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 (< 2x10
6 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.
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