Hepatitis
C virus (HCV) is a heterogeneous, single-stranded, positive-sense RNA virus
belonging to the Flaviviridae family. Like many other RNA viruses, HCV
has an inherently high mutation rate, resulting in considerable genetic
heterogeneity throughout the genome. This genetic heterogeneity subdivides
the hepatitis C virus into six major genotypes that vary in distribution
worldwide (
47). Genotype
1 appears to be the predominant type in Canada (
46-49).
Quasispecies are closely related variants of a single genotype within a
single individual
, which arise from mutations that occur during
viral replication. Quasispecies diversity may increase with time and contribute
to interferon resistance and viral persistence.
Information
on the rates of development of chronicity after an initial HCV infection
comes largely from studies of post-transfusion hepatitis. In these studies
viral clearance from serum occurred in about 20-30% of patients initially
infected with hepatitis C. It is not known whether this is also true for
hepatitis C acquired through other routes. To be confident that viral clearance
has been achieved PCR-based assays must be used. Negative HCV RNA by PCR
assays indicate viral clearance from serum, but give no information about
the state of HCV in the liver or in other privileged niches (e.g., lymphocytes).
Thus, given the current state of knowledge complete viral clearance cannot
be ascertained with certainty. Therefore, patients who are anti-HCV-positive
who have spontaneously developed negative HCV RNA by PCR should continue
to be monitored at intervals for the presence of liver disease.
The outcome of chronic
hepatitis C virus infection is not well defined. A proportion of patients
will ultimately develop cirrhosis and
hepatocellular
carcinoma (
50-52).
However, the proportion of patients at risk for this outcome has not been
accurately determined. Various reports have suggested that the lifetime
risk of cirrhosis in HCV carriers is between 20-50%. Although several factors
have been identified which increase this risk, e.g., alcohol consumption
(
53-55), the magnitude
of increase in risk has not been well defined. Furthermore, the rate at
which disease progresses has also not been completely defined (
56-58).
Some studies have indicated that after 17 years of infection the prevalence
of cirrhosis is no more than 2% (
60).
Other studies have indicated that the mean duration between infection and
the first diagnosis of cirrhosis is about 20 years (
50).
The differences in these studies are accounted for by referral bias.As
a result there is considerable uncertainty about the rate of disease progression.
Factors that increase the risk of progression to cirrhosis include
age over 40, consumption of even moderate amounts of alcohol (53-55),
and increased age of acquisition of infection.Patients infected by
transfusion are also thought to have more aggressive disease, but in this
cohort having a transfusion may be a surrogate marker for increased age
at acquisition of disease, since the transfused population is considerably
older than the average population.
The risk of progression to cirrhosis
also appears related to the degree of liver inflammation and fibrosis seen
at the time of a biopsy. Patients with persistently normal ALT have a lower
likelihood of progression to cirrhosis (
56,60,61).There
is no clear association of disease progression with genotype or viral load.
Co-infection with HIV is associated with higher viral loads, and a more
rapid progression to cirrhosis.
Co-infection
with hepatitis B is associated with a greater risk of HCC than either disease
alone.
Predictions of disease progression depend on the assumption that the
rate of disease progression is linear, and that it takes an equal amount
of time to progress from e.g., stage 1 fibrosis to stage 2 fibrosis as
from stage 3 to stage 4 fibrosis. This assumption may not be correct.
Once cirrhosis has developed the 10 year survival is about 80%. However,
the rate of development of complications of cirrhosis over the same time
period is about 40% (
62).
Over the next 10-20 years
chronic hepatitis C is predicted to be come a major burden on the health
care system in Canada as patients who are currently asymptomatic with relatively
mild disease progress to end-stage liver disease and develop hepatocellular
carcinoma. Predictions in the USA indicate that there will be a 60% increase
in the incidence of cirrhosis, a 68% increase in hepatoma incidence, a
279% increment in incidence of hepatic decompensation, a 528% increase
in the need for transplantation, and a 223% increase in liver death rate.
There are no comparable studies to assess the future health burden in Canada,
but since the demographics in the US and Canada are similar, we can expect
a similar increase in these disease states in Canada.
