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HEPATITIS C: TRANSMISSION RISK, NATURAL HISTORY, AND PREVENTION
Epidemiology
Hepatitis C virus (HCV) is a significant healthcare problem,
affecting more than 170 million people worldwide, or 3-4% of the world’s
population. Prevalence of HCV in different geographic regions varies
from 0.1-12%, with rates of 1.8% in the United States, 2.5-10% in South
America and Africa, and more than 10% in Egypt and Bolivia. Worldwide,
as many as 4 million new infections occur annually. In the United
States, 65% of those infected with HCV are aged 30-49 years.
Risk factors for transmission include intravenous (ie, injection) and
intranasal drug use, contaminated blood products, organ transplantation,
long-term hemodialysis, and vertical transmission during pregnancy. Less
common modes include nosocomial and sexual transmission. In the United
States, most new HCV cases (approximately 36,000 annually, although
underestimation is likely) are related primarily to injection drug use,
while in less developed countries, contaminated injection therapy is
frequently the source of transmission. Although the number of new cases
in the United States is declining because of blood product screening,
the long latency period from time of infection to clinical recognition
portends a substantial clinical impact. By the year 2015, the prevalence
of HCV-associated cirrhosis, decompensated liver disease requiring liver
transplantation, and hepatocellular carcinoma (HCC) will increase
dramatically, making HCV a “silent epidemic.” HCV already accounts for
approximately 8,000-10,000 deaths annually in the United States.
Of additional concern is the impact of HIV co-infection on the
natural history of HCV infection, its transmission, and its response to
treatment strategies. In the United States, an estimated 16% of patients
with HCV are co-infected with HIV and nearly one third of HIV-positive
individuals are also HCV positive. Most of those dually infected
acquired HCV by injection drug use, although unprotected sexual activity
between homosexual males is also a risk factor.
All known HCV isolates have been divided into 6 phylogenetically
distinct groups known as clades, and more than 70 subtypes based on
nucleotide sequences and genetic analysis have been identified.
Epidemiologically and clinically, 11 genotypes have been identified (see
Table 1). Genotype 1b is the most common genotype globally and is
principally transmitted through contaminated blood products. The most common
genotypes in the United States include 1a, 1b, and 3a, with 1a most often
transmitted through injection drug use and accounting for nearly 70% of all
infections. Genotypes 1a, 2a, 2b, and 3a are prevalent in Europe, and
genotypes 6-11 are common in Southeast Asia and Indonesia. Typically, the
genotype, or clade, does not regularly predict clinical presentation,
progression of liver disease, or incidence of HCC, but it does predict
response to antiviral therapy.
Table 1. Epidemiology of the Major HCV Genotypes
| HCV Genotype |
Geography |
Clinical Significance |
| 1a |
United States, Northern Europe |
Most common genotype in the United States |
| 1b |
Worldwide |
Often transmitted by transfusion;
may have a more
aggressive clinical course than other genotypes and higher incidence of HCC;
associated with recurrent hepatitis in patients with liver transplants |
| 2a, 2b |
Europe, Japan, North America |
With genotype 3, excellent treatment responses |
| 2c |
North Italy |
|
| 3a |
India, Europe, United States |
Associated with intravenous drug use; often associated with
hepatic steatosis |
| 6-11 |
Southeast Asia |
|
Data adapted from Hnatyszyn HJ;
Antiviral Therapy 2005;10:1-11.
Transmission
Risk factors associated with HCV infection include injection drug use
(or intranasal if using a blood-contaminated device), receipt of blood
products (prior to 1990 in the United States), long-term hemodialysis,
organ transplantation, receipt of a tattoo from an unsanitary facility,
vertical transmission during pregnancy, and sexual or nosocomial
exposure. Sexual transmission is relatively inefficient, and the risk of
HCV following needle stick injury from contaminated needles ranges from
0-10% (average, 3%). Co-infection with HIV increases the sexual and
vertical transmission rates of HCV. Intrafamily transmission is
uncommon, and the risk of transmission from an infected patient to a
healthcare worker is about 2-5%. Weaker associations include poverty,
high-risk sexual behavior, divorce, and fewer than 12 years of formal
education. With the advent of blood and blood product screening for all
donors in the United States, the risk of acquiring HCV from transfusion
is low (see Table 2). Screening all blood donors with antibody testing
reduced the risk of acquiring HCV to an estimated 1 in 199,000 as
compared to 1 in 144,000 for hepatitis B virus or 1 in 1,048,000 for
HIV. Furthermore, the addition of nucleic acid testing to screening
likely reduces the risk another 5- to 10-fold. Transmission risk also
varies with age and geography.
Table 2. Risk of Acquiring Hepatitis C Virus Infection*
| Route |
Risk of Acquiring |
| |
Hepatitis C |
Hepatitis B |
HIV |
| Transfusion of blood product^ |
1:199,000 |
1:144,000 |
1:1,048,000 |
| Needle stick |
3% |
30% |
0.3% |
Data derived from Lauer
G, Walker BD; N Engl J Med 2001;345:41-52 and Dodd RY; Int J
Hematol 2004;80:301-305.
*Data apply to US only.
^Data are for all donors to the American Red Cross voluntary blood supply
and do not reflect the use of nucleic acid testing (NAT) for detection of
HCV or HIV. If NAT is applied, the risk of transfusion-associated HCV is
1:1,390,000 and 1:1,525,000 for HIV.
Clinical manifestations and natural history of HCV infection
HCV most commonly results in a chronic infection. Acute HCV infection is not
commonly diagnosed because most patients are asymptomatic. The incubation period
of symptomatic acute HCV ranges from 2-12 weeks, and clinical features include
fatigue, malaise, right-sided abdominal pain, and nausea. Jaundice is uncommon,
occurring in fewer than 25% of patients. Fulminant hepatitis is extremely rare.
Within 1-3 weeks after exposure, HCV RNA is detectable in the blood;
however, only 50-70% of patients have anti-HCV antibodies detectable by
enzyme immunoassay at the onset of their symptoms, whereas 90% are proven
positive by week 12. As transaminases return to reference range levels,
symptoms resolve, usually over several weeks. Spontaneous clearance of HCV
does occur and is usually seen in those infected at a younger age, among
women, and in those with certain human leukocyte antigen (HLA) haplotypes
(HLA-DRB1 and HLA-DQB1). Spontaneous clearance is uncommon if the viremia
has persisted for more than 6 months. Also, evidence suggests that treatment
of acute HCV infection with interferon-α2b or pegylated interferons prevents
progression to chronic infection.
Studies suggest that up to 85% of individuals with HCV develop a chronic
infection, defined as viremia and/or abnormal levels of hepatic
transaminases persisting longer than 6 months. Patients with chronic
infection are usually asymptomatic or have nonspecific symptoms such as
fatigue, anorexia, or weight loss. Symptoms do not accurately predict the
extent of liver disease. Most infections lead to chronic hepatitis and some
degree of hepatic fibrosis; furthermore, 20-30% of infected adults develop
progressive fibrosis over time that leads to cirrhosis. This development is
less common in infected children. Risk factors for developing progressive
fibrosis include older age at time of infection, male sex, use of alcohol,
and co-infection with either chronic hepatitis B virus or HIV. Other factors
may include hepatic steatosis and iron overload and use of hepatotoxins. The
rate of progressive hepatic fibrosis is also higher in patients with
persistently abnormal hepatic transaminase levels. African Americans appear
to have a lower risk of advanced disease; however, they also have a lower
response rate to available therapies.
Life-threatening complications and death usually occur in patients with
cirrhosis. The lifetime risk of developing cirrhosis is approximately
15-20%. After the development of cirrhosis, HCC occurs at a rate of 0-3% per
year, and HCV accounts for nearly one third of all HCC cases in the United
States. The risk of developing HCC is 25 times higher in patients who are
infected with HCV as compared to those who are not. Currently, end-stage
liver disease due to HCV accounts for most liver transplants in the United
States. Even in the absence of significant liver disease, chronic HCV has
been shown to have a negative impact on health-related quality of life
scores.
HCV infection accounts for 8,000-10,000 deaths annually in the United
States. Predictors of death from liver failure, the development of HCC, or
the need for liver transplantation include a history of hepatic
decompensation (ie, ascites, jaundice, hepatic encephalopathy, variceal
bleeding) or serum albumin levels less than 4.1 mg/dL.
Impact of HCV infection on the liver
Since hepatic transaminases do not reliably predict the extent of
hepatic injury, liver biopsy has been used to determine the inflammatory
activity and the degree of fibrosis and, hence, disease prognosis. Key
histologic features of chronic HCV infection include 1) patchy
enlargement of the portal tracts with a predominant lymphocytic
infiltrate, lymphoid aggregates, and piecemeal necrosis into adjacent
lobules; 2) variable bile duct damage and loss; 3) varying degrees of
microvesicular and macrovesicular steatosis; and 4) sinusoidal cell
hyperplasia. Less commonly observed findings include lobular necrosis,
hepatic cell dysplasia, multinucleation, and accumulation of
Mallory-like bodies in hepatocytes. Definitive tissue diagnosis is based
on the identification of viral RNA from tissue homogenates by polymerase
chain reaction, although this is rarely used in clinical practice.
Several disease activity and fibrosis scoring systems (eg, Ishak,
Knodell, Scheuer, Metavir and Batts, Ludwig) are used by pathologists,
although no schema is universally considered most reliable. The extent
of fibrosis and inflammation observed on liver biopsy can predict the
progression of HCV to cirrhosis and can aid in the decision to treat
(see
Hepatitis C Feature Series 2, Issue 5). The risk of cirrhosis
increases over time when the liver biopsy demonstrates significant
periportal inflammation, bridging fibrosis, or both. By univariate
analysis, several factors influence the progression of fibrosis. These
factors include alcohol consumption of more than 50 g/d, male sex, age
at infection, a serum ferritin level of 290 ng/mL or higher, and hepatic
steatosis. Multiple regression analysis indicates that steatosis and
periportal activity correlate with severe fibrosis.
Approximately 25-40% of patients with anti-HCV antibodies have
transaminase levels within the reference range. In many of these patients,
the HCV status is discovered incidentally during blood donation. Some
patients have undetectable HCV RNA levels and therefore appear to have
immunologically cleared their infection spontaneously, while others have
active inflammation and possibly even cirrhosis. The reason for the latter
observation is not clear, but it may be related to an association with HLA
antigen DR13. Patients with reference range transaminase levels have a lower
incidence of advanced inflammation and fibrosis relative to those with
elevated transaminase levels. In patients with reference range transaminase
levels and minimal pathologic changes on biopsy, one option is to monitor
the disease without providing specific treatment.
Prevention of HCV infection
To date, screening the general population for HCV infection has been
controversial. The 2004 US Preventive Services Task Force does not
recommend screening for HCV infection in asymptomatic adults. Although
further studies are needed, screening populations at high risk, such as
injection drug users and pregnant females, especially if they are
infected with HIV, may be reasonable.
Currently, no licensed vaccine to prevent HCV infection exists. However,
counseling individuals infected with HCV may help prevent spread of the
disease. Patients who do not have serologic evidence of immunity to
hepatitis A and B should be vaccinated, especially since infection with the
hepatitis A virus in patients with chronic HCV may result in a more severe
infection than in patients without HCV.
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