Hepatitis viruses: Hepatitis C
Ponni V. Perumalswami, M.D., M.C.R.1 and Robert S. Klein, MD2
1
2
Division of Liver Diseases, Mount Sinai School of Medicine, New York, New York
Division of Infectious Disease, St. Luke's-Roosevelt Hospital Center, New York, New York
Correspondence:
Ponni V. Perumalswami, MD
Box 1123, Division of Liver Diseases
Mount Sinai School of Medicine
1425 Madison Ave., Room 11-70
New York, NY 10029-6574
Tel 212-241-7783
Fax 212-241-8377
Abstract
Hepatitis C virus (HCV), a member of the Flaviviridae family, is a bloodborne pathogen infecting
approximately 170 million persons representing around 3 percent of the population worldwide, with
substantial variability in prevalence in different geographic regions. It is a leading cause of chronic liver
disease, cirrhosis, and hepatocellular carcinoma, as well as the most common indication for liver
transplantation in many countries. It is a major public health problem and a leading cause of morbidity
and mortality. The major route of transmission is via exposure to infected blood, so that infections are
commonly seen resulting from transfusions where the blood supply is not screened or the sharing of
works by injection drug users. Sexual, perinatal, and occupational injury transmission also occur.
Although limited in scope, health care related outbreaks have been seen due to poor infection control.
While the incidence of HCV infection has decreased during the last several decades, because of the
prolonged duration between infection and the development of the major liver-related complications
resulting from infection, the prevalence of those complications continues to rise. A minority of persons
infected with HCV clears the virus spontaneously; most develop chronic infection. In the U.S. it is
estimated that three quarters of infected persons are unaware of their HCV infection. Because HCV
infection is most often asymptomatic until the late complications of advanced liver disease, diagnosis of
chronic HCV infection usually depends on asymptomatic screening of at-risk individuals or those with
elevations of serum transaminases. Among persons with chronic HCV infection, factors associated with
more rapid liver fibrosis include older age at time of infection, male gender, obesity, hepatic steatosis,
insulin resistance, hepatic iron overload, and co-infection with hepatitis B virus or human
immunodeficiency virus. However, not all persons with chronic HCV infection progress to cirrhosis or
end stage liver disease. More than one-third of persons with chronic HCV infection have one of more
symptomatic extra-hepatic manifestations. Because HCV infection is preventable, it should be a key
focus of clinical and public health interventions. Unless a vaccine becomes available, prevention of HCV
acquisition depends on minimizing exposure by eliminating transfusion of infected blood products,
reducing high risk behaviors, and optimizing infection control practices. HCV is also treatable, and when
successful, infection can be eradicated with elimination of transmission risk for the treated individual.
While treatments options are increasing with the recent and ongoing development of oral therapies,
optimizing reduction of transmission depends on identifying and treating asymptomatic infected
persons as well as those who are ill. It is important to note that cure does not prevent reinfection, since
there is no long term natural immunity to HCV reinfection.
Introduction
Hepatitis C virus (HCV) is a bloodborne human pathogen with a current global prevalence rate of
approximately 2-3%, representing approximately 130-180 million infected individuals. 1-5 Infection with
HCV may cause acute hepatitis, but the majority of persons with acute infection are asymptomatic.
Persons chronically infected with HCV are at risk of chronic hepatitis and of developing serious hepatic
complications such as cirrhosis, hepatocellular carcinoma (HCC), or liver failure. In the developed world,
HCV is the leading cause of cirrhosis and primary liver cancers 6,7 and the major cause of end-stage liver
disease leading to liver transplantation8,9. A recent report commissioned by the Institute of Medicine
(IOM) of the National Academies estimates that up to 75% of HCV-infected persons have not been
diagnosed. 10
Historical Background
The recognition of what was eventually identified as HCV began in the 1970s with the first descriptions
of post transfusion hepatitis not attributable to hepatitis A virus (HAV) or hepatitis B virus (HBV). This
disease entity was termed at that time “non-A, non-B” (NANB) hepatitis. 8,11,12 Hepatitis C virus was
discovered in 1988 and was shown to be the primary etiologic agent of parenterally transmitted NANB
hepatitis. 8,11-14 Leading up to the discovery of HCV, both cohort and case-control studies of persons
with NANB hepatitis demonstrated specific risk factors associated with acquiring the disease, including
transfusion of blood and blood products, occupational exposure to blood, sex with known infected
partners, injection drug use, and sex with multiple partners. 15-21 Together, these studies led to the
conclusions that the primary etiological agent of NANB was predominantly both transfusion-related and
community acquired.
Methods for Epidemiologic Analysis
-Sources of Morbidity and Mortality Data
Morbidity and mortality data on HCV infection are acquired from a variety of sources including death
certificates, hospital admissions, surveys, research studies, and required reporting of cases. In the
United States, HCV is a separate reportable disease and health-care providers, hospitals, and
laboratories are required to send reports of cases of HCV infection to state and local health departments
that include them within their jurisdiction.
Among HCV-infected persons there are a rapidly increasing number of deaths, which in the U.S. now
surpass deaths among HIV-infected persons. U.S. multiple-cause mortality data from 1999 to 2007 of
approximately 21.8 million death certificates demonstrated an increase in the mortality rate from HCV
infection over that time period.22 A statistically significant average annual age-adjusted mortality rate
increase of 0.18 death per 100 000 persons per year related to HCV was observed (P =0.002). In
addition, the relatively young ages at death (45 to 64 years) of most HCV-infected persons portend a
large and ever-increasing health care burden in the years to come. In the U.S. alone, estimates forecast a
peak in the number of incident cases of end-stage liver disease due to HCV of approximately 38,600 in
the year 2030, 3.9 times the predicted annual incidence in 2010.23 The annual number of liver
transplants and deaths are forecast to peak about 2–3 years later at approximately 3200 transplants and
36,100 deaths. Of the approximately 2.9 million pre-cirrhotic patients infected with chronic hepatitis C
in 2005, it is estimated that without treatment 24,900 or 0.9% will have died from hepatitis C by 2010;
379,600 or 13.1% by 2030; and 1,071,229 or 36.8% by 2060. Globally, estimates indicate that up to four
million persons are newly infected each year, 170 million people are chronically infected and at risk of
developing cirrhosis and liver cancer, and 350,000 deaths occur annually due to all HCV-related
causes.24,25
-Surveys
The National Health and Nutrition Examination Survey (NHANES) refers to a series of assessments that
have periodically collected data on the health and nutritional status of a large sample of adults and
children in the U.S. The information includes HCV prevalence, based on interview, physical examination,
and laboratory testing, allowing clinicians to target at-risk groups with educational services and
therapeutic options. The latest NHANES survey from 1999 to 2002 included 15,079 total participants
and is the largest epidemiological study ever conducted on HCV prevalence in the U.S. According to
NHANES, 1.6% or 4.1 million persons in the U.S., most of whom were born between 1945 and 1964,
were anti-HCV seropositive.3 The survey, however, sampled from a non-institutionalized civilian
population and did not include certain high-risk persons, namely the incarcerated, homeless, nursing
home residents, hospitalized patients, those in active military service and immigrants. The survey also
missed some groups with an expected high prevalence of HCV infection (e.g., healthcare workers and
persons on long-term hemodialysis) because of their under-representation in the sample studied. As a
result, it has been estimated that NHANES likely underestimated the true prevalence of HCV in the U.S.,
and by at least 1 million infected persons
26,27
Globally, the prevalence of HCV varies geographically. Recent developments in modeling allow the
seroprevalence of anti-HCV to be used to estimate the global burden of disease for HCV infections.
Specifically, an international collaborative, The Global Burden of Diseases, Injuries, and Risk Factors 2010
(GBD2010) Study, is an effort to estimate the global burden of HCV infection. The GBD Study defined 21
regions such that detailed data in one country can plausibly be extrapolated to other countries in the
region in order to create burden estimates.25,28 Based on a systematic review and meta-analysis of
primary national data sources and articles published for peer review between 1980 and 2007, the
following global estimates of HCV have been made: Central and East Asia and North Africa/Middle East
are estimated to have a high prevalence of HCV infection(>3.5%); South and Southeast Asia, subSaharan Africa, Andean, Central, and Southern Latin America, Caribbean, Oceania, Australasia, and
Central, Eastern, and Western Europe have moderate prevalence (1.5%-3.5%); whereas Asia Pacific,
Tropical Latin America, and North America have low prevalence (<1.5%).
-Laboratory Diagnostics
There are two different types of assays that are used in the diagnosis and evaluation of HCV infection serologic and molecular assays. Serologic assays detect antibody to HCV (anti-HCV) and can be used to
screen for and diagnose prior or current HCV infection. Serological assays include widely used enzyme
immunoassays (EIAs) with specificities greater than 99% and therefore remain the best screening tests
for the diagnosis of hepatitis C. False-negative anti-HCV testing may occur, albeit rarely, in the setting of
severe immunosuppression such as HIV infection, solid organ transplantation, aggammaglobulinemia or
in patients on hemodialysis.29-32 False-positive anti-HCV with EIA tests may also occur, particularly in
populations with a low prevalence of HCV infection. Signal to cut-off ratios (>4.0 associated with true
HCV exposure or infection) with EIAs can be used to help guide whether further confirmatory testing
with recombinant immunoblot assay (RIBA) can be helpful. The RIBA test assesses the serological
reaction of a patient to multiple HCV antigens and is a confirmatory test to the anti-HCV EIA test. A
positive RIBA in conjunction with a positive anti-HCV antibody test indicates a true past or present
infection with HCV. A negative RIBA in conjunction with a positive anti-HCV antibody test indicates a
false-positive anti-HCV antibody test and the patient can be reassured without further testing. 33 In
persons with positive HCV screening tests, molecular assays to detect viral nucleic acid, and therefore
active viral infection, are recommended and can be either qualitative or quantitative. Real time
polymerase chain reaction (PCR) based assays and transcription mediated amplification (TMA) assays
have largely replaced qualitative molecular assays and are widely used for monitoring during response
guided-therapy. These assays have sensitivities of 10-50IU/mL and have excellent specificity (98%99%). Serologic and molecular assays do not assess disease severity or prognosis. Additionally, the
most current consensus proposal distinguishes six genotypes based on phylogenetic cluster analysis of
complete genomes. Genotype testing is performed in the evaluation of HCV infection in order to
maximize the chance of successful treatment outcome for each individual patient as treatment type,
duration, dose and effectiveness is influenced by genotype. While phylogenetic analysis with direct
sequencing of an HCV genomic region is considered the gold standard for identifying difference HCV
genotypes, this method is expensive and time-consuming. For this reason, commercial genotyping kits
were developed for routine determination of HCV genotypes.
Biological Characteristics
A member of the family Flaviviridae, HCV is classified within a separate genus, Hepacivirus, due to
differences from other members of the family in the organization of the structural proteins that make
up the amino terminal third of its polyprotein. The virus has an enveloped, positive-sense, single strand
RNA genome of approximately 9.6kb in length with extraordinary genetic diversity. 34 The RNA contains
a single large open reading frame that encodes for a 327kD polyprotein of approximately 3000 amino
acids that is flanked by nontranslated segments.35 The polyprotein is processed by host cell peptidases
and viral proteases that cleave it into structural and non-structural proteins needed for viral
replication.36 The 5’-end includes structural proteins (core, E1, and E2) that encode nucleocapsid and
envelope proteins, and the 3’-end includes nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and
NS5B) required for replication (see figure 1).
Figure 1
HCV RNA
Data from Swiss Med Wkly. 2012;142:w13586
The nonstructural proteins have distinct enzymatic functions including production of proteases (NS3,
NS4A), helicases (NS3) and polymerases (NS5B). The HCV genome contains both highly conserved and
highly variable regions. Six major genotypes of HCV have been described, and there are subtypes within
each genotype. The genotypes are differentiated by sequences in the relatively conserved core, E1 and
NS5B regions.36 Pairwise differences in the nucleotide sequences of the six HCV genotypes are on the
order of 31% to 33% and the geographic distribution of specific genotypes varies. 34 In the U.S.,
genotype 1 is the most common (75%). In Europe, genotypes 1 and 3 are most common, while in Egypt
genotype 4 predominates. Additional variants, known as quasispecies, are present in infected individuals
and are a result of the high error-rate of the viral RNA polymerase during replication.
Descriptive Epidemiology
Morbidity and Mortality
Global morbidity and mortality from HCV infection is a tremendous public health burden. Available
estimates indicate that worldwide there were 54,000 deaths and 955,000 disability adjusted life-years
associated with HCV infection. 25 The major burden from HCV infection comes from sequelae from
chronic infection. Estimates indicate that three to four million persons are newly infected each year, 170
million people are chronically infected and at risk of developing liver disease including cirrhosis and liver
cancer, and 350,000 deaths occur each year due to all HCV-related causes.25
24
Prevalence and Incidence
The available data suggest that the global prevalence of HCV infection has increased from 2.3% (95%
uncertainty interval [UI]: 2.1%-2.5%) to 2.8% (95% UI: 2.6%-3.1%) and >122 million to >185 million
between 1990 and 2005. 4,24 These estimates are based on systematic reviews of published prevalence
data, including volunteer blood donor studies and therefor they may underestimate the true population
prevalence.37 Although HCV infection is endemic worldwide, there is a large degree of geographic
variability in its distribution (see figure 2).
Figure 2
Geographic Prevalence of Hepatitis C Virus Infection
Data from the CDC accessed online September 19, 2012 from:
http://www.cdc.gov/immigrantrefugeehealth/guidelines/domestic/viral-hepatitis-figure5.html
The prevalence of anti-HCV antibody is quite variable throughout the general population, with the
highest rates among persons with repeated percutaneous exposures through injection drug use.
Additional risk groups include hemophiliacs, patients on hemodialysis, patients transfused with
unscreened blood and blood products, inmates of long-term correctional facilities, and persons with
occupational exposure. 38-45 Data regarding the incidence of HCV infection are difficult to obtain, since
most acute infections (60-70%) are asymptomatic and there is no widely available test to distinguish
acute from chronic infection.46,47 Surveillance data from the CDC demonstrate a decrease in the annual
number of incident cases (see figure 3). These data are derived by adjusting rates from the Sentinel
Counties Study of Viral Hepatitis (1982–2006) and the Emerging Infection Program (2007) for
underreporting and asymptomatic infection.
Figure 3
Decrease in the number of acute HCV cases, by year in the U.S.
Data from the CDC. Accessed online September 19, 2012 from:
http://www.cdc.gov/hepatitis/Statistics/index.htm
Epidemic behavior
Outbreaks of hepatitis C are limited in scope because of the predominantly blood-borne route of
transmission. Historically, most early outbreaks of HCV infection were reported in the setting of
hemodialysis, and blood or plasma donation. 48-52 However, many outbreaks have occurred in other
health care settings as a result of poor infection control practices; failure to use aseptic technique during
preparation or delivery of therapeutic injections has commonly led to cross-contamination from reused
needles and syringes, multidose saline vials, infusion bags, heparin solutions and pain treatments. 53-64
Additionally, outbreaks of acute HCV infection have been reported in IDUs and HIV infected MSM.65,66
Geographic distribution
Data from WHO and CDC concur in their indication that the prevalence of HCV infection varies in
different geographic regions.67 Data from GBD2010 estimates higher prevalences of HCV in east and
central asia (3.7-3.8%), eastern Europe (2.9%), North African with (3.6%), and central and west subsaharan African with (2.3-2.8%) while prevalence is lower in North America (1.3%), Latin American (1.22.0%).5,68 Additionally, there are variances with respect to age and peak prevalence. 24 The highest
prevalence of HCV is 15% in Egypt, while the lowest reported prevalences are <1.0% in the United
Kingdom and Scandinavia. 24,67
Temporal
Countries with similar overall prevalence of HCV infection have different age-specific prevalence
patterns; three main patterns have been described.
67
The first pattern, found in the US and Australia, is
characterized by a low age-specific prevalence among persons less than 20 years and greater than 50
years with the majority of HCV infection occurring in persons 30-49 years old. This pattern suggests that
most HCV transmission occurred in the last 20-40 years, and primarily in young adults.3,69,70 The second
pattern, found in a number of countries including Turkey, Spain, Italy, Japan and China, is characterized
by low age-specific prevalence in children and young adults with the majority of infections occurring in
persons over 50 years old.
occurred 30-50 years ago.
71-74
This pattern suggests a cohort effect where most HCV transmission
The third pattern, found in Egypt, is characterized by high prevalence of
infection among persons in all age groups with HCV infection increasing steadily with age.
75,76
This
pattern suggests increased risk in the distant past followed by ongoing high risk of transmission.
Age
Acute hepatitis C infection may occur in all age groups but appears to occur mostly among young adults.
According to U.S. data from NHANES, prevalence of anti-HCV increased with age from 1.0% in those 20
to 29 years of age to a peak of 4.3% in those 40 to 49 years of age. 3 Two-thirds of HCV positive cases in
this survey were born between 1945 and 1964. Among young injection drug users, the annual incidence
of HCV infection ranges from 10% to 36%. 77-81 The overall age distribution of disease is likely related to
patterns of exposure (injection drug use in young and middle aged adults; transfusion in older adults)
and possibly to age-specific variation in clinical expression of disease.
This is in contrast to the age-specific prevalences of HCV infection which increase steadily with age in
many countries as outlined above. 72-74,82-84 This suggests a cohort effect in which the risk for HCV
infection was higher in the past. Where the emergence of HCV infection occurred in the distant past,
the burden of HCV-related chronic disease might already have reached its highest magnitude. However,
changes in disease transmission patterns that result in younger persons acquiring infection could lead to
future increases in chronic disease as this cohort ages. In Egypt, where there has been an ongoing high
risk for decades, the high magnitude of the current burden of HCV-related chronic disease is predicted
to continue.85
Sex
Data from the U.S. demonstrates that HCV infection is more common in men (2.1%) than women (1.1%).
It is not well understood why this difference exists, although differences by gender in risk factors such as
injection drug use likely contributes. 3 Males with HCV infection are more likely (2.5 times) to develop
cirrhosis and hepatocellular carcinoma when compared with females, suggesting that estrogens may
have protective affects against fibrosis progression. 86-88
Race
Hepatitis C occurs worldwide in all racial/ethnic groups studied. In the U.S., data from the most recent
NHANES demonstrated a higher overall prevalence among non-Hispanic black persons (3.0%) compared
with non-Hispanic white persons (1.5%) and was almost entirely attributable to differences among older
participants. 3 According to Armstrong and colleagues, this finding suggests that younger non-Hispanic
black persons may not be subject to the disproportionately high burden of disease that was seen in the
previous generation. However, the authors do note that the small number of younger anti-HCV–positive
participants limits definitive conclusions. 3 Although sparse data make comparisons difficult, observed
racial differences in prevalence or mortality rates are likely due to the differences in exposures and risk
factors in different locations.
Occupation
The route of acquisition of HCV is similar to that of hepatitis B virus (HBV) in the developed world, with
exposure to blood playing the principal but not exclusive role in transmission. HCV is not transmitted as
efficiently as HBV through occupational exposures to blood and is largely confined to health care
workers who have sustained contaminated needlestick injuries. The average incidence of anti-HCV
seroconversion after accidental percutaneous exposure from an HCV-positive source is 1.8% (range: 0%
to 7%). 89-91Transmission has been associated with hollow-bore needles, deep injuries, HIV co-infection,
and a high titer of HCV in the source patient’s blood.
89-93
Study of dentists has demonstrated an
increased risk of HCV infection compared to controls (1.75% vs. 0.14% OR 12.9, 95% CI 1.7 to 573),
particularly among oral surgeons, as has also been shown for HBV.94
Mechanisms and Routes of Transmission
HCV entry into hepatocytes is assumed to be a multistep process that requires sequential interactions
between cellular factors and viral proteins. Replication depends on viral and host proteins, and occurs in
association with intracellular membranes. 95 Historically, HCV research has been hampered by a lack of
adequate in vitro and in vivo model systems. In vivo study of HCV infection is restricted to humans and
chimpanzees due to a lack of small animal models. Another major limitation in the study of the HCV life
cycle is the inability to culture wild-type strains of HCV efficiently in cell culture. Much has been learned
regarding RNA replication from replicons, each of which contains an adapted HCV genome encoding a
selectable marker.
96
However, replicons do not reproduce other aspects of the life cycle such as virion
production and infection.96,97 Two additional advances came in 2003 and 2005 with the development of
retroviral pseudoparticles bearing unmodified HCV glycoproteins (HCV gp) and the discovery that a
genotype 2a isolate (JFH1) from a patient with acute fulminant hepatitis could undergo the complete
virus life cycle in cell culture, respectively.98
Direct percutaneous exposure to blood is the most efficient mode of HCV transmission. Higher rates of
transmission occur with large and repeated percutaneous exposures such as injection drug use, and with
transfusions or transplantation from infectious donors (see figure 4).
99
Lower rates of transmission
occur with single, small dose percutaneous exposures such as accidental needlesticks 91,99or by mucosal
exposures to blood or serum-derived fluids (e.g., birth to an infected mother, sex with an infected
partner).99-101
Figure 4
HCV Infection By Route of Transmission
Data from CDC. Accessed online September 19, 2012 from:
http://commons.wikimedia.org/wiki/File:Hepatitis_C_infection_by_source_(CDC)_-_en.svg
Iatrogenic Exposure
Transfusion-associated HCV infection was a major worldwide risk before HCV testing became available
in 1989. Prior to screening of the blood supply, transmission of HCV occurred in 5-18% of people
receiving a transfusion. 102-104 In some groups who were transfused large amounts of blood or pooled
blood derived products prior to screening, such as hemophiliacs, prevalence of HCV infection ranged
from 59% to 99%. 105,106 The risk of acquiring HCV via blood transfusion has been virtually eliminated in
countries that have implemented routine HCV testing of donors (less than one in a million per unit
transfused).107 However, some countries have not prioritized blood transfusion safety and/or lack the
resources to implement donor screening, and in these countries blood transfusion remains an important
source of infection. 108
Worldwide, there is a substantial preventable burden of HCV due to iatrogenic transmission. There is a
high prevalence of transfusions, reuse of needles and syringes, needle-stick injuries among health care
workers, and unnecessary medication injections.109,110 It has been estimated that contaminated health
care injections cause approximately 2 million of the HCV infections acquired annually and may account
for up to 40% of all HCV infections worldwide.111 In addition to unsafe injection practices, in some
countries, poor or nonexistent infection control in health and dental care facilities may be a source of
HCV transmission.
112
In Egypt, where the prevalence of HCV is the highest in the world, the reuse of
glass syringes during the parenteral therapy campaigns to control endemic schistosomiasis is a widely
suspected to be the source of iatrogenic transmission.113 However, there may have been considerable
other concurrent iatrogenic exposure at the time. 114 More recent evidence in Egypt supports a
continuation of iatrogenic exposures including unsafe medical and dental practices that is contributing
to ongoing HCV transmission.112,115
Iatrogenic transmission of HCV is not limited to resource poor countries. Outbreaks of HCV transmission
have occurred in resource rich countries as well. 55,56,59,61-63 Most of these outbreaks were reported in
the setting of hemodialysis and poor infection control leading to cross-contamination from reused
needles and syringes, multidose saline vials, infusion bags, heparin solutions and pain treatments.
Injection Drug Use
Injection drug users (IDUs) have the highest overall prevalence of HCV infection compared with any
other risk group. Worldwide, it is estimated that 16 million people injected drugs in 2007.116 Data from
one systematic review suggests that 10 million IDUs globally are HCV seropositive. 117 Anti-HCV
prevalence is noted to be as high as 60-80% in IDUs. Injection drug use has been the leading mode of
transmission during the past four decades in the US and Australia and now accounts for most newly
acquired infections in many countries in Europe. Eastern Europe, East Asia and Southeast Asia have the
largest populations of IDUs infected with both HBV and HCV.
WHO recommends that IDUs be a key target group for prevention and treatment of HCV (WHO
Resolution A63/15 2011). Indirect drug sharing and preparation practices including back loading and
using cotton (filters), cookers (drug solution containers, such as spoons), and rinse water, have all been
associated with HCV transmission. 81,118-120
Sexual Transmission
Sexual practices and exposures predictive of anti-HCV positivity include the number of recent and
lifetime partners, high risk sexual practices, other STDs (HSV-2 and Trichomonas) , and HIV infection
particularly in MSM.71,121-128 The magnitude of risk for transmission of HCV infection by sexual activity
has been controversial. Sexual transmission of virus occurs when infected body secretions or infected
blood are exchanged across mucosal surfaces.
99
The presence of virus in body secretions or blood is
necessary but may not be sufficient for transmission to occur. 101 Other factors that may influence
transmission include the titer of virus in body fluids, the integrity of the mucosal surfaces, and the
presence of other genital infections. Studies to detect HCV RNA in semen, vaginal secretions, cervical
smears, and saliva have yielded mixed results.
121,122,125,129,130
Studies have demonstrated that when HCV
RNA is detected in these secretions, it is present in lower concentrations than in blood. Low levels of
virus in genital secretions may be one reason that HCV is sexually transmitted less efficiently than HBV
or HIV. Also, the absence of appropriate target cells in the intact genital tract may require the presence
of abnormal mucosa for transmission. A review of the literature demonstrated that the risk for sexual
acquisition of HCV appeared to be related in large part to HIV coinfection. 131 There have been at least
two cross-sectional studies demonstrating increased risk of acquiring HCV infection among heterosexual
HIV infected persons.
132,133
The clearest and least equivocal sexual risk behavior that leads to HCV transmission is unprotected sex
among HIV-positive men who have sex with men (MSM). 131 The risk of HCV transmission by sexual
activity differs by the type of sexual relationship. Persons in long-term monogamous partnerships are at
lower risk of HCV acquisition (up to 0.6% per year) than persons with multiple partners or those at risk
for sexually transmitted infections (up to 1.8% per year). 101 Data from the CDC Acute Hepatitis Sentinel
County Surveillance program demonstrated that 18% of individuals with acute HCV infection reported
no other risk factor except sexual contact with an anti-HCV positive person in the preceding 6-month
period or multiple sexual partners.
HIV coinfection appears to increase the rate of HCV transmission by sexual contact although the precise
mechanism is unknown. Cross-sectional studies from the U.S. have demonstrated a two to four-fold
higher risk of heterosexual HCV infection in HIV-infected than in HIV-uninfected subjects.
132,134
Epidemics of sexually transmitted HCV infection among HIV-infected MSM have emerged in Northern
Europe, the United States, and Australia in the last decade.65,128,135-138 Risk factors for transmission in
HIV-infected MSM include multiple partners, fisting, use of sex toys and presence of genital ulcerative
disease. 139
Mother-to-Child Transmission
Prior to the testing of blood for HCV in 1992, blood transfusion was the predominant mode of
acquisition for HCV infection in children. Since then, mother-to-child transmission has become the
leading source of HCV infection in children where blood screening is routine. The rate of perinatal
transmission of HCV is 4% to 7% per pregnancy and requires detectable HCV RNA in maternal serum at
delivery. 67 The exact timing of transmission of HCV from the mother to the child is unknown. Both in
utero and intrapartum infections are possible. The outcome of perinatal transmission of HCV in twin
pregnancies is often discordant, with transmission of HCV more likely to affect the second twin and with
neonatal HCV RNA undetectable at delivery; these observations suggest that intrapartum transmission
may be more frequent than in utero transmission. 140 Risk factors for vertical transmission include
higher maternal serum HCV RNA levels (above 106 copies per mL), prolonged labor after membrane
rupture, internal fetal monitoring, and co-infection with HIV. 100,141-150. There is no apparent increased
risk of vertical transmission of HCV with the mode of delivery except in women who are also infected
with human immunodeficiency virus (HIV). The increased risk of perinatal HCV transmission in mothers
co-infected with HIV may be related to higher HCV viral loads in co-infected persons as a result of HIVmediated immunosuppression.
145
Other factors may increase perinatal transmission in HIV coinfected
mothers. One such factor is facilitation by HIV infection of HCV entry into blood cells with subsequent
replication; another is concomitant use of injection drugs by co-infected mothers. 151-153 The reason for
increased risk of vertical transmission in co-infected mothers who are IDUs is not known. It has been
postulated that greater maternal peripheral blood mononuclear cell (PBMC) infection confers an
increased risk for vertical transmission. Internal fetal monitoring and prolonged rupture of membranes
should be avoided if possible in all HCV infected pregnant women. Patients should be advised that
breastfeeding is permissible since there is no evidence that breastfeeding increases risk of HCV
transmission.
Hepatitis C Virus Transmission to Healthcare Workers
HCV is not transmitted efficiently through occupational exposures to blood. Nosocomial transmission is
largely confined to health care workers who have sustained contaminated needlestick injuries. The
average incidence of anti-HCV seroconversion after accidental percutaneous exposure from an HCVpositive source is 1.8% (range: 0% to 7%).89-91 This risk is intermediate between that resulting from
similar exposures to HIV (~0.3%) and in a susceptible person from exposure to HBV (6-30%). 154
Transmission has been associated with hollow-bore needles, deep injuries, HIV co-infection, and a high
level of HCV viremia in the source patient. 92,93 Transmission rarely occurs from mucous membrane or
non-intact skin exposures to blood, and no transmission to health care workers has been documented
from intact skin exposures to blood. 155 The prevalence of HCV infection among health care workers is no
greater than in the general population, averaging 1%-2%. 67 Even more rarely, HCV-infected health-care
workers have transmitted HCV to patients through needle stick injuries or other percutaneous exposure,
with an extremely low risk - averaging about 0.5%, even for those episodes involving surgeons.
Hepatitis C Virus Transmission in Other Settings
Percutaneous exposure to blood can occur in a variety of other practices, during which transmission of
HCV may occur. These exposures include but are not limited to tattooing, body-piercing, intranasal drug
use, ritual scarification, circumcision, acupuncture and cupping. There are currently insufficient data to
determine the extent to which these risks factors may contribute to overall HCV transmission.
Pathogenesis and Immunity
The majority of people with acute HCV infection progress to chronic infection (85%). 156-159 The key
features of acute and chronic hepatitis C virus infection are reviewed in this section.
-Acute Infection
The natural history of HCV infection generally begins with a subclinical and unrecognized acute phase
following infection. Symptomatic acute hepatitis occurs within 2 weeks to 6 months of infection in only
a minority of cases (10-15%) and is clinically indistinguishable from acute hepatitis of other causes—with
a combination of fever, fatigue, loss of appetite, nausea and vomiting, dark urine, jaundice, and liver
tenderness, accompanied by elevated levels of serum bilirubin and alanine and aspartate
aminotransferases (ALT and AST, respectively). 160 The majority of cases of HCV infection progress to
chronic infection, but in up to 15% of people infection may resolve spontaneously. Evidence suggests
that patients with symptoms in the setting of acute HCV infection tend to have a higher rate of
spontaneous clearance.
161-163
Other factors that might contribute to spontaneous clearance include
infection in infants and young women, selected host polymorphisms near the gene encoding IL28b,
infection with HCV genotype 3, having a low peak viral load, Caucasian race, and rapid decline in viral
load within the first four weeks of diagnosis.161-166 Persons with alcohol consumption and HIV
coinfection are less likely to spontaneously clear acute HCV infection. 159,163,167
Early detection of progression to chronic HCV infection can be difficult, as it almost always occurs in the
absence of symptoms. The differentiation of acute from chronic HCV infection depends largely on the
clinical presentation including presence of symptoms, recognition of a time-limited exposure, and
documentation of ALT elevation and its duration. After exposure, HCV RNA is usually detectable before
antibody appears in serum. HCV RNA can be identified as early as 7-21 days following exposure, whereas
anti-HCV is generally not detectable before 8-12 weeks.
30,156,168,169
When symptoms of acute HCV
infection occur, they may include malaise, fatigue, myalgias, nausea and right upper quadrant pain.
Fulminant hepatic failure is a rare presentation of acute HCV infection unless other underlying chronic
liver disease is present. 170,171
-Chronic
Individuals with chronic hepatitis C (CHC) are at increased risk of liver-related morbidity and mortality.
The majority of persons with CHC are asymptomatic. The most common symptom of CHC infection is
fatigue.
172,173
Other symptoms may include myalgias, nausea, anorexia, arthralgias and difficulty
concentrating. Progressive hepatic fibrosis leading to cirrhosis is the major complication of chronic HCV
infection and accounts for almost all HCV-related morbidity and mortality. 9 In patients who develop
cirrhosis, symptoms include worsening fatigue and anorexia, fluid overload, difficulty concentrating or
confusion due to hepatic encephalopathy, and gastrointestinal bleeding. Physical examination findings
can include signs of chronic or end stage liver disease including palmar erythema, spider angiomas,
ascites and asterixis. Laboratory changes include abnormal liver tests including transaminase elevations.
Patterns of Host Response
Persons with CHC are at risk for progression to cirrhosis, liver failure, and/or hepatocellular carcinoma
(HCC). However, the disease course in persons with CHC is generally protracted and variable (see figure
5)174. The risk of developing cirrhosis is 5% to 25% over 25 to 30 years. 175,176 There are a number of
host, viral, and environmental factors that are associated with disease progression.
Figure 5: Natural History of HCV
Reprinted with permission from International Journal of Medical Sciences. Chen SL, Morgan TR.
The Natural History of Hepatitis C Virus (HCV) Infection. Int J Med Sci 2006; 3(2):47-52.
Available from http://www.medsci.org/v03p0047.htm
Host factors associated with more rapid fibrosis progression include older age (above 40 years old),
longer duration of infection, male gender, obesity, hepatic steatosis, insulin resistance and hepatic iron
overload.
67,86,176-186
Age appears to be the predominant risk factor for more accelerated fibrosis
progression. 86,177 Data from Poynard and colleagues indicate that median time to cirrhosis was 44 years
in patients infected at under 20 years of age, 30 years in patients infected between 31 and 40 years of
age, and 12 years in patients infected over the age of 50 years. The concept that the aging liver is more
susceptible to fibrosis is also supported by experience with liver transplantation, where older donor age
is a strong risk factor for rapid fibrosis in the graft. 187,188 A number of mechanisms have been proposed
to explain this: increased vulnerability to oxidative stress, a reduction in hepatic blood flow and
mitochondrial capacity.189-191 Additionally, there are genetic factors that influence the natural history of
HCV and treatment response. Both the innate and adaptive immune responses are important for
clearance of an acute HCV infection. After an HCV infection, the innate immune response is initially
important for controlling viral replication with the adaptive immune response peaking at 8 weeks after
infection. 192 Ultimately, a coordinated effort between the innate and adaptive immune responses is
necessary to eliminate HCV from the liver.192 Genetic variation of the host immune system may affect
fibrosis progression rates by way genetic factors that may influence activators of hepatic stellate cells,
the family of proteolytic enzymes known as matrix metalloproteases (MMPs), and the tissue inhibitors
(TIMPs) of MMPs.
Co-infection with HIV and/or HBV is also associated with progression of CHC.
193-198
While viral
interactions with interference between HBV and HCV in patients with HBV-HCV dual infection with
inhibition of the replication of one of the viruses has been described in several studies,199-205 this
phenomenon is incompletely understood, and the mechanism by which this occurs is yet to be
established. 206,207 Dual infection with HBV and HCV is characterized by one virus dominating over the
other and can result in more accelerated progression to cirrhosis. 193,194 Approximately 15-30% of HIV
infected persons are coinfected with HCV.
208
With HIV coinfection there is an increased rate of end-
stage liver disease, hepatocellular carcinoma and death, in addition to the increased progression to
cirrhosis. 195-198,209-211 Accelerated fibrosis progression is also seen with high alcohol intake (daily
consumption >50 grams of alcohol) and marijuana use. 212-215
While the incidence of HCV infections is decreasing in the U.S. and other developed nations, due to the
prolonged course of CHC, the number of infected people with complications related to end-stage liver
disease is still increasing. The prevalence of hepatitis C–related cirrhosis and its complications, including
hepatic decompensation and HCC, are expected to continue to increase through the next decade.216
Patients with HCV related cirrhosis are at increased risk of hepatic decompensation with
signs/symptoms of liver failure and/or portal hypertension including ascites, portosystemic
encephalopathy and portal hypertension related gastrointestinal bleeding.
217,218
Patients with HCV
related cirrhosis are at an approximately 3% per year risk for developing hepatocellular carcinoma. 219-221
-Extra-hepatic manifestations
Chronic HCV infection can have serious consequences for organ systems other than the liver. HCV
infection may affect the central nervous system, endocrine system, lymphatic system, eyes, kidneys,
blood vessels, skin, joints and peripheral nerves. 222,223 Approximately 38% of patients with chronic HCV
infection will manifest at least one symptomatic extra-hepatic manifestation during the illness. 224 Most
extra-hepatic manifestations of chronic HCV infection are immunologically mediated, and chronic
infection seems to be necessary for their development. The most prominent manifestations include
mixed cryoglobulinemia (MC) vasculitis, lymphoproliferative disorders, renal disease, insulin resistance,
type 2 diabetes, sicca syndrome, and rheumatoid arthritis-like polyarthritis. Presence of these
conditions can have a substantial impact on patient management as they can affect morbidity and
mortality (for a detailed reviewed, see 223).
Control and Prevention
Public health approaches
Prevention of HCV-related liver disease should remain a key focus of clinical and public health
interventions. 10 Major steps to prevent new HCV infections have been taken in several countries
including routine screening of blood donors, implementation and enforcement of standard precautions,
eliminating reuse of injection equipment, and facilitating safer drug injecting behaviors with adoption of
harm reduction programs. Interventions using combined strategies of education, behavioral
interventions, substance-use treatment, syringe access, and syringe disinfection can reduce the risk of
HCV seroconversion by 75%.225 Therefore, efforts to prevent infection, reduce harms and treat HCV
infected IDUs are essential. These steps should be extended worldwide. As part of secondary
prevention, HCV-infected individuals should be counseled to minimize their risk of transmitting HCV and
referred for medical evaluation and consideration of antiviral therapy. Of course, the latter approaches
rely on the identification of persons with chronic HCV infection. In the U.S., the CDC estimates that
although 27% of the population was born during the interval 1945–1965, they account for
approximately three-fourths of all HCV infections and 73% of HCV-associated mortality; and they are at
greatest risk for hepatocellular carcinoma and other HCV-related liver disease. As a result, CDC has
recently revised prior recommendations to include one-time testing for persons born during 1945–1965
without prior ascertainment of HCV risk.226
To address occupational risk of HCV infection, individual institutions should establish policies
and procedures for HCV testing of persons after percutaneous or mucosal exposures to blood, and they
should ensure that all personnel are familiar with these policies and procedures. Health care
professionals who provide care to persons occupationally exposed to HCV should be knowledgeable
regarding the risk for HCV infection and appropriate counseling, testing, and medical follow up.
Finally, while there is currently no approved vaccine for HCV, attempts towards developing a
vaccine are currently underway. Despite difficulties associated with extreme variability and mutability of
hepatitis C virus (HCV), several vaccines that prevent initial infection or viral persistence, or that clear
viraemia in individuals with chronic HCV infections, are currently in development.227 The likely goal for a
prophylactic vaccine against HCV is to present persistence of the virus, rather than to prevent primary
infection. The is based on the fact that a small proportion of people infected with acute HCV
spontaneously clear it and this appears to be prominently mediated by cellular immunity.228 Current
HCV vaccine approaches include peptide, plasmid DNA, recombinant proteins and vector-based
vaccines. Virally vectored vaccines are the most promising in terms of T-cell induction - in particular
Adenoviral and modified vaccinia Ankara vectors. An understanding of the combination of functions
possessed by the T-cell population is needed to effectively assess HCV vaccine efficacy. Parameters of
interest when assessing a vaccine- induced HCV-specific T-cell population include breadth, cytokine
production, cytolytic capacity, magnitude, phenotype and proliferative capacity. A major challenge in
HCV vaccinology will be the assessment of vaccine efficacy in well-characterized at-risk populations.
Early phase vaccine trials are currently underway.
Treatment
The first successful therapies for HCV infection became available with the use of interferon to
treat NANB hepatitis in 1986. 229 Sustained virological response (SVR) is analogous to a cure and the goal
of treatment. An SVR is defined by the absence of detectable HCV RNA in a patient’s blood 6 months
after the conclusion of antiviral therapy. Viral genotype testing is performed in the evaluation of HCV
infection in order to maximize the chance of successful treatment outcome for each individual patient as
treatment type, duration, dose and effectiveness is influenced by genotype. Historically, persons
infected with HCV genotypes 1 and 4 have required longer durations of treatment and have had lower
SVR rates. Since the early treatments, significant and rapid progress has been made in establishing
effective therapy for HCV infection. There are now an increasing number of potent options for
treatment, as summarized in Table 1.
Table 1. Approved (and Promising) Agents for the Treatment of HCV Infection
Agent
Genotype
Side effects
Pegylated Interferon alfa
All
Fatigue, Flu-like symptoms
-pegylated interferon alfa-2a
(fever, arthralgias,
-pegylated interferon alfa-2b
myalgias), bone marrow
suppression (anemia,
leucopenia,
thrombocytopenia), thyroid
disease, depression, GI side
effects (nausea and
vomiting), rash, alopecia
Ribavirin
All
Rash, anemia
1
Fatigue, anemia, nausea,
Protease inhibitors
Boceprevir
headache, dysgeusia,
insomnia, alopecia
Telaprevir
1
Rash, uric acid elevation,
fatigue, pruritus,
hemorrhoids, anorectal
discomfort, anal pruritus
Other (most promising in late development)
No significant adverse
Sofosbuvir
All
effects attributable to the
Simeprevir
All
developing agent have been
Faldaprevir
All
reported in clinical trials.
Asunaprevir
All
Daclatasvir
All
*Pegylated = polyethylene glycol(PEG) is covalently linked to the standard interferon alfa
The standard of care for HCV treatment for the last decade has been a combination of pegylated
interferon and ribavirin.
30
Pegylated interferon alfa is a potent inhibitor of HCV replication that acts by
inducing interferon-stimulated host genes that have antiviral functions and given its diverse actions it is
not associated with viral resistance.95 Ribavirin acting synergistically with pegylated interferon alfa is an
integral component of the treatment for HCV although the mechanism of action is not well known.
Treatment for HCV infection varies according on genotype. The new treatment paradigm for
patients with genotype 1 infection includes one direct-acting antiviral agent (protease inhibitor) in
combination with pegylated interferon and ribavirin.230-234 Challenges with these new regimens include
additional side effects, increased pill burden, increased drug-drug interactions and antiviral resistance.95
Many agents with different mechanisms of action and improved safety profiles are currently in
difference stages of clinical development. 235,236 The short-term prospects for continued improvements
in treatments with other direct acting antivirals in conjunction with pegylated interferon and ribavirin
are in the pipeline and are quite promising, and these advances will likely lead to increased rates of cure
in the coming years. 237-239 Additionally, all oral interferon-free regimens are now on the horizon, which
will lessen treatment side effects and likely increase patient adherence and tolerability.240,241 However,
it is important that both patients and providers be aware that there is no protective immunity and
reinfection is possible with ongoing risk behavior and exposure.
Successful treatment of HCV infection eliminates transmissibility by eradication of viral infection
(i.e. cure). It is reasonable to assume that transmissibility is likely reduced by reduction in HCV viral load
even if cure is not accomplished.
- Perinatal HCV infection
Immune globulin and antiviral agents are not recommended for postexposure prophylaxis of infants
born to HCV-positive women. Children born to HCV-positive women should be tested for HCV infection.
Early diagnosis of HCV infection can be done by testing for HCV RNA at age 1 to 2 months and should be
repeated after 3 months within the first year. 100,153,242,243 Umbilical cord blood should not be used for
the diagnosis of perinatal HCV infection because cord blood can be contaminated by maternal blood.
Testing of infants for anti-HCV should be performed no sooner than 15 to 18 months of age, when
passively transferred maternal anti-HCV declines below detectable levels. If positive for either anti-HCV
or HCV RNA, children should be evaluated for the presence or development of liver disease, and those
children with persistently abnormal alanine aminotransferase levels should be referred to a specialist for
medical management.
Post-exposure Management
It has been estimated that in the year 2000, 16,000 HCV infections may have occurred worldwide among
health care workers due to their occupational exposure to percutaneous injuries. 244 Although no
immediately prophylactic regimen exists for HCV, effective treatment is available. When a needle stick,
percutaneous injury from other sharp instruments, or mucosal exposure to blood occurs, the human
source of the exposure should be tested for antibody to HCV (anti-HCV), and all repeatedly reactive
results by enzyme immunoassay should be confirmed by RIBA for anti-HCV. If the source is anti-HCV
positive, the exposed person should be tested for anti-HCV and alanine aminotransferase level at
baseline and follow-up (e.g., at 4 to 6 months). 245,246For earlier diagnosis of HCV infection, testing for
HCV RNA may be performed at 4 to 6 weeks. There are no recommendations for restriction of activities
during the post-exposure follow-up period. There is consistent evidence that treatment reduces the risk
that acute hepatitis C will evolve to chronic infection. 247,248 Currently, the American Association for the
Study of Liver Diseases (AASLD) practice guidelines recommend treatment initiation in patients with
acute HCV if serum HCV-RNA is not eliminated spontaneously within 12 weeks of HCV transmission.30
When HCV infection is identified early, the individual should be referred for medical management to a
specialist knowledgeable in this area.
Unresolved Problems
Although effective diagnostic tools and treatments are available, HCV remains a major public
health problem. In many countries, including the U.S., HCV-associated disease is the leading indication
for liver transplantation, and it is a leading cause of HCC in the US. 37,89,249HCC and cirrhosis have been
increasing among persons infected with HCV 250,251, and these outcomes are projected to increase
substantially in the coming decade.23,252 HCC is the fastest growing cause of cancer-related mortality,
and infection with HCV accounts for approximately 50% of incident HCC. 7
Transmission of HCV Infection continues despite current prevention strategies. Early diagnosis of
persons with HCV infection has been difficult. Because 80% of acute HCV infections are asymptomatic,
and more than 60% of persons with chronic HCV infection are asymptomatic, 156,253 early diagnosis has
relied on screening for asymptomatic infection and disease. Most persons with HCV do not know they
are infected, are not evaluated for treatment, and do not receive needed care (e.g., education,
counseling, and medical monitoring).254-256 In the U.S. alone, 75% of infected persons remain unaware of
their infection257. Additional strategies for and resources to support prevention and treatment of HCV
are still needed. Education of persons at risk, implementation of standard precautions and infection
control, and screening of blood donors for HCV are partially or entirely lacking in many parts of the
world.
Finally, not all persons with HCV infection progress to end stage liver disease or cirrhosis.
However, we currently have no good predictors of who will suffer disease progression and therefore
have only limited ability to target therapy towards those individuals. The morbidity and mortality
associated with this disease continue to rise rapidly along with the costs of care. While treatment
regimens with newly licensed drugs and others in clinical trials are evolving at a rapid pace, the
challenge will be to make these therapies available and affordable to all persons with infection.
Suggested Reading
Lemon SM, W.C., Alter MJ, Yi M., Hepatitis C Virus, in Field's Virology, K.D.a.H. PM, Editor. 2007,
Lippincott Williams and Wilkins: Philadelphia, PA. p. 1253-304.
Alter, M.J., Epidemiology of hepatitis C virus infection. World J Gastroenterol, 2007. 13(17): p. 2436-41.
El-Serag, H.B., Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology, 2012.
142(6): p. 1264-1273 e1.
Davis, G.L., et al., Projecting future complications of chronic hepatitis C in the United States. Liver
Transpl, 2003. 9(4): p. 331-8.
Ly, K.N., et al., The increasing burden of mortality from viral hepatitis in the United States between 1999
and 2007. Ann Intern Med, 2012. 156(4): p. 271-8.
Jacobson, I.M., et al., Manifestations of chronic hepatitis C virus infection beyond the liver. Clin
Gastroenterol Hepatol, 2010. 8(12): p. 1017-29.
Acknowledgements
We would like to acknowledge Dr. Scott L. Friedman, Fishberg Professor of Medicine, Dean for
Therapeutic Discovery and Chief, Division of Liver Diseases at Mount Sinai School of Medicine for his
review and input on this chapter.
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