Hepatitis C

Hepatitis C, first known as non-A, non-B hepatitis, was first identified in 1974 by Albert
Prince. Much was involved in studying this unknown infectious agent. Finally, in 1988,
scientists at the Chiron Corporation cloned and discovered the cause of non-A, non-B
hepatitis as a virus and labeled the disease as hepatitis C. Extensive research led to the first
blood antibody screening test for HCV in 1990. Since then, hepatitis C infections have
decreased significantly as all donated blood is now screened for the virus. Despite the
decrease, more than 170 million people are infected, making hepatitis C the most common
cause of liver disease worldwide.

1. Virology and Pathogenesis

Hepatitis C is a single-stranded RNA virus belonging to the Flaviviridae family and the
Hepacivirus genus. The
9.6 kilobase long virion contains structural and nonstructural (NS) peptides. A
nucleocapsid core and glycoproteins are within the structural part of the genome that
functions to assemble and enter the host. The NS genome contains proteins labeled NS2 to
NS5. The function of each protein is still in question; however, it is known that NS5 may be
responsible for RNA viral replication. What makes HCV unique is there are at least six
identifiable genotypes and more than 90 subtypes. The genotypes are numbered 1 to 6,
and are further divided into subtypes (e.g., genotype 1a, 1b, 2a, or 2b). Genotypes are
geographically specific. For example, genotype 1a is commonly found in patients located in
the United States and in Northern Europe, whereas genotype 4 is common in Africa and the
Middle East. In the United States, about 75% of those infected with HCV have either genotype
1a or 1b, followed by about 14% for genotype 2a or 2b, and a little more than 5% for genotype
3a. There is no difference in disease severity or clinical outcomes based on genotype. Its
primary function may be used to determine the likelihood of therapeutic response. For
example, those with genotype 2 are more likely to benefit from treatment than those who
have genotype 1. Regardless of genotype, hepatitis C is a chronic disease that persists for
years. Viral resistance may be associated with the host’s ineffective immunity against the
HCV. It is believed that the cytotoxic T lymphocytes against the HCV infection are ineffective
in eradicating the virus, thus allowing it to continue damaging the hepatic cells. Thus,
immunocompromised individuals are less likely to eliminate HCV.

2. Epidemiology and Risk Factors

Hepatitis C is a bloodborne infection that affects individuals worldwide. In the United

States alone, it is estimated that close to 4 million people are infected with HCV and

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almost 75% of this population have chronic hepatitis C infections. The prevalence is
highest among non-Hispanic blacks (3.2%) compared to non-Hispanic whites (1.3%) and
men are more likely to be infected than women. The incidence of hepatitis C has
decreased significantly from 230,000 new cases in the 1980s to 38,000 cases in the 1990s.
The decreased incidence is a result of screening blood donors for the hepatitis C
antibodies. By and large, the most common risk factors associated with acquiring the
HCV are blood transfusions before the 1990s and intravenous drug use. Currently, the risk
for HCV infection from blood transfusions is minimal. At present, intravenous drug use
is responsible for most hepatitis C transmissions. The risk includes the use of
contaminated paraphernalia used for drug preparation which is shared among the users.
It is encouraging that awareness is increasing on how to decrease the transmission of the
virus through needle programs. Another risk factor (2%) is accidental needle sticks in the
health care environment (e.g., surgeons, correctional facility personnel, or emergency
medical technicians). The rate of becoming anti-HCV- positive is about 2% for those who
are infected with an accidental needle stick from a HCV-positive source. Individuals
engaged with multiple sexual partners are at greater risk of being infected with HCV
compared to individuals in long-term monogamous relationships, where the prevalence of
HCV infection is less than 5%. There also is a 5% prenatal risk for infants born to mothers
who are anti-HCV-positive; however, this rate increases to about 15% when coinfected
with both HCV and HIV. The HCV transmission is more likely to occur when the mother
has active viremia at the time of birth. Transmission of HCV through breast milk is
unknown. Percutaneous exposures such as body piercing and tattooing performed
unprofessionally may be a possible transmission mode of the virus. About 10% of the
individuals infected with HCV have no identifiable risk factors.

3. Natural History
the natural history of the progression to cirrhosis is not clear and is estimated to occur
in 10–20% of cases, it may take up to 20–40 years from the time of exposure to advance
from fibrosis to cirrhosis. Factors contributing to the development of cirrhosis include
alcohol use, gender, infection at an older age, and coinfection with HIV or HBV. The rate
of developing HCC increases 1–4% per year when cirrhosis is confirmed. The estimated
death rate is 1.8 deaths per 100,000 people per year. Cirrhosis caused by HCV is one of the
primary reasons for liver transplantation in the United States.

4. Clinical Course and Clinical Manifestation

As with other types of hepatitis, individuals infected with HCV usually are asymptomatic;
less than 30% actually present with symptoms that affect quality of life. Elevated serum
aminotransferases associated with acute hepatitis C may develop 2–26 weeks after

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exposure. The incubation period may span between 7 and 12 weeks; however, almost all
cases occur within 5–12 weeks. When an acute infection is documented, it is not uncommon
to have ALT concentrations elevated to more than 15 times the upper limit of normal. In
addition to having positive anti-HCV, HCV RNA is detectable early in the disease course and
the presence of anti-HCV develops 5–6 weeks after exposure. Symptoms are mostly
nonspecific, consisting of weight loss, anorexia, flu-like complaints, fatigue, abdominal pain,
and arthralgias. In less than about 33% of the cases, jaundice can occur with other uncommon
symptoms such as fever and rash. Acute hepatitis C resolves within 6 months from the
time of exposure. However, when disease persists beyond 6 months, it is then considered
chronic hepatitis C. The most common symptoms are fatigue and dull upper right quadrant
pain. Uncommon symptoms include nausea, pruritus, arthralgia, and anorexia. Serum
aminotransferases, specifically ALT concentrations, are mildly elevated, with about 25%
having a level more than 2 times the upper limit of normal. About 30–40% of the chronic
hepatitis C cases have detectable HCV RNA with ALT concentrations less than 2 times the
upper limit of normal. Those with documented bridging fibrosis or cirrhosis may have
splenomegaly and/or hepatomegaly on examination. They also may present with
complications of cirrhosis, such as encephalopathy or ascites.

5. Diagnosis and Serological Testing

As with hepatitis A and B, diagnosing patients with hepatitis C may be difficult because
most patients present with minimal or no complaints. Moreover, acute hepatitis C often is
dismissed by the patient because of the flu-like symptoms. Serological screening assays
for anti-HCV are used to identify individuals who are infected with HCV. These assays
include either the enzyme immunoassays or the chemiluminescence immunoassay. These
tests are effective in screening and detecting the virus in more than 97% of infected
individuals. However, a confirmation test is required because of high false-positive rates
with enzyme immunoassays and chemiluminescence immunoassay tests. Confirmation
tests include either the recombinant immunoblot assay or the nucleic acid test that
may qualitatively or quantitatively measure HCV RNA. The Centers for Disease Control
and Prevention has developed recommendations for laboratories to assist health care
professionals in confirming the diagnosis of HCV (Figure 1-3).

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 Negativea
Screening test for anti-HCV REPORT

OR

Positivesa defined by s/co ratios

Positives with highb s/co ratios Positives with lowb s/co

OR
REPORT

RIBA for anti-HCV Nucleic acid test for HCV RNA

Negative Positive
REPORT

Positive Negative Indeterminate RIBA for anti-HCV

REPORT REPORT REPORT Positive Negative Indeterminate

REPORT REPORT REPORT

6. Managing Hepatitis C
a) Prevention

The Centers for Disease Control and Prevention has recommended primary and secondary
methods for reducing the risk of contracting HCV infection and minimizing the
development of chronic liver disease and its complications. Primary prevention strategies
include screening and testing blood, plasma, organ, tissue, and semen donors; virus
inactivation of plasma-derived products; risk-reduction counseling and services; and
implementation and maintenance of infection-control practices. No vaccines are currently
available to immunize against hepatitis C; thus, identifying and counseling patients at
high risk are reasonable to decrease their chance of acquiring the infection. Secondary
prevention is done by identifying people who are HCV-positive through diagnostic testing
and initiating treatment if necessary. Those who should be routinely screened for the HCV
include past and current intravenous drug users, people with clotting factor disorders who
received products manufactured before 1987, long- term hemodialysis patients, and those
having persistently elevated ALT concentrations. Others who should be screened include
people who received transfusions or organ transplants who received blood from a donor
who later tested positive for HCV and/or who received blood products or an organ transplant
before July 1992. Health care providers, emergency medical technicians, and public safety
workers who are exposed to HCV-positive blood after an accidental needle stick also are at
risk. Baseline and follow- up testing of anti-HCV and ALT should be obtained immediately
and 4–6 months after exposure. Finally, infants born to mothers who are HCV-positive should

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be screened for HCV no sooner than 1 year of age, as the anti-HCV usually will be
undetectable before this time. Hepatitis C virus RNA levels should be measured at 1–2
months of age if earlier testing is sought. Immunoglobulin, which is effective for
postexposure prophylaxis against hepatitis A and B, is ineffective for hepatitis C.

b) Treating Hepatitis C
The primary treatment goal for hepatitis C is HCV eradication measured by undetectable
HCV RNA concentrations (virological). Other goals include normalization of ALT
concentrations (biochemical) and improving fibrosis scores to minimize the risk of
developing cirrhosis (histological) and the progression to end-stage liver disease and HCC.
Ultimately, treatment should improve signs and symptoms associated with hepatitis C
and its complications to decrease morbidity and mortality.

c) HIV/HCV Coinfection
Patients coinfected with HIV should be considered for hepatitis C therapy as end-stage
liver disease can develop much faster compared to those without HIV. The development
of cirrhosis may be associated with highly active antiretroviral therapy; however, this
is still being debated. Even though highly active antiretroviral therapy significantly
decreased hospital admissions for opportunistic infections, hospitalizations associated
with liver complications have increased. In addition, immune deficiency may support
fibrosis progression; however, this is controversial. Conflicting studies have shown
fibrosis scores increased and decreased when CD4 cell counts were less than 250 cells/mm3;
further studies are being conducted to determine who is more likely to develop fibrosis.
The severity of liver disease also may depend on patient age at onset of the infection, as
those older than 40 years of age are more likely to have significant scaring of the liver.
Regardless, early treatment may achieve SVR, minimize the risk of developing active
necroinflammation or fibrosis, and prevent end-stage liver disease. Coinfected patients
treated with PEG-IFN and ribavirin have an overall end of treatment response of 41–47%
and a more variable SVR between 27% and 40%. Similar to monoinfected patients,
genotype is a significant factor in determining SVR. Only 14–29% of individuals infected
with genotype 1 sustain response compared to 62–73% in patients infected with
genotype 2 or 3. In addition, patients are more likely to achieve SVR (37–51%) if HCV
RNA levels become undetectable by week 12 of therapy compared to those who did not
achieve SVR. Therefore, week 12 of treatment is the significant time point in determining
the likelihood of responding to therapy.

d) Treating Recurrent HCV after Liver Transplantation

Treatment for the recurrence of hepatitis C after liver transplantation should be
decided on a case-by-case basis. It is known that as early as 2–4 days after the

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transplantation, HCV RNA levels may become detectable. About 25% develop moderate
hepatitis confirmed by liver biopsy at 1 year after liver transplantation. It is estimated
that by
5 years after transplantation, about 20% will develop cirrhosis and increase their risk
of allograft rejection

e) Treating Nonresponders
Currently, the Hepatitis C Antiviral Long-term Treatment against Cirrhosis trial is ongoing
to determine if maintenance therapy would be beneficial in delaying fibrosis progression
and reducing the risk for hepatic decompensation and HCC in patients who did not
respond to retreatment with PEG-IFN and ribavirin.

f) Treatment Duration for Hepatitis C

Patients with genotype 1 should be treated with PEG-INF and ribavirin (1 g if patient weighs
75 kg or less and 1.2 g if patient weighs more than 75 kg) for 48 weeks (Figure 1-5), whereas
patients with genotype 2 or 3 should be treated with PEG-INF and ribavirin 800 mg for 24
weeks (Figure 1-6). In most cases where patients have compensated liver disease, SVR is
achieved in 75–85% of those with non-genotype 1 disease.
Side Effects Associated with HCV Therapy and Management. There are several side
effects associated with treating hepatitis C (Table 1-10). The overall rate of discontinuing
therapy ranges between 10% and 20%. Dose reductions associated with either drug usually
range from 25% to 35%.

Flu-like Symptoms. Almost all patients treated with any IFN formulation will experience
mild to moderate flu-like symptoms (fevers, chills, rigors, myalgias, arthralgias, and
fatigue) and some will have headaches. Temperatures up to 104°F are not uncommon. These
initial symptoms usually subside with continued therapy, and diminish by the second to
fourth IFN dose. Administering antipyretic drugs (acetaminophen and nonsteroidal anti-
inflammatory drugs) before the IFN injection is effective in minimizing flu-like symptoms.
It is important to ensure adequate hydration, drink at least 64 ounces/day of fluid,
and to avoid caffeinated beverages. If symptoms persist, administering either a PEG-IFN
or IFN injection before bedtime may be beneficial to decrease the patients’ awareness of
the fevers and chills.
Psychological Symptoms. Cases of psychiatric adverse effects have been reported with
IFN treatment. The most common adverse effects include depression and irritability and
rarely suicidal ideations have occurred. An estimated 30–60% of patients may have
pretreatment depression. Interferon-induced depression occurs in about 20–35% of
patients who have no psychiatric history before starting HCV therapy. Patients
complaining of depression describe it as slow thinking, fatigue, decreased attention or
increased restlessness, and in some cases hopelessness, sadness, and anger. Less than 2%

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of patients have suicidal ideation. The risk versus benefit for hepatitis C treatment must
be weighed, especially in patients with a history of or uncontrolled neuropsychiatric
disorders, as treatment may exacerbate or worsen their psychiatric illness.
Hematological Adverse Effects. About 10–20% of the patients treated with IFN with
or without ribavirin will develop hematological abnormalities, including neutropenia,
thrombocytopenia, and/or anemia. In most cases, dosage reduction and discontinuation
of therapy are required, but when this occurs, the response to viral clearance decreases.
Adherence to treatment is significant in increasing SVR.

Anemia. The primary toxicity associated with ribavirin is a dose-dependent hemolytic anemia
that usually resolves within 7–8 weeks after drug discontinuation. The mechanism by
which this side effect occurs is red blood cell uptake of ribavirin and transformation into
ribavirin triphosphate. This formation in the red blood cells depletes intracellular adenosine
triphosphate that normally acts as an antioxidant. Thus, with the depletion of adenosine
triphosphate, the antioxidant defense mechanism is impaired, causing oxidative
membrane damage to the red blood cells and leading to premature extravascular red blood
cell destruction by the reticular endothelial system. In addition, IFN also may play a
minor role in producing anemia by bone marrow suppression of erythroprogenitor cells.
Therefore, it is believed that ribavirin and IFN cause a “mixed” anemia. In most cases,
hemoglobin drops between
2.9 g/dl and 3.7 g/dl within 4 weeks of treatment initiation. A decrease in hemoglobin
concentrations to less than 10 g/dl is seen in about 10–15% of the patients taking PEG-IFN and
ribavirin. Dosage reductions are more commonly required in women than men. A decrease
in hemoglobin by more than 3 g/dl from baseline is observed in at least 50% of the
patients treated. About 10–25% of the patients will require dosage reductions when
hemoglobin concentrations are low and 5–26% of the patients require all therapies to be
discontinued because of intolerable symptoms associated with anemia.
Hemoglobin and hematocrit concentrations should be monitored after initiating therapy
at weeks 2 and 4 as these concentrations usually decrease within the first 1–2 weeks of
treatment. Thereafter, these concentrations can be monitored on a monthly basis if results
are clinically stable. Laboratory monitoring is imperative, especially in patients with a history
of cardiac disease, and appropriate screening for cardiac abnormalities should be done
before beginning treatment.
Other Adverse Effects. There are several uncommon adverse effects that can occur with
IFN, PEG-IFN, or ribavirin treatment. If side effects do occur, HCV therapy may need to be
discontinued. Therefore, patients should be screened for any of these disorders before
initiating therapy as treatment may exacerbate or worsen these medical conditions (Table
1-10).
Contraindications and Warnings. Ribavirin is documented to cause significant
teratogenic and embryocidal effects and is pregnancy category X. Animal trials have shown

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that ribavirin causes malformation of the eye, jaw, limbs, palate, skeleton, skull, and
gastrointestinal tract. Therefore, precaution must be taken to prevent pregnancy. Women
of childbearing age and men with female partners should use two forms of contraception
during therapy and 6 months after therapy.
Ribavirin should not be used in patients with renal insufficiency, especially if the
creatinine clearance is less than 50 ml/minute. Patients with uncontrolled endocrine
disorders (e.g., diabetes or thyroid disease), ophthalmic conditions, and cardiac
disturbances must first have the disease stabilized before starting HCV therapy.

7. Investigational Drugs for Chronic Hepatitis C

The highest overall SVR rate is about 50–60% for the treatments available for HCV,
which is far from perfect. In addition, the drugs used for hepatitis C have significant
adverse effects profiles, and in most cases require dosage reductions or discontinuations.
Currently, several drugs are in clinical trials for HCV treatment.

a) Viramidine
Viramidine is a prodrug that is converted by adenosine deaminase in vivo to the active
component, ribavirin. This investigational drug is associated with less erythrocyte uptake,
thus causing less hematological toxicity. In addition, it has at least a 3-fold increased
duration within the hepatic cells, which could result in better outcomes.

b) Merimepodib
Merimepodib (VX-497) is a selective inhibitor of inosine monophosphate dehydrogenase,
an enzyme that decreases DNA and RNA replication by regulating and decreasing the
production of intracellular guanosine triphosphate. Merimepodib exhibits potent
antiviral effects, including activity against HCV.

c) Thymosin Alpha 1
Thymosin alpha 1 (Thymosin) is a synthetic, nonglycosylated, 28 amino acid peptide
that acts as an immunomodulator by stimulating type 1 helper T-cell and natural killer cell
production. In addition, it stimulates the activity of IFN- , interleukin-2, and interleukin-3.

d) Therapeutic Vaccine
The most effective therapy for treating hepatitis C includes PEG-IFN and ribavirin.
However, not all patients respond to treatment. It has been theorized that therapeutic
vaccines can enhance the immune response and possibly treat the disease rather than
prevent it. The first hepatitis C therapeutic vaccine developed is a 135 amino acid
recombinant HCV E1 protein derived from the HCV genotype 1b strain.

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