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The Scope Of The Hepatitis C Problem:
The hepatitis C virus (HCV) is one of the most significant health problems
affecting the liver. More than 4 million Americans (1.3% of the U.S.
population) and 170 million individuals in the world (3% worldwide) are
infected with hepatitis C virus. The prevalence (number of cases in a
population at a specific time) of hepatitis C virus infections varies in
different parts of the world. For example, the prevalence of hepatitis C virus
in Scandinavia is less than 0.5% of the population, whereas the prevalence in
Egypt is over 20%. In the U.S. and Western Europe, the complications of
hepatitis C virus chronic hepatitis and cirrhosis are the most common reasons
for liver transplantation.
One of the major problems with hepatitis C virus infections is that 85% of
individuals initially infected with this virus will become chronically
infected, usually for decades. The other 15% of hepatitis C virus infected
individuals simply have an acute infection; that is, one that resolves
spontaneously in a few weeks or months. The propensity of hepatitis C virus to
cause chronic infection is explained by the extraordinary ability of this virus
(in contrast to most other viruses, including hepatitis A) to avoid destruction
by the body's immune defense system. (The immune system includes antibodies and
specialized white blood cells, called lymphocytes).
Once established, chronic hepatitis C virus infection causes an inflammation of
the liver called chronic hepatitis. This condition can progress to scarring of
the liver, called fibrosis, or more advanced scarring, called cirrhosis. Some
patients with cirrhosis will go on to develop liver failure or the
complications of cirrhosis, including liver cancer.
In the U.S., the number of new cases of hepatitis C has declined over the last
10 years from a peak of some 200,000 annually to about 28,000 in 1999. This
striking reduction is the result of a drop in the number of cases of acute
hepatitis C among intravenous drug users. Perhaps this decrease among the drug
users is due to changes in their practices brought on by their awareness of HIV
infection. Furthermore, sensitive blood tests for the detection of hepatitis C
virus became available to screen the blood supply and individuals at high risk
for hepatitis C virus.
Indeed, with blood being routinely screened for hepatitis C virus, the risk of
a single unit of blood transmitting hepatitis C today is less than 1 in
100,000. Still, because of the many individuals who became infected 10 to 20
years ago, the number of deaths (or the need for liver transplantation) due to
the complications of chronic hepatitis C virus liver disease is expected to
triple within the next decade or two. On the other hand, in recent years, our
understanding of the hepatitis C virus and its management has increased
substantially.
The Nature Of The Hepatitis C Virus (HCV)
Hepatitis C virus is one of several viruses that can cause hepatitis, which is
inflammation of the liver. It is unrelated to the other common hepatitis
viruses (A, B, D, and E). Hepatitis C virus is a member of the Flaviviridae
family of viruses. Other members of this family of viruses include those that
cause yellow fever and dengue.
Viruses belonging to this family all have ribonucleic acid (RNA) as their
genetic material. They are, therefore, referred to as RNA viruses. The RNA of
hepatitis C virus is made up of almost 10,000 units called nucleotides that are
organized to serve as the virus's genetic blue print for the manufacture of
proteins. Thus, the virus contains structural proteins to build its structure,
including its coat (envelope), and non-structural proteins (e.g., the enzyme
polymerase) to carry out its functions. Understanding the nature (biology) of
hepatitis C virus allows scientists to develop therapy that specifically
targets the virus's structure or functions.
There are considerable differences in the genetic structure of hepatitis C
virus. Accordingly, hepatitis C virus is categorized into six major genetic
types (genotypes) and many more subtypes, based on the sequence (order) of
nucleotides in the virus. Although the different genotypes are found throughout
the world, there is a distinct distribution of genotypes in certain geographic
regions. For instance, the most common genotype in the U.S. is genotype 1 (1a
and 1b), which accounts for 80% of hepatitis C virus cases in the U.S.
The influence of genotype on the long-term prognosis of hepatitis C virus
disease is still unclear. However, what is clear is that patients infected with
genotypes 2 or 3 are much more likely to respond to interferon therapy. In
contrast, patients infected with genotype 1 (particularly 1b) or genotype 4 do
not respond very well to interferon therapy.
In addition, within a single host, there are minor genetic differences in the
hepatitis C virus. These minor differences give rise to what are called
quasispecies (quasi means resembling each other). Where do the quasispecies
come from? Well, one of the non-structural hepatitis C virus proteins mentioned
above is the enzyme polymerase. This enzyme is the machine that allows the
virus to reproduce its genetic material (RNA) in order to multiply. Now, this
RNA polymerase is very prone to making mistakes, resulting in changes
(mutations) in the genetic material. The majority of these mutations result in
a non-viable (not living) new quasispecies of hepatitis C virus, but sometimes
the mutation results in viable quasispecies. With time, the accumulation of
these viable mutations results in multiple quasispecies of the virus within the
same host.
Perhaps the different varieties confer an advantage to the survival of this
virus over the years. For example, some of the new species may become more
efficient in reproducing themselves (replication). By the same token, however,
the genetic variability of hepatitis C virus has made the development of a
protective vaccine against all of these genotypes and quasispecies a near
impossible task with our present technology. Moreover, this variability
probably also explains how this virus results in such a high rate of chronic
infection. Thus, the genetic variability may enable the hepatitis C virus to
avoid destruction by the host's cellular immune cells or antibodies, and so
maintain (perpetuate) the chronic infection.
The Liver Damage Occur In Hepatitis C Infection
The basis (mechanism) of liver damage in chronic hepatitis C virus infection is
not very well understood. The virus itself probably does not cause liver cell
damage directly. Indeed, the level of the virus in the blood does not correlate
with the actual liver damage seen on the liver biopsy. Liver damage in chronic
hepatitis C virus is probably caused by the interplay between the virus and the
body's immune system, which includes cytotoxic (injurious to cells) lymphocytes
and specific inflammatory messengers (cytokines).
Spread And Transmission: Hepatitis C Virus
Hepatitis C is spread (transmitted) most efficiently through the blood. Therefore,
hepatitis C virus is transmitted by infected blood or blood products,
transplantation of infected solid organs (e.g., liver, kidney, heart), and the
sharing of contaminated needles among intravenous drug users. In retrospect,
hepatitis C virus was the most common cause of hepatitis that resulted from
blood transfusions in the 1980's. At that time, hepatitis C virus had not yet
been identified and post-transfusion cases of hepatitis were called non-A non-B
hepatitis.
In the early 1980's, the risk of contracting hepatitis C virus from a blood
transfusion was as high as 15%. In the mid 1980's, when the practice of using
commercial (paid) donors was stopped and blood was screened for the human
immunodeficiency virus (HIV), the risk of post-transfusion hepatitis fell to
about 5%. This risk was then cut in half when blood was screened with the
substitute (surrogate) markers, elevated alanine aminotransferase (ALT, the
liver enzyme), and hepatitis B core antibodies. Finally, the isolation of the
hepatitis C virus and the development of a screening test for hepatitis C virus
dramatically lowered the risk of acquiring hepatitis C virus infection through
blood transfusions.
All blood donors are currently screened with the following panel; hepatitis C
antibodies, hepatitis B surface antigen, hepatitis B core antibodies, elevated
alanine aminotransferase, HIV antibodies, and syphilis. As a result, the risk
of contracting hepatitis C virus from a single unit of blood is less than
1:100,000. This risk will be even lower one day when tests that measure minute
quantities of hepatitis C viral nucleic acids are universally adopted for blood
screening.
Today, hepatitis C virus is most commonly transmitted by intravenous drug
abuse, which accounts for about 60% of new cases. Moreover, 50 to 60% of new
intravenous drug users are infected within the first 6 months of use, and
nearly 90% are infected by one year. Other types of illegal drug usage, such as
snorting cocaine, have also been associated with an increased risk of acquiring
an hepatitis C virus infection.
Hepatitis C virus can be sexually transmitted, but not very efficiently.
Hepatitis C virus has been isolated in the semen, vaginal fluid, and saliva.
Nevertheless, the risk of transmission of hepatitis C virus from an infected
individual to a non-infected spouse or partner without the use of condoms over
a lifetime is only about 1 to 4%. The Centers for Disease Control (CDC) and
Prevention has not recommended using a barrier technique (for example, condoms)
for hepatitis C virus infected individuals in a long-term monogamous
relationship. On the other hand, individuals with multiple sexual partners
should definitely use condoms. Furthermore, the practice of safe sex is key in
preventing the transmission of other sexually transmitted diseases, such as HIV
and hepatitis B.
Food, water, breast-feeding, sneezing, coughing, hugging, casual contact, or sharing
eating utensils or drinking glasses have not been shown to spread hepatitis C.
What's more, hepatitis C is not transmissible by kissing, unless an open wound
is involved. However, to further recognize that hepatitis C is transmitted
through blood, the sharing of razors and toothbrushes should be avoided.
Interestingly, the CDC has not found a definite association between tattoos and the
transmission of hepatitis C virus. It is critical, nevertheless, that
appropriate precautions be taken in applying tattoos, including the artist
wearing gloves and using disposable equipment. In contrast to hepatitis B, the
transmission of hepatitis C from the mother to the newborn around the time of
delivery is unusual.
Hepatitis C virus infection can also be acquired through occupational exposures. Thus,
health care workers in contact with contaminated bloods, fluids, and needles
are at an increased risk for hepatitis C virus. The risk of acquiring hepatitis
C virus from a needle stick involving an individual who has detectable virus in
the blood is as high as 5% and about 2% on the average. The risk is higher if a
hollow bore needle makes the needle stick since the potential for a greater
amount of blood is higher with this type of needle. In the medical setting,
patients receiving hemodialysis and medical providers in renal dialysis units
have a higher frequency of hepatitis C virus infection than people in the
general population.
What else can be done to prevent hepatitis C? Immune serum globulin, given
after an exposure to hepatitis C virus, would not be expected to protect a
susceptible individual from acquiring an hepatitis C virus infection. Moreover,
no vaccine is currently available for hepatitis C virus. It should be noted,
however, that hepatitis A and B vaccinations are recommended for patients who
have hepatitis C virus liver disease. As already mentioned, intravenous drug
abuse remains the most common mode of transmission of hepatitis C. Ideally,
users should stop using drugs and enter a rehabilitation program. However,
active users of drugs should not reuse or share needles, syringes, water, and
other materials.
Symptoms Of Hepatitis C Infections:
At the beginning of an hepatitis C virus infection, only about 25% of patients exhibit
the characteristic symptoms of acute (rapid onset) hepatitis. These symptoms
include fatigue, muscular aches, poor appetite, and low-grade fever. Rarely,
yellowing of the skin and/or eyes (jaundice) also occurs. However, most
patients (about 75%) experience minimal or no symptoms at the onset of
hepatitis C virus.
As the hepatitis becomes chronic, most individuals remain asymptomatic (without
symptoms). Indeed, many persons with chronic hepatitis C are diagnosed while
undergoing routine blood work for unrelated purposes. Infected individuals may
exhibit no symptoms despite progressive liver inflammation, necrosis (death of
liver cells), and fibrosis (scarring). Other patients may experience chronic or
intermittent fatigue and a diminished sense of well-being as a result of
advancing disease. On the other hand, fatigue has been described in some
individuals with relatively mild disease.
With the subsequent development of cirrhosis of the liver (more advanced
scarring), hepatitis C virus patients can have muscle wasting, generalized
weakness, and easy bruising. Later symptoms, which are due to the complications
of cirrhosis, include fluid retention, which leads to edema (swelling of the
lower extremities) or ascites (fluid in the abdominal cavity), internal
bleeding (usually from dilated esophageal veins called varices), and mental
confusion or sleepiness (due to hepatic encephalopathy). Another complication
of hepatitis C virus cirrhosis is cancer of the liver (hepatocellular carcinoma
or hepatoma), which can cause abdominal pain, weight loss, and fever.
What Conditions Outside The Liver Are Associated With
Hepatitis C?
Several extra-hepatic (outside of the liver) conditions are associated with chronic
hepatitis C. These conditions are not very common and their occurrence does not
correlate with the severity of the underlying liver disease. The most widely
described associated condition is cryoglobulinemia. This condition is due to
the presence of abnormal antibodies (called cryoglobulins) that come from
hepatitis C virus stimulation of lymphocytes (white blood cells). These
antibodies can deposit in small blood vessels, thereby causing inflammation of
the vessels (vasculitis) in tissues throughout the body. For example, the skin,
joints, and kidneys (glomerulonephritis) may be involved.
Patients with cryoglobulinemia can have quite a variety of symptoms. These
symptoms may include weakness, joint pain or swelling (arthralgia or
arthritis), a raised, purple skin rash (palpable purpura) usually in the lower
portion of the legs, swelling of the legs and feet due to loss of protein in
the urine from the kidney involvement, and nerve pain (neuropathy). In
addition, these patients may develop Raynaud's phenomenon, in which the fingers
and toes turn color (white, then purple, then red) and become painful in cold
temperatures.
The diagnosis of cryoglobulinemia is made by doing a special test in the
laboratory to detect the cryoglobulins in the blood. In this test, the
cryoglobulins are identified when the blood sample is exposed to the cold (cryo
means cold). In addition, a finding of typical inflammation of small blood
vessels in certain tissue biopsies (e.g., the skin or kidney) supports the
diagnosis of cryoglobulinemia. All of the symptoms of cryoglobulinemia often
resolve with successful treatment of the hepatitis C virus infection.
B-cell non-Hodgkin's lymphoma, a cancer of the lymph tissue, has also been
associated with chronic hepatitis C virus. The cause is thought to be the
excessive stimulation by the hepatitis C virus of B-lymphocytes, which results
in the abnormal reproduction of the lymphocytes. Interestingly, the
disappearance (remission) of an hepatitis C virus-associated low-grade (not
very active) non-Hodgkin's lymphoma has been reported with interferon therapy.
Most individuals with hepatitis C virus-associated high-grade non-Hodgkin's
lymphoma, however, will require the usual anti-cancer therapies.
Two skin conditions, lichen planus and porphyria cutanea tarda, have been
associated with chronic hepatitis C virus. It is important to know that both of
these skin conditions can resolve with successful interferon therapy for the
hepatitis C virus. In addition, up to 25% of hepatitis C virus patients have
autoimmune antibodies (against one's own proteins), such as anti-nuclear
antibody, anti-smooth muscle antibodies, and rheumatoid factor.
What Is The Usual Progression Of Chronic Infection With
Hepatitis C Virus?
Our understanding of the natural progression (history) of hepatitis C infection is still
evolving. About 15% of patients with acute hepatitis C virus infection
spontaneously recover (clear the virus). Eighty five percent, however, develop
chronic liver disease. How many of these patients progress to cirrhosis of the
liver? Is there a way to predict who will develop cirrhosis? And then, how many
will develop liver failure, including the complications of cirrhosis, or liver
cancer? Once a person has cirrhosis, how long is he/she expected to live? These
are very pertinent questions for which there are no clear-cut answers, only
reasonable estimates.
There are several ways to examine the natural history of chronic hepatitis C
infection; retrospective (looking back in time), prospective (looking forward),
or combined retrospective/prospective studies. A retrospective study involves
identifying patients with established chronic hepatitis C infection and
correlating their current stage of liver disease to the duration of their
infection. Several such investigations have suggested that after acquiring
hepatitis C virus, it takes about 10 to14 years for biopsy evidence of chronic
hepatitis to appear, about 20 years to develop cirrhosis, and about 28 years to
develop liver cancer.
There are problems with retrospective studies, however. For example,
retrospective studies are inclined (biased) to select chronic hepatitis C
patients who have symptoms, which is the reason the patients sought medical
attention. Accordingly, information about the actual duration of infection in
these patients may be inaccurate, that is, underestimated. Furthermore,
retrospective studies do not tell what proportion of patients with chronic
hepatitis C virus will develop cirrhosis, liver failure, or HCC.
In a prospective study, an entire group of hepatitis C patients are followed
from the time they first become infected. These studies have necessarily
involved patients who received contaminated blood, since in these individuals,
the time of acquisition of hepatitis C virus can be accurately determined.
However, the follow-up in most of these studies is relatively short.
Furthermore, since some of these patients are being treated with antiviral
therapy, the natural progression of the disease may be modified by the
treatment. Anyway, these prospective studies suggest that about 10 to 25% of
patients develop cirrhosis within a 10 to 15 year follow-up. Moreover, only
about 10% of patients develop symptoms related to their liver disease.
Retrospective/prospective studies involve identifying a group of patients who
were exposed to hepatitis C virus many years ago, accounting for almost all of
these patients, and then following them prospectively. The advantage of these
studies is that there is a head start to the follow-up as compared to a
prospective study. These retrospective studies confirm that the natural
progression of chronic hepatitis C virus is quite slow and in general,
complications develop over decades, not years.
Again, these retrospective/prospective studies have involved patients who were
exposed to contaminated blood or blood products (such as immunoglobulin). On
average, these studies have looked at patients who were exposed over twenty
years ago. In two studies involving women who acquired chronic hepatitis C
virus after receiving contaminated immunoglobulin over 20 years ago, less than
3% of the patients developed cirrhosis. The vast majority of patients had only
mild inflammation and no fibrosis (scarring) of the liver. About one third of
patients had aminotransferase (liver enzyme) levels over 100 U/L (2 to 3 times
normal) and one third had normal liver tests. However, one quarter of the
patients reported fatigue.
According to these retrospective/prospective studies, once cirrhosis is
established, the risk of developing liver failure, that is, the complications
of cirrhosis, is about 10% per year. These complications include bleeding from
varices (dilated veins, usually in the esophagus), ascites (fluid in the
abdomen), encephalopathy (confusion), and jaundice. The risk of developing
liver cancer in a cirrhotic patient with hepatitis C virus is 1.4% per year.
However, patients who have cirrhosis without complications (compensated
cirrhosis) have an 80% likelihood of surviving 10 years. On the other hand,
patients who have cirrhosis with complications (referred to either as
decompensated cirrhosis or liver failure) have a much lower likelihood of
survival, less than 50% at 5 years.
It is unclear which factors promote the progression of chronic liver disease in
hepatitis C virus infection. Earlier studies suggested that individuals
infected with genotype 1b may develop more serious disease, but these findings
could not be substantiated. Moreover, as previously mentioned, the level of
virus in the blood does not correlate with disease severity. What is clear,
however, is that the regular use of alcohol, even in moderation, is detrimental
in hepatitis C virus chronic liver disease.
Who Is At High Risk And Should Be Tested For Hepatitis C Infection?
The Centers for Disease Control and Prevention recommend that certain people who are at
high risk for hepatitis C infection should undergo testing for hepatitis C
virus. These include individuals who:
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Have been notified that they received a blood transfusion from a donor who
later tested positive for hepatitis C
-
Injected illegal drugs, even if they experimented only a few times many years
ago
-
Received a blood transfusion or solid organ transplant before July, 1992
-
Received a blood product for clotting problems that was produced before 1987
-
Have ever been on long term kidney dialysis (filtering blood to treat kidney
failure)
-
Have evidence of liver disease (e.g., persistently abnormal ALT levels)
Guidelines for hepatitis C virus testing are less clear in certain other people
who may also be at increased risk of acquiring hepatitis C virus). These
include individuals who:
" Are recipients of transplanted tissue (e.g., cornea, skin, heart, kidney)
" Used intranasal cocaine and other non-injecting illegal drugs
" Have had tattoos and/or body piercing
" Have had multiple sex partners or a history of sexually transmitted disease
" Are long term steady sex partners of an hepatitis C virus positive
person
" The National Institutes of Health Consensus Development Conference recommends
that these persons be tested.
Diagnostic Tests:
A number of diagnostic tests are currently available for hepatitis C
virus. They are categorized below according to the function of the specific
tests.
Screening Tests
Screening tests are done to determine the presence of antibodies to hepatitis C virus in
the blood. The enzyme immunosorbent assay (EIA) is the conventional, initial
screening test to diagnose hepatitis C infection. The EIA measures specific
antibodies to small pieces of the hepatitis C virus proteins (antigens). This
test, therefore, is referred to as the anti-hepatitis C virus antibody test.
Patients who have elevated liver enzymes (ALT/AST) and/or any of the risk
factors for hepatitis C virus can be diagnosed to have hepatitis C virus with a
greater than 95% certainty when the EIA is positive.
On the other hand, certain patients whose immune systems are impaired
(suppressed) may not have detectable anti-hepatitis C virus antibodies even if
they are actually infected with hepatitis C virus. Such immunosuppressed
patients include those who are on renal dialysis, suffer from cancer and are
receiving chemotherapy (drugs to kill cancer cells), or have active HIV
infection. These patients cannot produce enough anti-hepatitis C virus
antibodies necessary to generate a positive EIA test.
When there is a low likelihood (risk) of hepatitis C infection, individuals who
test positive for hepatitis C by EIA should undergo confirmatory testing using
a specialized assay that likewise tests for antibodies against the hepatitis C
virus proteins. This assay is called the Recombinant Immunoblot Assay (RIBA).
Both the EIA and RIBA tests, however, do not distinguish among acute, chronic,
and resolved hepatitis C virus infections because the anti-hepatitis C virus
antibodies are in the blood in all three of these situations. Although EIA and
RIBA are tests that measure antibodies against hepatitis C virus, these
antibodies do not confer protection to the patient against acquiring hepatitis
C virus. Rather, they only indicate exposure of the patient to the virus.
Molecular Tests For Hepatitis C Virus
As previously described, hepatitis C virus is an RNA virus. The code of the genetic
material, hepatitis C virus RNA, is unique to this virus. Several types of
tests (assays) are available to measure the hepatitis C virus RNA in a person's
blood. These tests are referred to as molecular tests because they examine the
virus at the molecular level. The two most common systems for measuring
hepatitis C virus RNA are the reverse transcription polymerase chain reaction
(RT-PCR) assay and the branched chain DNA (bDNA) assay. Recently, a third type
of assay, called transcription-mediated amplification (TMA), has been released.
First of all, it is important to put in perspective the relative amount of
virus in an individual infected with hepatitis C virus as compared to some
other types of chronic viral infection. The average number of virus
particles/milliliter of blood in an individual with chronic hepatitis C virus
is hundreds of thousands to several million. In contrast, someone with active
hepatitis B infection has several hundred million to billions of copies (virus
particles) per milliliter of blood. The relatively low concentration of the
hepatitis C virus in the blood is one of the reasons it took so long for
scientists to characterize the hepatitis C virus.
RT-PCR is a very powerful tool for detecting relatively low amounts of genetic
material (RNA or DNA). The basis of this technique is the amplification of a
target piece of nucleic acid several million times so that this target becomes
measurable. Due to the extreme sensitivity of this technique, however, the
slightest contamination can lead to a false positive result. On the other hand,
RNA is relatively unstable (degrades easily), so that blood and tissue samples
need to be handled with special precautions. If not, this instability would
lead to a false negative result, that is, a negative result in someone who has
hepatitis C virus.
In the early 1990's, each laboratory had its own in-house technique for the
RT-PCR assay and the reliability of these assays was quite variable. Even as of
now, the FDA has not approved any of the RT-PCR assays. However, most
laboratories currently use one of the several available diagnostic kits that
are automated and designed to reduce the likelihood of contamination. There are
two types of RT-PCR, qualitative and quantitative. Qualitative hepatitis C
virus RT-PCR provides the greatest sensitivity, meaning that it can measure as
few as 100 copies (viral particles) of hepatitis C virus/ml of serum. As the
name implies, however, qualitative RT-PCR provides only a positive (presence of
hepatitis C virus) or negative (absence of hepatitis C virus) result.
By contrast, quantitative RT-PCR measures the amount of virus. These tests,
however, are only accurate within a certain range of viremia (circulating virus
in the blood). This means that quantitative assays are not as sensitive as
qualitative assays and can only detect as few as 500 copies/ml. Moreover, these
assays are less accurate at extremely high viral levels (over 2 million
copies/ml). In the past year, there has been an attempt to standardize these
various quantitative assays so that the levels of virus that are measured by
different assays can be compared. As a matter of fact, results of quantitative
RT-PCR are now reported in standard International Units/ml (IU/ml).
Branched chain DNA (bDNA) is the other quantitative technique. It is based on
the amplification of the detection signal rather than of the nucleic acid
itself. As a result, this test is less prone to contamination and is more
accurate when measuring higher levels of the virus as compared to RT-PCR.
However, the bDNA assay is not as sensitive as the RT-PCR and is unable to
measure levels of virus below 200,000 copies/ml.
Finally, transcription mediated amplification (TMA) is a qualitative technique
that is distinct from PCR. This test can measure as few as 2 to 5 copies of
virus/ml.
What is the role of the qualitative molecular tests?
Qualitative RT-PCR is a useful test in determining whether or not a patient has
circulating virus in the blood (viremia). Hence, it can be used to confirm that
a reactive (positive) anti-hepatitis C virus result reflects active hepatitis C
virus infection. However, confirmatory testing is usually not necessary in
someone who tested reactive (positive) for anti-hepatitis C virus and also has
risk factors and abnormal liver tests. In this situation, the RT-PCR most
certainly would be positive. On the other hand, an individual who is
anti-hepatitis C virus reactive and has risk factors but normal liver tests
should undergo confirmatory testing with RT-PCR. This person may have cleared
the viral infection some time ago, leaving the anti-hepatitis C virus as a
marker of past exposure.
Qualitative hepatitis C virus RNA testing should also be done in individuals
who may have been recently exposed to hepatitis C. Hepatitis C virus RNA is
more sensitive (that is, will detect more cases) than the conventional
anti-hepatitis C virus (EIA) testing in this setting. The reason for this
greater sensitivity is that it may take a person as many as six to eight weeks
after exposure to hepatitis C virus to develop the antibodies, whereas
hepatitis C virus RNA becomes detectable five to ten days after exposure.
Finally, qualitative hepatitis C virus RNA testing may be helpful to assess the
patient's virologic response at certain time points during antiviral therapy
(see treatment of hepatitis C virus below).
How are the results of the hepatitis C virus tests
interpreted?
The table provides guidelines for interpreting the results of testing for anti-hepatitis
C virus by EIA and RIBA and for hepatitis C virus RNA by qualitative RT-PCR or
TMA.
Anti-HCV (EIA) Anti-HCV (RIBA) HCV RNA
(Qualitative RT-
PCR or TMA) Interpretation
Non-reactive Non-reactive Undetectable No present or past infection
Reactive Non-reactive Undetectable False positive EIA; no present or past
infection
Reactive Undeterminate Undetectable In the absence of risk factors, probable
false positive EIA
Reactive Positive Undetectable Probable past exposure with clearance of
infection. Qualitative RNA testing should be repeated to exclude fluctuating
low levels of viremia
Reactive Positive Detectable Ongoing infection
Non-reactive Non-reactive Detectable Acute HCV infection or chronic HCV
infection in an immunocompromised person unable to make adequate antibodies
What is the role of quantitative hepatitis C virus RNA testing?
It should be noted that a single quantitative measurement of the level of hepatitis C
virus in the blood (viral load) does not correlate with the severity of
hepatitis C virus liver disease. Moreover, the viral load fluctuates in a given
infected individual, although the variation is usually insignificant, that is,
less than a log-fold (ten times) difference. So, there is no practical value in
quantitatively measuring viral loads in patients who are not undergoing
treatment.
Quantitative hepatitis C virus RNA measurements are pertinent, however, in
patients who are being considered for antiviral therapy or who are being
monitored during therapy. For example, patients with hepatitis C virus RNA
initial levels of greater than 2 million copies/ml(>800,000IU/ml) are less
likely to have a sustained response to conventional interferon alone or to
combined interferon and ribavirin therapy. What is more, patients who
experience less than a 100-fold (2-log) drop in the viral load after 12 weeks
of pegylated interferon therapy are also unlikely to have a sustained response.
What tests identify the virus genotypes?
PCR assays of nucleic acids are available to determine the hepatitis C virus genotype.
In some instances, the purpose of obtaining genotype information is to tailor
the duration of antiviral therapy. Thus, patients with genotype 2 or 3 can be
treated with a six-month course of Rebetron combination therapy (see treatment
of hepatitis C virus below) instead of the conventional twelve-month course for
patients infected with genotype 1. Furthermore, patients infected with genotype
2 or 3 are more likely to respond to interferon therapy than those with
genotype 1. Thus, knowledge of the genotype may be useful in predicting the
likelihood of a favorable response to interferon therapy.
What is the role of a liver biopsy in the management of
chronic hepatitis C?
A considerable amount of discussion has focused on the role of a liver biopsy in the
management of patients with chronic hepatitis C. Many liver specialists feel
that a biopsy should be part of the work-up of any individual with chronic
hepatitis C infection. For one thing, patients may have significant underlying
liver disease without having any symptoms or abnormal physical or laboratory
findings. For another, the biopsy provides important information about the
severity and, therefore, the outcome (prognosis) of the liver disease.
Some pathologists use the Knodell Histological Activity Index (HAI), which is a
composite score that incorporates evaluations of four different features of the
liver biopsy. With the HAI, a normal liver biopsy has a score of 0, whereas a
biopsy showing cirrhosis with highly active inflammation receives a top score
of 22. Most pathologists (specialists who study tissues), however, now use a
newer system. This system reports the cause (etiology) of the hepatitis, the
extent of scarring (fibrosis) on a scale from 0 (no fibrosis) to 4 (cirrhosis),
and the amount of inflammation (lymphocytes causing liver cell damage) on a
scale from 0 to 4.
A frequently cited study suggests that the initial biopsy can predict the
likelihood of the patient progressing to cirrhosis within ten years. Not
surprisingly, patients with moderate fibrosis and inflammation are much more
likely to progress to cirrhosis than persons with no fibrosis and only minimal
inflammation. Moreover, with respect to therapy, patients with cirrhosis are
much less likely to respond to
conventional interferon alone (monotherapy) than patients without
cirrhosis. The information gained from the liver biopsy, therefore, can help
the patient and doctor weigh the potential risks versus benefits of antiviral
therapy.
On the other hand, there are other liver specialists who do not advocate the
need for a liver biopsy, citing, among other reasons, the cost of the biopsy in
relation to its benefit. A liver biopsy costs anywhere between $1500 and $2000.
In view of this, many individuals who are otherwise suitable candidates for
antiviral therapy may consider this treatment without having a liver biopsy.
Hepatitis C At A Glance:
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In the U.S., hepatitis C virus (HCV) infection is the most common cause of
chronic hepatitis, and the complications of hepatitis C virus cirrhosis are the
most common reasons for liver transplantation.
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Hepatitis C virus is one of several viruses (A, B, C, D, and E) that can cause
hepatitis (inflammation of the liver). hepatitis C virus is distinct from these
other viruses.
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One of the major problems with hepatitis C virus is that 85% of individuals who
are initially (acutely) infected with hepatitis C virus will become chronically
(long duration) infected. About one third of individuals chronically infected
with hepatitis C virus will progress to cirrhosis.
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Hepatitis C virus is spread (transmitted) through the blood. Intravenous drug
abuse is the most common mode of transmission, while the risk of acquiring
hepatitis C virus through sexual contact is quite low.
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Generally, patients do not develop symptoms until they have progressed to
advanced cirrhosis. Some individuals, however, may have fatigue and other
non-specific symptoms in the absence of cirrhosis. A minority of hepatitis C
virus patients may have symptoms coming from involved organs outside of the
liver.
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Hepatitis C is diagnosed by anti-hepatitis C virus antibody tests, which
diagnosis is then confirmed by nucleic acid based tests for the virus itself.
The amount of the virus in the blood (viral load) does not correlate with the
severity of the disease.
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A liver biopsy is used to assess the amount of liver damage (liver cell injury
and scarring), which may be important in determining the outcome (prognosis)
and in planning treatment.
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Considerable progress has been made in the treatment of hepatitis C virus. For
patients infected with genotype 2 or 3, successful treatment with combined
interferon (conventional or pegylated) and ribavirin can be achieved in up to
80% of patients.
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Treatment for patients infected with genotype 1 hepatitis C virus, for whom the
success rate with combined pegylated interferon and ribavirin is just under
50%, remains a challenge.
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Treatment is recommended for patients with detectable hepatitis C virus RNA who
have persistently elevated liver tests and evidence of scarring and at least
moderate inflammation on their liver biopsy, but without outward signs of liver
failure.
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Treatment results in improvement in the inflammation and scarring of the liver
in most sustained responders and also occasionally (and to a much lesser
extent) in relapsers and non-responders.
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Clinical trials are underway to evaluate combinations of various antiviral
agents and pegylated interferon in the treatment of hepatitis C.
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