| Introduction It
has only been possible to diagnose
hepatitis C since 1990. However, great progress has been made
in the treatment of hepatitis C in this short period. Currently, all
western therapy for hepatitis C is based on the use of alpha
interferons.
However, alpha interferons alone (monotherapy) have provided only limited
success. The allopathic standard of care as of this writing (August 2004)
is combination therapy with
pegylated interferon plus
ribavirin. Hepatologists
generally agree that it is no longer advisable to treat hepatitis C with
interferon alone unless the use of ribavirin is contraindicated.
Treatment Options
The term used in western medicine for
people who have never been treated for hepatitis C is treatment naïve.
Generally, therapy is considered when a person's
liver enzymes have been
elevated for more than six months. At that point, he or she is considered
to have chronic hepatitis
C.
When a western doctor determines a person is a candidate for treatment, he
or she has five major goals in mind:
1. eliminate the virus from the body
2. restore normal liver function (as shown by liver-specific blood
tests)
3. prevent further liver damage (shown by improvement or stabilization
on the liver
biopsy)
4. improve overall health and well-being
5. produce a response to therapy (a
durable or
sustained response) that will last for the rest of the
patient's life
Interferon Monotherapy
Interferon alpha-2b (Intron A®) injections (three
times weekly for six months) was the first therapy approved by the Food
and Drug Administration (FDA) for chronic hepatitis C. The results of
interferon monotherapy were somewhat disappointing.1,
2 Approximately 30-40%
of those who received this treatment experienced a normalization of their
liver enzymes and undetectable levels of the hepatitis C virus (HCV) while
on treatment. However, half of the people who experienced a response while
on treatment relapsed during the six month follow-up period after therapy
ended. As a result, the overall durable response rate was less than 20%.
Less than 10% of people with pre-existing
cirrhosis and/or HCV
genotype 1 had durable
responses.3-5 The results were
similar with two other types of interferon, alpha-2a (Roferon A®)6-10
and consensus interferon alpha (Infergen®).11, 12 It was quickly
discovered that 12 months of treatment rather than six approximately
doubled the durable response rate to 20-25%.13-18 It also became
clear that those with genotypes 2 and 3 had a much higher durable response
rate than those with genotype 1. Those with cirrhosis showed the poorest
response.
Anecdotal Story of
Successful Interferon Therapy
A 36-year-old female with a history
of alcohol and intravenous (IV) drug abuse was found to have hepatitis
C while undergoing drug rehabilitation. She had one tattoo, but had
not received any blood transfusions. Her
ALT level was 2-3 times
above normal. Her liver biopsy showed mild activity with
mild-to-moderate fibrosis
and marked fatty infiltration. She had HCV genotype 3a. She was
asymptomatic, and her physical exam was unremarkable.
At the time of evaluation, she had been drug and alcohol free for 20
months. She was treated with 3 million units of interferon alpha-2b
three times per week for 48 weeks. Her ALT returned to normal, and her
HCV RNA
fell from 28,000,000 to 500 within four weeks. HCV RNA was
undetectable at 12 weeks. Two years after completing therapy, the
patient continues to have undetectable virus, normal liver enzyme
levels, and is in good health. A liver biopsy six months after
completion of therapy showed clear improvement with no inflammation or
fibrosis. The patient experienced mild
fatigue and mild hair
loss during therapy. Both side effects disappeared after therapy was
completed.
This patient's experience demonstrates the rapid clearance of even
very high levels of HCV that is seen in people who have a durable
response to therapy. It also demonstrates the relationship between
having the virus become undetectable, maintaining a sustained
response, and improved liver health.
Combination
Therapy with Interferon Plus Ribavirin
The addition of ribavirin to interferon was a big breakthrough in the
western treatment of hepatitis C. Ribavirin is an oral drug taken daily
along with thrice weekly injections of interferon. This
combination therapy was initially given for one year, and
was the standard western treatment until the introduction of the pegylated
interferons.12-21 Combination
therapy with interferon plus ribavirin produces an overall durable
response rate of approximately 40%. Among those with genotypes 2 or 3, the
durable response rate is 60-70%, and therapy is generally reduced to only
six months. Those with genotype 1 have a more modest 30% durable response
rate.22-25
Anecdotal Story of
Success with Interferon Plus Ribavirin Combination Therapy
RT was first noted to have elevated
liver enzymes in 1990 at the age of 36. He had briefly used IV drugs
18 years previously. He drank two beers per day. He had no history of
blood transfusions, and was
monogamous and
heterosexual. A liver biopsy showed mild activity and minimal
fibrosis. He had no symptoms. Despite discontinuing alcohol, his ALT
level remained 3 to 4 times the normal level. A repeat biopsy 18
months later revealed liver disease progression with
moderate-to-severe activity.
RT was treated with 3 million units of interferon alpha-2b three times
a week for six months. His ALT levels quickly dropped to normal.
However, he relapsed within one month of stopping the interferon in
July 1993. A follow-up biopsy in March 1994 showed only mild activity.
However, because his ALT remained 3-4 times above normal, he enrolled
in a clinical trial
in which he was treated with repeated 6-month courses of 3 million
units of interferon alpha-2b three times a week. Between June 1994 and
January 1998, he underwent six courses of therapy. During each
treatment course, his enzyme levels dropped to normal, but his viral
HCV PCR test generally remained
positive. His ALT always went back up within one month of stopping
interferon. In addition, a follow-up liver biopsy in 1996 showed
significant disease progression with moderate-to-severe fibrosis.
In December 1998, RT began treatment with 3 million units of
interferon alpha-2b three times weekly plus 600 mg of ribavirin twice
each day. Again, his enzyme levels promptly dropped to normal, and on
the combination protocol,
his virus also became undetectable. Therapy was stopped after six
months in July 1999. When last seen, more than 3 years after the
completion of combination therapy, RT's liver enzyme levels remained
normal and the virus continued to be undetectable.
RT's experience demonstrates the
importance of using
viral clearance rather than normalization of
enzyme levels to
determine success with any given therapy. He also demonstrates the
important advantage of adding ribavirin to interferon therapy.
Interestingly, RT proved to have HCV genotype 3a, a subtype of the
virus that is generally more responsive to therapy than genotype 1,
and that usually requires only six months of treatment. RT's follow-up
liver biopsy at the end of therapy showed marked improvement with a
decrease in both activity and fibrosis. This demonstrates the
histologic improvement seen in patients after
successful therapy.
Pegylated
Interferons
The hepatitis C virus replicates very rapidly, doubling in number every
2-3 hours. Standard interferon is cleared from the body very quickly,
within 6-7 hours. When standard interferon is given three times a week,
there are long periods when there is no interferon circulating in the
blood. This gives the virus time to recover from the effects of the
interferon. Studies have shown larger or more frequent doses of standard
interferons produce more side effects with no significant improvement in
durable response rates. The development of pegylated interferons came
about from an effort to solve these problems and to keep interferon
continuously circulating in the blood.26, 27 It was hoped
that a longer-acting form of interferon would provide a great improvement
in the treatment success rate, and this has proven to be the case. It was
already known that the attachment of polyethylene glycol (a long-chain
sugar molecule known as "peg") to a protein such as interferon slows its
absorption, and decreases its breakdown and clearance from the body. Based
on this knowledge, pegylated interferons were developed and have been
recently tested.28-40
Treatment with pegylated interferon provides a relatively constant level
of interferon in the blood when given only once a week. This makes it more
convenient (one injection each week rather than three) and produces a
continuous interferon level to combat the virus. Without continuous,
consistent levels of interferon in the body, the virus has time to
replicate when the interferon levels are low. Landmark studies have shown
that approximately 80% of people with genotypes 2 and 3 who receive
pegylated interferon plus ribavirin achieve a durable response. Just under
50% of people with genotype 1 achieve a durable response with this
treatment protocol.32, 41, 42 Side
effects are similar to those seen with standard combination therapy.31, 32
41, 43 Studies
also suggest that pegylated interferons may be better tolerated than
standard interferon therapy.32, 41,
47 Pegylated interferon plus ribavirin is now the
allopathic standard of care for chronic hepatitis C as approved by the FDA
and the recent National Institutes of Health Consensus Development
Conference on the Management of Hepatitis C: 2002.48
Recent data presented at the meeting of the American Association for the
Study of Liver Diseases in November 2002 (available at the time of
publication only in abstract form) indicate that aggressive treatment with
the combination of ribavirin and consensus interferon (interferon
alfacon-1, Infergen®) may be effective in historically
difficult to treat patients such as those with a high viral titer
(>2,000,000 copies), genotype 1 infection, those with cirrhosis, and/or
non-responders to standard combination therapy.49-51 Full details of
these small studies have not yet been published and combination therapy
with consensus interferon has not as of yet been approved by the FDA.
Special Situations
Treatment of
Acute HCV Infection
The initial hepatitis C infection, called acute
hepatitis C, generally goes undetected because the
symptoms are usually mild and
are often mistaken for the flu. We do not know the actual rate of
spontaneous clearance of HCV in people with acute
infection. Many experts think it is in the range of 15-30%, but it may
vary by age, gender, genotype, and other factors yet to be identified.
Small studies in the past have shown that treatment of acute hepatitis C
with interferon monotherapy can produce response rates of 39-64%. A more
recent study in Germany found 43 out of 44 patients with acute hepatitis C
who were treated with interferon monotherapy had undetectable levels of
rch HCV RNA and normal ALT levels both at the end of therapy and at
follow-up.52
It should be recognized that these studies included only small numbers of
patients and were uncontrolled. The role of interferon plus ribavirin in
people with acute hepatitis C is unknown. Clinical trials need to be
conducted to determine if combination therapy is a valuable option to
reduce the frequency of chronic hepatitis C.
Treatment of HCV
Infected Individuals with Normal Liver Enzymes
It is not known if there is any benefit to be gained from treating people
with acute or chronic HCV infection who have normal liver enzyme levels.
Many of these individuals appear to clear the virus following treatment in
a way similar to those who have elevated liver enzymes. Some studies have
shown an actual rise in enzyme levels during treatment in a few patients
who had normal enzymes prior to therapy.53 Other studies have
shown a much better response rate in patients who have at least a
three-fold elevation of ALT levels prior to treatment.28
Research must be conducted to look at the natural course of hepatitis C
disease when ALT levels remain normal. Clinical trials are also needed, to
determine whether combination therapy or alternative therapeutic
approaches are helpful in this situation. It is hoped that a more
standardized approach will be developed for defining what normal liver
enzyme levels are. This should include correction for body weight or body
mass, and gender. Often, the upper limit of what is considered a normal
ALT level in women is lower than the upper limit of normal in men.
Treatment of
Chronic Hepatitis C in Patients with Cirrhosis
A study that evaluated the effectiveness of interferon monotherapy in
people with cirrhosis found ALT levels returned to normal in 27% of people
with cirrhosis, but only 5-10% of these patients maintained an
undetectable viral load for more than six months after the trial ended.13 Small studies in which interferon plus ribavirin
were used found undetectable virus in 20% of those with cirrhosis
following treatment. These data support the belief that some people with
cirrhosis are able to eliminate the virus, and possibly have fewer
complications of liver disease.22-24, 42, 54
A more recent study of pegylated interferon monotherapy showed similar
response rates in people with and without cirrhosis. Thirty percent of
those in the study with cirrhosis achieved a durable response, suggesting
this newer therapy might provide a better outlook for people with
cirrhosis.29
This notion was confirmed in two studies using combined pegylated
interferon plus ribavirin. In these studies, 43% and 44% of patients with
cirrhosis achieved a durable response. While these response rates are
lower than the durable response rates seen in patients without cirrhosis,
they represent a great improvement. These study data indicate that even
patients who are already cirrhotic may benefit from state of the art
interferon-based therapy.32,41, 42
Potential
Therapy-Related Complications
If you have cirrhosis and are undergoing treatment, you are at risk during
therapy for serious bacterial infections and other liver disease
complications that may occur because your liver is not functioning
properly. You are also more liable to have low
neutrophil,
platelet, or
hemoglobin levels than
someone without cirrhosis. Neutrophils are a type of white blood cell, and
a low level makes you more susceptible to bacterial infections. A low
platelet count makes it more difficult for your blood to clot normally,
and may cause you to bleed and/or bruise easily. A low hemoglobin level
can make you feel more fatigued than normal.
If you have cirrhosis and are undergoing treatment, it is very important
that you tell your health care provider about any problems you experience.
Your health care provider should check your blood counts frequently to
identify potential complications early.
Treatment
Options for Patients with HCV-Related Diseases Outside the Liver
HCV has been associated with a wide variety of diseases outside the liver,
including
cryoglobulinemia,
lichen planus, and
porphyria cutanea tarda.55, 60
All of these cause disfiguring skin problems. Cryoglobulinemia can also
cause kidney, nerve, blood vessel, and other tissue damage that may be
life threatening.
If you have an immune complex disease that is the result of your HCV
infection, you may still be a candidate for therapy with interferon alone,
which may decrease or control the disease by reducing or clearing the HCV
virus. This is true even if you have little evidence of liver disease.
There are few data available on the effects of standard or pegylated
interferon plus ribavirin on long-term control of
extrahepatic HCV-related
diseases. However, since combination therapy is more effective than
monotherapy in clearing HCV, it is also likely to be more effective in the
control of extrahepatic disease.
Options for
People Coinfected with Hepatitis B Virus or Human Immunodeficiency Virus
Hepatitis B
Virus
Coinfection with HCV and the
hepatitis B virus (HBV) increases
your risk of developing cirrhosis and other liver complications compared
to infection with either virus alone. If you are coinfected with HBV and
HCV, your health care provider may consider interferon therapy including
the higher coinfected doses used to treat patients who are infected only
with HBV.
Human Immunodeficiency Virus
People infected with both HCV and the
human immunodeficiency virus
(HIV) often have higher HCV viral loads and more rapidly progressive
liver disease compared to people infected with HCV alone.
57-59
A number of studies have shown that HCV/HIV coinfected people have a
lower antibody response rate to the HCV infection than do people
infected with HCV only.
A similar rate of response to interferon has been shown for patients
coinfected with HIV and HCV compared to patients infected with HCV only,
provided the CD4 cell count is greater than 500. No response to
interferon has been observed when the CD4 cell count was less than 180.
A low CD4 count (less than 200), high alcohol consumption (more than
1.75 ounces per day), and older age at the time of HCV infection are
associated with an increased rate of progression to liver fibrosis.58
The treatment of HCV/HIV coinfected people remains an area of active
investigation, and firm recommendations cannot yet be made. However, you
may be a candidate for interferon-based combination therapy if
aggressive liver disease is found on liver biopsy and you have a
significantly long life expectancy (based on your CD4 cell counts,
history of opportunistic infections, and HIV viral load). Be aware that
anti-HCV drugs may cause more frequent treatment complications among
people who are coinfected. Nonetheless, results from two small studies
60, 61 and two
large clinical trials
62, 63 have found
overall sustained response rates of 26-40% among coinfected patients
treated with combination pegylated interferon plus ribavirin therapy.
See Chapter 20,
Sections 1 and
2 for additional
information about western treatment for HCV/HIV coinfection.
Discuss your treatment options with a
hepatologist or infectious diseases specialist. Regardless of the
treatments you decide upon, you should definitely eliminate all alcohol
intake.
Response to Therapy
Western medicine's key measurement of
successful treatment of hepatitis C is undetectable virus in the blood.
Among those for whom therapy is successful, this usually occurs very early
during the treatment course. If therapy fails to produce an undetectable
or very low viral load test after 12 weeks of treatment, it is very
unlikely that the therapy will be successful.32, 41
Most doctors discontinue therapy if viral levels are not undetectable by
12 weeks, though some will continue therapy for another 12 weeks if the
viral load has dropped by at least two logs, that is, by a factor of 100
(for example from 1,000,000 to 10,000). It is a rare and unusual
occurrence for a doctor to continue therapy for an additional 12 weeks if
there is no viral response to treatment within the first 12 weeks.
If a durable response is to occur, the virus should be undetectable after
24 weeks of therapy. It is important to recognize that measurements of
viral levels are not very precise and will vary greatly from one
laboratory to another. Therefore, you should make sure the same laboratory
always performs your viral tests. Also, be aware
that small changes in viral load are not significant. Recall
that viral levels must fall at least 100-fold to be considered
significant. For example, even a seemingly large drop from 800,000 to
200,000 would not be considered significant, and would not be an
indication of successful therapy.
Undetectable viral load at completion of therapy is currently the
determinant of a successful response to treatment. A durable or sustained
response to treatment is declared if the virus remains undetectable six
months after you have completed therapy. A relapse
is defined as having no detectable virus during treatment, but the return
of detectable virus after treatment ends. If the virus becomes detectable
after treatment, there are usually no symptoms but ALT levels usually
begin to rise. A relapse typically occurs within 4-24 weeks after
completing therapy. Developing detectable virus more than 12-24 weeks
after completing treatment is rare and occurs in less than 5% of those
treated.15,
64 Relapse beyond
two years after completing therapy is exceedingly rare. Retreatment for
people who have a relapse is discussed in
Section 3 of this chapter.
The best measure of treatment success is improvement on liver biopsy.
However, a follow-up liver biopsy after successful therapy is rarely
performed outside of research studies. This is because a liver biopsy is
an invasive procedure with potential complications such as bleeding and
infection. It is also much more costly and time-consuming to do than
simple blood tests for liver enzyme levels and viral load. If the virus is
undetectable and ALT levels have returned to normal, it is assumed that
the biopsy will show improvement based on a large amount of information
obtained from carefully controlled research studies. In addition to
improved liver histology, there is some evidence that antiviral therapy
may reduce the risk of developing hepatocellular carcinoma (liver cancer).65-71
Side Effects From Therapy and
Their Management
Most therapies produce one or more
uncomfortable side effects in at least a small percentage of individuals.
There are side effects from treatment with both interferon alone
(monotherapy) and combination therapy. Many of these side effects can be
managed. However, side effects are unpredictable and quite variable. Some
side effects can be severe enough that your doctor will either reduce the
dose of the drug you are taking or discontinue therapy altogether.
Side Effects of
Interferon
The currently available interferons all
have similar side effects. The most common side effects are flu-like
symptoms. Other potential side effects include thyroid abnormalities,
injection site reactions,
bone marrow suppression, and hair
loss. The most serious side effects of interferons are depression, and the
worsening of existing depression or other psychiatric disorders. With the
exception of
hypothyroidism, virtually of all of these side effects go
away after treatment has ended. Following are brief discussions of these
potential side effects of interferon therapy.
Flu-Like
Symptoms
Up to 66% of people taking interferon experience flu-like symptoms
including fever, chills, fatigue,
myalgia (muscle pains),
arthralgia (joint pains),
and weight loss. These symptoms usually lessen after the first two or
three treatments. Acetaminophen or a
nonsteroidal analgesic
(pain medicine) such as ibuprofen or naproxen 30 to 60
minutes before treatment can further reduce these symptoms. However, you
should discuss using these or any other medicines with your doctor
before taking them.
Most patients prefer taking their interferon in the late afternoon or
early evening, so that the worst side effects occur while they are
asleep. However, this must be individualized as some patients do better
when they get their injections early in the morning. The timing of
injections appears to be less critical with long-acting, once-a-week
pegylated interferons. People also find that drinking at least eight
eight-ounce glasses of non-caffeinated or decaffeinated beverages per
day markedly reduces their flu-like symptoms. Those who have tried this
approach swear by the value of increasing their intake of fluids. A good
rule of thumb to determine how much water you should be drinking each
day is to divide your weight in pounds in half, and drink that many
ounces of fluid per day. For example, a 120 pound female should drink at
least 60 ounces of fluid, preferably water, per day. Good indicators
that you are drinking enough fluids are clear to very pale yellow urine,
and having to get up at least once during the night to urinate.
Bone Marrow Suppression
Mild bone marrow suppression, especially leukopenia (low white cell
count) and thrombocytopenia (a low platelet count) are common. This can
be easily monitored and managed.
Thyroid Abnormalities
Hypothyroidism among people taking interferon is usually due to
stimulation of an unsuspected autoimmune
thyroid
disorder. This side effect of treatment can occur in 3-5% of patients.
Hypothyroidism is managed with thyroid hormone replacement therapy.
Patients may require continued thyroid hormone replacement after
treatment has ended.
Injection Site Reactions
The development of redness and warmth with or without itchiness at the
injection site is a common side effect of interferon treatment. This
often does not occur until 24 to 48 hours after the injection. This is a
common local reaction and does not lead to complications. However, it is
important to rotate injection sites in order to avoid injecting the same
spot over and over again. This is particularly true with the pegylated
interferons, which are absorbed more slowly and may stay in the skin for
a prolonged period. Injection sites can take 2 to 3 weeks to clear. It
is important not to inject interferon into an area that is still red
from a prior injection. Repeated injections into the same area can lead
to severe skin reactions including deep skin ulcers that take many weeks
or months to heal.
Hair Loss
Limited hair loss occurs in about 20% of patients taking interferon.
Depression and Psychiatric Disorders
Interferon can worsen existing depression and other psychiatric
disorders, and can lead to new depression among people who have not
previously suffered from this condition. Studies show that about
one-third of those on interferon therapy suffer from depression.
However, suicidal thoughts or attempts occur in less than 1% of those
taking interferon. It is very important to tell your health care
provider if you have had any psychiatric counseling or have been dealing
with depression before you consider treatment. If you have ever
attempted or even seriously considered suicide, you must tell your
doctor. You should not be treated with interferon if you have recently
struggled with thoughts of or have attempted suicide because interferon
could cause you to reconsider suicide. Once you and your health care
provider are confident that you have successfully dealt with any issues
of suicide, you may reconsider therapy. Discontinuation of therapy is
most frequently due to depression and emotional disturbances attributed
to interferon. However, depression and suicidal thoughts can usually be
managed with counseling and/or antidepressant medications.
Anecdotal Story of
Success with Interferon Therapy Despite Psychiatric Complications
A 44-year-old female was found to
have elevated liver enzymes when she donated blood in 1990. A liver
biopsy showed mild activity and no fibrosis. She tested positive for
hepatitis C in 1992. Enzyme levels remained 1-2 times normal until
1998 when they were noted to be 4-6 times above normal. The patient
had abused alcohol and used multiple oral and IV drugs until 1994. She
was asymptomatic, and her physical exam was unremarkable. She had a
history of depression while actively using drugs, but no suicide
attempts. A liver biopsy showed moderate activity and moderate
fibrosis. She had genotype 1b virus.
The patient was treated with pegylated interferon alpha 2b plus
ribavirin for 48 weeks. Enzyme levels dropped to normal within four
weeks. Fever, decreased appetite, "weird dreams," and increased
moodiness complicated the patient's therapy during the first few
weeks. These symptoms resolved except for worsening mood swings. Three
months into therapy, the patient was referred for psychiatric help due
to decreased ability to concentrate, insomnia, excessive crying,
anxiety, feelings of loss of control, and hopelessness. She was
diagnosed with a mood disturbance related to interferon and started
taking Xanax® and Effexor® Because of
intolerance to Effexor®, she was switched to Prozac®
with occasional Xanax®. Xanax® was changed to
Klonopin® to manage residual anxiety. This was later
switched to Ativan® due to over-sedation with the Klonopin®.
The patient was also started on intensive psychotherapy to address her
personal problems. She remained on Prozac® and a variety of
antianxiety drugs throughout therapy with no more active depression.
She has continued with psychotherapy since completing her hepatitis C
treatment
The patient remains virus free with normal liver enzymes for more than
one year after completing therapy. Follow-up liver biopsy showed a
definite decrease in activity and fibrosis.
This patient's experience demonstrates the importance of close
follow-up for early recognition of the development of psychological
problems. It also shows that the majority of such problems can be
successfully overcome and therapy completed successfully with the
cooperation of a psychiatrist experienced in the management of
interferon-related depression. This patient's experience stresses the
concept that there is no simple "one drug fits all" approach to
interferon-related psychiatric problems. Patient therapy must be
individualized.
Side Effects of
Ribavirin
Ribavirin can lead to side effects such as cough,
dyspnea (difficulty
breathing), insomnia, pruritus
(itching), rash, and reduced appetite (anorexia). These side effects are
generally mild and usually do not require discontinuation of therapy or
dose modification. Most side effects go away over several weeks to months
after stopping therapy.
Ribavirin is also associated with two serious side effects,
hemolytic anemia and birth defects, which are discussed
below.
Hemolytic
Anemia
The most serious side effect of ribavirin is hemolytic anemia, which
occurs in up to 54% of patients on the medication.42
The severity of this type of anemia
depends on the amount of ribavirin you are taking. Hemolytic anemia
means your red blood cells are breaking down. Red blood cells are
necessary to carry oxygen from your lungs to all the tissues of the
body. Without sufficient oxygen, your cells cannot function well. With
anemia, you will feel increasingly tired as the number of red blood
cells decreases. Your blood will be checked frequently during the first
few months of therapy with ribavirin to test for hemolytic anemia. Your
hemoglobin should be checked at 2, 4, 8, and 12 weeks after starting
therapy at a minimum. After 12 weeks of treatment, your hemoglobin
should be checked every 4 to 8 weeks. This is especially important if
you have coronary artery disease, or have suffered a stroke or
transient ischemic attacks
(TIAs) in the past.
Hemoglobin levels decrease by 2-3 grams/dL during the first 4 to 8 weeks
of therapy in most patients. Adding interferon does not make this side
effect worse. If your hemoglobin value falls below 10 grams/dL, your
health care provider will probably reduce your ribavirin dosage.
Hemolytic anemia is the most common reason for reducing the dose of
ribavirin, however it rarely causes therapy to be stopped. Hemoglobin
levels usually increase within 4 to 8 weeks of completing therapy.
If you already have severe anemia, active coronary artery disease,
peripheral vascular disease, or if you cannot tolerate anemia for any
other reason, you are not a suitable candidate for combination therapy.
Your health care provider may suggest treatment with pegylated
interferon monotherapy or may advise no treatment. An injectable form of
erythropoietin, a hormone produced by the body to stimulate red blood
cell production, is sometimes used to counteract the effects of
hemolytic anemia and enable you to complete therapy.72-75
Anecdotal Story
of Pegylated Interferon and Use of Erythropoietin to Manage Anemia
Due to Ribavirin
A 49-year-old nurse was diagnosed
with hepatitis C in 1993, two years after an accidental needle stick
from a known hepatitis C patient. She also had a remote history of
IV drug use in 1969. She was asymptomatic and had a normal physical
exam. A liver biopsy revealed minimal nonspecific changes with no
fibrosis. She had genotype 2b virus. The patient's ALT remained
elevated two-fold or less above normal over the next six years. A
repeat liver biopsy in 1999 showed the development of mild activity
and moderate fibrosis.
The patient was treated with pegylated interferon a-2b plus
ribavirin, but suffered a 5.4 gram drop in hemoglobin to a level of
8.7 grams/dL. She had severe fatigue and was unable to carry out her
normal work. Ribavirin was initially stopped, allowing her
hemoglobin to rise back to 10.4 grams/dL. Ribavirin was then
restarted at half dose, but her hemoglobin again fell to 8.7 grams/dL.
Erythropoietin therapy was added to stimulate red blood cell
production. This allowed the patient to continue ribavirin therapy
and to return to work with a hemoglobin of 11.0-12.1 grams/dL. Three
years after completion of therapy, the patient has undetectable
virus and her liver enzymes remain normal.
This patient's experience demonstrates the value of working through
side effects to complete treatment if early viral tests indicate
that therapy is likely to be successful. It also demonstrates the
usefulness of the red blood cell growth factor, erythropoietin, in
raising the hemoglobin level so that the patients was able to
complete therapy. (See, "Making Therapy Work" for additional tips.)
Birth Defects
Another major concern with ribavirin is
its ability to harm a developing baby. Ribavirin can cause birth
defects, or may even cause the death of a fetus. If you are a woman of
child-bearing age and have not had a hysterectomy, you must have a
pregnancy test prior to starting therapy, and periodically thereafter.
Reliable birth control is essential during therapy with ribavirin.
Neither the male nor the female in a partnership can take ribavirin if
the female is pregnant or could become pregnant. Ribavirin cannot
be given to pregnant women, nor to men or women who cannot comply with
the requirement for adequate birth control for the duration of treatment
and six months following discontinuation of treatment. If you are
planning to have children, it is important to discuss this with your
health care provider.
Making Therapy Work
As discussed elsewhere in this book, the
most important risk factors contributing to rapid progression of hepatitis
C are being over age 40 years, being male, and drinking alcohol. Of
course, you cannot change your age or sex. Therefore, the single most
important thing you can do to slow the progression of hepatitis C is to
eliminate all alcohol from your diet (hard liquor, beer, and wine), and
avoid all products that may contain alcohol such as certain
over-the-counter cough remedies, mouth washes, and other products.
Remember that even so-called nonalcoholic beer contains some alcohol.
Your liver is damaged by infection with the hepatitis C virus. It has to
both fight the virus and repair itself. As discussed in other chapters in
this book, a well-balanced diet will give your liver the building blocks
and energy it needs to repair itself. Adequate exercise and sleep will
also help the repair process and improve your immune function. Finally, a
positive attitude is critical. A positive attitude helps your body fight
disease and repair damage. It also makes it easier to tolerate the side
effects of both the disease and its treatment. If you are struggling with
persistent moodiness or sadness, feelings of hopelessness, irritability,
and/or anxiety, talk with your health care provider. He or he may be able
to offer treatment options to help alleviate these symptoms and improve
your overall sense of well-being.
Alternative approaches to managing the symptoms of hepatitis C and the
side effects associated with interferon and ribavirin treatment are
discussed elsewhere in this book. It is critical to make sure your western
doctor is aware of everything you are taking so that he or she can
coordinate all of your medicines, including both prescription and
over-the-counter medicines such as aspirin, vitamins, and cold or allergy
medicines. This also includes other supplements you may be taking such as
Chinese and Ayurvedic herbs, amino acids, nutritional supplements,
minerals, and any other substances you are taking. In other words, you
should tell your doctor about anything you ingest, put on your
skin, inject, or in any other way introduce into your body. Your doctor
must have the full picture in order to best advise you and evaluate the
results of your treatment.
The 80-80-80
Goal
Combination therapy with interferon plus ribavirin is not easy. It
requires serious commitments from both you and your health care provider.
Recent studies have shown that if you do not take at least 80% of the
prescribed interferon and ribavirin doses at least 80% of the time, your
chances of long-term success are dramatically reduced.76 The studies
further show that achieving the 80-80-80 goal increases overall durable
response rates to at least 60%. Careful attention on the part of you and
your health care provider to prevent and treat side effects, anticipate
complications, and support one another's efforts will produce a high
likelihood of success. Failure to make every effort to achieve at least
the 80-80-80 goal described above is likely to be a fruitless exercise,
wasting your effort and causing discomfort. While this goal may sound like
a formidable task, remember that you are only committing to a 12-week
trial of therapy. At the end of that period, it should be clear if therapy
is not working and should be stopped.32,
41, 42 However,
if therapy appears to be successful at 12 weeks, every effort should be
made to complete the full course of treatment. In one study, 75% of
patients who had an early virologic response (at 12 weeks) and completed
more than 80% of their therapy achieved a sustained virologic response.
Only 12% of those who discontinued therapy achieved a sustained response.
Even among patients who were forced for one reason or another to decrease
their therapy to less than 80% but completed the full 48 weeks of
treatment, 67% had durable response.41 A second study found
67% of people with genotype 1 and 88% of people with genotype 2 or 3 who
completed more than 80% of combination therapy (pegylated interferon plus
ribavirin) achieved a durable response. Among study participants who
stopped therapy early, only 7% with genotype 1 and 19% with genotype 2 or
3 had a durable response. However, 56% with genotype 1 virus and 86% with
genotype 2 or 3 who had a dose reduction but were able to complete the
full course of therapy had a durable response.
42 Thus, it is
critical that you make every effort to complete a full course of therapy
if you appear to be responding to treatment at 12 weeks, even if it is
necessary to reduce your dose of medication in order to do so.
Recent studies suggest that taking full dose therapy, especially of
ribavirin, during the first 12 weeks of treatment is the single most
important factor in achieving a durable response.
42,
76-78 The use of
substances called growth factors to stimulate the body's production of red
and white blood cells is sometimes necessary to enable a person to
complete a full course of adequate dose therapy.72-75
Reasons for Using the
Allopathic Approach and Who Might Benefit
Chronic hepatitis C is often a silent
disease in the early years of infection, but eventually progresses to
liver cirrhosis, liver failure, and/or liver cancer in 20-30% of those
infected. Now that successful therapy is available, these serious
consequences can be avoided in over 50% of patients. Most people infected
with HCV remain asymptomatic until the disease is quite advanced. However
during this time, infected people can pass HCV on to others.
You are urged to consider combination therapy if one or more of the
following circumstances applies to you.
Reasons for Not Using the
Allopathic Approach
You may wish to delay therapy if you are
asymptomatic, have minimal disease on liver biopsy (stage 0-1, grade 0-1),
and have no manifestations of hepatitis C outside the liver. This is
particularly true if you have had the disease for over 20 years, are over
60 years of age, and/or have HCV genotype 1 or 6 (the most difficult
genotypes to treat). However, even if you decide not to pursue treatment
at this time, you still need regular medical follow-up and a repeat liver
biopsy in 3 to 5 years to look for evidence of disease progression.
You cannot safely take interferon if you have had a severe psychiatric
condition, a history of suicide attempt(s) or suicidal thoughts, continued
alcohol and/or drug abuse, severe heart disease, very low white blood cell
or platelet counts, organ transplantation (except liver), and/or
uncontrolled seizures. If you have
decompensated cirrhosis, you should be evaluated at a transplant
center promptly to determine whether you are a candidate for liver
transplantation. You may be put on carefully monitored therapy in an
attempt to reduce HCV viral load prior to transplant.
Other conditions such as uncontrolled diabetes and hypertension,
moderately decreased white blood cells or platelets, uncontrolled
autoimmune disease, psoriasis, and rheumatoid arthritis may make
interferon treatment unsafe. Your doctor will advise you of the relative
safety of interferon treatment if you have one or more of these
conditions.
Pregnant women and women of child-bearing age who do not use a reliable
form of birth control cannot take ribavirin because of the risk of birth
defects. Because ribavirin is cleared from the blood by the kidneys,
patients on hemodialysis or with end-stage renal failure cannot take
ribavirin. Severe anemia (hemoglobin less than 11gm/dL),
hemoglobinopathies, or other conditions in which anemia can
be dangerous may also make it unsafe to take ribavirin.
What You Need to Know Regarding
Therapy
There are a number of things you and your
doctor need to know about your situation before you decide to begin
therapy and at various stages of treatment once it has begun. Most of this
information can only be gained through testing.
Before Starting Therapy
Before therapy begins, you will need to have the following tests, and
discuss these aspects of your medical history.
During Therapy
During therapy, the following tests need to be done.
You must eliminate all alcohol and
strive to take more than 80% of your prescribed interferon and ribavirin
doses more than 80% of the time in order to have the best chance of
achieving a durable response.
After Therapy
If your viral load is negative at the end of treatment, the following
tests need be done after therapy is completed.
If you have detectable virus at the end
of treatment, or if the virus becomes detectable again after the
completion of treatment, see
Section 3 for
additional treatment options.
Summary
With recent advances in the treatment of
chronic hepatitis C, many people are candidates for treatment. You may be
a candidate for therapy if you have elevated ALT levels, other conditions
related to your HCV infection, a detectable viral load, and/or chronic
inflammation or fibrosis on liver biopsy. Currently, the best initial
therapy is pegylated interferon plus ribavirin. This combination has
resulted in a sustained response in 54-56% of patients studied in clinical
trials. If you are not a candidate for combination therapy, you may be a
candidate for pegylated interferon monotherapy.
Therapy for hepatitis C is rapidly changing with the primary goals of
eliminating the virus, improving quality of life, and alleviating the
effects of HCV infection on organs other than the liver. The
recommendations for therapy will probably change every few years, and it
is hoped that new approaches will provide effective therapy for the
majority of people infected with hepatitis C.
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If you have HCV genotype 2 or 3,
combination therapy should be considered because the durable response
rate is greater than 70-80% after 24 weeks of therapy with pegylated
interferon plus ribavirin.