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Hepatitis C virus: Epidemiology and transmission
HEPATOLOGY Concise Review
Hepatitis C Virus: Epidemiology and Transmission TOBIAS HEINTGES
AND JACK
come apparent because of improved diagnostic techniques and physicians’ awareness to the possibility of therapeutic intervention. This short review will focus on selected aspects of the epidemiology and modes of transmission of HCV. MODES OF TRANSMISSION
R. WANDS
Hepatitis C virus (HCV) is an RNA virus with a genomic size of 9.6 kb. More than 50% of individuals exposed to HCV develop chronic infection. Of those individuals chronically infected, approximately 20% to 30% will develop liver cirrhosis and/or hepatocellular carcinoma when followed for twenty to thirty years. Methods to identify HCV include a highly sensitive third generation immunoassay that detects antibodies to structural and nonstructural proteins in serum. Viremia may be detected by reverse transcriptase–polymerase chain reaction (RT–PCR) technology. The role of HCV infection in acute and chronic liver disease has recently be
HCV is generally transmitted by the parenteral route. Well known and common modes of transmission involve transfusions and/or parenteral contact with blood products.1 However, up to 50% of individuals deny exposure to any of these known risk factors, and infection is often designated as ‘‘community acquired.’’1 Before the initiation of HCV antibody screening, approximately 10% to 20% of individuals, who had received multiple blood transfusions or plasma products, seroconverted to anti-HCV positive. Thus, the relative risk was 0.45% per unit transfused.2,3 However, the introduction of routine HCV antibody screening of blood products has led to a sharp decrease in the transmission rate of HCV. For
FIG. 1. World map illustrating the prevalence of HCV antibodies in blood donors as measured by second or third generation assays.35,38-50,57,74,85-95
Abbreviations: HCV, hepatitis C virus; HIV, human immunodeficiency virus. From the Molecular Hepatology Laboratory, Massachusetts General Hospital Cancer Center; and Harvard Medical School, Charlestown, MA. Received January 23, 1997; accepted May 2, 1997. Supported by Grants CA-35711 and AA-02169 from the National Institutes of Health. T.H. is supported by Grant HE 2655/1-1 from Deutsche Forschungsgemeinschaft, Bonn, Germany. Address reprint requests to: Tobias Heintges, M.D., Molecular Hepatology Laboratory, MGH Cancer Center, 149 13th St., Charlestown, MA 02129. Fax: (617) 726-5609. Copyright q 1997 by the American Association for the Study of Liver Diseases. 0270-9139/97/2603-0001$3.00/0
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example, the risk of acquiring antibodies to HCV by blood transfusions using current screening procedures was calculated as 1/100,000 units transfused.4 This remaining low risk is believed to be principally caused by blood’s susceptibility to infection just after acquisition of HCV infection and before the appearance of anti–HCV antibodies.4 Therefore, the detection of HCV RNA by RT–PCR would potentially allow for the identification of such infectious units, although this technique is not in routine use for screening blood donor populations. More recently, it has been found that HCV infection is transmitted by parenteral exposure to contaminated preparations of immunoglobulins.5,6 Indeed in 1993, one investigation demonstrates that HCV RNA was detectable in more than one-half of the intramuscular preparations of immunoglobulins.7 Thus, patients with immunoglobulin deficiency and who received such prophylactic antibody preparations frequently developed chronic HCV infection.8 Two large outbreaks of HCV infection have been linked to the inoculation of contaminated anti-rhesus D preparations in young women.9,10 Other known risk factors include ear piercing, acupuncture, tattoos, and cultural procedures involving blood contact.11,12 The use of inadequately sterilized nondisposable medical materials, e.g., needles and scalpels, has also been shown to transmit HCV.13 Perinatal Transmission. Although intrauterine infection has been postulated, perinatal transmission of HCV most likely occurs during labor or at the time of delivery.14 In that regard, HCV RNA has been found in puerperal fluid and in menstrual blood.15,16 The rate of chronic infection following perinatal exposure has been reported to vary between 0% and 7%.15,17-20 It is noteworthy that HCV RNA has been transiently found in cord blood of 40% of newborns delivered from anti–HCV positive mothers.15,21 If the mothers are co-infected with the human immunodeficiency virus (HIV), the rate of chronic HCV infection increases (22%).18,20 In these immunocompromised mothers, higher titers of HCV RNA in serum have been described and this phenomenon leads to increased infectivity of maternal blood.20 Indeed, a correlation between the rate of chronic perinatal HCV infection and the amount of detectable HCV RNA in serum has been established.17,20,22 Perinatal infection is very unlikely if HCV RNA is absent in the mother’s blood.15,17 Most investigators have reported that HCV RNA is undetectable in breast milk;15,22 however, it is not clear whether breast feeding is without risk of HCV transmission from mother to child. Needlestick. HCV is transmitted by contaminated needles. The rate of transmission probably depends, in part, on the quantity of blood transferred to the recipient by the needlestick, the titer of virus, and the depth of inoculation. Approximately 2% of exposed individuals will develop viremia and/or anti–HCV antibodies after needlestick exposure.23,24 The rate of HCV infection after sticks with solid needles appears to be lower as compared with accidents with hollow cannula devices.24 Sexual Transmission Sexual transmission of HCV infection has been demonstrated but is less frequent compared with hepatitis B. Studies in the United States and Europe have revealed low rates of exposure (0%-6.3%) in heterosexual partners of individuals with chronic HCV infection.10,25,26 Interestingly, recent reports from Asian countries have found higher positivity rates of 7.3% to 27.5%.27-29 The prevalence
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of anti–HCV increases if other known risk factors, such as i.v. drug abuse, are present.28 In addition to sexual transmission, some studies have described other percutaneous routes of inoculation that involve the shared use of razor blades and toothbrushes.25 Moreover, the genotype of HCV, which should be identical if the infection was acquired from the partner, has been found to be different in some instances.28,29 Therefore, modes of transmission that have yet to be defined must have occurred. It is noteworthy that HCV RNA has not generally been found in semen, vaginal fluid, urine, stools, and saliva.30,31 However, there is one study describing low amounts of HCV RNA in saliva.32 Patients with acute and chronic hepatitis C should be informed that sexual transmission of HCV is possible but that the risk appears to be low. Furthermore, it may be assumed that the use of condoms will add to an even lower risk of transmission, as shown for other viruses, such as HIV and hepatitis B virus. Antibodies to HCV have been found in 1% to 12% of prostitutes.33-35 Contributing risk factors include a high number of partners, sexual activities more likely to result in trauma, failure to use condoms, a positive serology for syphilis, and i.v. drug abuse.33-35 An increase of the HCV antibody positivity rate from 4% to 9% has been described in heterosexual partners if there is co-infection with HIV.34 In contrast to HBV, a higher prevalence of HCV infection has not been associated with the number of sexual partners in gay men.36 Finally, it appears that the prevalence of HCV antibodies in sexual partners of heterosexual and homosexual relationships is similar.34 GENERAL POPULATION AND BLOOD DONORS
HCV infection has been found worldwide. In the United States the greatest number of cases occur in Caucasians, whereas the highest incidence of infection is among other ethnic groups, such as Hispanics.37 There is no sex predilection.37 Studies from the Centers for Disease Control in Atlanta, GA, suggest that the incidence of hepatitis C in the United States has been declining since 1989.37 Blood donors have similar characteristics to the general population, although underrepresentative of children and senior citizens. Figure 1 demonstrates the prevalence of HCV antibodies as measured by second or third generation enzyme linked immunoassays in blood donors derived from different geographical regions of the world. Infectivity rates vary widely between 0.3% and 14.5%. There is a relatively low prevalence of HCV antibodies in blood donors derived from the United States and Northern Europe, including the United Kingdom, France, and Germany.38-41 Higher prevalence rates have been found in Southeast Asian countries, such as Thailand, Malaysia, and India.42-44 Even higher prevalence rates between 1.4% and 2.1% have been observed in northern African and Arabian countries, such as Libya, Yemen, Saudi-Arabia, and Ethiopia.45-48 The highest prevalences have been reported in the Ukraine and in the central African countries of Gabon and Cameroon, as well as in Egypt where up to 14.5% of the population has HCV antibodies.49,50 RISK GROUPS Drug Abuse. There is a very high prevalence of HCV antibodies among i.v. drug addicts because of the shared use of contaminated needles and syringes. In most studies, HCV exposure and antibody positivity rates have been reported
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TABLE 1. Chronic Hepatitis C Infection in Unselected Individuals With Alcohol Abuse HCV-Ab pos (n)
%
Country
12/180 29/201 23/100 45/310 53/288
6.7 14.4 23.0 14.5 18.4
Spain79 Sweden82 USA77 Sweden83 USA84
Total 127/799
Median 15.9
to be higher than 50% and close to 100% in some populations.51-54 It is not yet known whether public education and the use of disposable syringes will lead to a decrease of HCV infection in this population over time. The prevalence of anti–HCV antibodies in drug users who employ oral and/or nasal, instead of intravenous, routes of administration has been found to be substantially lower (5%) but higher than in blood donors.54 Thus, nonparenteral transmission of HCV in drug users is likely to occur. Hemophiliacs. Chronic HCV infection is common in hemophiliacs. Previously, more than one thousand units of donor plasma was pooled to produce a single lot of clotting factors. This mixing of donor plasma, as well as the lack of procedures to inactivate potential viral contaminates such as heat inactivation or pasteurization, led to very high rates of HCV transmission.32 Indeed, when hemophiliacs received concentrates of clotting factors in which inadequate procedures were used to inactivate viruses, the prevalence of antibodies to HCV following administration was found to vary between 84% and 100%.55,56 It is now very encouraging that hemophiliacs treated with clotting factor preparations that use more recent viral inactivating procedures are rarely positive for HCV antibodies.55 Nevertheless, the mean HCV antibody positivity rate is still approximately 76% in hemophiliacs.55-59 Finally, with respect to HIV positive hemophiliacs, co-infection with HCV has been shown to be very frequent and to vary between 69% and 100%.58,59 HIV Infected Individuals. It is apparent that the modes of transmission for HIV and HCV are similar. Therefore, dual infection with these two viral agents is common particularly in i.v. abusing drug addicts. In a cohort of unselected HIV positive patients, approximately 35% were co-infected with HCV. However, co-infection rates varied between 8% and 51% and depend, in part, on the presence of other parenteral risk factors in these populations.60-62 It is important to note that the prevalence of HCV antibodies decreases with advanced immune deficiency, as defined by the number of CD4/ cells.60 Therefore, in patients with severe acquired immune deficiency syndrome, HCV RNA should be determined in addition to the measurement of HCV antibodies to assure accurate diagnosis. Moreover, the titer of HCV RNA in serum may increase due to a general impairment of the immune response by HIV.63 It is also not surprising that the liver disease is generally mild in individuals with HCV and HIV infection and results from a diminished cellular immune response to HCV.61 However, one study observed liver failure in about 10% of HIV positive individuals prior to the development of an acquired immune deficiency syndrome–defining disease following 10 to 20 years of chronic HCV infection.64
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Patients on Dialysis. HCV infection is frequent among patients on chronic hemodialysis. The prevalence of HCV antibodies varies between 8% to 69%.65-68 Individuals with terminal renal insufficiency may be immunocompromised to variable degrees. Therefore, HCV RNA has been found by reverse transcriptase polymerase–chain reaction in 5% of individuals who are negative for anti-HCV antibodies.65 Indeed, HCV RNA has been detected between 10% and 52% of patients on hemodialysis.65,67 Aminotransferase levels may be normal in approximately 70%, even in the presence of viremia.65,66 The risk of HCV infection appears to correlate with the duration and frequency of hemodialysis.66,69 All environmental factors associated with this high rate of infection have not been precisely defined. The shared use of dialysis machines may not be the major mode of transmission because many centers dialyse HCV positive patients on separate machines. However, blood transfusions are frequent, and the inapparent transmission of HCV from patient to patient by other medical procedures is possible. For example, there is one report in which investigators observed a dramatic decrease of the incidence of HCV infection after dialysis personnel strictly adhered to changing gloves when moving from one patient to another.70 The prevalence of HCV antibodies is much lower (5%) in patients on chronic abdominal peritoneal dialysis.69 With this procedure, cross contamination of body fluids between individuals rarely occurs. However, precautions should be taken since HCV RNA has been found in dialysis fluid of patients with chronic abdominal peritoneal dialysis and with HCV infection.69 Persistent HCV infection is common in renal transplant recipients.71,72 In general, most infections were probably acquired while on hemodialysis and before kidney transplantation. However, it has been found that HCV is transmitted following renal transplantation of an organ derived from an anti–HCV positive donor. Subsequent studies reveal that HCV transmission was almost 100% when organs were taken from HCV RNA positive donors.73 It is controversial whether kidneys obtained from infected donors should be used for renal transplantation. Most investigations have found no significant increase in mortality, morbidity, or loss of the renal graft in HCV infected individuals on immunosuppressive therapy.71,74 There is, however, one study that reports liver failure in 7% of HCV positive patients following renal transplantation.75 Alcohol Abuse. Surprisingly high rates of HCV infection have been found in patients with alcohol abuse. Indeed, anti– HCV antibodies were detected in approximately 16% of unselected patients with alcoholism, as shown in Table 1. More important, such antibodies have been found in 32% of individuals with alcohol abuse and co-existing liver disease (TaTABLE 2. Chronic Hepatitis C Infection Associated With Alcohol-Induced Liver Disease HCV-Ab pos (n)
12/130 51/137 48/97 17/40 Total 128/404
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%
HCV-RNA (n)
%
9.2 37.2 49.5 42.5
9/130 33/137 29/97 16/40
6.9 24.1 29.8 40.0
Median 31.7%
Total 87/404
Median 21.5%
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Germany85 USA78 Italy80 USA77
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ble 2). Approximately 21% of these individuals have detectable HCV RNA in their serum as well. HCV infection amongst alcoholics varies in different geographical regions of the world; for example, an anti–HCV prevalence rate of 7% has been found in alcoholic populations in Germany, whereas the rate has been reported to be as high as 49% in Italy (Table 2). HCV infection has been associated with severe liver disease in many studies;76-79 therefore, HCV antibodies have been found most often in alcoholics with advanced cirrhosis and hepatocellular carcinoma.76-79 It is also of interest that the level of HCV RNA in serum was found to be substantially higher in individuals with severe alcohol abuse.80 This observation suggests that alcohol may interfere with the host immune response to HCV. It is important to recognize the striking association of persistent HCV infection in alcoholics with severe liver disease because it raises the possibility that HCV and alcohol abuse are additive in causing liver injury. Acknowledgment: The authors are grateful for the assistance of Rolf Carlson and Karen Grosso.
17. 18.
19.
20.
21.
22. 23.
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61. Quan MC, Krajden M, Grigoriew GA, Salit IE. Hepatitis C virus infection in patients infected with the human immunodeficiency virus. Clin Inf Dis 1993;17:117-119. 62. Quaranta JF, Delaney SR, Allemann S, Cassuto JP, Dellamonica P, Allain JP. Prevalence of antibody to hepatitis C virus (HCV) in HIV-1-infected patients. J Med Virol 1994;42:29-32. 63. Thomas DL, Shih JW, Alter HJ, Vlahov D, Cohn S, Hoover DR, Cheung L, Nelson KE. Effect of human immunodeficiency virus on hepatitis C virus infection among injecting drug users. J Infect Dis 1996;174:690695. 64. Telfer P, Sabin C, Devereux H, Scott F, Dusheiko G, Lee C. The progression of HCV-associated liver disease in a cohort of haemophilic patients. Br J Haematol 1994;87:555-561. 65. Bukh J, Wantzin P, Krogsgaard K, Knudson F, Purcell RH, Miller RH, and the Copenhagen Dialysis HCV Study Group. High prevalence of hepatitis C virus (HCV) RNA in dialysis patients: failure of commercially available antibody tests to identify a significant number of patients with HCV infection. J Infect Dis 1993;168:1343-1348. 66. Cassidy MJ, Jankelson D, Becker M, Dunne T, Walzl G, Moosa MR. The prevalence of antibodies to hepatitis C virus at two hemodialysis units in South Africa. S Afr Med J 1995;85:996-998. 67. Dussol B, Chicheportiche C, Cantaloube JJ, Roubicek C, Biagini P, Berthezene P, Berland Y. Detection of hepatitis C infection by polymerase chain reaction among hemodialysis patients. Am J Kidney Dis 1993; 2:574-580. 68. Lin DY, Lin HH, Huang CC, Liaw YK. High incidence of hepatitis C virus infection in hemodialysis patients in Taiwan. Am J Kidney Dis 1993;21:288-291. 69. Gladziwa U, Schlipkoter U, Lorbeer B, Cholmakow K, Roggendorf M, Sieberth HG. Prevalence of antibodies to hepatitis C virus in patients on peritoneal dialysis– –a multicenter study. Clin Nephrol 1993;40:4652. 70. Okuda K, Hayashi H, Kobayashi S, Irie Y. Mode of hepatitis C infection not associated with blood transfusion among chronic hemodialysis patients. J Hepatol 1995;23:28-31. 71. Ban BK, Yang CW, Yoon SA, Kim YS, Chang YS, Koh YB. Prevalence and clinical course of hepatitis B and hepatitis C liver disease in ciclosporintreated renal allograft recipients. Nephron 1995;70:397-401. 72. Genesca J, Vila J, Cordoba J, Sauleda S, Quer J, Esteban JI, Estaban R, et al. Hepatitis C virus infection in renal transplant recipients: epidemiology, clinical impact, serological confirmation and viral replication. J Hepatol 1995;22:272-277. 73. Pereira BJG, Milford EL, Kirkman RL. Prevalence of hepatitis C virus RNA in organ donors positive for hepatitis C antibody and in the recipients of their organs. N Engl J Med 1992;327:910-915. 74. Ilako FM, McLigeyo SO, Riyat MS, Lule GN, Okoth FA, Kaptich D. The prevalence of hepatitis C virus antibodies in renal patients, blood donors and patients with chronic liver disease in Kenya. East Afr Med J 1995;72:362-364. 75. Pouteil-Noble C, Tardy JC, Chossegros P, Mion F, Chevallier M, Gerard F, Chevallier P, et al. Co-infection by hepatitis B virus and hepatitis C virus in renal transplantation: morbidity and mortality in 1098 patients. Nephrol Dial Transplant 1995;10:122-124. 76. Coelho-Little M, Jeffers LJ, Bernstein DE, Goodman JJ, Reddy KR, de Medina M, Li X, et al. Hepatitis C virus in alcoholic patients with and without clinically apparent liver disease. Alcohol Clin Exp Res 1995; 19:1173-1176. 77. Fong TL, Kanel GC, Conrad A, Valinluck B, Charboneau F. Clinical significance of concomitant hepatitis C infection in patients with alcoholic liver disease. HEPATOLOGY 1994;19:554-557. 78. Gonzalez-Quintela A, Alende R, Aguilera A, Tome S, Gude F, Perez Becerra E, Torre A, et al. Hepatitis C virus antibodies in alcoholic patients. Rev Clin Esp 1995;195:367-372. 79. Zignego AL, Foschi M, Laffi G, Monti M, Careccia G, Romanelli RG, De Majo E, et al. ‘‘Inapparent‘‘ hepatitis B virus infection and hepatitis C virus replication in alcoholic subjects with and without liver disease. HEPATOLOGY 1994;19:577-582. 80. Oshita M, Hayashi N, Kasahara A, Hagiwara H, Mita E, Naito M, Katayama K, et al. Increased serum hepatitis C virus RNA levels among alcoholic patients with chronic hepatitis C. HEPATOLOGY 1994;20:11151120. 81. Befrits R, Hedman M, Blomquist L. Chronic hepatitis C in alcoholic patients: prevalence, genotypes, and correlation to liver disease. Scand J Gastroenterology 1995;30:1113-1118. 82. Verbaan H, Andersson K, Eriksson S. Intravenous drug abuse - the major route of hepatitis C virus transmission among alcohol-dependent individuals? Scand J Gastroenterology 1993;28:714-718.
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83. Mendenhall CL, Moritz T, Rouster S, Roselle G, Polito A, Quan S, diNelle RK. Epidemiology of hepatitis C among veterans with alcoholic liver disease. Am J Gastroenterol 1993;88:1022-1026. 84. Bode JC, Alscher DM, Wisser H, Bode C. Detection of hepatitis C virus antibodies and hepatitis C virus RNA in patients with alcoholic liver disease. Alcohol alcohol 1995;30:97-103. 85. Thomas DL, Mahley RW, Badur S, Palaoglu E, Quinn TC. The epidemiology of hepatitis C in Turkey. Infection 1994;22:411-414. 86. Ducos J, Mondain AM, Perney P, Balavoine M, Zurek V, Petrukh Y, Pavlosky M, et al. Estimation of hepatitis C virus (HCV) prevalence in Lviv, Ukraine [Abstract]. HEPATOLOGY 1996;24:267A. 87. Kuperan P, Choon AT, Ding SH, Lee G. Prevalence of antibodies to hepatitis C virus in relation to surrogate markers in a blood donor population of Singapore. Southeast Asian J Trop Med Public Health 1993;24:127-129. 88. Khan M, Husain M, Yano M, Hashizume K, Yousuf M, Tanaka E, Matsumoto A, et al. Comparison of seroepidemiology of hepatitis C in blood donors between Bangladesh and Japan. Gastroenterology Jpn 1993;28:28-31. 89. Bar Shany S, Green MS, Slepon R, Shinar E. Ethnic differences in the prevalence of anti-hepatitis C antibodies and hepatitis B surface antigen in Israeli blood donors by age, sex, country of birth and origin. J Viral Hepatol 1995;2:139-144.
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90. Fest T, de Wazieres B, Agis F, Viel JF, Gordien E, Dupond JL, Herve P. A unique seroepidemiologic situation for hepatitis B marker in Guadeloupe. Results of a prospective study in blood donors. Gatroenterol Clin Biol 1993;17:207-211. 91. Vasconcelos HC, Yoshida CF, Vanderborght BO, Schatzmayr HG. Hepatitis B and C prevalences among blood donors in the south region of Brazil. Mem Inst Oswalso Cruz 1994;89:503-507. 92. Develoux M, Boni G, Aguessy-Ahyi B, Gnahoui L, Delaporte E. The prevalence of anti-hepatitis C antibodies in pregnant women and blood donors in Benin. Bull Soc Pathol Exot 1995;88:115-116. 93. el Gohary A, Hassan A, Nooman Z, Lavanchy D, Mayerat C, el Ayat A, Fawaz N, et al. High prevalence of hepatitis C virus among urban and rural population groups in Egypt. Acta Trop 1995;59:155-161. 94. Sheu JC, Wang JT, Wang TH, Wang CY, Yang PM, Huang GT, Shih LN, et al. Prevalence of hepatitis C viral infection in a community in Taiwan. Detection by synthetic peptide-based assay and polymerase chain reaction. J Hepatol 1993;17:192-198. 95. Song P, Duc DD, Hien B, Nakata S, Chosa T, Watanabe J, Tsuda F, et al. Markers of hepatitis C and B virus infections among blood donors in Ho Chi Minh City and Hanoi, Vietnam. Clin Diagn Lab Immunol 1994;1:413-418.
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Hepatitis C Virus: Epidemiology and Transmission TOBIAS HEINTGES
AND JACK
come apparent because of improved diagnostic techniques and physicians’ awareness to the possibility of therapeutic intervention. This short review will focus on selected aspects of the epidemiology and modes of transmission of HCV. MODES OF TRANSMISSION
R. WANDS
Hepatitis C virus (HCV) is an RNA virus with a genomic size of 9.6 kb. More than 50% of individuals exposed to HCV develop chronic infection. Of those individuals chronically infected, approximately 20% to 30% will develop liver cirrhosis and/or hepatocellular carcinoma when followed for twenty to thirty years. Methods to identify HCV include a highly sensitive third generation immunoassay that detects antibodies to structural and nonstructural proteins in serum. Viremia may be detected by reverse transcriptase–polymerase chain reaction (RT–PCR) technology. The role of HCV infection in acute and chronic liver disease has recently be
HCV is generally transmitted by the parenteral route. Well known and common modes of transmission involve transfusions and/or parenteral contact with blood products.1 However, up to 50% of individuals deny exposure to any of these known risk factors, and infection is often designated as ‘‘community acquired.’’1 Before the initiation of HCV antibody screening, approximately 10% to 20% of individuals, who had received multiple blood transfusions or plasma products, seroconverted to anti-HCV positive. Thus, the relative risk was 0.45% per unit transfused.2,3 However, the introduction of routine HCV antibody screening of blood products has led to a sharp decrease in the transmission rate of HCV. For
FIG. 1. World map illustrating the prevalence of HCV antibodies in blood donors as measured by second or third generation assays.35,38-50,57,74,85-95
Abbreviations: HCV, hepatitis C virus; HIV, human immunodeficiency virus. From the Molecular Hepatology Laboratory, Massachusetts General Hospital Cancer Center; and Harvard Medical School, Charlestown, MA. Received January 23, 1997; accepted May 2, 1997. Supported by Grants CA-35711 and AA-02169 from the National Institutes of Health. T.H. is supported by Grant HE 2655/1-1 from Deutsche Forschungsgemeinschaft, Bonn, Germany. Address reprint requests to: Tobias Heintges, M.D., Molecular Hepatology Laboratory, MGH Cancer Center, 149 13th St., Charlestown, MA 02129. Fax: (617) 726-5609. Copyright q 1997 by the American Association for the Study of Liver Diseases. 0270-9139/97/2603-0001$3.00/0
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example, the risk of acquiring antibodies to HCV by blood transfusions using current screening procedures was calculated as 1/100,000 units transfused.4 This remaining low risk is believed to be principally caused by blood’s susceptibility to infection just after acquisition of HCV infection and before the appearance of anti–HCV antibodies.4 Therefore, the detection of HCV RNA by RT–PCR would potentially allow for the identification of such infectious units, although this technique is not in routine use for screening blood donor populations. More recently, it has been found that HCV infection is transmitted by parenteral exposure to contaminated preparations of immunoglobulins.5,6 Indeed in 1993, one investigation demonstrates that HCV RNA was detectable in more than one-half of the intramuscular preparations of immunoglobulins.7 Thus, patients with immunoglobulin deficiency and who received such prophylactic antibody preparations frequently developed chronic HCV infection.8 Two large outbreaks of HCV infection have been linked to the inoculation of contaminated anti-rhesus D preparations in young women.9,10 Other known risk factors include ear piercing, acupuncture, tattoos, and cultural procedures involving blood contact.11,12 The use of inadequately sterilized nondisposable medical materials, e.g., needles and scalpels, has also been shown to transmit HCV.13 Perinatal Transmission. Although intrauterine infection has been postulated, perinatal transmission of HCV most likely occurs during labor or at the time of delivery.14 In that regard, HCV RNA has been found in puerperal fluid and in menstrual blood.15,16 The rate of chronic infection following perinatal exposure has been reported to vary between 0% and 7%.15,17-20 It is noteworthy that HCV RNA has been transiently found in cord blood of 40% of newborns delivered from anti–HCV positive mothers.15,21 If the mothers are co-infected with the human immunodeficiency virus (HIV), the rate of chronic HCV infection increases (22%).18,20 In these immunocompromised mothers, higher titers of HCV RNA in serum have been described and this phenomenon leads to increased infectivity of maternal blood.20 Indeed, a correlation between the rate of chronic perinatal HCV infection and the amount of detectable HCV RNA in serum has been established.17,20,22 Perinatal infection is very unlikely if HCV RNA is absent in the mother’s blood.15,17 Most investigators have reported that HCV RNA is undetectable in breast milk;15,22 however, it is not clear whether breast feeding is without risk of HCV transmission from mother to child. Needlestick. HCV is transmitted by contaminated needles. The rate of transmission probably depends, in part, on the quantity of blood transferred to the recipient by the needlestick, the titer of virus, and the depth of inoculation. Approximately 2% of exposed individuals will develop viremia and/or anti–HCV antibodies after needlestick exposure.23,24 The rate of HCV infection after sticks with solid needles appears to be lower as compared with accidents with hollow cannula devices.24 Sexual Transmission Sexual transmission of HCV infection has been demonstrated but is less frequent compared with hepatitis B. Studies in the United States and Europe have revealed low rates of exposure (0%-6.3%) in heterosexual partners of individuals with chronic HCV infection.10,25,26 Interestingly, recent reports from Asian countries have found higher positivity rates of 7.3% to 27.5%.27-29 The prevalence
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of anti–HCV increases if other known risk factors, such as i.v. drug abuse, are present.28 In addition to sexual transmission, some studies have described other percutaneous routes of inoculation that involve the shared use of razor blades and toothbrushes.25 Moreover, the genotype of HCV, which should be identical if the infection was acquired from the partner, has been found to be different in some instances.28,29 Therefore, modes of transmission that have yet to be defined must have occurred. It is noteworthy that HCV RNA has not generally been found in semen, vaginal fluid, urine, stools, and saliva.30,31 However, there is one study describing low amounts of HCV RNA in saliva.32 Patients with acute and chronic hepatitis C should be informed that sexual transmission of HCV is possible but that the risk appears to be low. Furthermore, it may be assumed that the use of condoms will add to an even lower risk of transmission, as shown for other viruses, such as HIV and hepatitis B virus. Antibodies to HCV have been found in 1% to 12% of prostitutes.33-35 Contributing risk factors include a high number of partners, sexual activities more likely to result in trauma, failure to use condoms, a positive serology for syphilis, and i.v. drug abuse.33-35 An increase of the HCV antibody positivity rate from 4% to 9% has been described in heterosexual partners if there is co-infection with HIV.34 In contrast to HBV, a higher prevalence of HCV infection has not been associated with the number of sexual partners in gay men.36 Finally, it appears that the prevalence of HCV antibodies in sexual partners of heterosexual and homosexual relationships is similar.34 GENERAL POPULATION AND BLOOD DONORS
HCV infection has been found worldwide. In the United States the greatest number of cases occur in Caucasians, whereas the highest incidence of infection is among other ethnic groups, such as Hispanics.37 There is no sex predilection.37 Studies from the Centers for Disease Control in Atlanta, GA, suggest that the incidence of hepatitis C in the United States has been declining since 1989.37 Blood donors have similar characteristics to the general population, although underrepresentative of children and senior citizens. Figure 1 demonstrates the prevalence of HCV antibodies as measured by second or third generation enzyme linked immunoassays in blood donors derived from different geographical regions of the world. Infectivity rates vary widely between 0.3% and 14.5%. There is a relatively low prevalence of HCV antibodies in blood donors derived from the United States and Northern Europe, including the United Kingdom, France, and Germany.38-41 Higher prevalence rates have been found in Southeast Asian countries, such as Thailand, Malaysia, and India.42-44 Even higher prevalence rates between 1.4% and 2.1% have been observed in northern African and Arabian countries, such as Libya, Yemen, Saudi-Arabia, and Ethiopia.45-48 The highest prevalences have been reported in the Ukraine and in the central African countries of Gabon and Cameroon, as well as in Egypt where up to 14.5% of the population has HCV antibodies.49,50 RISK GROUPS Drug Abuse. There is a very high prevalence of HCV antibodies among i.v. drug addicts because of the shared use of contaminated needles and syringes. In most studies, HCV exposure and antibody positivity rates have been reported
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TABLE 1. Chronic Hepatitis C Infection in Unselected Individuals With Alcohol Abuse HCV-Ab pos (n)
%
Country
12/180 29/201 23/100 45/310 53/288
6.7 14.4 23.0 14.5 18.4
Spain79 Sweden82 USA77 Sweden83 USA84
Total 127/799
Median 15.9
to be higher than 50% and close to 100% in some populations.51-54 It is not yet known whether public education and the use of disposable syringes will lead to a decrease of HCV infection in this population over time. The prevalence of anti–HCV antibodies in drug users who employ oral and/or nasal, instead of intravenous, routes of administration has been found to be substantially lower (5%) but higher than in blood donors.54 Thus, nonparenteral transmission of HCV in drug users is likely to occur. Hemophiliacs. Chronic HCV infection is common in hemophiliacs. Previously, more than one thousand units of donor plasma was pooled to produce a single lot of clotting factors. This mixing of donor plasma, as well as the lack of procedures to inactivate potential viral contaminates such as heat inactivation or pasteurization, led to very high rates of HCV transmission.32 Indeed, when hemophiliacs received concentrates of clotting factors in which inadequate procedures were used to inactivate viruses, the prevalence of antibodies to HCV following administration was found to vary between 84% and 100%.55,56 It is now very encouraging that hemophiliacs treated with clotting factor preparations that use more recent viral inactivating procedures are rarely positive for HCV antibodies.55 Nevertheless, the mean HCV antibody positivity rate is still approximately 76% in hemophiliacs.55-59 Finally, with respect to HIV positive hemophiliacs, co-infection with HCV has been shown to be very frequent and to vary between 69% and 100%.58,59 HIV Infected Individuals. It is apparent that the modes of transmission for HIV and HCV are similar. Therefore, dual infection with these two viral agents is common particularly in i.v. abusing drug addicts. In a cohort of unselected HIV positive patients, approximately 35% were co-infected with HCV. However, co-infection rates varied between 8% and 51% and depend, in part, on the presence of other parenteral risk factors in these populations.60-62 It is important to note that the prevalence of HCV antibodies decreases with advanced immune deficiency, as defined by the number of CD4/ cells.60 Therefore, in patients with severe acquired immune deficiency syndrome, HCV RNA should be determined in addition to the measurement of HCV antibodies to assure accurate diagnosis. Moreover, the titer of HCV RNA in serum may increase due to a general impairment of the immune response by HIV.63 It is also not surprising that the liver disease is generally mild in individuals with HCV and HIV infection and results from a diminished cellular immune response to HCV.61 However, one study observed liver failure in about 10% of HIV positive individuals prior to the development of an acquired immune deficiency syndrome–defining disease following 10 to 20 years of chronic HCV infection.64
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Patients on Dialysis. HCV infection is frequent among patients on chronic hemodialysis. The prevalence of HCV antibodies varies between 8% to 69%.65-68 Individuals with terminal renal insufficiency may be immunocompromised to variable degrees. Therefore, HCV RNA has been found by reverse transcriptase polymerase–chain reaction in 5% of individuals who are negative for anti-HCV antibodies.65 Indeed, HCV RNA has been detected between 10% and 52% of patients on hemodialysis.65,67 Aminotransferase levels may be normal in approximately 70%, even in the presence of viremia.65,66 The risk of HCV infection appears to correlate with the duration and frequency of hemodialysis.66,69 All environmental factors associated with this high rate of infection have not been precisely defined. The shared use of dialysis machines may not be the major mode of transmission because many centers dialyse HCV positive patients on separate machines. However, blood transfusions are frequent, and the inapparent transmission of HCV from patient to patient by other medical procedures is possible. For example, there is one report in which investigators observed a dramatic decrease of the incidence of HCV infection after dialysis personnel strictly adhered to changing gloves when moving from one patient to another.70 The prevalence of HCV antibodies is much lower (5%) in patients on chronic abdominal peritoneal dialysis.69 With this procedure, cross contamination of body fluids between individuals rarely occurs. However, precautions should be taken since HCV RNA has been found in dialysis fluid of patients with chronic abdominal peritoneal dialysis and with HCV infection.69 Persistent HCV infection is common in renal transplant recipients.71,72 In general, most infections were probably acquired while on hemodialysis and before kidney transplantation. However, it has been found that HCV is transmitted following renal transplantation of an organ derived from an anti–HCV positive donor. Subsequent studies reveal that HCV transmission was almost 100% when organs were taken from HCV RNA positive donors.73 It is controversial whether kidneys obtained from infected donors should be used for renal transplantation. Most investigations have found no significant increase in mortality, morbidity, or loss of the renal graft in HCV infected individuals on immunosuppressive therapy.71,74 There is, however, one study that reports liver failure in 7% of HCV positive patients following renal transplantation.75 Alcohol Abuse. Surprisingly high rates of HCV infection have been found in patients with alcohol abuse. Indeed, anti– HCV antibodies were detected in approximately 16% of unselected patients with alcoholism, as shown in Table 1. More important, such antibodies have been found in 32% of individuals with alcohol abuse and co-existing liver disease (TaTABLE 2. Chronic Hepatitis C Infection Associated With Alcohol-Induced Liver Disease HCV-Ab pos (n)
12/130 51/137 48/97 17/40 Total 128/404
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%
HCV-RNA (n)
%
9.2 37.2 49.5 42.5
9/130 33/137 29/97 16/40
6.9 24.1 29.8 40.0
Median 31.7%
Total 87/404
Median 21.5%
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Germany85 USA78 Italy80 USA77
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ble 2). Approximately 21% of these individuals have detectable HCV RNA in their serum as well. HCV infection amongst alcoholics varies in different geographical regions of the world; for example, an anti–HCV prevalence rate of 7% has been found in alcoholic populations in Germany, whereas the rate has been reported to be as high as 49% in Italy (Table 2). HCV infection has been associated with severe liver disease in many studies;76-79 therefore, HCV antibodies have been found most often in alcoholics with advanced cirrhosis and hepatocellular carcinoma.76-79 It is also of interest that the level of HCV RNA in serum was found to be substantially higher in individuals with severe alcohol abuse.80 This observation suggests that alcohol may interfere with the host immune response to HCV. It is important to recognize the striking association of persistent HCV infection in alcoholics with severe liver disease because it raises the possibility that HCV and alcohol abuse are additive in causing liver injury. Acknowledgment: The authors are grateful for the assistance of Rolf Carlson and Karen Grosso.
17. 18.
19.
20.
21.
22. 23.
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