information on treatment
options for viral hepatitis
Hep C: Presentation,
Sexual transmission of
the hepatitis C virus
How Will I Know If I
history of chronic hepatitis C
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
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
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
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.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. Co-infection
with hepatitis B is associated with a greater risk of HCC than
either disease alone.
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.
of Hepatitis C Virus Infection
Range 2-26 weeks
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
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
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
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 (< 2x106
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
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.
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.
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
Absolute contraindications to therapy with interferon and
ribavirin are decompensated liver disease, active alcohol abuse,
pregnancy or lack of appropriate contraception and expected
Hep C: Presentation, Diagnosis, Prevention
Since many patients with hepatitis C are
may be incidental or fortuituos. Some patients may progress to the point
of cirrhosis or even decompensated liver disease without any antecedent
symptoms. Some patients may present with a wide variety of symptoms, not
all necessarily due to hepatitis C. Some of the ways in which patients
abnormal Ast or Alt on routine screening:
- insurance exams
- prenatal clinic
- assessment for various symptoms, e.g. abdominal pain
positive anti hepatitis C on screening:
- Blood donor clinics
- Red Cross Lookback Program
contacts of positive case:
- partner: but sexual transmission has a lifetime risk of about 3% and
most partners have contracted hep C by sharing needles
- children of positive mothers (Hepatitis Knowledge Network Vol.1 No. 2)
screening of high risk persons:
- previous blood transfusion or blood products (prior to 1990)
- previous or present IVDU
- multiple sexual partners (particularly if other STD's present)
- previous body piercing, tattoos
- snorting of cocaine with common straw
- a small number of persons present with fatigue (subsequent newsletter)
evidence of liver disease:
- spider angiomata
- palmar erythema
decompensated liver disease:
- portal hypertension with varices and ascites
autoimmune diseases accentuated by hep C:
(see Hepatitis Knowledge Network Vol. 1 No. 1)
Although this means of presentation is not common, some presenting
conditions are: - arthritis
- lichen planus
Although the diagnosis of chronic hepatitis C can be made by checking
for the antibodies and determining the presence of the HCV RNA, patients
must be thoroughly assessed relative to their liver disease and other
complications. A good progressive approach is as follows:
a medical history of risk factors and symptoms
a history of liver disease:
- jaundice, pale stools, dark urine
- bleeding (nose bleeds, bleeding gums), bruising
- abdominal swelling, peripheral oedema
examination for signs of liver disease:
- spider angiomata
- gynecomastia, loss of body hair
- testicular atrophy
- nail changes
examination for signs of portal hypertension:
- abdominal and chest wall veins
- ascites with or without peripheral oedema
hematological tests indicating liver disease:
- thrombocytopoenia (and possibly neutropoenia)
- prolonged INR or prothrombin time
- macrocytic anemia, often with target cells biochemical tests of liver
disease: - Ast, Alt over one and a half times normal for three months
phosphatase and gamma GT are cholestatic enzymes not
- decreased albumin
- elevated bilirubin
- polyclonal increase in gamma globulins serological tests for hepatitis
- antibody poistive (anti hepatitis C by ELISA then by RIBA)
- HCV RNA (usually by PCR, qualitative adequate)
rule out other causes of liver disease: (subsequent newsletter)
pathological confirmation by liver biopsy: (subsequent newsletter)
Treatment is important, prevention is vital. Hepatitis C is spread
predominantly by blood to blood and other ways are infrequent. Logical
means of prevention are:
ฎ personal health measures:
- avoid sharing toothbrushes, razors, etc.
- avoid unprotected sex during menstrual period (Hepatitis Knowledge
Network Vol.1 No. 2)
- clean all blood contamination with bleach
- cover open sores and burns with a bandage
ฎ general health measures:
- do not share needles or rigs
- do not share straws to snort cocaine
- avoid unprotected, promiscuous sex
- only use tattoo parlours which use disposable needles
- do not share body piercing needles
Consumption of alcohol makes hepatitis C more active and progress
more rapidly. Thus, all patients with chronic hepatitis C should be
advised to minimize, if not elimate, alcohol use.
vertical transmission of hepatitis C
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.
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
Management of Hepatitis C in the Patient With Normal ALT
Ira M. Jacobson, MD
Prior to the advent of techniques to detect and quantify hepatitis C
virus (HCV) RNA in serum, the status of HCV infection in patients with
HCV antibodies and normal alanine aminotransferase (ALT) levels was
unclear. Once these techniques became available, it became clear that
many such persons are viremic, and that about 25% of patients with
chronic hepatitis C have persistently normal ALT levels. Levels of
viremia in these patients are not significantly different from those of
patients with elevated ALT levels. Moreover, normal ALT levels are
usually not paralleled by normal liver histology. Qualitatively, at
least, these patients are subject to the same type of necroinflammatory
activity and, potentially, fibrosis as the more typical patient with
The abundance of published experience suggests that, quantitatively,
the patient with persistently normal ALT levels is more likely to have
mild inflammation and fibrosis than other HCV-infected patients. In a
1997 review by Hoofnagle, 37% of HCV-infected patients with normal ALT
levels had no inflammation or minimal change, 63% had portal hepatitis
or mild chronic hepatitis, and only 0.5% had significant fibrosis or
cirrhosis. In a French study led by Mathurin in 1998, 102 patients with
normal ALT levels were compared with 102 patients with elevated ALT
levels. The grade of inflammation and stage of fibrosis were
significantly lower in the normal ALT group, and over time the rate of
progressive fibrosis in the normal ALT group was half that in the other
group. The most recent contribution to this field, echoing the theme of
slow progression, came from a just-published Italian study by Persico
and colleagues, in which 35 patients with initially normal ALT levels
were followed for 5 years. According to their protocol, the few patients
who developed de novo ALT elevations during the observation period were
place don antiviral therapy, while the 73% who maintained normal ALT
levels were rebiopsied. In these patients, no change in mean grade or
stage was found.
In perhaps the most notable exception to these conclusions, Puoti et
al (1997) found no difference in histology between patients with normal
versus high ALT levels. A preponderance of genotype 2a was found among
the normal ALT patients. Although not a comparative study, in 1997
Gholson et al reinforced the potential for progressive fibrosis in 50
patients with normal ALT, 70% of them female (a gender ratio that
reflects the experience of others, as well). Nine of the patients had
stage 3 fibrosis, while one had stage 4. Equally notable was the
presence of grade 2 or 3 inflammation in more than half the patients.
The potential for normal ALT patients to have progressive liver
disease led to a number of studies with interferon monotherapy. Each of
these studies was relatively small, and while some created the
impression of poor efficacy, when reviewed cumulatively, the data
indicate rates of sustained virologic response (SVR) similar to those
seen in other patients. In Marcellin and coworkers' 1997 analysis of
seven prior studies presented at the National Institutes of Health (NIH)
Consensus Conference, the SVR rate was 19%. Beyond efficacy
considerations, the factor that led to diminished enthusiasm for
treating normal ALT patients with interferon was the observation of de
novo ALT elevations, while on therapy, in more than half the patients.
It has been speculated that these ALT elevations may be related to
stimulation by interferon of immunologic activity against infected
hepatocyles. The NIH Consensus Statement, published in 1997, concluded,
"Current studies suggest that treatment of patients with
persistently normal ALT is not beneficial and may actually induce liver
enzyme abnormalities. Therefore, these patients should not receive
therapy outside placebo-controlled trials. "This conclusion was
accepted by some hepatologists; others felt that these patients, like
others with hepatitis C, need to be evaluated individually and therapy
considered on the basis of liver histology and other factors, such as
the mind-set of the patient.
Interest in combination therapy for normal ALT patients has been an
inevitable outgrowth of the recent adoption of interferon/ribavirin as
standard therapy for chronic hepatitis C. A number of trials have been
initiated, and preliminary results are available from several of them.
In a New York multicenter study, the author and coworkers randomized
patients to 12 months of interferon 5 MU versus 3 MU t.i.w. plus
ribavirin 1,000 to 1,200 mg/day. Eighteen patients have thus far been
followed up for 6 months after cessation of treatment, with seven (39%)
showing sustained virologic response. Only one transient ALT elevation
Another trial from San Diego was reported preliminarily by Hassanein
et al at the last annual meeting of the American Association for the
Study of Liver Diseases. In this ongoing study, 75% of patients
responded to treatment, but data on SVR are still pending. These
researchers pointed out that ALT reductions within the normal range were
characteristic responses to antiviral therapy.
At the most recent International Symposium on Viral Hepatitis held in
Atlanta, Bacon et al presented data on 24 interferon nonresponders with
normal ALT levels who were given a course of combination therapy. They
showed an SVR rate of 25%, with a reduction in mean ALT from 42 to
19IU/I. This is similar to the response rate to combination therapy
noted in their larger series of monotherapy nonresponders with high ALT
As further data on SVR rates are expected from these trials,
clinicians regularly continue to see HCV-infected patients with normal
ALT. Some researchers maintain that these patients should be biopsied so
that the same kind of individualized therapeutic decision making that
applies to other patients with hepatitis C can be applied to this group
as well. The alternative view is that treatment of these patients is
still investigational, and that biopsies and therapy should be withheld
until some consensus emerges from the ongoing trials. The shortcoming of
the latter position is that those patients with high grades of
inflammation or fibrosis will not be identified and may experience
further progression. Early data suggesting equivalent rates of SVR to
combination therapy in this population further support an individualized
approach, with biopsy playing an important role.
A 45-year-old woman learned that she was positive for HCV antibodies
when she attempted to donate blood 3 years ago. The patient, who works
with institutionalized children, has no risk factors for HCV infection.
Although she says she used to consume one glass of wine per day, she
says she is now consuming less alcohol. Her past medical history
includes a hysterectomy 4 years ago (with no blood transfusion),
cholecystectomy, and tonsillectomy. She is currently taking hormone
Current physical examination reveals no jaundice, spiders, palmar
erythema, hepatosplenomegaly, or ascites. Laboratory findings are shown
in Table 1. A liver biopsy performed 1 year ago showed mild chronic
inflammation, focal mild piecemeal necrosis, and bridging
portal-to-portal fibrosis (ie. Grade 1-2, stage 3).
click for enlarged image
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The patient was treated with interferon a-2b 3 MU
ribavirin 1,000 mg/day. Laboratory values over the first 24 weeks of
treatment are shown in Table 2. Adverse effects of therapy included
flu-like symptoms with initial dose, mild fatigue, mild exertional
dyspnea, and anemia. At week 4, hemoglobin was <10 g/dL, so the
ribavirin dose was reduced to 600 mg/day. At week 24, the patient
developed tremulousness and mild insomnia, and experienced a 5-lb weight
loss. Physical examination revealed a pulse rate of 92 beats/minute (up
from 72 beats/minute at her last examination).
At week 24, the patient's thyroid-stimulating hormone
(TSH) level was
0.03 and free T4 level was 13.2 ng/dL. At week 28, treatment was
discontinued. Propranolol (40 mg/day) was administered to control
symptoms of hyperthyroidism, and an endocrine.
Cholson CP, Morgan K, Catinis G, et al. Chronic hepatitis C with
normal aminotransferase levels, a clinical histologic study. Am J
Hassanein TI, Monson P, Behling C, et al. Combination therapy results
in a significant reduction of transaminase levels in patients with
normal pretreatment transaminase levels. Hepatology. 1999;30(pt
Hoofnagle JH. Hepatitis C the clinical spectrum of disease. Hepatology
Jacobson JM, Russo M, Lebovics E, et al. Interferon alfa-2b and
ribavirin in treatment-na๏ve patients with chronic hepatitis C and
normal ALT levels. Hepatology. 1999:30:459A.
Marcellin P, Levy S, Frlinger S. Therapy of hepatitis C: patients
with normal aminotransferase levels. Hepatology 1997;26(suppl
Mathurin P, Moussalli J, Cadranel JH, et al. Slow progression rate of
fibrosis in hepatitis C virus in patients with persistently normal
alanine transaminase activity. Hepatology 1998:27:868-872.
National Institutes of Health Consensus Development Conference Panel
statement: management of hepatitis C. Hepatology. 1997;26(suppl
Persico M, Persico E. Suozzo R, et al. Natural history of hepatitis C
virus carriers with persistently normal aminotransferase levels. Gastroenterology
Puoti C, Magrini A, Stali T, et al. Clinical, histological, and
virological features of hepatitis C virus carriers with persistently
normal or abnormal alanine transaminase levels. Hepatology. 1997;26:1393-1398.
Serfaty L, Chazouilleres O, Pawlotsky JM, Andreani T, Pellet C,
Poupen R. Interferon alpha therapy in patients with chronic hepatitis C
and persistently normal aminotransferase activity. Gastroenterology. 1996;110:291-295.
Shindo M, Araj K, Sokawa Y, Okuno T. The virological and histological
states of anti-hepatitis C virus-positive subjects with normal liver
biochemical values. Hepatology. 1995;22:418-425.
By Howard J. Worman, M. D.
This page provides general information on treatment options for
viral hepatitis B and C.
It is not an endorsement of the any of the products by the author or by any institution with which the author is affiliated.
Various type I interferons administered by intramuscular or subcutaneous injection are indicated for the treatment of chronic hepatitis B and chronic hepatitis C. Interferon alfa is a naturally occurring glycoprotein that is secreted by cells in response to viral infections. It exerts its effects by binding to a membrane receptor. Receptor binding initiates a series of intracellular signaling events that ultimately leads to enhanced expression of certain genes. This leads to the enhancement and induction of certain cellular activities including augmentation of target cell killing by lymphocytes and inhibition of virus replication in infected cells. Various recombinant forms of interferon alpha (interferon alpha-2a and interferon alpha-2b) and a recombinant non-naturally occuring type I interferon (interferon alfacon-1) are approved to treat viral hepatitis.
THIS PAGE PROVIDES ONLY AN INTRODUCTION TO TREATMENT OF CHRONIC HEPATITIS B OR HEPATITIS C WITH INTERFERON. YOU SHOULD CONSULT A PHYSICIAN EXPERIENCED IN THE CARE OF PATIENTS WITH LIVER DISEASES FOR ADDITIONAL INFORMATION.
Chronic Hepatitis B
Interferon alfa-2b is effective in the treatment of adults with chronic hepatitis B virus infection and evidence of viral replication. The patient should have evidence of infection with hepatitis B virus, documented by the presence of hepatitis B surface antigen in the blood, for six months. The patients should also have evidence of virus replication, documented by the presence of hepatitis B e antigen in the blood. Ongoing inflammation of the liver should also be present as documented by an elevation in serum aminotransferase activities. A liver biopsy should also be performed prior to treatment. Patients with severe, decompensated liver disease
(eg. encephalopathy, ascites, very high serum bilirubin, prolonged prothrombin time, etc.) should not generally be treated with interferon alfa-2b except in the setting of an approved clinical study.
The recommended dose of interferon alfa-2b for the treatment of chronic hepatitis B is 5,000,000 units daily, administered by subcutaneous or intramuscular injection, for a total of 16 weeks. The patient must be monitored carefully during the treatment period for side effects including flu-like symptoms, depression, rashes, other reactions and abnormal blood counts.
A meta-analysis of several randomized trials of interferon alfa-2b in the treatment of patients with chronic hepatitis B showed such treatment to be cost-effective (Wong et al. Annals Intern. Med. 1995;122:664-675). This analysis showed that treatment with interferon alfa-2b decreased viral replication, documented by loss of serum hepatitis B e antigen, in about 45% of patients compared to less than 10 % of untreated patients. About 8% of patients also lost hepatitis B virus surface antigen (cured) within one year of treatment compared to a rate of about 1% a year for untreated patients.
Interferon alfa-2b treatment of chronic hepatitis B
requires careful medical attention. Consult a physician who has experience with this type of treatment for more information.
Chronic Hepatitis C
Interferon alfa-2a (Roferon-A; Hoffmann-La Roche), inteferon alpha-2b (Intron-A; Schering-Plough) and interferon alfacon-1
(Infergen; Amgen) are all approved in the United States for the treatment of adults with chronic hepatitis
C. The patient should have evidence of chronic liver disease and infection with hepatitis C virus as documented by the presence of serum antibodies against this virus or serum viral RNA. Inflammation of the liver should also be present as documented by elevations in the serum aminotransferase activities and liver biopsy. Treatment of patients without evidence of inflammation (e.g. normal serum aminotransferase activities), or treatment of patients with decompensated liver disease (e.g.
encephalopathy, ascites, very high serum bilirubin, abnormal prothrombin time, etc.), should only be considered in the setting of an approved clinical study.
The recommended dose of interferons alfa-2b and alpha-2a for the treatment of chronic hepatitis C is 3,000,000 units three times a week, administered by subcutaneous or intramuscular injection. For interferon alfacon-1, the recommended dose is 9mcg three times a week for first time treatment. Six months of treatment was originally recommended for interferons alpha 2a and 2b, however, several studies have shown that treatment for a year or longer may be more effective
(Poynard et al. Hepatology. 1996;24:778-789). Treatment times of 1 to 2 years with these drugs are now approved by the FDA. For interferon alfacon-1, a six month treatment course of 9 mcg three times a week is approved and a dose of 15 mcg three times a week for another six months is approved for patients who do not respond or relapse. During the treatment periods with any of these recombinant
interferons, the patient must be monitored carefully for side effects including flu-like symptoms, depression, rashes, other unusual reactions and abnormal blood counts.
The results of several published clinical studies demonstrate that about 50% to 70% of patients with chronic hepatitis C respond to treatment with interferon alfa-2b as documented by reductions in the serum aminotransferase activities to near normal. Several studies have also shown that about 70% of patients have a decrease in liver inflammation on follow-up liver biopsy. Unfortunately, most patients relapse and have recurrent liver inflammation after treatment is discontinued.
Several studies have tested a combination of interferon alfa-2b and
ribavirin. This drug combination was approved by the United States Food and Drug Administation in June, 1998 for patients with chronic hepatitis C who have been treated perviously with interferon alone and "relapsed" after treatment was discontinued. It may also be useful in patients never treated previously or in those who did not respond at all to previous interferon treatment. Study results suggest that a combination of interferon alpha-2b and ribavirin induce a sustained response in more patients than treatment with interferon alpha-2b alone. Patients interested in such treatment should consult their physician.
Interferon treatment of chronic hepatitis C requires careful medical attention. Consult a physician who has experience with this type of treatment for more information.
ต้นฉบับจาก สคต.3 ชลบุรี
โรคตับอักเสบ ซี เป็นโรคติดต่อสำคัญ โรคหนึ่งซื่งเกิดจากเชี้อ ไวรัสตับอักเสบ ซี (Hepatitis C virus)
ทำให้เซลล์ตับเสียหาย และก่อให้เกิดโรคตับอักเสบ และประมาณครึ่ง หนึ่งของผู้ป่วยตับ อักเสบ ซี
เฉียบพลัน จะกลายเป็นพาหะของเชื้ออย่างเรื้อรัง และประมาณร้อยละ 20
ตับแข็งและ มะเร็งตับภายในระยะเวลา 5-40 ปี จากการสำรวจความชุกของการติดชี้อไวรัสนี้ในคนไทย
โดยกรมวิทยาศาสตร์การแพทย์ กระทรวง สาธารณสุข พบว่าในกลุ่มคนที่มาบริจาค
ติดเชื้อ ไวรัสนี้ ร้อยละ 1.5 และในกลุ่มผู้ติดยาเสพติดชนิดฉีดเข้าเส้นที่ติด เชื้อโรคเอดส์ พบว่ามีไวรัส
ตับอักเสบ ซี สูงถึงร้อยละ 99.1 สำหรับการสำรวจในกลุ่มผู้ที่ป่วยโรคตับอักเสบซึ่งมีสาเหตุได้หลาย
ประการ นั้น พบว่าเกิดจากไวรัสตับอักเสบ ซี ร้อยละ 12.5
อาการ โรคไวรัสตับอักเสบ ซี มีระยะฟักตัว 6-10 สัปดาห์ ผู้ติดเชื้อส่วนใหญ่ไม่แสดงอาการ
อาการที่พบระยะเเรก ได้แก่ อาการอ่อนเพลีย ไข้ เบื่ออาหาร คลื่นไส้ อาเจียน ปวดท้อง ตามด้วยตัวเหลีอง
การติดต่อ โรคไวรัสตับอักเสบ ซี ติดต่อเช่นเดียวกับไวรัส ตับอักเสบ บี และ ไวรัสเอช ไอ วี
การรับเลือด หรือ ผลิตภัณฑ์จากเลือดที่มีเชื้อ ไวรัสตับอักเสบ ซี ปนเปื้อน การใช้เข็ม
ผู้ติดยาเสพติดชนิดฉีดเข้าเส้น นอกจากนี้ยัง สามารถติดต่อได้ทางเพศสัมพันธ์
สู่ทารก นั้นพบ ได้น้อย
การป้องกันและรักษา เนื่องจากไวรัสตับอักเสบ ซี ที่ระบาด
พันธุกรรมค่อนข้างมาก การศึกษาวิจัยเพื่อผลิตชุดน้ำยาตรวจวินิจฉัยและการผลิตวัคซีนจึงทำ ได้ยาก
ในปัจจุบันการรักษาด้วยสาร Inteferon ให้ผลเพียงร้อยละ 40-50
ดังนั้น จึงควรเน้นที่การ ป้องกัน ซึ่งวิธีที่ดีที่สุดในขณะนี้คือการตรวจคัดกรองเลือดบริจาคก่อนนำ ไป