV
RNA by PCR should continue to be monitored at intervals for the presence
of liver disease.
Factors
that increase the risk of progression to cirrhosis include age over 40,
consumption of even moderate amounts of alcohol, and increased age of acquisition
of infection.
The
risk of progression to cirrhosis also appears related to the degree of
liver inflammation and fibrosis seen at the time of a biopsy.Patients
with persistently normal ALT have a lower likelihood of progression to
cirrhosis.
Use
of HCV RNA testing
Qualitative
HCV-RNA testing is not essential to make the diagnosis of hepatitis C in
typical patients who are anti-HCV positive.
Quantitative
HCV RNA testing is not routinely required for all patients.
Sexual
transmission of the hepatitis C virus
HCV
intra-spousal transmission appears to be rare in the absence of a parenteral
risk in the partner.
The
infected person should inform sexual partners.Testing
should be offered to the sexual partner.Patients
should be advised to avoid sharing items of personal hygiene.In
short-term sexual relationships condom use is advised.Unprotected
sex during menstruation should be avoided.Couples
should be given information about the risks of transmission, and about
precautions which may reduce the risk of transmission in stable monogamous
relationships.The committee neither
recommends nor recommends against the use of condoms.The
choice belongs to the couple.
Mother-to-Infant
Transmission of the Hepatitis C Virus
Rates
of transmission of hepatitis C from mother to newborn infant vary between
0 and 3% according to different reports.
Breast
feeding is considered safe and is not contraindicated
Testing
for hepatitis C infection within the first 18 months of life should be
by PCR assays.
Therapy
for Chronic Hepatitis C
The
prime indication for treatment in chronic hepatitis C is an ALT level more
than 1.5 times the upper limit of normal on three consecutive occasions
over more than three months.
A
liver biopsy is recommended for grading and staging of the liver disease.
It
is recommended that response to treatment be defined in virologic terms.
Successful
treatment is indicated by clearance of hepatitis C virus RNA from serum
(by sensitive PCR-based assays) 24 weeks after the completion of therapy
(sustained response).
Dose
and Duration of Treatment
The
recommended treatment for chronic hepatitis C is with a combination of
interferon alpha 2b and ribavirin. The dose of interferon is 3 mu TIW,
and the dose of ribavirin is 1000 mg for patients weighing less that 75
kg, and 1200 mg daily for patients weighing more than 75 kg
Patients
who carry genotypes 2 or 3 may be treated for 24 weeks.Patients
carrying any other genotype should be treated for 48 weeks.
A
positive HCV RNA assay after 24 weeks of therapy is an indication to stop
treatment.
Interferon
monotherapy should now be reserved for patients who cannot tolerate ribavirin
Contraindications
to therapy
In
assessing whether a patient is a good candidate for therapy with interferon
and ribavirin, it is essential to consider the benefits and risks for that
individual.
Absolute
contraindications to therapy with interferon and ribavirin are decompensated
liver disease, active alcohol abuse, pregnancy or lack of appropriate contraception
and expected non-compliance.
Treatment
Failures
Relapse
after interferon monotherapy: - These patients should be offered treatment
with interferon and ribavirin.
Non-responder
to interferon monotherapy: -There is insufficient information to make a
recommendation on the effectiveness of any of the therapeutic options for
patients who were non-responders to interferon monotherapy.
Failure
of combination therapy: - There are no proven treatment options for these
patients at present
Hepatitis
C Infection in Children
Chronic
hepatitis C in children should not be treated except in controlled trials.
Acute
hepatitis C
No
recommendations can be made about the timing of therapy of acute hepatitis
C
Healthcare
workers or others subjected to needle-stick injury or equivalent exposure
should be tested by anti-HCV at the time of the injury at 12 weeks to detect
infection. Treatment should be with standard combination therapy of interferon
and ribavirin for the standard duration despite the lack of prospective
studies proving efficacy.Given the
urgent need to gather data on such cases it is strongly recommended that
patients with acute hepatitis C be treated in the setting of a clinical
trial or a registry.
COMBINED
INFECTIONS
In
patients who are HBeAg-positive with detectable HBV DNA, undetectable HCV
RNA and elevated aminotransferases, treatment is with interferon 27-36
mu weekly for 4 months.In patients
who are HBeAg-positive with detectable HBV DNA, undetectable HCV RNA and
elevated aminotransferases, treatment is with interferon 27-36 mu weekly
for 4 months.Chronic hepatitis B
in HIV-infected patients must not be treated with lamivudine monotherapy.
There are no recommendations about therapy in patients co-infected with
hepatitis C and HIV.
HEPATITIS
SCREENING PATIENTS WITH CHRONIC HEPATITIS B AND C FOR HEPATOCELLULAR CARCINOMA
In
the absence of documented benefit of mass screening, the committee makes
no recommendations for or against screening for HCC in HBsAg-positive patients,
nor for patients with chronic hepatitis C.Screening
may be justified in high risk cases (presence of cirrhosis, long duration
of infection, HBV/HCV co-infection, past curative resection for HCC, family
history of HCC [HBV only]).
HEPATITIS
B VACCINATION
The
vaccination strategy for Canada should be universal vaccination of all
neonates, combined with screening of all pregnant women.Newborns
of infected mothers should given hepatitis B immunoglobulin in addition
to the vaccine.A catch up program
should be instituted for all children and young adults who have not yet
been vaccinated. There should be a standardized national policy, so that
vaccination is assured for all children when their families move between
provinces.
Serologic
testing post-immunization is not recommended routinely
HEPATITIS
A VACCINATION
Current
recommendations by NACI with regard to populations in whom vaccination
is appropriate remain pertinent.
HEPATITIS
G VIRUS
Routine
screening of blood donors or wide spread testing for HGV is not recommended
TRANSFUSION
TRANSMITTED VIRUS
No
active attempt at diagnosing this infection is required.
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seroepidemiologic survey of chronic hepatitis B virus infections in Southeast
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Sweet LE; Brown MG; Lee SH; Liston RM; MacDonald MA; Forward KR.Hepatitis
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Chernesky MA; Blajchman MA; Castriciano S; Basbaum J; Spivak C; Mahony
JB.Analysis of a pregnancy-screening
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Delage G; Montplaisir S; Remy-Prince S; Pierri E.Prevalence
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Minuk GY; Nicolle LE; Postl B; Waggoner JG; Hoofnagle JH.Hepatitis
virus infection in an isolated Canadian Inuit (Eskimo) population.J
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Baikie M; Ratnam S; Bryant DG; Jong M; Bokhout.Epidemiologic
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Pessoa MG; Terrault NA; Detmer J; Kolberg J Collins M; Hassoba HM; Wright
TL.Quantitation of hepatitis G and
C viruses in the liver: evidence that hepatitis G virus is not hepatotropic.Hepatology
1998;27:877-80
122.
Berenguer M, Terrault NA; Piatak M; Yun A; Kim JP; Lau JY et al.Hepatitis
G virus infection in patients with hepatitis C virus infection undergoing
liver transplantation.Gastroenterology.
1996;111:1569-75.
123.
Naoumov NV, Petrova EP, Thomas MG, Williams R.Presence
of a newly described human DNA virus (TTV) in patients with liver disease.Lancet
1998,352:195-97
124.
Simmonds P, Davidson F, Lycett C, Prescott LE, MacDonald DM, Ellender J
et al.Detection of a novel DNA virus
(TTV) in blood donors and blood products. Lancet 1998 352:191-5
125.
Hsieh Sy, Wu YH, Ho YP, Tsao KC, Yeh CT, Liaw YF.High
prevalence of TT virus infection in healthy children and adults and in
patients with liver disease in Taiwan.
Table
1
|
|
|
Estimated
number of cases in Canada
|
|
Native/Inuit
|
|
|
|
Immigrant
|
|
|
Non-immigrant
|
0.2% - 0.5% |
49862 – 124655 |
|
Total
|
|
|
Table
2.Initial investigation of the
hepatitis B carrier
Tests of liver inflammation |
ALT |
|
Liver
function tests
|
|
|
|
|
|
|
|
|
Viral
serology
|
|
|
|
|
|
Other
important tests
|
|
|
|
|
Table
3.Manufacturer’s reported dynamic
ranges for HBV DNA assays
|
Method
|
Working
range
|
|
Abbott
Solution Hybridization Assay
|
1.6
to~800 pg/ml
|
|
Digene
1st Generation Hybrid Capture Assay
|
5-2000
pg/ml (1.4x106 –5.6x108 copies/ml)
|
|
Digene
2nd Generation Hybrid Capture Assay
Standard
test Ultra-sensitive
method |
1.4x105
– 1.7x109 copies/ml 4.7x103
– 5.6x107 copies/ml |
|
Chiron
Quantiplex™ bDNA Assay
|
0.7
– 5000 Meq/ml (7x105 – 5x109 copies/ml)
|
|
Roche
AMPLICOR™ HBV Monitor™ PCR Assay
|
1000
– 1x107 copies/ml
|
Table
4
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Table
5.Manufacturer’s reported dynamic
ranges for HBV RNA assays
|
Method
|
Working
range
|
|
Roche
AMPLICOR™ HCV Monitor™(Quantitative)
PCR Assay
|
1-2x103
– 5x107 copies/ml
|
|
Roche
AMPLICOR™ HCV (Qualitative) PCR test
|
100
copies/ml (lower limit of sensitivity)
|
|
Chiron
Quantiplex™ bDNA HCV RNA Assay version 2
|
0.2
– 120 Meq/ml (2x105 – 1.2x109 copies/ml)
|
|
NGI
(National Genetics Institute) HCV SuperQuant™
|
100
- 5.0x107 copies/ml
|
Table 6 Interpretation
of hepatitis C virus RNA testing in anti-HCV-positive patients.
|
ALT
Concentration
|
HCV RNA Result
|
Interpretation
|
|
|
Positive |
Patient
is infected, with undetectable liver disease
|
|
|
|
False-positive
anti-HCV
Spontaneous
viral clearance False
negative HCV RNA Dormant
infection with no or minimal liver disease |
|
|
|
Infected
with active liver disease,
|
|
|
|
False-positive
Spontaneous
viral clearance False
negative HCV RNA Dormant
hepatitis C infection, but some other cause for liver disease |
Table
7 Recommended usage for pre-exposure prophylaxis against hepatitis A.
|
1.Potential
candidates for the vaccine are
|
|
2.Travelers
to countries where hepatitis A is endemic, especially when travel involves
rural or primitive conditions
|
|
3.Residents
of communities with high endemic rates or recurrent outbreaks of HAV
|
|
4.Members
of the armed forces, emergency relief workers and others likely to be posted
abroad at short notice to areas with high rates of HAV infection
|
|
5.Residents
and staff of institutions for the developmentally challenged where there
is an ongoing problem with HAV transmission
|
|
6.Inmates
of correctional facilities in which there is an ongoing problem with HAV
infection
|
|
7.People
with life-style determined risksof
infection, including those engaging in oral or intravenous illicit drug
use in unsanitary conditions
|
|
8.Men
who have sex with men
|
|
9.People
with chronic liver disease who may not be at increased risk of infection
but are at increased risk of fulminant hepatitis A
|
|
10.Others,
such as patients with hemophilia A or B receiving plasma-derived replacement
clotting factors; zoo-keepers, veterinarians and researchers who handle
non-human primates; certain workers involved in research on hepatitis A
virus or production of hepatitis A vaccine.
|