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Diagnosis and Management of Hepatitis C CME
David Bernstein, MD
Author affiliations and disclosures are at the end of
Release Date: February 2, 2001
The material presented here does not reflect the views
of Medical Education Collaborative, Medscape, or the
companies providing unrestricted educational grants.
These materials may discuss uses and dosages for
therapeutic products that have not been approved by
the United States Food and Drug Administration. All
readers and continuing education participants should
verify all information and consult a qualified health
care professional before treating patients or
utilizing any therapeutic product discussed in this
continuing education activity.
Table of Contents
Natural History of Hepatitis C
The Role of Pegylated Interferon
Quality of Life
The elucidation of the hepatitis C genome in 1989 has
led to the realization that this virus is a major
health problem worldwide.[1a] Infection with the
hepatitis C virus (HCV) is one of the most common
causes of chronic liver disease in the United States
and HCV-related disease is a leading indication for
liver transplantation. An estimated 3.9 million
Americans carry the antibody to HCV, while 2.7 million
have detectable virus in the blood (ie, active
infection). This means that about 1% of the United
States population has hepatitis C.
In the NHANES (National Health and Nutrition
Examination Survey) study, it was determined that
1.5% of whites, 3.2% of blacks, and 2.1% of Hispanics
are infected with HCV. The prevalence of hepatitis C
in the Asian-American population is unknown. At the
time of this study, the greatest prevalence was seen
in patients aged 20-39 years. Because this study was
performed about 10 years ago, however, the age of
these patients has now shifted to the 30- to 49-year
The hepatitis C virus has very little in common with
the better-known hepatitis viruses -- hepatitis A and
B. It is a member of the Flaviviridae family, which
includes such viruses as those that cause yellow fever
and dengue. The viral particle consists of an envelope
derived from host membranes, into which are inserted
the virally encoded glycoproteins E1 and E2,
surrounding a nucleocapsid and a positive-sense,
single-stranded RNA genome of approximately 9500
The hepatitis C virus has been classified into 6 major
genotypes based on phylogenetic analyses. The 6 major
genotypes are named by number and are as follows:
1,2,3,4,5, and 6.
Hepatitis C is transmitted parenterally (see Table 1).
The most common risk factor for hepatitis C is
intravenous drug use.[1b] Prior to 1992 -- before the
introduction of blood donor screening and surrogate
hepatitis tests -- transfusion of blood or
plasma-derived products was associated with
significant risk of transmission of hepatitis C.
Other potential risk factors for hepatitis C include:
intranasal cocaine use, tattooing, body piercing,
accidental needle-stick injury, and the sharing of
household items, such as nail clippers, razor blades,
Table 1. Potential Hepatitis C Risk Factors
Intravenous drug use Intranasal cocaine
Blood transfusions prior to 1992 Body piercing
Accidental needle-stick injury Tattoos
Sexual transmission Sharing of household items
Perinatal transmission Fistfights involving blood
Transplant prior to 1992
Case reports have also documented transmission of
hepatitis C between patients who underwent colonoscopy
with an inadequately disinfected colonoscope,
between 2 family members who had engaged in a
fistfight during which there was blood exposure,
and during cardiothoracic surgery.
Additionally, accidental needle-stick injury in
healthcare workers may lead to the transmission of
virus. The rate of transmission of hepatitis C as a
result of needle-stick injury is less than that seen
for hepatitis B, but greater than that which occurs
with HIV. After a needle-stick injury, there is no
prophylactic role for gammaglobulin or hepatitis B
immune globulin in the prevention of HCV infection.
Unfortunately, watchful waiting is an important
strategy in determining whether disease will develop.
If possible, it is appropriate to check the hepatitis
viral load in the source patient to assess the risk of
hepatitis C transmission. The risk of hepatitis C
transmission from a patient without detectable
hepatitis C RNA is negligible. If, however, the source
patient is unavailable for testing or tests positive
for HCV RNA, the needle-stick recipient should then be
tested periodically for HCV and treated if indeed
found to be HCV-RNA-positive.
Sexual transmission of hepatitis C remains
controversial and probably accounts for less than 5%
of cases.[1b] Risk factors for sexual transmission
include multiple sex partners, prostitute use, rectal
intercourse, and traumatic sex. Sexual intercourse
during menstruation or without adequate vaginal
lubrication may increase the transmission rate.
Studies in married couples have indicated a greater
risk of spousal transmission with increasing duration
of marriage.[9,10] Whether this risk is secondary to
sexual transmission, the potential role of more
frequent sharing of household (razors, toothbrushes,
etc.) items or other factors remains to be determined.
Perinatal transmission of hepatitis C occurs in
approximately 3% to 5% of infants born to women
infected with HCV. Perinatal transmission is
associated with 2 independent risk factors: high viral
load at time of delivery and having a mother who is
Italian investigators recently reported the decreased
risk of perinatal transmission of hepatitis C with
cesarean section when compared with vaginal
delivery. The risk of perinatal transmission of
hepatitis C in a woman who is HIV-positive is
estimated to be 15% to 35%. Infants born to hepatitis
C-infected mothers may initially be hepatitis
C-antibody-positive due to passive transfer of this
antibody across the placenta. This antibody may be
present throughout the first year of an uninfected
newborn's life before disappearing. Therefore, the
determination of hepatitis C infection in the newborn
requires the demonstration of a positive HCV RNA in
the serum. Breastfeeding by mothers with hepatitis C
appears to be safe, with no reported cases of viral
transmission to newborns.
Other groups at high risk for hepatitis C infection
include persons who received clotting factor
concentrates prior to 1987, persons on hemodialysis,
hemophiliacs, and individuals who received either a
solid organ or bone marrow transplant prior to
1992.[1b] Contamination of the ultrafiltrate dialysis
membrane may help explain the high rate of hepatitis C
infection seen in dialysis units.
Natural History of Hepatitis C
The precise natural history of hepatitis C remains
unknown because of the lack of prospective data, the
inability to determine time of initial onset of
disease, and the variable influences of multiple
cofactors leading to disease progression. What has
been determined, however, is that a subset of
hepatitis C patients will progress to cirrhosis and
its associated complications.
Chronicity is the hallmark of hepatitis C infection.
Approximately 15% to 30% of patients exposed to HCV
recover spontaneously, while the remaining 70% to 85%
develop chronic infection. Most patients with
chronic hepatitis C infection appear to have mild to
moderate histologic disease.[16-20] Cirrhosis may
develop in as many as 15% to 30% of infected patients
(see Figure 1). Although fulminant disease is rare in
hepatitis C, its occurrence has been reported.
Figure 1. Natural history of hepatitis C.
Several studies have attempted to determine the rate
of histologic disease progression in
transfusion-acquired disease.[22-24] Tong and
colleagues found a mean interval of 20.6 years
from time of infection to development of cirrhosis,
and a mean interval of 28.3 years from time of
diagnosis to development of hepatocellular carcinoma
The infusion of hepatitis C-contaminated anti-D immune
globulin in 1977 and 1978 in Ireland has allowed the
prospective evaluation of 376 women, 17 years after
exposure. Most of the hepatitis C-infected women
had evidence of moderate hepatic inflammation on liver
biopsy, while 51% had fibrosis, and only 2% had
cirrhosis. The results of a similar German study of
152 women infected with hepatitis C-contaminated Rh0
immune globulin showed no evidence of cirrhosis 15
years after exposure.
In a recent study published in the Annals of Internal
Medicine, Seeff and coworkers conducted a 45-year
follow-up of hepatitis C infection in healthy young
adults. In this retrospective study, stored sera from
8568 US Air Force recruits in Wyoming dating from
1948-1955 were evaluated for hepatitis C. Ten patients
were found to be positive for HCV. Based on their
findings, the study authors concluded that individuals
with hepatitis C had low liver-related morbidity and
mortality. However, because of the small sample size,
these conclusions are suspect.
Factors Influencing Disease Progression
Several factors appear to influence the rate of
progression of hepatitis C to cirrhosis. These
factors include alcohol use, age at time of exposure,
sex, and coinfection with either hepatitis B or HIV
(see Table 2).
Table 2. Factors Affecting Disease Progression
Adverse No Effect
Alcohol use Serum aminotransferase level
Disease acquisition at age greater than 40 years Viral
Male sex Genotype
HBV coinfection Mode of transmission
Alcohol. Alcohol ingestion and chronic hepatitis C
infection appear to be synergistic in accelerating the
progression of liver disease (see Table 3).[30,31] An
increased risk of cirrhosis and decompensated liver
disease is associated with sustained alcohol
consumption of greater than 40 g/day. Other
effects of concomitant alcohol use in the setting of
hepatitis C include increased transaminase levels,
higher hepatitis C viral loads, and increased
number of hepatitis C quasispecies. These
elevations have been shown to be significantly reduced
with a decrease in daily alcohol intake.
Table 3. Extrahepatic Manifestations of Hepatitis C
Essential mixed cryoglobulinemia
Porphyria cutanea tarda
The mechanism by which alcohol effects a more rapid
progression of disease is not known. The amplification
of cytokine signals is believed to play a role in this
process by stimulating stellate cells and increasing
fibrosis. Alcohol consumption also increases the
risk of developing HCC.
Age and gender. Acquisition of hepatitis C after age
40 is associated with a more rapid disease
progression. The reasons for this effect are uncertain
but may be related to an aging immune system. Male sex
is also associated with more rapid disease progression
(see Table 2).
Coinfection. Hepatitis C and HIV coinfection appears
to lead to rapid progression of liver disease.
Progression to cirrhosis or liver failure may occur
within 10-15 years after infection with HCV, and this
progression occurs at approximately twice the rate as
what occurs with hepatitis C infection alone.
Hepatitis C and related liver disease are now the
leading cause of non-AIDS-associated death in patients
Role of other factors. Many factors initially
considered to be important predictors of disease
progression appear, in fact, not to have such a
predictive role. These factors include mode of
transmission, serum transaminase levels, hepatitis C
viral loads, and hepatitis C genotype. The authors of
one paper, however, concluded that
transfusion-acquired disease was associated with more
rapid disease progression than was disease acquisition
due to other risk factors.
Most patients with hepatitis C are asymptomatic. But
if symptoms do occur, the most common complaints are
fatigue, abdominal pain, poor appetite, weight loss,
and pruritus. The diagnosis of hepatitis C is made
following the completion of specific tests requested
by the clinician. The primary care physician generally
performs this testing if risk factors are identified
or abnormal liver chemistries noted. Blood banks and
life insurance companies routinely test blood donors
and applicants for hepatitis C. Hepatitis C testing,
unlike testing for HIV, does not require that consent
Hepatitis C can lead to a broad spectrum of liver
disease. Patients may develop mild disease as
evidenced by mild inflammation and/or fibrosis. Others
may develop increasing amounts of inflammation or
fibrosis, which can lead to the development of
significant fibrosis or cirrhosis.
In addition to liver disease, hepatitis C is
associated with a number of extrahepatic effects,
including hematologic, renal, dermatologic, endocrine,
and autoimmune disorders (see Table 3).[36-39]
Essential mixed cryoglobulinemia. Essential mixed
cryoglobulinemia (EMC) is a condition that results in
the deposition of circulating immune complexes in
small- to medium-sized blood vessels. Patients with
EMC usually present with rash, arthralgias, and
A review of the literature reveals that hepatitis C
can be found in 95% of all patients with EMC.[40-43]
Several investigators have suggested that hepatitis C
may have a causative role in EMC. Anti-HCV antibodies
can be detected in the vessel walls of skin biopsies
taken from patients with EMC and chronic vasculitis.
Interferon therapy has been shown to reduce the
cryocrit and allow symptomatic improvement of both
rash and joint pains. The response is short-lived,
however, because symptoms almost universally reappear
upon cessation of therapy.[44-48]
Lymphoma. Several reports have described an increased
incidence of B-cell lymphoma in patients with
hepatitis C. Rasul and colleagues studied 16
patients with chronic hepatitis C and cryoglobulinemia
for the presence of lymphoma. Results of bone marrow
biopsy were consistent with non-Hodgkin's lymphoma in
2 patients and suspicious for lymphoma in 7. While
this finding needs to be evaluated further in larger
studies, the development of lymphadenopathy or
unexplained chronic anemia in a patient with hepatitis
C infection should raise concern about the possibility
of underlying lymphoma.
Glomerulonephritis has been associated with hepatitis
C.[50,51] These patients are found to have
proteinuria, which can be significant and in the
nephrotic range. Most cases of glomerulonephritis are
associated with cryoglobulinemia. The most common
histologic lesion seen is membranoproliferative
glomerulonephritis. Interferon therapy may reduce
proteinuria, but a sustained response is seldom
achieved in these patients.[52,53] Ribavirin should be
avoided in patients with significant renal impairment.
Some may benefit from the use of plasmapheresis,
although the relief tends to be short-lived.
Several dermatologic disorders have been described in
association with hepatitis C. These include porphyria
cutanea tarda, lichen planus, and cutaneous
Porphyria cutanea tarda. Porphyria cutanea tarda (PCT)
is the most common form of porphyria. PCT has been
associated with hepatitis C infection, particularly in
those patients with significant alcohol use.[38,55,56]
Hepatitis C may occur in 58% to 71% of all PCT
patients. This dermatologic disorder tends to present
at an earlier age in patients with hepatitis C than in
those PCT patients without hepatitis C. Despite this
association, the clinical changes seen in the setting
of PCT do not appear to be a direct consequence of the
Lichen planus. This condition has been associated with
hepatitis C, although hepatitis C has not been shown
to be the causative agent.
Cutaneous necrotizing vasculitis. This condition has
been associated with hepatitis C as well, although
hepatitis C has not been shown to be the causative
Hepatitis C has also been linked to both diabetes
mellitus and an increased incidence of anti-thyroid
Diabetes mellitus. An association between hepatitis C
and diabetes mellitus has recently been
demonstrated.[57-59] Mason and colleagues
retrospectively evaluated 1117 patients with chronic
hepatitis C and found this infection to be an
independent predictor of diabetes.
Additionally, Mehta and associates found that
among individuals older than 40 years of age, those
with hepatitis C infection were more than 3 times as
likely to have type 2 diabetes mellitus than those
without hepatitis C infection. The prevalence of type
1 diabetes was not increased. The link between these 2
disorders must be further investigated in an effort to
improve available therapies.
Other Extrahepatic Manifestations
Finally, hepatitis C has been associated with a number
of other extrahepatic disorders as well, including
sialadenitis, uveitis, corneal ulceration,
polyarteritis nodosa, peripheral neuropathy, and the
development of autoimmune phenomena.[37,38]
Hepatitis C Antibody Testing
Two primary forms of testing are available for the
detection of the anti-hepatitis C antibody (anti-HCV
Ab): enzyme immunoassays (EIA) and recombinant
immunoblot assays (RIBA).[60,61] These antibody tests
are useful screening tools for hepatitis C, but they
do have limitations.
Both of these antibody tests will yield a positive
result for current (active) and resolved disease.
Antibody testing may not become positive for 3-6
months after exposure, resulting in a delay in the
diagnosis of acute disease. Immunosuppressed patients
-- such as those with renal failure, those infected
with HIV, or those post-organ transplantation -- may
not express the hepatitis C antibody yet still may
have hepatitis C infection. False-positive antibody
testing may occur in low-risk blood donors.
EIA. Three generations of EIA antibody testing have
been developed since 1989. The EIA antibody is the
main screening test for hepatitis C. The
first-generation EIA antibody, which incorporated the
c100-3 epitope from the nonstructural NS4 region, was
used until 1992, at which time it was replaced by a
second-generation EIA [EIA-2]. EIA-2 contains
hepatitis C antigens from the viral core and from
areas of the nonstructural NS3 and NS4 regions. A
third-generation EIA that contains reconfigured core
and NS3 antigens and a newly incorporated antigen from
the NS5 region was recently approved by the United
States Food and Drug Administration (FDA) for
screening blood products and is now in use at some
institutions for diagnostic purposes (see Figure 2).
EIA-3, with a sensitivity of 97%, offers slightly
improved sensitivity over the 95% sensitivity seen
with EIA-2.[62,63] Most centers in the United States
use EIA-2 testing.
Figure 2. Hepatitis C antibody tests categorized by
EIA testing offers several distinct advantages in the
diagnostic setting because these assays are easy to
perform, are relatively inexpensive, and have high
sensitivity. A positive EIA-antibody test requires a
second confirmatory assay to make the diagnosis of
hepatitis C. False-positive EIA testing may occur in
low-risk patients and in patients with underlying
autoimmune diseases. These patients may benefit from
RIBA assay testing to differentiate a false-positive
from a true-positive test.
RIBA. These tests are supplemental assays to EIA
testing. Both classes of antibody assays contain the
same HCV antigens. RIBA testing is currently in its
third generation of development. RIBA-2 uses the same
recombinant antigens as EIA-2.
Results from a RIBA-2 assay may be interpreted as
positive if 2 or more antigens are positive,
interpreted as indeterminate if 1 antigen is positive,
or finally, interpreted as negative if all antigens
are negative. RIBA testing is not more sensitive than
EIA testing, but a RIBA-2 test can be used to
distinguish between a false-positive EIA test and true
previous exposure to hepatitis C. A third-generation
RIBA test (RIBA-3) has recently been licensed in the
United States. This assay incorporates the NS5 antigen
with the standard antigens used in RIBA-2 (see Figure
2). This third-generation test produces a reduced
number of indeterminate results and is more specific
than the RIBA-2 assay.[60,63]
The demonstration of hepatitis C viral particles in
blood confirms the diagnosis of hepatitis C infection
(see Figure 3). Two principal methods used to detect
hepatitis C viral RNA are target amplification and
Figure 3. Algorithm for hepatitis C diagnostic
Target amplification assays such as the polymerase
chain reaction (PCR) rely on sequence-specific primers
and a heat-stable DNA polymerase to generate a large
number of copies of a portion of the viral genome.
Signal amplification, as used in bDNA assays, uses a
series of hybridization reactions between probes
specific for several regions of the target molecule
and subsequent hybridization to a DNA amplifier.
Viral load may be measured as either a qualitative or
quantitative function. Qualitative testing is the most
sensitive and specific and, therefore, the most
accurate when used for initial diagnosis. Both
qualitative and quantitative viral load testing have a
role in the evaluation and treatment of patients with
hepatitis C. Qualitative testing is important in
confirming a positive anti-HCV test and in assessing
sustained response to therapy. Quantitative testing is
useful in determining diagnosis, predicting response
to therapy, and monitoring response while on therapy.
Many different "brands" of quantitative testing are
available and until recently, results could not be
compared across assays because of a lack of
standardization. As of the year 2000, results of all
quantitative assays are standardized as international
units per milliliter. Viral load testing is useful in
evaluating the patient with suspected acute hepatitis
C infection because these assays should be positive
within 1-2 weeks of initial exposure. These tests,
however, do not correlate with disease severity or the
rate of disease progression.
Hepatitis C core antigen immunoassays, currently
undergoing testing, may approach the clinical
sensitivity of HCV-RNA testing.
Genetic analysis of HCV reveals the existence of
numerous viral sequences, termed genotypes. These
various genotypes differ in genetic composition by as
much as 35%. Six major genotypes have been identified
and these can be further subdivided into more than 100
Genotype distribution is worldwide. However, 1a and 1b
are the most common types in the United States,
accounting for more than 75% of all infections.
Genotype 1b is the most prevalent viral species found
in Japan. Genotype 3, which is uncommon in the United
States except in younger intravenous drug users, is,
however, highly prevalent on the Indian subcontinent.
Genotype 4 accounts for the majority of HCV infection
in Egypt and is also seen in other areas of Africa.
Genotype 5 is common in South Africa and accounts for
more than 50% of all cases of hepatitis C seen in that
region. Finally, genotype 6 is found primarily in
Hepatitis C genotype does not appear to affect the
rate of disease progression. Genotype is, however, a
predictor of response to therapy.[69-71] Patients with
genotype 2 or 3 are more likely to respond to therapy
and, based on published data, may be treated with
combination interferon and ribavirin for a 6-month
course. By contrast, patients infected with HCV
genotypes 1 and 4 are less likely to respond to
therapy and should be treated with combination
interferon and ribavirin therapy for 1 year.
Genotyping should be performed in all patients with
hepatitis C for whom treatment is being considered.
Obtaining the results of genotype testing can allow a
more cost-effective approach to therapy.
The grading and staging of liver disease in patients
with hepatitis C is crucial in helping guide
treatment. Unfortunately, serum aminotransferase
levels, HCV viral load, and hepatitis C genotype are
all poor predictors of underlying histology.
Therefore, despite the cost and discomfort associated
with liver biopsy, it is recommended that it be
performed in the initial evaluation of all hepatitis C
patients, barring obvious contraindications.
Information obtained from the biopsy can help exclude
other causes of liver disease, help gauge the rate of
progression of disease, and aid the treating physician
in adjusting or terminating therapies if the patient
is experiencing significant side effects.
The primary aim of therapy in the patient with
hepatitis C is to achieve a sustained virologic
response, which is defined as undetectable HCV RNA 6
months after termination of antiviral therapy.
Secondary goals of antiviral therapy include
improvement in histology and quality of life, and the
prevention of HCC (see Table 4). Patients with
persistently abnormal liver enzymes, detectable HCV
RNA, and an abnormal liver biopsy are candidates for
Table 4. Goals of Therapy
Slow disease progression
Improve underlying histology
Prevent the development of hepatocellular carcinoma
Improve quality of life after therapy
Three discrete regimens are licensed in the United
States for the treatment of chronic hepatitis C. These
regimens include 3 approved interferons (IFN) --
IFN-alfa-2a, IFN-alfa-2b, IFN-alfa con (consensus)-1
-- and combination IFN-alfa-2b plus ribavirin.
The Naive Patient
Interferon monotherapy was the first antiviral regimen
approved for chronic hepatitis C. Sustained response
rates with IFN monotherapy were similar among the 3
approved IFNs. Sustained response rates for
IFN-alfa-2b administered at a dose of 3 million units
3 times per week for 6 or 12 months were 8 % and 12%,
respectively. The sustained response rate
associated with IFN-alfa con-1 given at a dose of 9
mcg 3 times per week for 6 months was 12.1%.
Higher doses of IFN monotherapy were associated with
increased end-of-treatment responses but without any
improvement in sustained response. Induction trials
using IFN monotherapy have not shown any increased
efficacy over standard 3-times weekly dosing.
Therefore, IFN monotherapy is currently recommended
only for those patients who do not tolerate
combination therapy with IFN and ribavirin.
Patients should be followed on IFN monotherapy, with
serial testing of alanine aminotransferase and HCV-RNA
levels. Therapy should be discontinued in those
patients who fail to demonstrate undetectable viral
levels at week 12 of treatment.
Several factors are associated with a favorable
response to therapy with IFN monotherapy. The most
important of these factors include the lack of
cirrhosis on liver biopsy, the presence of either HCV
genotype 2 or 3, and low HCV-RNA levels
Interferon is associated with numerous side effects.
The most common of these is a flu-like illness that
occurs in the first 4 weeks of therapy and which
generally resolves on its own. After the first month
of therapy, late side effects such as fatigue,
headache, and neuropsychiatric changes may occur.
Depression is also a common side effect of IFN, and
patients with prior history of depression should be
carefully monitored. Other less common adverse events
may include hypothyroidism, hyperthyroidism,
arthralgias, rash, and reversible alopecia.
Neutropenia, and especially thrombocytopenia, may
occur in patients on IFN therapy and can be managed
with dose reduction.
Combination therapy: the naive patient. Two large,
randomized controlled trials compared combination
IFN-alfa-2b plus ribavirin with IFN-alfa-2b
monotherapy, given for 24 or 48 weeks to previously
untreated hepatitis C patients (see Figure 4).[69,70]
Individuals treated with the combination regimen had
sustained virologic responses at 24 and 48 weeks of
33% and 41%, respectively. This outcome compared
favorably with the 6% and 16% sustained response rates
achieved with 24 and 48 weeks, respectively, of IFN
Figure 4. Sustained virologic response in US
Combination Therapy Trial.
ETR = end-of-treatment response; SVR = sustained
Careful analysis of these trials revealed the
importance of genotype in both predicting response to
therapy and determining duration of therapy. Genotype
1 patients treated with combination therapy had
sustained response rates at 24 and 48 weeks of 17% and
29%, respectively. Genotype 2 and 3 patients had
sustained response rates at 24 and 48 weeks of 66% and
65%, respectively. Based on these data, it seems
reasonable to treat genotype 2 and 3 patients for a
total of 24 weeks. The presence of bridging fibrosis
or cirrhosis resulted in reduced response rates in
patients treated with combination therapy for 6
months, but not in those treated with combination
therapy for 12 months. Genotype 1 patients with high
viral loads were the least likely to respond to
The sustained response to 24 weeks of therapy with
combination IFN and ribavirin vs IFN monotherapy was
evaluated in 112 noncirrhotic hepatitis C patients
infected with genotype 4. The sustained response rate
in the combination-therapy group was 42% compared with
only 8% in the monotherapy group.
Although the prevalence of the hepatitis C antibody is
2-3 times greater among blacks than whites in the
United States,[1b] blacks have been underrepresented
in the many large published hepatitis C treatment
trials. In these trials, blacks are reported to
have a lower response rate than whites to IFN
monotherapy. Of the 1744 patients enrolled in the 2
large, multicenter trials evaluating IFN plus
ribavirin for the treatment of previously untreated
hepatitis C patients, 53 were classified as
black.[69,70]Among these 53 patients, 96% were
genotype 1. The sustained response of these patients
to 24 and 48 weeks of combination therapy were 20% and
23%, respectively. None of the black patients
treated with IFN monotherapy had a sustained response.
Five independent factors have been identified as
predictors of sustained response in patients treated
with combination therapy. These factors are genotype 2
or 3, baseline viral load < 3.5 million copies/mL,
minimal fibrosis, female sex, and age < 40 years.
Early loss of HCV RNA while on therapy may also be
predictive of a sustained response.
Common side effects of ribavirin include anemia,
depression, fatigue, irritability, rash, cough,
shortness of breath, and insomnia. The anemia is the
result of a dose-dependent hemolysis of red blood
cells and occurs in nearly 100% of patients, with
patients frequently showing a drop of 2-3 g from
baseline hemoglobin. Therefore, ribavirin must be used
with caution in patients with pre-existing anemia,
diabetes, or coronary artery disease. Also important
to note is that ribavirin is teratogenic, so patients
and their sexual partners must be carefully counseled
prior to initiation of therapy.
Treatment of the Relapse Patient
Relapse is defined as the reappearance of serum HCV
RNA in a patient who had previously undetectable
levels at the end of antiviral therapy. Occurrence of
relapse following IFN monotherapy is more common than
following combination IFN and ribavirin therapy.
While re-treatment of IFN-monotherapy relapse patients
with a repeat course of similar therapy is
ineffective, treatment with higher doses may
improve sustained response rates. A large,
multicenter trial evaluated the use of high-dose
consensus IFN (IFN-alfa con-1) in patients who had
relapse following a 24-week course of standard dose
IFN-alfa-2b or IFN-alfa con-1. Subjects were
randomized to receive 15 mcg of IFN-alfa con-1 for
either 24 or 48 weeks. The sustained viral response
was 28% at 24 weeks and 58% at 48 weeks. Re-treatment
at this higher dose was not associated with more
significant side effects than treatment with the
standard IFN regimen. Factors predictive of a
sustained virologic response in this trial included
low initial viral load, HCV genotype 2 or 3, and the
absence of cirrhosis.
A second large study evaluated the use of combination
IFN and ribavirin therapy in IFN monotherapy relapse
patients. Patients were treated for a total of 6
months and randomized to receive standard-dose
IFN-alfa-2b with or without ribavirin. A sustained
virologic response was seen in 49% of patients treated
with combination therapy and in only 8% of those
treated with IFN monotherapy. Genotype other than type
1 and low pretreatment HCV-RNA levels were positive
predictive factors of a sustained response in this
trial. Twelve percent of subjects treated with
ribavirin required a dose reduction or interruption
secondary to anemia, whereas only 3% of those
receiving IFN monotherapy required dose reduction.
As previously indicated, patients who relapse
following IFN monotherapy may be effectively
re-treated with either higher-dose IFN monotherapy or
with combination IFN and ribavirin. But the increasing
problem facing physicians today is how to approach the
patient who relapses following combination therapy. At
present, there are no large published studies to help
answer this question. Several studies are ongoing with
either pegylated interferon (peginterferon) alfa-2a or
peginterferon alfa-2b in patients who relapsed
following treatment with combination therapy of IFN
Treatment of the Nonresponder
Nonresponse to antiviral therapy is defined as the
persistence of detectable HCV RNA throughout therapy,
with detectable serum HCV RNA at the end of the
therapeutic course. The sustained response to
re-treatment of nonresponders to any form of antiviral
therapy has been disappointing.
Re-treatment of nonresponders to IFN monotherapy was
evaluated in several small studies. In the consensus
interferon trial, nonresponders to IFN monotherapy
showed a 13% sustained virologic response rate at 48
weeks of therapy with IFN-alfa con-1. The use of
combination IFN and ribavirin therapy in IFN
nonresponders has resulted in sustained response rates
ranging from 0% to 15%.[83-85] Of interest, a recent
trial reported a 42% sustained response to intravenous
recombinant IFN-beta in previous IFN
Approximately 60% of all patients treated with
combination IFN and ribavirin are nonresponders. The
approach to this group represents a growing challenge
to the treating clinician. Although it seems
reasonable that higher doses of IFN plus ribavirin or
a weight-based system of ribavirin dosing should
improve response to treatment in these patients,
there are little if any published data to support such
an approach. The peginterferons may, however, prove
useful in combination with IFN and ribavirin, and
clinical trials designed to test this notion are
Virologic nonresponders to antiviral therapy may
derive some benefit from re-treatment that is aimed at
preventing histologic disease progression. Patients
with underlying bridging fibrosis or cirrhosis are at
a greater risk for developing complications of
cirrhosis than are those without fibrosis. In addition
to its antiviral effect, IFN was shown to have
antiproliferative and antifibrotic activity through
its downregulation of transforming growth factor
b.[88,89] Recent studies showed improvement in
underlying histology in nonresponders to antiviral
therapy.[90,91] Several studies have also demonstrated
a significant reduction in the relative risk of
developing HCC among nonresponders to IFN
These studies have brought the issue of IFN
maintenance therapy for prevention of fibrotic
progression to the fore. Shiffman and colleagues
reported that a 2-year course of IFN monotherapy
administered to nonresponders stabilized fibrosis and
improved inflammation on serial biopsies. This concept
has now led to the launch of a National Institutes of
Health-sponsored trial -- the Hepatitis C Antiviral
Long-term Treatment Against Cirrhosis or HALT-C trial
-- to evaluate the effect of long-term
peginterferon-alfa-2a therapy in patients with
advanced fibrosis or cirrhosis who did not respond to
combination pegylated IFN plus ribavirin.
Treatment of the Post- Liver Transplant Patient
Hepatitis C is the leading indication for liver
transplantation in the United States. In patients who
undergo liver transplantation secondary to hepatitis
C, the reappearance of HCV RNA posttransplantation is
an almost universal occurrence.
The natural history of posttransplantation hepatitis C
appears to be rapid, with as many as 20% of recipients
developing cirrhosis within 5 years of
transplantation. Studies with IFN monotherapy in
this setting have reported biochemical responses in up
to 25% of patients, but virologic response is
rare. One study reported a sustained response rate
of 24% with a 6-month course of combination IFN and
ribavirin. After loss of HCV RNA with combination
therapy, ribavirin monotherapy has been used as
maintenance therapy. Although combination therapy
has not been associated with rejection, significant
anemia secondary to hemolysis is common. Larger trials
are needed to better address the issue of recurrence
of hepatitis C after transplantation.
The Role of Pegylated Interferon
Pegylated IFNs are currently under investigation, and
at this time are not approved for the treatment of
hepatitis C in the United States. The concept behind
the pegylation of IFN is to produce a molecule that
can maintain longer-lasting therapeutic concentrations
by optimizing both the absorption and distribution
while decreasing the rate of clearance and reducing
proteolysis at the same time. This is accomplished by
the addition of a polyethylene glycol molecule (PEG)
to standard IFN by means of a covalent bond. This PEG
molecule is a nontoxic polymer that is readily
excreted in the urine and this moiety may be either
linear or branched. Larger PEG molecules lead to a
greater reduction in renal clearance and provide
greater subcutaneous absorption. Pegylated IFN is
metabolized primarily in the liver, and its
excretion is not affected by renal abnormalities.
Two pegylated formulations of IFN are currently under
investigation in the United States: a linear 12-kD
peginterferon-alfa-2b (PegIntron) and a branched chain
40-kD peginterferon-alfa-2a (Pegasys).
A double-blind, randomized, controlled trial was
presented at the 2000 meeting of the European
Association for the Study of the Liver that compared 3
regimens of peginterferon-alfa-2b (0.5, 1.0, and 1.5
mcg/kg per week) with standard IFN-alfa-2b 3 MU given
3 times weekly in previously untreated patients with
hepatitis C. The sustained response rates for patients
who received 0.5, 1.0, and 1.5 mcg/kg of the pegylated
IFN were 18%, 25%, and 23%, respectively, compared
with a 12% sustained response rate found in patients
who received the conventional IFN. The overall
genotype 1 response rate was 14% in both the 1.0- and
1.5-mcg/kg groups (see Figure 5).
Figure 5. End-of-treatment viral response, sustained
viral response, and genotype response with
EOT = end-of-treatment response; SVR = sustained
Zeuzem and colleagues reported the results of a
trial comparing once-weekly peginterferon-alfa-2a at a
dose of 180 mcg with standard-dose interferon-alfa-2a
3 times weekly for 48 weeks in previously untreated
patients with hepatitis C. All patients were assessed
at week 72 for a sustained virologic response. These
investigators obtained a sustained response rate of
39% for the pegylated-IFN group compared with a 19%
response rate for the standard-IFN group. A sustained
response rate of 28% was seen in patients infected
with HCV genotype 1 who received peginterferon-alfa-2a
(see Figure 6). The frequency and severity of adverse
events were similar in both treatment groups.
Pretreatment factors associated with a sustained
response, in order of significance, included genotype
other than type 1, alanine aminotransferase quotient >
3, HCV RNA level < 2 million copies by the Cobas
Amplicor HCV PCR (version 2.0 ; Hoffmann-LaRoche,
Basel, Switzerland), body surface area < 2 M2, lack of
bridging fibrosis or cirrhosis, and age < 40 years.
Figure 6. End-of-treatment viral response, sustained
viral response, and genotype response with
EOT = end-of-treatment response; SVR = sustained
In the largest trial of cirrhotic hepatitis C patients
receiving IFN therapy performed to date, Heathcote and
colleagues reported on the use of pegylated
IFN-alfa-2a in the treatment of patients with bridging
fibrosis or cirrhosis (see Figure 7). Patients were
randomized to receive IFN-alfa-2a 3 MU 3 times per
week, 90 mcg of peginterferon-alfa-2a weekly, or 180
mcg of peginterferon-alfa-2a weekly, for a total of 48
weeks, and were followed up for 24 weeks. In an
intention-to-treat analysis, a sustained response
(response at week 72) was seen in 8%, 15%, and 30% of
patients treated with standard IFN-alfa-2a, 90 mcg of
peginterferon-alfa-2a, and 180 mcg of
peginterferon-alfa-2a, respectively. The difference in
rate of response between the standard-IFN and
180-mcg-peginterferon groups was statistically
significant. The sustained response of patients
infected with genotype 1 and non-1 who were treated
with the higher dose of peginterferon was 13% and 51%,
Figure 7. End-of-treatment virologic response and
sustained viral response in pegylated IFN alfa-2a
Cirrhotic Trial.[105 ]
A previous small dose-finding study by Glue and
coworkers showed that peginterferon-alfa-2b and
ribavirin were safe when used in combination. The
results of a larger trial using combination
peginterferon-alfa-2b plus ribavirin in previously
untreated patients with hepatitis C were reported in
October 2000 at the annual meeting of the American
Association for the Study of Liver Diseases (AASLD) in
Dallas, Texas. Results showed that the overall
sustained response of patients to
peginterferon-alfa-2b given at 1.5 mcg/kg per week,
plus ribavirin 1000-1200 mg/day, was 54%. The response
rates of patients with genotype 1 and non-1 to this
regimen were 42% and 82%, respectively.
The FDA approved pegylated IFN-alfa 2b monotherapy in
January 2001. The use of combination pegylated IFN
plus ribavirin is still under investigation, with
several large trials currently underway to determine
the effectiveness of this new regimen.
Mass screening for hepatitis C by means of hepatitis C
antibody testing does not appear to be a
cost-effective strategy. However, an abstract
presented at the AASLD meeting in October reported
that alanine aminotransferase screening for chronic
hepatitis C is cost-effective in individuals between
15 and 58 years of age (ie, across broad age groups).
Improvements in cost efficiency may be obtained
through identification of risk factors for HCV prior
Several models have been developed in an effort to
estimate the cost-effectiveness of both IFN
monotherapy and combination IFN/ribavirin therapy for
the treatment of patients with hepatitis
C.[72,108,109] Bennett and associates reported
that when using a 5% discount rate, the marginal
cost-effectiveness ratio of 6 months of IFN
monotherapy in previously untreated patients with mild
histologic disease was well within the range of other
well-accepted medical interventions. Kim and
colleagues, using a 3% discount rate, estimated
the marginal cost-effectiveness ratio for 6 months of
IFN monotherapy to be $4000 per quality-adjusted life
year gained, and $5000 per quality-adjusted life year
gained for 12 months of IFN monotherapy. Both of these
figures are within the range of acceptability to our
society, and therefore, therapy is considered
cost-effective. This study also found that IFN
monotherapy was not cost-effective in patients older
than age 60.
Combination therapy with IFN and ribavirin is
significantly more expensive than IFN monotherapy.
Wong and colleagues evaluated the
cost-effectiveness of combination therapy vs IFN
monotherapy for a treatment duration of 24 and 48
weeks. Both the 24- and 48-week IFN-plus-ribavirin
regimens were more cost-effective than 48 weeks of IFN
monotherapy. Combination therapy for a duration of 24
weeks was found to be more cost-effective in patients
with genotype 2 and 3 disease. In all other evaluated
parameters, including viral load and underlying
histology, combination therapy for a 48-week duration
was more cost-effective than the 24-week regimen.
The advent of pegylated IFN has raised questions about
its relative cost-effectiveness. This concept is
difficult to analyze at present, because pegylated IFN
has only just been approved for use in the United
States, and therefore, its pricing is unknown.
However, assuming that pegylated IFNs significantly
improve sustained response rates, cost-effectiveness
can be estimated in the absence of pricing. Based on
this assumption, Wong estimated that if
peginterferon-alfa-2b increases the sustained response
rate by 10% to 30% and increases relative costs by 10%
to 30%, a 48-week course should both prolong life and
One of the dilemmas facing clinicians is whether to
treat a patient who has hepatitis C and mild disease
on liver biopsy. Wong and colleagues evaluated
this scenario from the perspective of
cost-effectiveness. In a mathematical model, they
compared the cost of immediate combination IFN and
ribavirin therapy vs watchful waiting for patients
with histologically mild disease. While this model
suggested that periodic biopsies would avoid
institution of therapy in many patients, immediate
treatment of these patients was found to be
cost-effective by eradicating virus and thereby
potentially preventing disease progression.
Quality of Life
The affect of hepatitis C on the quality of life is
beginning to emerge as an important parameter in the
evaluation of infected patients. Physicians have the
perception that patients with hepatitis C are largely
asymptomatic, and that having the disease seldom has
an impact on patients' lives. However, studies with
large numbers of patients are showing that hepatitis C
does indeed negatively affect quality of
Until recently, quality-of-life instruments were not
validated for use in patients with chronic hepatitis
C. Several instruments -- such as the hepatitis
quality-of-life questionnaire (HQLQ) and the
short-form 36 (SF-36) -- have now been validated for
use in this setting (see Figure 8). The SF-36 is a
simple questionnaire that includes 36 questions that
evaluate 8 domains of general well-being. Higher SF-36
scores represent better quality of life.
Figure 8. Domains represented by Short Form-36.
Foster and colleagues evaluated quality of life
in noncirrhotic patients prior to initiation of
treatment. In all 8 domains of the SF-36, hepatitis C
patients reported a significantly lower quality of
life than did controls. The subgroup of patients with
hepatitis C who had used intravenous drugs in the past
showed the greatest impairment in quality-of-life
scores. The amount of inflammation on liver biopsy was
not associated with the degree of impairment of
quality of life.
Bonkovsky and coworkers confirmed in a study of
642 patients that individuals with hepatitis C report
lower quality-of-life scores than do healthy controls.
Additionally, findings showed that patients who had a
sustained response to IFN monotherapy experienced
significant improvements in perceived wellness and
functional status, which then translated into
significant improvements in quality of life. Ware and
colleagues used the HQLQ to evaluate changes in
quality of life in IFN monotherapy relapse patients
treated with combination IFN and ribavirin therapy. A
sustained virologic response was associated with
improvements in vitality, social functioning, and
Antiviral therapies are associated with a decline in
quality of life during therapy. This decline
returns to baseline with cessation of therapy.
This trend was recently demonstrated to be similar for
newer agents as well, such as
Hepatitis C patients have lower quality-of-life scores
than the general population, and the evaluation of
quality of life thus takes on greater importance in
the care of hepatitis C patients. Abnormalities in
quality of life are not entirely attributable to
histologic disease severity. Newer therapies, such as
the pegylated IFNs, may help improve quality of life
both during and after therapy.
The rate of complementary medicine use by hepatitis C
patients dissatisfied with conventional medications is
estimated to be as high as 60%. Various types of
agents and approaches are used in this setting,
including milk thistle, vitamin therapies, Chinese
herbal therapies, acupuncture, and
lifestyle-modification techniques. Despite the
widespread use of these modalities, few -- if any --
well-designed clinical trials evaluating the efficacy
of these therapies in hepatitis C have been published.
Silymarin or milk thistle is the most common
alternative medication used by patients with
hepatitis. Silymarin, which exhibits certain
antioxidant properties and may function as a
free-radical scavenger, has been used to treat all
forms of liver disease for more than 2000 years. It
appears to be safe for use in this setting. The
effects of this agent on HCV, however, have never been
formally evaluated in controlled trials. Recently,
results of a controlled trial showed no benefit of
silymarin use in patients with primary biliary
The widespread use of these products does present some
serious health risks. Many patients who take
alternative therapies either do not seek, or delay the
use of, conventional therapies, which may have been
effective. In addition, many alternative therapies are
associated with significant liver toxicity. Common
examples of hepatotoxic agents include chaparral leaf,
valerian, skullcap, mistletoe, germander, Jin Bu Huan,
and pyrrolizidine alkaloids. These products are
available over the counter. Therefore, alternative
medicines should be used with caution.
The increasing use of alternative medicines in
hepatology has been fueled by patient dissatisfaction
with conventional therapies. Physicians must keep an
open mind and familiarize themselves with the
purported efficacy and potential toxicities of
alternative medications in order to provide effective
counsel to their patients. Patients must inform their
physicians of all their medications, alternative or
conventional. Together, patients, pharmacists, and
physicians must ensure that hepatotoxic agents are not
Progress in the knowledge of the natural history and
treatment of hepatitis C has expanded tremendously
since the discovery of the hepatitis C antibody in
1989. This viral disease is transmitted primarily in a
parenteral manner, with previous recreational drug use
and previous blood or blood product transfusion being
the greatest risk factors. Diagnosis of hepatitis C is
made by the detection of viral particles in the blood,
and liver biopsy is essential to determine the extent
of damage caused by this virus. Current therapies are
based upon dual treatment with IFN and ribavirin.
Recently, a new long-acting pegylated IFN has been
approved for use as monotherapy in the United States,
and any new agents are under development for the
treatment of hepatitis C. The next decade hopefully
will bring even greater advances in our knowledge of
this common liver disease.
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