Chronic infection with hepatitis C virus (HCV) is a major cause of liver disease-related death and is also the most frequent indication for liver transplantation in USA. Infected individuals can remain asymptomatic for 20 years or more, but they remain at risk for progressive liver disease. They also represent a potential source of infection for others. For reducing the future disease burden due to HCV, obstetrician/gynecologists and primary health care practitioners should be aware of the factors that promote HCV transmission: how to provide counseling and testing, and when specialist referral is needed.
1. Introduction
Hepatitis C virus (HCV) is transmitted
mostly via infected blood or blood products [1] and is the most prevalent
blood-borne virus in the United States, where an estimated 3.2 million people
are chronically infected [2, 3]. Worldwide prevalence is estimated to be 170
million [4]. It is a single-stranded RNA virus of the family Flaviviridae. The
viral genome shows great variability in nucleotide sequence owing to a high
rate of mutation [3]. There are 6 major HCV genotypes and more than 50 subtypes
[3]. This variation is believed to partly account for the ability of the virus
to escape host immune defenses and sustain a chronic infectious state [3, 5].
The acute stage of HCV infection is
only infrequently associated with symptoms of hepatitis such as anorexia,
weakness, malaise, and jaundice [3]. It usually goes undiagnosed. Chronic
infection is defined as infection persisting for longer than 6 months [3]. In
most instances, HCV infection remains undetected until a chronic stage and is
discovered during the course of testing for an unrelated condition or during
blood donation [6]. It is estimated that acute infection develops into chronic
infection in 60% to 85% of cases. Younger age, female sex, non-African-American
race, and certain histocompatibility genes are all associated with improved
spontaneous clearance of the virus and a lower likelihood of chronic infection
[3].
HCV has been found in all regions of
the world where it has been sought [4]. Approximately, 1.3% of the population
of the United States is chronically infected [2]. Areas of higher prevalence
include certain countries in the Far East, Mediterranean, Africa, and Eastern
Europe. This worldwide reservoir of infection remains a potential source for
new infections [4]. Most of the morbidity and mortality from HCV is the result
of long-standing chronic infection. Of those chronically infected with HCV,
approximately 5% of individuals aged <40 years and 34% to 58% of individuals
aged ≥40 years develop cirrhosis of the liver 20 years after exposure and may
ultimately die from end-stage liver disease or hepatocellular carcinoma [7]. In
the United States, approximately 40% of chronic liver disease is HCV-related,
which would suggest that 8 000 to 10 000 deaths each year are caused by HCV. In
addition, HCV-associated end-stage liver disease is the most frequent
indication for liver transplantation in adults [1].
The estimated incidence of new
infections in the United States declined from 230 000 in the mid-1980s to 36 000
in 1996 [1]. The use of effective HCV tests has largely eliminated blood
transfusion as a route of infection in the United States and other developed
countries [1]. In addition, measures aimed at reducing the spread of human
immunodeficiency virus (HIV) may be responsible for the observed reduction in
new HCV infections in injection-drug users [8]. However, because liver disease
is the result of long-standing infection, the burden of disease continues to
rise. It is anticipated that there will be a 4-fold increase in the number of
Americans at risk of chronic liver disease in 2015 compared with 1990 [8].
2. Risk Factors for HCV Infection
Persons at the greatest risk of HCV
infection are those who have ever injected illicit drugs and those who have received
blood transfusions or organ transplants before universal testing of donors was
established. Also at risk are persons who received clotting factor
concentrates. Lesser but still measurable risk factors for HCV include birth from
an infected mother, sexual contact, accidental contamination during medical
procedures, and household contact [1].
2.1. Parenteral Transmission
Injection-drug users are at extremely
high risk of acquiring HCV infection. It has been shown that the prevalence of
HCV among older injectors (≥5 years of injection) is high (80% to 90%), whereas
studies of young injectors (1–3 years of
injection) in the last 10 years have shown that the cumulative infection rates
have slowed [9]. Only 20% to 40% of young injectors are positive for HCV
infection [10]. Injection-drug users become more rapidly infected with HCV than
with other blood-borne viruses, possibly because of high levels of HCV
chronicity in this population [11]. Injection-drug
use accounts for most of the current transmission of HCV in the United States [1].
Persons who received blood transfusions
or organ transplants before 1992 are considered to be at risk of having
acquired HCV infection. In the United States, introduction of second-generation
polyantigen testing from July 1992 largely eliminated the risk from donated
blood and organs [1].
2.2. Perinatal Transmission
The average rate of infection in
infants born to infected mothers is 5% to 6%. The chance of infection has been
shown to be greater with higher serum levels of HCV-RNA (17%) and in mothers
coinfected with HCV and HIV (14%). HCV-RNA can be detected within 2 to 3 months
of birth [1]. Children with HCV infection only rarely show symptoms or
significant elevations in liver enzymes. Progression to severe liver disease is
generally slower than in adults [12].
2.3. Sexual Transmission
The relevance of sexual transmission to
the epidemiology of HCV remains controversial. Epidemiologic surveys suggest
that 20% of patients with recently acquired hepatitis C have no self-reported
risk factor other than multiple sexual partners or an infected sexual partner [13].
However, studies of HCV transmission in stable monogamous couples show very low
rates of infection—in some instances, below the detection limits
of the study [14–18]. Most studies
of couples have been cross-sectional in design and have investigated
concordance rates for seropositivity. Only some of the studies included
nucleotide sequencing; in these instances, HCV strains were sometimes found to
be too dissimilar to be consistent with transmission between partners [19]. The
rate of sexual transmission between monogamous heterosexual partners has been
estimated to be between 0% and 0.6% annually [3, 19]. This low rate of HCV
infection after many years of sexual exposure would suggest that the risk of
sexual transmission of HCV is minimal. It is biologically plausible that rates
of sexual transmission of HCV may be higher if exposure to blood occurs, and
there is some supporting evidence for an association of acute HCV infection
with genital ulcers or sexual activity at risk for lacerations of the anal
epithelium [20, 21]. However, it is now widely believed that the observed
association of HCV with high-risk sexual practices is mostly the confounding
effect of unreported injection-drug use that is itself associated with
high-risk sexual practices [1]. Many persons are unwilling to admit to a
history of injection-drug use [22]. It should be emphasized that the
association between markers of high-risk sexual practices and HCV infection is
real, even if the underlying reasons are unclear. The Centers for Disease
Control and Prevention (CDC) states that “although HCV is not efficiently
transmitted sexually, persons at risk for infection through injection-drug use
might seek care in STD [sexually transmitted disease] treatment facilities” [23].
2.4. Nosocomial Transmission
In the United States and other
industrialized countries, the use of standard (universal) precautions to
prevent infection has eliminated most HCV transmission in health care settings.
Three exceptions remain. First, the average incidence of seroconversion after
needle stick or sharp exposure from an HCV-seropositive source has been
estimated to be 1.8% (range 0% to 7%) [1]. One study showed a 1.2% incidence of
seroconversion after injury from a hollow-bore needle but no instances of
seroconversion from injuries with sharp objects or from contamination of mucosa
or nonintact skin [24]. Second, despite stringent infection-control
precautions, HCV outbreaks continue to occur in hemodialysis centers.
Epidemiologic surveys show that the prevalence of seropositivity in patients in
hemodialysis centers averages 10% and, in some centers, can be greater than 60%
[1]. Third, during the last 15 years, there has been an increase of iatrogenic
HCV transmission not related to dialysis [25]. It is being recognized with
increasing frequency that HCV transmission is resulting from unsafe therapeutic
injection practices, such as contaminated multiple-dose medication vials, saline
bags from reinsertion of used syringes, and contaminated platforms for
spring-loaded finger-stick devices used to monitor blood glucose in multiple
patients. Interestingly, most of the instances occurred in developed countries,
such as Western and Northern Europe, the United States, Australia, and
Japan.
The CDC has hemodialysis and syringe/needle
safety guidelines to prevent nosocomial HCV transmission in ambulatory
healthcare settings [26]. The CDC recommends the following routine precautions
for the care of all hemodialysis patients:
patients should have specific dialysis stations assigned to them, and
chairs and beds should be cleaned after each use;
sharing among patients of ancillary supplies such as trays, blood
pressure cuffs, clamps, scissors, and other nondisposable items should be
avoided;
nondisposable items should be cleaned or disinfected appropriately
between uses;
medications and supplies should not be shared among patients, and
medication carts should not be used;
medications should be prepared and distributed from a centralized area;
clean and contaminated areas should be separated (e.g., handling and
storage of medications and hand washing should not be done in the same area or
an area adjacent to where used equipment or blood samples are handled).
The CDC recommends that all health care
workers
use a sterile, single-use, disposable needle and syringe for each
injection and to discard them intact in an appropriate sharps container after
use;
use single-dose medication vials, prefilled syringes, and ampules when
possible. Do not administer medications from single-dose vials to multiple
patients or combine leftover contents for later use;
if multiple-dose vials are used, restrict them to a centralized
medication area or for single patient use. Never reenter a vial with a needle
or syringe used on one patient if that vial will be used to withdraw medication
for another patient. Store vials in accordance with manufacturer’s
recommendations and discard if sterility is compromised;
do not use bags or bottles of intravenous solution as a common source
of supply for multiple patients;
use aseptic technique to avoid contamination of sterile injection
equipment and medications.
2.5. Household Transmission
Nonsexual transmission of HCV between
family members may infrequently occur, presumably via percutaneous or
permucosal exposure to blood. HCV seropositivity concordance rates average 4%
in nonsexual household contacts, including siblings and others [27, 28].
However, most such studies did not use confirmatory sequence analysis [28].
Moreover, many of the studies were conducted in areas where transmission from
contaminated medical equipment is known to have occurred in the past, and this
would alternatively explain HCV concordance in families [1].
3. Antiviral Therapy
The standard therapy for chronic HCV
infection is a course of weekly subcutaneous injections of pegylated interferon
alfa (PEG-IFN) combined with once-daily oral ribavirin [12, 29]. Duration of
treatment is 48, 24, or 12 weeks, depending on HCV genotype and other treatment
prognostic factors. The principal goal of treatment is a sustained virologic
response (SVR), defined as elimination of detectable virus during treatment and
continued absence of virus 6 months after the end of treatment [12]. Long-term
followup of patients in clinical trials has shown that an SVR usually presages
long-term eradication of the infection and a marked reduction in the histologic
and biochemical markers of liver disease [30, 31].
Pegylated interferon has a covalently
attached water-soluble polymer of polyethylene glycol that improves the
pharmacokinetic profile over that of standard interferon and allows for
once-weekly dosing. Ribavirin is an antiviral drug that is effective against
HCV only when combined with interferon. Although PEG-IFN has a greater efficacy
than older anti-HCV therapies, it remains less effective against HCV genotype 1
than genotypes 2 and 3 [29]. Safety and efficacy of PEG-IFN have also been
established in patients with HCV and compensated cirrhosis and in patients with
HCV/HIV coinfection [32].
PEG-IFN can cause bone marrow
suppression, and ribavirin can cause hemolytic anemia, resulting in the need
for periodic hematologic testing during therapy. Thyroid function testing
(thyroid stimulating hormone) is required because of the risk of autoimmune
thyroiditis [29]. Emotional side effects of interferon are common [29], and
patients need to be monitored for depression. Patients should be advised to
report any sign or symptom of depression to their prescribing physician [32].
Ribavirin is contraindicated in pregnancy and in male partners of pregnant
women. Thus pregnancy testing is required in women of childbearing potential
immediately before and at monthly intervals during therapy. Women of childbearing
potential and their male partners must use reliable forms of contraception if
either partner is receiving PEG-INF/ribavirin, both during treatment and for at
least 6 months after treatment has concluded [32].
For those individuals infected with the
HCV virus, the CDC recommends treatment based on the level of clinical risk
(Table 1). Treatment is generally recommended for patients who are at an increased
risk of developing cirrhosis [29]. Such patients are characterized by
detectable viremia, and a liver biopsy shows portal or bridging fibrosis and
moderate inflammation and necrosis [3]. Some patients with milder disease than
this also choose to be treated [3]. About one third of those with chronic HCV
have a highly favorable prognosis and are unlikely ever to develop cirrhosis [33].
An informed choice between starting or deferring treatment is based on
prognostic factors, the likelihood of treatment success, the potential for side
effects, any relative or absolute contraindications, and on the patient’s
motivation [3, 34]. Patients deferring antiviral therapy should undergo a liver
biopsy every 4 or 5 years to monitor disease progression [12].
Treatment groups for patients with
hepatitis C virus (HCV) [1].
Individuals recommended for treatment
(i) Patients with persistently elevated alanine aminotransferase (ALT)
levels
(ii) Patients with detectable HCV ribonucleic acid
(iii) Patients with a liver biopsy indicating either portal or bridging
fibrosis or at least moderate degrees of inflammation and necrosis
Individuals for whom treatment is unclear
(i)
Patients with compensated cirrhosis (without jaundice, ascites,
variceal hemorrhage, or encephalopathy)
(ii) Patients with persistent ALT elevations but with less severe
histologic changes (i.e., no fibrosis and minimal necroinflammatory changes)
(In these patients, progression to cirrhosis is likely to be slow, if at all;
therefore, observation and serial measurements of ALT and liver biopsy every
3–5 years is an acceptable alternative to treatment with interferon)
(iii) Patients <18 years of age or >60 years of age (note that
interferon is not approved for patients younger than 18 years)
Individuals for whom treatment
is not recommended
(i)
Patients with persistently normal ALT values
(ii) Patients with advanced cirrhosis who might be at risk for
decompensation with therapy
(iii) Patients who are drinking excessive amounts of alcohol or who are
injecting illegal drugs (treatment should be delayed until these behaviors
have been discontinued for ≥6 months)
(iv) Persons with major depressive illness, cytopenias, hyperthyroidism,
renal transplantation, evidence of autoimmune disease, or who are pregnant
4. Screening and Diagnosis
Obstetrician/gynecologists and other
providers of primary health care services can screen for patients at risk of
HCV infection, perform an initial diagnostic workup, and provide appropriate
counseling to those infected or at risk of becoming infected. Routine screening
of all adults is not recommended; instead, screening is focused on individuals
with known risk factors for HCV infection [1]. These include the following:
persons who have injected illegal drugs, even if this took place in the
remote past; this includes those who injected once or a few times [1]; many of
these persons may not consider themselves to be drug users [22];
persons who received an organ transplant or blood transfusion before
July 1992, when second-generation enzyme immunoassay (EIA) anti-HCV testing was
introduced [1]; women who had cesarean sections before that date may have been
at risk of infection via transfusion;
persons
notified that they received blood from a donor who later tested positive for
HCV [1];
persons who received clotting factor concentrates produced before 1987,
when heat inactivation was introduced [1];
persons who have ever been on long-term hemodialysis [1];
persons with HIV infection [1];
patients with biochemical or clinical evidence of liver disease, for
example, persistent elevations of alanine aminotransferase (ALT) [1, 29];
health care, emergency medical, and public service workers with needle stick
injury or mucosal exposure to HCV-positive blood [1];
children born to HCV-infected mothers [1];
current sexual
partners of HCV-infected persons. Although risk in this group is low, a
negative test in the partner provides reassurance [12].
Patients can be screened for risk
factors during any visit. An unexplained elevation of ALT may be caused by HCV,
but many of those with chronic HCV infection have normal ALT. Signs and
symptoms are sometimes present but are mostly nonspecific and include malaise,
anorexia, and fatigue; these may be accompanied by low-grade fever and
abdominal discomfort. Physical examination may reveal signs of liver disease
such as hepatosplenomegaly, spider nevi, and palmar erythema [35]. Counseling
and testing should be offered if a risk factor is identified [1]. Testing for
HCV is not recommended for pregnant women without risk factors. Certain
settings such as STD clinics and correctional facilities serve large numbers of
patients at high risk for blood-borne infections, and it is especially
important to screen for a history of injection-drug use in these settings [23].
5. Testing Procedures
EIA tests are inexpensive, reproducible
serologic tests that detect anti-HCV antibodies. The version in current use (third-generation)
has high sensitivity and specificity, making confirmatory testing unnecessary
in many instances. EIA tests are recommended for initial testing of patients [3].
A positive test may be considered conclusive in patients with evidence of liver
disease, such as abnormally high ALT, together with risk factors for infection
[3]. Qualitative polymerase chain reaction (PCR) tests detect viral RNA with a
greater sensitivity than the quantitative PCR tests that are used to measure
viral load. Qualitative PCR tests can be used to confirm a positive EIA. A
negative PCR result may require confirmatory immunoblot testing for anti-HCV. A
repeat negative qualitative PCR result and confirmed anti-HCV test is suggestive
of a spontaneously cleared acute infection. Patients with immune deficiencies
or on hemodialysis may test false-negative for anti-HCV, and patients with
autoimmune disease may test false-positive. A qualitative PCR test may be used
as the primary test in these instances [3]. Infants born to infected mothers
should be tested using EIA not earlier than 15 months of age to avoid the
possibility of a false-positive result caused by maternal antibody. A PCR test
can be performed during or after the first well-child visit at ages 1 to 2
months if an earlier result is required [3].
6. Counseling
Obstetrician/gynecologists and other
primary care physicians can have an important role in counseling patients on
how to slow disease progression and prevent transmission of the virus to
others. Alcohol and HCV have independent and synergistic effects on the risk of
cirrhosis [36]. Counseling patients to eliminate or at least reduce alcohol
consumption may therefore be an effective primary care intervention for
preventing progression to cirrhosis. Acceleration of progression to cirrhosis
has been clearly established with heavy alcohol consumption, and the results of
one study suggest that moderate consumption may be deleterious [12, 37]. The
CDC recommends that patients with chronic HCV infection abstain from alcohol [1].
Counseling should also stress the
importance of weight control. Both obesity and its accompaniment, fatty liver
disease, are associated with progression of HCV-associated liver disease. Thus weight reduction for those with body mass
index >25 kg/m2 may be especially beneficial in persons with
chronic HCV infection. Hepatitis A and B vaccinations are recommended for all
persons with chronic HCV infection because of the increased risk of
complications from coinfection, including fulminant hepatitis [12, 38].
Persons with HCV need reliable advice
on how to avoid transmitting the infection to others, and uninfected persons
need to know how to reduce the risk of infection. Health care professionals
should routinely obtain a history that inquires about use of illegal drugs and
evidence of high-risk sexual practices (e.g., multiple sex partners or a
history of STDs) [1]. Knowing the risk
factors and cross-checking the patient’s history for these can have a positive
impact on prevention of HCV transmission. Guidance in obtaining a sexual
history is available from the curriculum provided by CDC STD/HIV Prevention
Training Centers (http://www.stdhivpreventiontraining.org/)
[23].
Current injection-drug users, regardless
of HCV status, should be advised to stop using and injecting drugs and to enter
and complete substance abuse treatment. If they continue to inject, they must
use only sterile needles and syringes from a reliable source and never reuse or
share drug preparation equipment, plus they must safely dispose of used materials
[1].
Primary prevention of illegal drug
injection will eliminate the greatest risk factor for HCV infection [1]. A
study showed that injection-drug users, even before they become identified as
high-risk by prevention services, may engage in more high-risk practices than
individuals who remain nonusers [39]. Thus identifying risk factors for
starting injecting could increase the opportunities to intervene and, in turn,
cut transmission of HCV. Counseling
and education to prevent the initiation of drug-injection or high-risk sexual
practices is important, especially for adolescents [6].
Obstetrician/gynecologists
should be aware that although consistent data are lacking on the extent to
which sexual activity contributes to HCV transmission, persons with multiple
sex partners are at risk for STDs, including HIV, human papillomavirus, hepatitis
B virus, syphilis, gonorrhea, and Chlamydia [1].
Obstetrician/gynecologists
should counsel persons at risk for STDs with regard to what they can do to
minimize their risk of becoming infected or of transmitting infectious agents
to others. Data on long-term sexual partners with no other risk factors
suggest that the rate of sexual transmission of HCV is very low. Guidelines
state that HCV-positive individuals do not need to change their sexual
practices and that barrier forms of protection, such as condoms, are not
required [12, 23]. Although monogamous sexual relationships carry a low risk of
HCV transmission, the risk is higher in HCV-infected individuals with multiple
sexual partners or in short-term relationships. In persons at risk for sexually
transmitted diseases, guidelines advise the correct use of latex condoms during
all sexual encounters [1].
HCV-positive women do not need to avoid
pregnancy or breastfeeding [1]. However, prospective and expectant mothers
concerned about HCV should be advised that
routine testing for HCV is not recommended for pregnant women unless
there is a known risk factor [1];
approximately 5% of infants born to infected mothers become infected at
birth, and there is no known treatment that can prevent this from happening.
The choice of cesarean versus vaginal delivery does not appear to modify the
risk of transmission [1];
infants and children with HCV are less likely than adults to have
symptoms, and liver disease develops more slowly. Spontaneous clearance of HCV
is more common in children than in adults [1, 12];
available evidence suggests that breastfeeding does not transmit HCV,
although mothers should consider avoiding breastfeeding if the nipples are
cracked or bleeding [1].
7. Conclusion
Hepatitis C and its associated liver
disease is a global health problem that is likely to increase in coming decades
because of a greater number of persons with long-standing chronic infection.
Antiviral therapies have improved in recent years and can eradicate HCV
infection in many individuals. Because of the subclinical nature of chronic
HCV, identification of infected individuals who might benefit from therapy is
central to the overall management of the disease. Obstetrician/gynecologists
and other health care providers should be able to screen patients for risk
factors and offer counseling and testing. All patients testing positive for HCV
are potential candidates for antiviral therapy and should therefore be referred
to specialists. Alcohol avoidance and weight control may be effective in
delaying or preventing the onset of cirrhosis in those who choose to defer
antiviral therapy.
Screening and counseling guidelines for
hepatitis C that emphasize the role of nonspecialists include CDC guidelines on
sexually transmitted diseases at http://www.cdc.gov/std/treatment/default.htm,
which has a section on hepatitis C, and guidelines from the World Health
Organization at http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/.
Patient education leaflets on hepatitis C can be located at the US Department
of Veterans Affairs at http://www.hepatitis.va.gov/vahep?page=prtop02-00-rr#S16X
and at the National Library of Medicine Medline Plus at http://www.nlm.nih.gov/medlineplus/hepatitisc.html.
Screening for HCV risk factors take
place at any health care visit. Obstetrician/gynecologists should note that
patients in certain settings, such as STD treatment clinics, may be at
increased risk of HCV infection. Sexual transmission of HCV appears to occur
only rarely in stable monogamous couples, and precautions to prevent sexual
transmission are not needed in these circumstances. HCV testing need not be
offered to pregnant women with no identifiable risk factor; however, prenatal
visits are a good opportunity to screen for HCV risk factors and to offer
testing and counseling where appropriate. This is in part because health care
visits may be more frequent than at other times in a woman’s life and also
because of the need to follow up children born to infected mothers.
Acknowledgment
The authors acknowledge the editorial
assistance provided by Insight Medical Communications, Inc. supported by Roche
Laboratories, which did not play any role in or see the manuscript during its
development.
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