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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 INTRODUCTION 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. METHODOLOGICAL ISSUES IN ASSESSING ROUTES OF HCV TRANSMISSION 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. 1 National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, New South Wales, Australia. 2 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. 137 Downloaded from http://epirev.oxfordjournals.org/ 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. 138 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 (18). 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). BLOODBORNE TRANSMISSION 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 Downloaded from http://epirev.oxfordjournals.org/ at Pennsylvania State University on February 23, 2013 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). Downloaded from http://epirev.oxfordjournals.org/ at Pennsylvania State University on February 23, 2013 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). 139 140 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. SEXUAL TRANSMISSION 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 Downloaded from http://epirev.oxfordjournals.org/ at Pennsylvania State University on February 23, 2013 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 staff. 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 TABLE 1. 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) Study site (reference no.) Study HCV Population Population % with HCV antibody % 95% Cl* Years of relationship Male-female ratio in spouses Largely women Italy (79) 1993 EIA*-2 RIBA*-4 Sexual partners of multitransfused HCV-positive patients 18 0 0-19 Mean 10 (range 2-35) Amsterdam (80) 1993 EIA-2 RIBA-2 Sexual partners of HCV-positive individuals 50 0 0-7 Median 13 (range 0.25-46) 1:4.5 EUSA*-2 Noninjecting drug using sexual partners of heterosexual HCVpositive injecting drug users 37 11 3-25 Mean 4 (range 0.1-23) 1:5.5 EIA-2 Synthetic EIA Sexual partners of patients with chronic HCV liver disease and HCV-RNA* Married <10 years Married 10-30 years Married >30 years 154 27 20-34 7 60 87 0 23 32 0-»1 13-36 23-43 Spain (32) 1984-1988 Japan(81) 1991 1:2,0 • 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 Downloaded from http://epirev.oxfordjournals.org/ at Pennsylvania State University on February 23, 2013 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 141 142 MacDonald et al. TABLE 2. Seroprevalence of HCV* antibodies in populations at higher risk for sexual transmission Study site (reference no.) Somalia (84) Spain (83) Study period 1990 1985-1990 1993 1990 Baltimore, MD (85) 1990-1992 France (8) 1985-1991 Spain (83) 1984-1990 Spain (32) 1984-1988 EIA*-1 and 2 RIBA*-2 EIA-2 RIBA-4 ELISA*-2 EIA-1 and 2 RIBA-2 ELISA-2 RIBA-2 ELISA-3 RIBA-3 EIA-2 RIBA-4 ELISA-2 Population Population size % with HCV antibody Sex workers 236 1.8 Sex workers 547 6 Sexual health clients Sexual health clients 80 1.7 2.5 Sexual health clients 1,039 5.4 Homosexual men 106 4 Homosexual men 168 4 Homosexual men 105 16 * 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. HOUSEHOLD CONTACT 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 Downloaded from http://epirev.oxfordjournals.org/ at Pennsylvania State University on February 23, 2013 New Zealand (86) Somalia (84) HCV assay Transmission of Hepatitis C Virus MOTHER-TO-CHILD TRANSMISSION 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 Study (reference no.) Marcellin et al., 1993 (104) Manzini et al., 1995 (90) Zanetti et al., 1995(99) Wejslal et al., 1992 (91) Linetal., 1994 (94) Ohtoetal., 1994 (92) % 95% Cl* 1988 No. Of infants born to mothers with HCV antibody 10 0 0-31 Italy 1991-1992 27 0 Italy 1990-1993 94 Sweden 1981-1990 Taiwan Japan Country France Study period Infants with HCV-RNA No. of infants born to mothers with HCV-RNA Infants with HCV-RNA % 95% Cl 5 0 0-52 0-13 19 0 0 0-4 23 21 5 0.1-24 1989-1990 15 7 1990-1992 54 6 Infants with HCV-RNA NO 01 infants born to mothers without HCV-RNA % 95% Cl 5 0 0-52 0-18 8 0 0-37 0 0-15 71 0 0-5 21 5 0.1-24 0 0.2-32 15 7 0.2-32 0 1.2-15 32 9 2-25 22 0 0-15 * Cl, confidence interval; HCV, hepatitis C virus; HCV-RNA, hepatitis C virus genome; HIV, human immunodeficiency virus. Epidemiol Rev Vol. 18, No. 2, 1996 Downloaded from http://epirev.oxfordjournals.org/ at Pennsylvania State University on February 23, 2013 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 HCV. 143 144 MacDonald et al. TABLE 4. 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 Study (reference no.) Country Study period NO. Of infants born to mothers with anti-HCV and anti-HIV 1992 58 5 1.1-14 59 0.1-27 50 Infants with HCV-RNA* 95% Cl* Lametal., 1993(93) United Kingdom Manzini et al., 1995(90) Italy 1990-1992 18 6 Zanetti et al., 1995(99) Italy 1990-1993 22 36 17-59 mothers with HCVRNA 82 Comment 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 Downloaded from http://epirev.oxfordjournals.org/ at Pennsylvania State University on February 23, 2013 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 infection. 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. DISCUSSION 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 http://epirev.oxfordjournals.org/ 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 145 146 MacDonald et al. REFERENCES 1. Aach RD, Szmuness W, Mosley JW, et al. Serum alanine aminotransferase of donors in relation to the risk of non-A, non-B hepatitis in recipients: the Transfusion-Transmitted Viruses Study. N Engi J Med 1981;304:989-94. 2. Alter MJ, Coleman PJ, Alexander WJ, et al. 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