1. Discuss the
potential clinical impact of Hepatitis C infections and how patients are diagnosed
2. Describe the different ways in which
the Hepatitis C virus can be transmitted between adults and to children through
perinatal transmission and breastfeeding.
3. Discuss the potential treatment options
for Hepatitis C infected individuals, the limitations of treatment, and the
potential for an effective future vaccine or immunoglobulin.
Background and Healthcare
different viruses can lead to injury of liver cells producing hepatitis. Some
of these are considered primary hepatitis viruses whereas others may produce
hepatitis as part of their overall infection. For the primary hepatitis
viruses, for years only two were distinctly known and were called Hepatitis A
and Hepatitis B. Everything else was labeled non-A non-B hepatitis. In 1989,
Choo and Kuo identified an RNA viral strand that was felt to be the cause of
non-A non-B hepatitis. This RNA virus was soon labeled Hepatitis C (HCV). Since
the discovery of the Hepatitis C virus, several distinct genetic variants have
been identified based on different nucleic acid sequences.
Currently, 7 major genotypes exist
and most of these have numerous subtypes, which are labeled progressively “a”,
“b”, “c”, etc. There are currently over 225 subtypes identified to date. Some
studies have reported genotypes 8 through 11, but most authorities list these
as primarily variants of genotypes 3 and 6. The most common genotypes in the
United States, Western Europe, and Japan are 1a, 1b, 2a, 2b, 3a, 4a, and 6a. The
most resistant to treatment is genotype 1. The hepatitis C virus has been
classified as a separate genus to the flavivirus family. This RNA virus is
approximately 9379 to 9481 nucleotides long and is 30 to 38 nanometers in
As more information is obtained on
the Hepatitis C virus, the potential clinical impact of this disease is
becoming apparent. Research showed that the majority of post-transfusion
hepatitis was caused by Hepatitis C. The Centers for Disease Control estimates
that more than 150,000 new cases occur per year in the United States alone
(mostly now related to substance abuse). Based on current information, it is
estimated that there are over 200 million carriers worldwide, with approximately
4 million in the United
States. Of acute infections, only 20% have symptoms
(meaning 80% or 4 out of 5 have no symptoms and do not realize they were
infected). Once infected, about 80% become chronic carriers and again they are
usually asymptomatic. Of these chronically infected HCV carriers, 75% will have
elevated liver function tests, which means that 25% have normal tests but are
still carriers. Chronic hepatitis C is slowly progressive, and it is estimated
that 10% to 30% progress to cirrhosis after 20 years. Of those with cirrhosis,
the risk of developing hepatocellular carcinoma is 2% to 5% per year. Therefore, the potential impact on healthcare
in the United States
and worldwide is enormous.
Furthermore, another difficulty that
occurs in evaluating patients infected with this virus is that a viral marker
antigen that denotes infectivity has not been identified. If one looks at
hepatitis B, the presence of the hepatitis B surface antigen (HBsAg) denotes
the possibility that a
person is infectious. A similar antigen marker for hepatitis C does not currently
exist. Infectivity is usually based on a positive HCV-RNA viral load.
cell culture of hepatitis C became reality by 3 different research groups
(Lindenbach et al, Wakita et al, and Zhong et al). This allowed every step of
the viral lifecycle to be studied including viral entry into the body,
replication, assembly of the virus, and release. What has made studying
hepatitis C difficult is that there are essentially no animal hosts other than
humans. There has been an attempt to develop a non-human primate host to study
this, but research is primarily left to humans.
structure of the virus is basically 11 proteins. There are 3 structural
proteins, which are the core protein and 2 envelope proteins designated E1 and
E2. There are 8 nonstructural proteins, which are primarily different enzymes.
Most of these enzymes are used for replication of the virus once a host is
infected. When hepatitis C enters the bloodstream, the envelope glycoproteins
E1 and E2 bind to apolipoproteins (B, C1, and E) found on circulating
cholesterol. The cholesterol that it attaches to is primarily VLDL and LDL. The
full viruses then circulate through the bloodstream connected to these
lipoproteins and are designated lipoviral particles. This allows the virus to
have access to the liver making entry into the liver cell easier because of its
connection to the cholesterol molecule. Once the virus is in the cell, the RNA
viral genome is replicated using the cells resources. The virus is then
reassembled again attached to lipoproteins and released back into circulation.
diagnosis of an HCV infection primarily relies upon the detection of antibodies
to the virus and identifying the nucleic acid of the virus by PCR testing
(polymerase chain reaction). The laboratory workup primarily involves an ELISA
screening test (enzyme linked immunosorbent assay) that looks for the presence
of antibody to the virus. Currently, most labs now use a third generation
anti-HCV ELISA test called an ELISA-3. This ELISA test, however, can have a very
high incidence of false positive results, especially if used in a low risk
patient tests positive for HCV antibody, in the past, the next step was to
evaluate by a RIBA test (recombinant immunoblot assay). This test was similar
to the Western Blot Assay used in evaluating infection of HIV (human
immunodeficiency virus). The RIBA test was a series of different antibodies to
other aspects of the hepatitis C virus, and if positive, would suggest that the
patient was infected or at least had been previously exposed (versus a false
positive antibody screening test if the RIBA was negative). Unfortunately, the
RIBA test is no longer available as of 2012. Therefore, a positive HCV antibody
screening test is now confirmed by the more specific test of HCV-RNA viral
detection by PCR. The problem associated with the RIBA test no longer being
available, is that it is not fully possible to tell a patient (who has a
positive HCV antibody screen test result and a negative HCV-RNA PCR test
result) whether the positive antibody screen result was a false positive test
versus the fact that an infection did occur, but the patient now has a negative
viral load. Not being able to differentiate between these 2 possibilities could
theoretically affect insurability.
time period from an HCV infection to the development of an anti-HCV antibody
response is 12 weeks but can take up to 6 months in some cases. Therefore,
during an acute episode of hepatitis, the anti-HCV antibody test may be
negative. Therefore, in evaluating a patient for acute hepatitis, the HCV
RNA-PCR test should be ordered. If an individual is confirmed to be infected
with HCV by a positive HCV-RNA viral load, they should have liver function
tests performed along with hepatitis C genotyping. Additionally, a consultation
with gastroenterology is recommended to determine if a liver biopsy is
indicated and whether the patient is a candidate for treatment (treatment based
on the patient’s current medical status and the genotype involved).
Transmission of HCV:
The spread of Hepatitis C is by a percutaneous or
permucosal pathway. Therefore, the transmission between individuals primarily
occurs in the following ways:
Through Blood or Blood Products
Through IV Drug Abuse
The risk of HCV transmission between family members or
sexual partners seems to be low at less than 1% (but is not reported to be zero).
In a study by Nakashima et al, of over 1100 residents in an HCV endemic
area of Japan,
anti-HCV antibody was detected in 14% of the population. However, the positive
rate amongst sexually active spouses was only 7% with half of those tested
showing different serotypes. In a study by Bresters et al, all 50 heterosexual
partners of HCV positive individuals were HCV-RNA and anti-HCV negative. The median duration of sexual relations was
13 years. Several other studies have also shown a low transmission rate by
sexual activity (in the range of 1% or less). However, transmission can occur
and it appears to be more common in patients with a history of multiple sexual
partners. The sexual transmission rate to an uninfected person is also higher if
the positive partner was infected through recurrent sources (IV drug abuse or
multiple sexual partners).
This low transmission rate through
sexual activity may be due to a low detection rate of the Hepatitis C virus in
human secretions (other than blood). Therefore, the larger risk for HCV
transmission in the population seems to stem from blood transmission such as
transfusion with blood products, IV drug abuse, organ transplantation, or other
external sources such as acupuncture, etc. As stated, the main area of concern
when the transmission of hepatitis C was originally examined was its relation
to post-transfusion hepatitis. Most studies revealed that the majority of
post-transfusion hepatitis was caused by HCV. With the addition of anti-HCV
testing and testing for the presence of virus by PCV of donated blood, the risk
of developing post-transfusion hepatitis C infection is now less than 1 in a
million units transfused. This testing of donated blood has markedly decreased
the incidence of post-transfusion hepatitis in the United States. Though several
papers report blood transfusion risks, the table below shows the approximant current
risks of becoming infected through transfusion, per unit of blood transfused.
Table: Current estimated risks of transmitting
infection per unit of blood
transfused from Units that are negative in
Hepatitis B 1 in 200,000 units transfused
Hepatitis C < 1 in 1,000,000 units
HIV I &
II < 1 in 2,000,000
Immunoglobulins have been used in
medicine for years to help prevent or reduce the risk of infections (for
example serum immune globulin, hepatitis B immune globulin, varicella zoster
immune globulin, etc.). In addition, anti-D immune globulin (Rh-hyper-immuneglobulin)
has nearly eliminated Rh sensitization in the United States. The safety of
these products over the years has been excellent, despite the fact that these
immune globulin products come from pooled plasma where some donors probably
carry transmissible infections. In the mid 1990’s, there were reports of
Hepatitis C transmission following the administration of some brands of serum
immune globulin. The frequency of this occurrence today is negligible and there
has not been a reported case of HCV transmission in nearly 20 years.
Immune globulin production starts
with a fractionation procedure that effectively removes most if not all
potentially infectious agents. However, due to these reported HCV transmissions
(from the over 20 years ago), most products (especially those used in the
United States) add other purification steps such as a solvent-detergent
treatment or a low pH treatment and pepsin. Therefore, Hepatitis C transmission
with these products will hopefully stay non-existent in the future.
Lastly, nearly every study on
patients with illicit drug abuse and addiction have found that about 70% to 75%
of those infected with hepatitis C report that they had intravenous use.
However, how the other 25% became infected (if intravenous drug use had not
occurred) is uncertain. Newer research is suggesting that another mode of blood
transmission might occur through the sharing of snorting utensils. Some of
these patients (who chronically snort) develop sores in the nasal cavity, and
this might lead to blood contamination of the snorting utensil. If this utensil
is shared, then the blood of the infected user could gain access through the
nasal mucosa of another user leading to possible infection.
Perinatal Transmission of
Vertical transmission from an
infected mother to the infant does occur during pregnancy. Several hundred studies
have been published on the topic of perinatal transmission during the past 15
years and the data is still not completely clear. When studies are combined,
the rate of perinatal HCV transmission in pregnant patients who are anti-HCV
antibody positive is about 5% (with a range of 0% to about 10%). These
variations in percent transmission may be due to differences in those who are
viral RNA positive in the bloodstream at the time of delivery and other factors.
More recent data have determined that transmission primarily only occurs in
patients who are HCV-RNA positive at the time of delivery (however, the
laboratory that performs the PCR testing is important, because it is an
extremely sensitive test). In addition, in patients who are HCV infected and
are also HIV positive, the rate of perinatal transmission increases to a range
of 15% to 25%.
The HCV positive carrier rate in
studies of pregnant populations from Japan
to Europe to the United
States ranges from 0.5% to 3% (meaning 1 in
33 to 1 in 200 pregnant women are HCV antibody positive). It is important to
understand that all babies born to women who are HCV-antibody positive are
HCV-antibody positive at birth. This does not mean they are infected. The
newborn’s positive antibody test is caused by the mother’s antibody that
crossed the placenta. Mother’s IgG antibodies can freely cross the placenta,
but unfortunately, they are not protective to the newborn. Most of these
newborns clear the antibody by 12 months of age. However, this maternal
antibody can remain positive for up to 18 months following delivery in some
Another question that has not been
fully answered is whether the virus can cross the placenta and infect the child
prior to delivery. Most studies would suggest that this is not the case.
Delamare et al tested the amniotic fluid obtained by genetic amniocentesis in
16 HCV-RNA positive women and in 15, the HCV-RNA probe was negative by PCR. The
HCV-RNA was positive in one case at a very low level of 230 copies per ml of
fluid. However, the amniocentesis procedure went through the placenta in a mother
whose viral load was 340,000 copies per ml. This child and 9 others were tested
at birth and all were negative for HCV-RNA. Therefore, the one positive
amniotic fluid was probably caused by maternal blood contamination of the
specimen. (Levels of HCV-RNA in the blood that are less than 10,000 copies per
ml are considered low titers). PCR testing is very sensitive and can detect as
few as 10 to 20 copies of virus in one milliliter of fluid. Therefore, a very
tiny contamination can result in false positive results.
The Delamare report and most other
studies suggest that the majority of perinatal transmission (when it occurs)
takes place around the time of delivery. Because of this finding, the next
question is whether the type of delivery affects this transmission rate. The
majority of studies on this topic have reported that the mode of delivery did
not seem to affect the perinatal transmission rate. However, it is important to
note that nearly all of these studies did not separate the cesarean section group
into elective cesarean prior to the onset of labor and those c-sections
performed for obstetrical reasons after labor begins or membranes have been
ruptured. One recent study by Gibb et al reported on the perinatal transmission
rate in 441 mother-child pairs from Ireland and England using an estimation
statistical approach. The perinatal transmission rate in 339 vaginal deliveries
was estimated at 7.7% and the transmission rate in 54 non-elective c-sections
was 5.9%. However, the transmission rate in 31 elective c-sections was 0%.
Despite this finding, these percentages were not statistically different. On-the-other-hand,
the European Pediatric Hepatitis C Network reported on 1,787 mother-child pairs
and the transmission rate for elective cesarean delivery was 7.3% versus 5.4%
for the vaginal delivery / non-elective cesarean delivery group. Therefore,
further studies are needed that analyze whether there is a difference between
elective cesarean delivery and routine obstetrical delivery.
The final issue regarding pregnant
women infected with HCV and their newborns is breastfeeding. No studies to date
have ever proven transmission to a newborn through breastfeeding. Several
studies have tested breast milk for the presence of HCV-RNA and most have not
detected the virus. In a few studies, HCV-RNA was detected in breast milk, but
at very low levels (of < 1000 copies per ml) and usually, this was only seen
in colostrum. Furthermore, it is also uncertain whether the virus can withstand
the elements of the intestinal tract. According to the American College of
Obstetricians and Gynecologists and American Academy of Pediatrics,
breastfeeding is not contraindicated in women who are HCV positive.
Treatment of HCV:
At the present time, there is no
available Hepatitis C immune globulin or vaccine that can be used in preventing
this infection. The current recommendations for treatment are still very
complex. Therapy in the past was limited to interferon (or its variation) along
with ribavirin and was dependent upon the patient’s age, general state of
health, risk of cirrhosis, likelihood of response, and life expectancy. In the
past several years, numerous anti-hepatitis C anti-viral agents have been
developed and marketed. Some of these include Boceprevir, Telaprevir, and
Faldaprevir (NS3/4A protease inhibitors) made for treating Genotype 1.
Sofosbuvir (a nucleoside inhibitor of HCV RNA-dependent RNA polymerase) and
Velpatasvir (NS5A inhibitor) for treating most all genotypes. Many other direct
acting antiviral agents are being tested against other protein/glycoprotein
parts of the virus. Patients usually have a liver biopsy before starting
treatment, which also establishes the individual’s baseline liver status. Only
patients who are HCV-RNA positive should be treated (and usually ones with
elevated liver function tests). Patients who are active heavy alcohol users,
active IV drug users, and patients with decompensated cirrhosis are usually not
be treated. Patients with genotype 1 are usually treated for up to 48 months
versus 24 months with types 2 through 7. Patients treated with interferon would
often rebound (up to 50%) after treatment was completed, but this occurs less
with the new direct acting antiviral drugs.
No vaccine is currently available,
and many hurdles still exist in its development. The first hurdle in this regard is testing.
The only way to test for the potential of infectivity is by PCR for the
presence of HCV-RNA. Secondly, the only species that can be infected are humans
and chimpanzees, which limit animal testing. The third issue is that many of
the HCV viral proteins have a high mutation rate (meaning they are not the same
from genotype to genotype). Finally, and possibly the most important, is that
researchers currently have not identified an antibody that kills the virus (for
example, anti-HBsAg antibody kills the hepatitis B virus). The best hope for a
vaccine might be one that prevents the development of the chronic carrier
In summary, HCV has rapidly become a
difficult and confusing topic with many questions still unanswered. However, the future impact of this virus on
society and healthcare is massive. Therefore, further research is needed along
with increasing public awareness of this infection. Hopefully, the future will
bring an effective immune globulin and vaccine for prevention and research will
identify a better mechanism to follow potential infectivity.
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