Hepatitis C virus (HCV) affects 170 mil-lion people
worldwide. Around 1.8 per-cent of the U.S. population is positive for HCV
antibodies. Given that about 75 per-cent of these individuals demonstrate viral
some time, blood transfusion was the primary cause of HCV infection in
developed countries. With the introduction of blood-screening measures in the
early 1990s, transmission by blood transfusion has decreased considerably.
However, new cases continue to emerge, primarily as a result of intravenous
drug use and percutaneous or mucous mem-brane exposure. Nosocomial infection is
also a cause of HCV as the rate of transmis-sion is estimated to be 3 percent
in needle-stick injuries.
HCV belongs to the family of flavivi-ruses. The
structural components include the core and two envelope proteins. One of the
envelope proteins, E2, contains the binding site for CD81, which is present on
hepatocytes and B lymphocytes and is thought to function as a cellular
recep-tor for the virus. The regulatory proteins include helicase, protease,
and polymerase. HCV replicates by means of an RNA-dependent RNA polymerase that
lacks a “proofreading” function. This process can result in the evolution of
genomic varia-tions of the virus within an individual, making immune-mediated
control of HCV difficult. In addition, six distinct genotypes and around 100
subtypes of HCV have been identified. Genotypes 1a and 1b are the most
prevalent in the United States and western Europe, followed by genotypes 2 and
3. Genotype helps to predict effective-ness of antiviral therapy, with
genotypes 2 and 3 demonstrating the best responses.
Study of acute HCV infection has been limited
because these individuals are often asymptomatic. It is currently thought that
the pathology, which results from HCV infection, is the result of both direct
cytopathic effects of the virus and the
immune response. The immune response to HCV, as
with HBV, is still incompletely understood.
Due to the strict affinity of HCV for human cells,
in the past only humans and higher primates such as monkeys could be infected
with HCV. However, rodents make for a more appropriate and useful biological
model in that their gestational periods are short, they are small, and cost
less to maintain. Some models, which are currently being developed, include an
immunotolerized rat and a Trimera mouse model. In the immunotolerized rat
model, human hepatoma cells (Huh7) are introduced to fetal rats in utero and
transplanted with the same cell line after birth. The rat is subsequently
infected with HCV using HCV-positive human serum. In the Trimera model, mice
are irradi-ated and reconstituted using SCID mouse bone marrow. HCV-infected
liver frag-ments from patients with HCV or ex vivo infected HCV liver fragments
are trans-planted into the ear pinna or under the kidney capsule. More research
is needed, but these particular models could be help-ful in studying the
effects of therapeutic regimens against HCV. In addition, several transgenic
mouse models have been stud-ied that have allowed for the analysis of the
direct cytopathic effects of HCV protein and its correlation with the
pathogenesis of chronic hepatitis C.
In the rare instances in which clinical acute
hepatitis has been identified, symp-toms have included jaundice, malaise, and
nausea. Although infection becomes chronic in about 75–80 percent of affected
individuals, it is often characterized by a prolonged asymptomatic period of
any-where from twenty to thirty years. Patients may present with nonspecific
symptoms of fatigue (90 percent). Severe complications
and death tend to occur primarily in indi-viduals
who progress to cirrhosis, which is around 15–20 percent of infected patients.
Extrahepatic manifestations of HCV tend to be associated with autoimmune and
lymphoproliferative states. These include cryoglobulinemia, vasculitis, and
mem-branoproliferative glomerulonephritis. In addition, a correlation between
HCV infec-tion and lichen planus, sicca syndrome, and porphyria cutanea tarda
has been noted. Co-infection with other viruses such as HIV-1 and HBV also tend
to accelerate the disease process.
Liver biopsy is the gold standard for determining
the activity of HCV-related disease as histologic staging is the only reliable
predictor of prognosis. A biopsy can also help to rule out other causes of
dis-ease. Patients who demonstrate fibrosis or cirrhosis on liver biopsy, have
genotypes 2 and 3, and present with symptoms such as fatigue and extrahepatic
manifestations of disease should strongly be considered for medical therapy.
The mainstay of treatment for HCV includes the
immunomodulatory drugs, pegylated (addition of polyethylene glycol prolongs the
half-life and duration of activ-ity) IFN-α-2a, -2b, and an antiviral agent, ribavirin. The HCV RNA level and HCV
genotype must be obtained before starting medical therapy. Serum HCV RNA
testing is the gold standard to determine effec-tiveness of medical therapy.
Treatment is aimed at a sustained response – HCV RNA should be undetectable
twenty-four weeks after discontinuation of medical therapy in individuals with
either genotype 2 or 3 and for forty-eight weeks in individuals with genotypes
1a or 1b.
Patients with decompensated HCV-related cirrhosis
and some patients with early stages of HCC require liver transplantation for
survival. Complications include reinfection of the graft with HCV and
recurrence of hepatitis and even cirrhosis. New therapies are necessary to
improve long-term outcome of liver transplanta-tion, either to prevent
infection of the liver transplant or to treat HCV infection more effectively.
With better characterization of the replicative cycle of HCV, it may be
pos-sible to develop virus-specific inhibitors. Potential targets include the
HCV prote-ases, helicase, and polymerase as well as the cell surface receptor