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Epidemiologic Reviews
Copyright © 1996 by The Johns Hopkins University School of Hygiene and Public Health
All rights reserved
Vol. 18, No. 2
Printed in U.S.A.
Transmission of Hepatitis C Virus: Rates, Routes, and Cofactors
M. MacDonald,1 N. Crofts,2 and J. Kaldor1
The existence of a viral cause of hepatitis other than
hepatitis A and hepatitis B was first recognized in the
early 1970s following the development of diagnostic
blood tests for hepatitis A and hepatitis B. Early studies showed that appreciable proportions of people presenting with acute hepatitis following blood transfusion or community-acquired hepatitis did not have any
serologic evidence of hepatitis A or hepatitis B (1-3).
While some epidemiologic aspects of a putative etiologic agent, including transmissibility by blood contact, could be inferred from early studies of nonA,
nonB hepatitis, it was not until tests for hepatitis C
virus (HCV) antibody became available in 1989 that it
was recognized that nonA, nonB hepatitis was predominantly caused by HCV in developed countries
(4-6), and the development of HCV epidemiology
began in earnest.
Significant advances have been made over the past
5 years in our understanding of the epidemiologic
patterns of HCV transmission, prevalence, and natural
history, but much remains to be learned in all these
areas. Transmission of HCV is recognized as being
primarily through blood contact, but this route does
not fully explain HCV transmission. There has been
less certainty about the role of other routes of transmission and factors which modify the efficiency of
transmission. In this presentation, we review the current state of knowledge regarding the transmission of
HCV and address the major methodological problems
and requirements for future research.
Ascertaining the routes by which a virus or other
infection is transmitted, and the factors associated with
transmission, present substantial methodological challenges. The crudest but most generally applied method
involves eliciting histories from people with the infection in question and inferring the routes of exposure on
the basis of factors that they have in common, as
compared with a group of people without the infection. Early studies of risk factors for HCV transmission were carried out in groups of people already being
tested for HCV antibodies, such as blood donors. In an
extension of this approach, studies which implicitly
used a case-control design then compared people with
HCV antibody with those without HCV antibody with
regard to possible risk factors for HCV transmission
(see section on Sexual transmission below).
Another methodological approach is to define a
population group on the basis of a common exposure
history and assess them for evidence of infection,
making comparison to an otherwise similar group
without the exposure. For example, in assessing
whether HCV can be transmitted through occupational
exposure, groups of health-care workers could be
compared with other people with regard to HCV prevalence. In practice, the requirement for control groups
in such comparisons is frequently ignored: A number
of studies have found such high rates of HCV among
injecting drug users that no control group was needed
to infer an association between HCV and the practice
of injecting (see the subsection on Injecting drug users
in the section on Bloodborne transmission below).
A more rigorous means of assessing routes of transmission involves monitoring rates of new infection in
people who are known to be exposed to the agent via
Received for publication January 15, 1995, and accepted for
publication June 18, 1996.
Abbreviations: AIDS, acquired immunodeficiency syndrome; Cl,
confidence interval; HBeAg, hepatitis B e antigen; HBsAg, hepatitis
B surface antigen; HCV, hepatitis C virus; HCV-RNA, hepatitis C
virus genome; HIV, human immunodeficiency virus.
National Centre in HIV Epidemiology and Clinical Research,
University of New South Wales, Sydney, New South Wales, Australia.
Macfarlane Burnet Centre for Medical Research, Melbourne,
Victoria, Australia.
Reprint requests to Prof. J Kaldor, National Centre in HIV Epidemiology and Clinical Research, Level 2, 376 Victoria Street, Darlinghurst, NSW 2010, Australia.
Downloaded from at Pennsylvania State University on February 23, 2013
Published studies were identified through a MEDLINE® search from January 1990 to October 1995.
Searches were limited to English language publications, and additional references were selected from the
bibliographies of identified articles. Only studies using
second or third generation and supplementary antibody tests have been reported unless otherwise stated.
MacDonald et al.
Prospective studies of transfusion recipients conducted before the availability of serologic tests for
HCV showed that acute nonA, nonB hepatitis led to
chronic liver disease in at least 50 percent of those
affected (6). Infection with hepatitis C is asymptom-
atic in 70-80 percent of people with HCV antibody,
and more recent estimates indicate that chronic hepatitis occurs in about 70 percent of transfusion acquired
hepatitis C infection (11). Long-term consequences of
infection are highly variable from patient to patient,
and the likelihood of progression to chronic hepatitis
appears to be unrelated to the clinical severity of acute
illness (11, 17). Chronic infection with hepatitis C, be
it symptomatic or not, leads to chronic liver disease
(70 percent of cases), cirrhosis (20-30 percent of
cases), or hepatocellular carcinoma after decades (20).
In a case-control study of transfusion recipients with
HCV who were followed for up to 18 years and
compared with recipients without HCV, there was no
increase in mortality from all causes and a small but
statistically significant increase in the number of
deaths related to liver disease (21). Although longterm studies of HCV remain limited, they have produced some evidence that outcome is also related to
host and viral factors such as HCV subtype, virus titer,
age at infection, duration of disease, mode of acquisition, coinfection with hepatitis B or human immunodeficiency virus (HIV), host immunity, or alcoholism
Six HCV subtypes have been defined on the basis of
nucleotide sequence analysis (22). A variety of classifications have evolved that distinguish the different
HCV genotypes (23, 24). A common system for nomenclature of HCV viral genome which has combined
the various approaches has been proposed; the types
classified as I, II, III, IV, and V (23) correspond to
types la, lb, 2a, 2b, and 3a, respectively (24). The
major genotypes show distinct geographic clustering
and may be associated with different rates of transmission and different levels of pathogenicity (25, 26).
HCV types 1 and 2 have been reported from almost all
countries, including Europe, North America, Japan,
and Australasia. HCV type 3 has been reported from
Europe, the United States, Thailand, India, and Australia, but not from Japan. HCV type 4 has been
reported from blood-donor populations in the Middle
East, and HCV types 5 and 6 have been reported from
South Africa and Hong Kong, respectively (20, 22).
The importance of blood contact in the transmission
of HCV was established through studies showing a
high prevalence of HCV antibody in people following
transfusion of blood or blood products (see subsection
on Recipients of blood and blood products, below) or
with a history of injecting drug use (see subsection on
Injecting drug users, below). Studies of health-care
workers have provided further evidence of transmisEpidemiol Rev
Vol. 18, No. 2, 1996
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the route under study. For example, the rate of sexual
transmission can be determined by prospectively measuring the rate of new infection in sexual partners of
people who already have the infection. Similarly, the
risk of vertical transmission can be assessed by measuring the rate of infection in children born to mothers
with HCV infection.
The assessment of HCV transmission has been complicated by the rapid pace of change in diagnostic
methods. The serologic diagnosis of HCV has evolved
considerably since antibody tests were first made
available in 1990. Second generation immunosorbent
assay (enzyme immunoassay (EIA) or enzyme-linked
immunosorbent assay (ELISA)) for HCV antibodies
provided improved sensitivity and specificity compared with first generation tests, and have shortened
the time for detection of seroconversion (5, 7). Third
and fourth generation assays have recently become
available (8-10). A major consequence of changing
diagnostic technology is that comparisons of prevalence estimates from different epidemiologic studies
have to be made cautiously.
A further difficulty in assessing HCV transmission
routes relates to the interpretation of a positive HCV
antibody test. There may be a prolonged period between the acquisition of infection and the detection of
antibody (4, 11), and once antibody is present, it is not
necessarily an indication of current or chronic infectiousness (11-13). The HCV genome (HCV-RNA)
can be identified in plasma or liver tissue by amplification of virus-specific nucleic acid sequences using
polymerase chain reaction (14). Although reproducibility between laboratories was poor and contamination produced misleading results in early studies (15),
HCV-RNA is currently the best marker of viremia and
infectivity. Knowledge is also limited about changes
in markers for HCV (whether antibody or HCV-RNA)
over the long-term course of infection. Depending on
the prevalence in the population surveyed, a positive
antibody test using second generation enzyme immunoassay appears to be associated with HCV-RNA positivity in 70 to 90 percent of cases, but it is not even
certain that all such RNA positive sera are infectious
(14, 16). HCV-RNA can persist for several years after
acute hepatitis C infection (13) or in asymptomatic
people with HCV antibody (12, 17, 18), and may be
accompanied by liver disease. Detection of HCVRNA can also be intermittent throughout the course of
infection (6, 12, 19).
Transmission of Hepatitis C Virus
sion through blood contact (see subsection on Transmission of HCV in the health-care setting, below).
Recipients of blood and blood products
Injecting drug users
Cross-sectional surveys and cohort studies among
groups of injecting drug users from Europe (31 32),
North America (33-37), Asia (38, 39), and Australia
(40-42) have found extremely high prevalences of
HCV antibody, from 50 to 90 percent. Even though
many of these studies used first generation HCV antibody tests, the results have been supported by further
studies using second and third generation tests. Incidence of new infection is also high: HCV seroconversion rates of around 10 per 100 person-years were
detected in injecting drug user cohorts in Amsterdam,
The Netherlands (31), and Baltimore (36), and 20 per
100 person-years in Australia (41, 43). In two Australian cities, where needle exchange had been widely
available since 1988, prevalence of HCV by second
generation assay was 26 percent in 1991 among 50
injecting drug users who had been injecting for less
than 3 years (40), and 40 percent in 1990/1991 among
101 injecting drug users who had been injecting for
less than 5 years (41, 44).
The strongest single predictor of risk among injecting drug users appears to be duration of injecting (31,
34, 36, 40-42, 44). Other factors associated with
increased risk have been opiate use (compared with
stimulant use) (34, 40, 41, 44), heterosexual orientation (36, 40), and prison history (41, 44), but not a
history of sex work (31, 40).
Epidemiol Rev Vol. 18, No. 2, 1996
HCV infection rates have been reported to be higher
in heterosexual injecting drug users than in homosexual men who inject drugs in the United States and
Australia, contrasting to the relative prevalence of
HIV in these groups (36, 40) which was much lower
than among homosexual men who inject drugs. The
differences between HCV and HIV infection patterns
among subgroups of injecting drug users defined by
sexual orientation may reflect the higher efficiency for
sexual transmission of HIV than HCV, different prevalence within social networks, or differences in injecting practices related to sexual orientation.
HCV incidence of 38 per 100 person-years was
found in Melbourne, Australia, among male prison
entrants with a history of injecting drug use (95 percent confidence interval (CI) 19-76 per 100 personyears) (45). In the United States, a much lower rate of
1 per 100 person-years was detected in 164 prison
inmates, a third of whom reported history of injecting
drug use (46). HCV prevalence of 57 percent and 64
percent of 40 and 1,561, respectively, was reported
among prison entrants who reported injecting drug use
in Norway (47) and Melbourne (44). In Great Britain,
a higher prevalence of HCV was reported among
injecting drug users with a history of imprisonment
compared with injecting drug users without such history (46 percent versus 29 percent) (48).
Tattoo and skin piercing
The presence of tattoos have been independently
associated with an increased risk of HCV infection
(49-53). In the only study specifically examining tattoos as a risk for HCV transmission (52), there was a
higher risk with multiple tattoos compared with a
single site, and tattooing carried out by nonprofessional compared with professional tattooists. Other
potential modes of unapparent blood contact include
skin piercing and folk medicine (54).
Transmission of HCV in the health-care setting
In addition to being detected in blood, HCV-RNA
has been detected in ascitic fluid, semen, and the urine
of HCV-positive patients with chronic liver disease
(55). Transmission of HCV from patient to health-care
worker has been generally documented following percutaneous exposure to blood (56-60). There has also
been one case report of transmission through mucous
membrane exposure, via a blood splash to the conjunctiva (61). Transmission to patients has been reported following exposure to an HCV-infected healthcare worker (62) and in the course of routine surgery
between patients (63).
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Early studies of HCV prevalence among transfusion
recipients and in people with medical conditions associated with high rates of blood transfusion, such as
hemophilia, thalassemia, chronic renal failure, and
cardiac surgery, showed, using first generation antibody tests, that the high rate of nonA, nonB hepatitis
in these groups was largely related to the acquisition of
HCV infection (4-6, 27, 28). Post-transfusion HCV
infection has become relatively rare in developed
countries since donors with risk factors for bloodborne viral infections and those found to have HCV,
HIV, or hepatitis B antibodies have been excluded
from donating blood (29, 30). One multicenter study
from Baltimore, Maryland, in a post cardiac surgery
population demonstrated a reduction in posttransfusion hepatitis from 45 per 10,000 units transfused in 1985/1986 to 3 per 10,000 units transfused
(0.6 percent per patient) in 1990 after screening for
HCV antibody was introduced (29).
MacDonald et al.
incidence was 0.55 per 1,000 person-years, and HBV
incidence among never vaccinated staff was 30.5 per
1,000 person-years.
Cross-sectional surveys of hospital staff members
with HCV antibody measured using second generation
and supplementary tests have generally not found elevated prevalence of HCV antibody; rates observed
ranged from none in 102 staff from a hospital for
people who are mentally handicapped (65) to 6 percent
among 1,033 staff at an acute-care hospital in Germany (66). Some of these studies have shown prevalence increased with age (67, 68) or length of employment (69), suggesting that infection might have
occurred before implementation of extensive prevention strategies. Alternately, it might be that the risk of
HCV transmission is low but cumulative over time. In
France, HCV prevalence of 0.9 percent was detected
in 430 hospital staff compared with 1.7 percent in 180
hospital office staff (70).
Transmission to patients of HCV antibody in a surgical setting has been reported from an Australian
hospital (63). Following routine notification of two
patients who presented with acute hepatitis C infection
after undergoing minor surgical procedures in the
same operating session, antibody screening and genotyping revealed that five patients who had undergone
surgery in the one session were infected with the same
HCV genotype (genotype 1). Only one patient, the
first in the surgical session, reported a history related
to potential prior exposure to HCV. It was proposed
that transmission had occurred through blood in respiratory secretions via anesthetic circuitry.
Transmission to patients has also been reported
from hemodialysis units (71-73). Cross-sectional surveys of hemodialysis patients without history of blood
transfusion have found HCV prevalence of 7 percent
(74) and 18 percent (75). Isolation of patients with
HCV antibody in a separate area reduced the incidence
of HCV in one unit (76).
There has been a recent case report of a patient who
developed symptomatic HCV infection following cardiothoracic surgery (62). The probable source of infection was a health-care worker.
Transmission of HCV through sexual contact was
first suggested in a case-control study comparing people with symptomatic nonA, nonB hepatitis with controls randomly selected from the general population.
More than two sexual partners, history of hepatitis in
household, sexual contact, and lower education status
emerged as significant risk factors for nonA, nonB
hepatitis after excluding people with a history of blood
transfusion or injecting drug use (2).
Epidemiol Rev Vol. 18, No. 2, 1996
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The risk of HCV transmission to health-care workers has been investigated in cohort studies of healthcare workers followed up after needle stick injury
involving body fluids from source patients with HCV
antibody, cohort studies of hospital staff who were
initially negative for HCV antibody, and crosssectional surveys of HCV prevalence among hospital
Three large studies have been reported from Japan
of health-care workers investigated following needle
stick injury involving material from source patients
with HCV antibody. The rate of HCV antibody seroconversion was 2.7 percent (56), 3.3 percent (57), and
9 percent (58) (corresponding 95 percent CIs 0.6-6.4
percent, 0.7-9.2 percent, and 3.7-17.6 percent), of
110, 92, and 76 health-care workers, respectively. In
the first two studies, HCV antibody was detected
30-40 days after the injury using first (56) and second
(57) generation antibody testing with supplementary
testing. In the third study (58), in which first and
second generation antibody testing with supplementary testing was used, source and recipients were also
tested for HCV-RNA. The prevalence of HCV-RNA
among source patients was 89 percent, and 13 percent
of recipients from these 68 source patients had HCV
antibody and/or HCV-RNA; 7 percent had both
HCV antibody and HCV-RNA, 3 percent had only
HCV antibody, and 3 percent had HCV-RNA alone.
None of the eight health-care workers exposed to
HCV-RNA-negative anti-HCV-positive source patients seroconverted, suggesting a trend for increasing
risk with increasing viral concentration.
The rate of HIV seroconversion following needle
stick injury involving blood or body fluid from patients with HIV antibody is substantially lower at
around 0.25 percent (95 percent CI0.11-0.47 percent)
(60). The rate of hepatitis B seroconversion following
needle stick exposure has declined since the introduction of hepatitis B vaccination (64).
The incidence of nonA, nonB clinical hepatitis was
21 per 100,000 health-care workers (six cases) in a
cohort of New York, New York, hospital staff followed from 1980 to 1989 (0.21 per 1,000 staff over 9
years) (59). One observed seroconversion gave a
slightly higher incidence of seroconversion to HCV
antibody, 0.8 per 1,000 person-years (95 percent CI
0.03-3.6) in a cohort of hospital staff from San Francisco, California, followed from 1984 to 1992 (60).
This study was based on first generation HCV antibody tests but confirmed all seropositives and a random sample of seronegatives with second generation
tests. The single incident in this study occurred in an
emergency department nurse who has been unable to
describe a specific exposure event. In this study, HIV
Transmission of Hepatitis C Virus
reported from a small study of 37 self-described noninjecting sexual partners of injecting drug users in
Spain, but the possibility remains that the partners did
in fact share injecting equipment at some point (32). In
all these studies, the true duration of exposure could
not be determined because it was not known how long
index patients or their sexual partners had been infected with HCV.
The prevalence of HCV in sexual partners of people
with HCV infection is low compared with the corresponding prevalence of HIV and hepatitis B. In the
Spanish study of sexual partners of injecting drug
users, the prevalence of HCV antibody was 11 percent,
HIV antibody was 17 percent, and hepatitis B surface
antigen (HBsAg) was 26 percent (32). Similarly, in the
Italian study the prevalence of HCV antibody was 0
percent, HIV antibody was 25 percent, and HBsAg
was 27 percent (79). In a prospective cohort of 45
sexual partners of HIV-positive injecting drug users,
the prevalence of HCV was 20 percent (82).
Sexual transmission of HCV has also been investigated by measuring HCV antibody prevalence in
groups recognized to be at a higher risk for acquiring
sexually transmitted agents, such as sex workers, people attending sexual health clinics, and homosexual
men (table 2). Prevalence of HCV was 6 percent
among 547 female sex workers in Spain, and increased
with years of sex work although the trend detected was
not significant (83). There was no reported history of
injecting drug use or blood transfusion in the study
population. A lower prevalence (1.8 percent) of HCV
was detected among 236 sex workers in Somalia (84).
Prevalence of HIV (2.1 percent) in this same population was similar to the prevalence of HCV. Crosssectional surveys of injecting drug users have not
shown an increased risk in those who gave a history of
sex work (31, 40). Prevalence of HCV was 7 percent
Seroprevalence of HCV* antibody in sexual partners of people with HCV infection (cross-sectional surveys)
(reference no.)
% with HCV
95% Cl*
ratio in
Largely women
Italy (79)
Sexual partners of multitransfused
HCV-positive patients
Mean 10 (range
Amsterdam (80)
Sexual partners of HCV-positive
Median 13 (range
Noninjecting drug using sexual
partners of heterosexual HCVpositive injecting drug users
Mean 4 (range
Synthetic EIA
Sexual partners of patients with
chronic HCV liver disease
and HCV-RNA*
Married <10 years
Married 10-30 years
Married >30 years
Spain (32)
• Cl, confidence interval; EIA, enzyme immunoassay; ELISA, enzyme-linked immunosorbent assay; HCV, hepatitis C virus; HCV-RNA, hepatitis C virus
genome; RIBA, recombinant immunoblot assay.
Epidemiol Rev
Vol. 18, No. 2, 1996
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After the antibody test for HCV was developed, a
case-control study among blood donors showed a significantly higher risk of HCV in people with more than
one lifetime sexual partner, compared with those with
one or less, after people with history of injecting drug
use; blood transfusion and tattoo were excluded (49).
A nonsignificant trend in HCV risk with multiple sex
partners was detected among French and English
blood donors on univariate analyses (50, 77).
Sexual transmission of HCV has been further investigated in seroprevalence studies of groups of people
defined on the basis of a higher sexual risk, such as
sexual partners of people with HCV infection and
sexual partners of injecting drug users. Most of these
studies have been cross-sectional, with HCV concordance assessed as a marker of transmission. In a prospective cohort study of 94 male sexual partners of
women with self-limited and chronic HCV antibody,
no HCV-RNA could be detected (78). The date of
hepatitis C exposure was known because it was from
a contaminated batch of anti-D immunoglobulin and
follow-up was from 10 to 15 years.
In cross-sectional surveys of sexual partners of people with HCV infection, predominantly based on female spouses of male index cases, the prevalence of
HCV antibody ranged from zero in two small studies
of 18 (79) and 50 (80) people to 27 percent in a study
of 154 sexual partners (81) (see table 1). In this larger
study, sexual partners reported no injecting drug use,
blood transfusions, extramarital sex, previous marriages, or history of hepatitis. Concordant HCV status
was only observed in couples who had been together
for more than 10 years, although there were very few
people in the study who had been married for less than
10 years. In both of the smaller studies, the median
length of the sexual relations was at least 10 years. A
relatively high prevalence (11 percent) has also been
MacDonald et al.
Seroprevalence of HCV* antibodies in populations at higher risk for sexual transmission
(reference no.)
Somalia (84)
Spain (83)
Baltimore, MD (85)
France (8)
Spain (83)
Spain (32)
EIA*-1 and 2
EIA-1 and 2
% with
Sex workers
Sex workers
Sexual health clients
Sexual health clients
Sexual health clients
Homosexual men
Homosexual men
Homosexual men
* EIA, enzyme immunoassay; ELISA, enzyme-linked immunosorbent assay; HCV, hepatitis C virus; RIBA,
recombinant immunoblot assay.
among 88 heterosexual men who had frequent sexual
intercourse with sex workers and who had a history of
sexually transmitted disease (83).
Surveys of patients with no history of injecting drug
use attending sexual health clinics in Baltimore (85),
Somalia (84), and New Zealand (86) found HCV prevalence of 5.4 percent, 2.5 percent, and 1.7 percent,
respectively. In the Baltimore study, the prevalence of
HCV antibody was associated with age greater than 28
years, more than 24 lifetime sex partners, the presence
of HIV infection, and male homosexual exposure,
although there was a strong interaction between HIV
infection and homosexual exposure. The prevalence of
HCV was similar to the prevalence of HBsAg (1.5
percent) in the New Zealand survey. The prevalence of
HCV in the survey of people attending a sexual health
clinic in Somalia was similar to the prevalence of
HCV measured among military personnel (1.3 percent) at the same time as the sexual health clinic
survey (84).
Homosexual men were recognized as being generally at increased risk of sexually transmitted diseases
prior to the acquired immunodeficiency syndrome
(AIDS) epidemic, but changes in sexual practices in
many Western countries over the past decade have
substantially reduced the sexually transmitted disease
risk differential, so the extent to which homosexual
men are a group can be viewed as representing sexually transmitted disease risk is now rather questionable. A cross-sectional study of homosexual men in
Spain (32) found a high prevalence of HCV (16 percent), much lower than the prevalence of hepatitis B
core antibody (40 percent) and HIV (84 percent). The
high prevalence of HIV reflects the recruitment of this
study population through an AIDS clinic. In another
Spanish study of 168 homosexual men, the prevalence
of HCV was 4 percent among self-described noninjecting drug users with no history of prior blood transfusion (83). This study included HIV-positive men but
did not report the proportion. The prevalence of HCV
was 3.8 percent in a hospital-based French study of
106 homosexual men admitted for chronic hepatitis
(8). The sample included 42 percent of men who were
HIV-positive, and there was no difference in HCV
prevalence according to HIV status. The prevalence of
past or present hepatitis B (any marker of hepatitis B
virus) was 74 percent. The HCV prevalence thus
seems raised compared with heterosexuals without
exposure to injecting or blood transfusion, but not
nearly to the same extent as HIV or hepatitis B virus.
Transmission of HCV to household contacts of people with HCV infection has been investigated in crosssectional prevalence surveys. The prevalence of HCV
in this group of people is low and it is difficult to rule
out bloodborne transmission as the route of transmission. A high prevalence (13 percent) was found in a
Italian study of 73 nonsexual household contacts of
people with chronic hepatitis C, but this contrasts
sharply with other studies in this area (87). The household contacts were predominantly older children of
index cases, and all household contacts who had HCV
antibody had shared reusable syringes within the family unit until 8-10 years ago. A prevalence of 2.2
percent was detected among 181 household contacts
with chronic HCV liver disease in Korea. Comparison
with 102 household contacts of people with non-HCV
Epidemiol Rev Vol. 18, No. 2, 1996
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New Zealand (86)
Somalia (84)
HCV assay
Transmission of Hepatitis C Virus
Although mother-to-child transmission of HCV has
been clearly documented in several studies, reported
rates of transmission as determined by detection of
HCV-RNA in the child range widely from 0 to 7
percent (table 3). HCV-RNA has been increasingly
used as a marker of infection in infants rather than
HCV antibody because maternal antibody which cannot be distinguished from antibody produced by the
infant, is passively acquired at birth and the duration
of its persistence in the newborn is variable.
HCV antibody progressively disappeared from birth
until 15 months in all children but one in an Italian
study of 45 infants (90), and gave a transmission rate
of HCV as determined by detection of HCV-RNA of
2.2 percent. The prevalence of HCV antibody was 8.9
percent at 12 months and 2.2 percent at 15 months. A
similar progressive reduction in HCV antibody was
found in a Swedish study of 21 infants (91). Trans-
mission of HCV as determined by HCV-RNA was 5
percent. The prevalence of HCV antibody was 19
percent at 12 months and 9.5 percent at 15 months.
These two small studies suggest that passively acquired maternal HCV antibody can be detected up to
12 months of age, and that antibody test results from
15 to 18 months, rather than at 12 months, better
define vertical HCV transmission. Furthermore, clearance of passively acquired HCV antibody was significantly slower among babies born to HIV-positive
mothers than babies born to HIV-negative mothers in
the Italian study (life-table analysis p = 0.03) (90).
Assessment of mother-to-child transmission by
HCV-RNA may underestimate the true rate, as detectable viremia can be transient and fluctuating, and
HCV infection transmitted from mother to child may
resolve before assays are carried out. For example, in
the Swedish study (91), three infants had at least one
positive HCV-RNA result, but HCV-RNA persisted at
12 months in only one child. Two studies have each
reported one child in whom HCV-RNA was not detected until 1 month of age (92, 93). In general, the
duration and timing of follow-up testing varies between studies, making comparison of estimated transmission rates difficult.
Overall, the number of children born to mothers
with HCV antibody investigated in individual studies
remains small. A large study from Japan (92) involved
54 newborns, and 6 percent were found to have HCVRNA by PCR. The presence of HCV-RNA in infants
was more likely if the mother had high levels of
viremia (>10 6 copies per ml). No other specific risk
factors could be identified. Similar transmission rates
from mothers with viremia have been reported in
smaller studies from Sweden (91) and Taiwan (94)
(see table 3). In contrast, studies from the United
TABLE 3. Mother to child transmission of HCV* from mothers with HCV antibody and no HIV* antibody and according to HCVRNA* status of mothers
(reference no.)
Marcellin et al.,
1993 (104)
Manzini et al.,
1995 (90)
Zanetti et al.,
Wejslal et al.,
1992 (91)
Linetal., 1994
Ohtoetal., 1994
95% Cl*
No. Of
born to
Infants with
No. of
born to
Infants with
95% Cl
Infants with
NO 01
born to
95% Cl
* Cl, confidence interval; HCV, hepatitis C virus; HCV-RNA, hepatitis C virus genome; HIV, human immunodeficiency virus.
Epidemiol Rev Vol. 18, No. 2, 1996
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liver disease showed an increased risk with a history of
hepatitis, blood transfusion, or acupuncture (88).
No HCV antibody was detected among 22 nonsexual household contacts of people with asymptomatic
HCV antibody (87) nor among 155 household contacts
of people with hemophilia and HCV antibody (89).
In a prospective study of 39 children born to women
who had seroconverted to hepatitis C following iatrogenic infection from anti-D immunoglobulin 10-15
years earlier, HCV prevalence was again zero (78).
In many of the studies of household contacts, the
numbers of nonsexual contacts are small and often
include children born to mothers with HCV infection.
It is impossible in such studies to elicit whether nonsexual, nonblood contact is a route of transmission for
MacDonald et al.
the United Kingdom in which HCV antibody was
detected using the second generation HCV test (93).
Coinfection with HIV and HCV antibody was present
in 82 percent of 56 mothers, and the rate of transmission was lower in HIV-positive women (5 percent)
than in the eight HIV-negative women (13 percent).
The rate of transmission of HCV from mother to
child appears to be lower than the rate of transmission
of HIV and hepatitis B. Estimates of perinatal transmission of HIV range from 14 to 39 percent globally
and from 15 to 20 percent in Europe (100). Transmission of hepatitis B from mother to child varies according to the hepatitis B e antigen (HBeAg) status of the
mother; up to 90 percent of infants who are born to
HBeAg seropositive mothers, and 10-20 percent of
those who are born to HBeAg seronegative mothers,
acquire hepatitis B virus infection (101).
There is little information about the role of breast
feeding in modifying transmission of HCV from
mother to child because of the small numbers of infants in individual studies and the low rate of HCV
transmission in these studies. Individual cases of
breast-fed infants in whom HCV transmission was
documented have been reported but the rates of transmission have not been reported separately for breastfed and non-breast-fed babies (91, 102).
In studies which found no infants who had seroconverted to HCV, 63 percent of 27 and 75 percent of 94
mothers breast fed their infants (89, 98). In studies
where small numbers of infants had HCV infection,
there was no difference in transmission between
breast-fed and non-breast-fed infants (91, 92. 103).
There is also limited information about the effect of
mode of delivery on HCV transmission. In a study of
66 children, two children born by Caesarean delivery
had no evidence of maternally acquired HCV compared with 6 percent HCV transmission to children
who were not born by Caesarean delivery (92). In a
smaller study of 15 children (93), five children born by
Caesarean delivery had no evidence of maternally
acquired HCV compared with 10 percent HCV trans-
Mother to child transmission of HCV* from mothers with HCV and HIV* antibody
(reference no.)
NO. Of
born to
Infants with
95% Cl*
Lametal., 1993(93)
United Kingdom
Manzini et al., 1995(90)
Zanetti et al., 1995(99)
HCV-RNA status of mothers of the three
infants with HCV infection was not known
HCV-RNA status of mother of infant with
HCV infection was not known
All eight infants with HCV infection were
born to mothers with HCV-RNA
' Cl, confidence interval; HCV, hepatitis C virus; HCV-RNA, hepatitis C virus genome; HIV, human immunodeficiency virus.
Epidemiol Rev Vol. 18, No. 2, 1996
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States (95) and Japan (96) did not detect HCV-RNA in
infants although the small sample sizes (24 and 16,
respectively), the short period of follow up (3 months),
and the use of first generation antibody testing to
determine the mothers' HCV status might account for
these results.
High rates of transmission of HCV were reported
from early studies in which first generation HCV
antibody tests were used to detect HCV transmission
from mothers with both HCV and HIV infection. In an
Italian study of 25 infants, 44 percent developed HCV
infection and were also simultaneously infected with
HIV (97). In a Spanish study (98) of 22 women with
HCV and HIV infection, the one infant who developed
HCV also developed HIV. In studies using HCV-RNA
in the child to determine HCV transmission from
mothers with both HCV and HIV antibody, the prevalence ranged from 5 to 36 percent (table 4). In an
Italian study of 116 infants born to mothers with HCV
antibody and where 19 percent of mothers also had
HIV infection, none of the 94 children born to mothers
with HCV antibody alone had HCV-RNA detected,
compared with 36 percent of the 22 babies whose
mothers were coinfected with HIV (99). Among mothers with HIV antibody, the proportion with HCV-RNA
was much higher than among mothers without HIV
antibody (82 percent compared with 24 percent).
In another Italian study, where mothers where diagnosed with HCV antibody using second generation
testing, the prevalence of HCV was 6 percent among
infants born to mothers with both HIV and HCV
infection (90). None of the infants born to mothers
without HIV antibody had HCV-RNA detected. Similar rates of transmission from HIV-positive and HIVnegative mothers cannot be excluded as the sample
size was small (18 and 27 infants, respectively) and
women with HCV alone were selected from a different
hospital than the group with both HIV and HCV
There was no increased risk for HCV transmission
associated with the presence of HIV in a study from
Transmission of Hepatitis C Virus
mission in children born by spontaneous vaginal delivery.
Epidemiol Rev Vol. 18, No. 2, 1996
number of sexual partners over a given time is problematic because of substantial variation in behaviors
over time and the potential for recall bias. There may
also be a tendency with self-report on injecting and
sexual behavior to respond in a socially desirable way
particularly when the studies are being carried out in
groups of people not readily identified with the healthcare setting where the exposure is under investigation.
For example, a history of injecting drug use may be
less readily elicited in a sexual health clinic than in a
health service aimed at people who inject, and a history of sexual and injecting behaviors may not be
acknowledged by blood donors.
Confounding may also distort risk factors that may
increase or decrease the likelihood of infection. For
example, when assessing coinfection of HIV and
HCV, the relation can be confounded by the fact that
both have similar risk factors. It is difficult to control
for confounding in the analysis when the sample size
and, consequently, the number in each cross-category
of risk factors are small. When statistical adjustments
cannot be made, there is a tendency to attribute HCV
to bloodborne transmission if the person reports a
history of drug injection or blood transfusion, even
though there may be a relevant history of sexual exposure to HCV as a result of unprotected sex with an
infectious partner.
Many of the population groups studied, such as sex
workers, homosexual and bisexual men, and injecting
drug users and their partners are difficult populations
to access. The studies cited have generally been convenience samples, and it is not possible to determine
whether the samples differ from nonresponders with
regard to the exposures of interest.
The role of nonsexual person-to-person contact,
other than direct blood contact, in HCV transmission
has not been well investigated. In studies of sexual and
nonsexual intrafamilial transmission, it is not possible
to exclude the role of unapparent blood spread through
mucosal injury or past medical practices involving
skin puncture. The mode of transmission has remained
undefined in 30-50 percent of cases in studies of risk
factors for HCV infection.
The rate of mother-to-child transmission is low
compared with HIV and hepatitis B virus but nonetheless is a significant public health problem in groups
of women with a high prevalence of HCV, such as
injecting drug users. Very few studies have addressed
the timing of transmission, that is in utero, at delivery,
or during breast feeding. Studies that do so have
reported mode of delivery and breast feeding in children with HCV infection. Although early studies suggested that coinfection with HIV facilitated mother to
child transmission of HCV, HIV coinfection is not
Downloaded from at Pennsylvania State University on February 23, 2013
Transmission of HCV through blood contact was
clearly established in studies of post-transfusion nonA,
nonB hepatitis, and an early case-control study of
community-acquired nonA, nonB hepatitis. HCV infection acquired through blood transfusion has been
virtually eliminated in developed countries by screening potential donors for HIV, hepatitis B virus, HCV,
and HIV-related risk behavior.
The extremely high prevalence and incidence of
HCV among people who have injected illicit drugs
clearly implies a high efficiency of transfer within this
population group. Incidence has remained high despite
harm reduction strategies to reduce HIV transmission
in a number of countries. HCV has a higher efficiency
of transmission via blood contact than HIV, it may be
also unapparent blood contact during the injecting
process, such as sharing equipment other than needles
and syringes and lapses in infection control when
helping others inject, presents a risk of HCV but not
HIV transmission.
Evidence for transmission of HCV through sexual
or household contact has been less clearly defined.
Almost all of the studies investigating sexual partners
and household contacts of people with HCV infection
have been cross-sectional in design and have been
unable to measure the duration and nature of exposure
to HCV. The duration of the current relation or the
time since diagnosis in the index case has been used as
a surrogate measure of exposure. In these studies, the
time of seroconversion of the partner in a concordant
couple is also unknown. The high prevalence of HCV
in couples married for more than 10 years may imply
a risk that increases with exposure over time. Alternatively, these findings may reflect failure to recall,
disclose or solicit a common risk factor in the couple
unrelated to sexual transmission, or a cohort-related
exposure, such as inadequate sterilization of immunization needles in early decades.
The lower prevalence of HCV compared with other
established sexually transmitted viruses, HIV and hepatitis B virus in sexual partner studies suggest a lower
efficiency for sexual transmission than these other
viruses. Nonetheless, cross-sectional studies of people
presumed to be more highly exposed to sexually transmitted agents have demonstrated prevalence of HCV
that, while low, cannot be explained by injecting drug
use or blood transfusion. Studies of blood donors
which essentially used the case-control approach suggested an association of HCV risk with increasing
numbers of sexual partners. The measurement of the
MacDonald et al.
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