3ournal of Gastroenterology and Hepatology (1992) 7 , 549-550
EDITORIAL COMMENT
Advances in hepatitis C: Sero-epidemiology and natural history MICHITAMI YANO
WHO Collaborating Centre for Viral Hepatitis and Institute for Clinical Research, Nagasaki Chuo National Hospital, Ku bara, Nagasaki, Japan
T h e study of the hepatitis C virus (HCV) has greatly advanced the understanding of liver diseases. There are several reasons for this. First, persistent HCV infection, even with minor necro-inflammatory change in the liver may ultimately progress to liver cirrhosis which is closely connected with the development of hepatocellular carcinoma. There are few cases of chronic HCV infection which show spontaneous improvement during the clinical course; a major difference from the natural history of hepatitis B virus (HBV) infection in which the outcome is transformed by seroconversion of hepatitis Be antigen (HBeAg).' Second, the course of HCV can be changed by treatment with interferon which occasionally leads to cure of the infection. Next, the development of detection and assay systems for HCV antigens and antibodies are dramatic models of the development and application of molecular biology to clinical practice. The application of diagnostic tests for HCV infection during the past 2 years, has provided an increasingly clear picture of the epidemiology, diagnosis and pathogenesis of HCV. Several epidemiological reports about the geographic incidence of HCV infection indicate positive rates of HCV antibody from 0.2 to 1.9% of the total In relation to the association of HCV with hepatocellular carcinoma, which is the final stage of liver disease, positive rates are from 16 to 7 2 9 ' 0 . ~Moreover, ~~ the epidemiology of HCV infection is quite different from that of HBV infection which is also a blood-borne infectious disease. In particular, the proportion of people infected with HCV is low in several high-risk places of HBV infection, including China, Africa and several other countries. Is it possible, from these facts, to guess the infectious routes by which HCV is transmitted? Blood transfusion, medical accident, sexual intercourse, drug abuse and tattooing are usually considered to be the infectious routes of HCV. In several countries, however, there are many people in whom the route of infection is not clear. This is particularly the case for countries in which the prevalence of HCV infection is known to be high. In Japan for instance, it is clear that age is an important determinant of prevalence.' Thus, the antiHCV positive rate of people aged over 50 years is more than 10 times that of those aged under 20 years. It has been suggested that the main reason for the higher
prevalence in older people is dissemination caused by past medical treatment. Conversely, it has been proposed that the lower positivity of anti-HCV in younger people is accounted for by the introduction of disposable syringes and needles during the past 30 years.' A significant problem in elucidating the epidemiology of hepatitis C is that early tests for HCV antibodies lacked sensitivity and specificity. T h e original enzyme-linked immunosorbance assay (ELISA- 1) was developed using ClOO (a non-structural epitope of HCV) as the target antigen. It has been replaced by a second generation antibody test (ELISA-2) in which various epitopes from the HCV core and non-structural regions are combined. A problem arises from reports which mix the results of assays performed by the past (ELISA-1) and present (ELISA-2) kits. In epidemiological studies of normal populations the anti-HCV positive rate can be almost 30%higher if the second generation test kit is used than if the first generation test kit is used. For exam le, in blood donor screening or mass population studies.?' Moreover, the result of HCV antibody tests by the ELISA-1 method has a higher false-positive rate than the passive haemoagglutination (PHA), radio-immunoassay method, and recombinant immunoblot assays (RIBA). This makes the evaluation of epidemiological studies difficult. Epidemiological studies using PHA, RIA or RIBA assays have low rates of false-positive results and are a significant improvement over the EIA methods.',' T h e significance of various antibodies in anti-HCV positive individuals needs to be clarified. Judging from the clinical course, antibodies to both core and nonstructural (NS) regions are positive during the active period of hepatitis C. Non-structural region antibodies, especially those against NS3 and NS4 region sensitively reflect the replication of HCV. On the other hand, the presence of antibodies against the core region with no antibodies against the NS region is a frequent finding among cases who have normal liver function tests who are detected from mass examination or blood donor screening tests. Such cases probably have inactive infection with HCV, an assertion supported by HCV-RNA testing which shows no evidence for HCV replication. T h e majority of the cases whose antibody is positive only for core region are found in those who are normal for liver function tests from mass examination and blood donor screening.
Correspondence: M. Yano, Director, Institute for Clinical Research, Nagasaki Chuo National Hospital, Kubara 2-1001 Omura City, Kubara 856, Japan. Accepted for publication 15 April 1992.
M. Yano
5 50
The biological significance of anti-HCV positive cases requires further investigation. For instance, does antibody positive only for the HCV core region reflect an immune response to past infection or does the possibility remain of future transition to more active forms of hepatitis C? The widespread use of HCV antibody screening with second generation tests together with longitudinal studies of marker-positive cases will allow the qualitative significance of these findings to be elucidated. An outstanding problem of clinical research in hepatitis C is to link precisely the stage of HCV infection with the natural course of the associated liver disease, such as development to chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. In post-transfusion hepatitis C, for example, many cases continue to experience the symptoms of severe acute hepatitis for several weeks, following which liver function gradually normalizes. Then, after 5-10 years, patients may exhibit severe clinical symptoms of chronic hepatitis. As for the effects of treatment with interferon in various stages of infection with HCV, such as acute hepatitis C, chronic hepatitis C, liver cirrhosis C, it is becoming apparent that the earlier the stage the better is the effect of treatment.'-'' This is particularly so for the cure rate. More than 60% of post-transfusional hepatitis C becomes prolonged with chronic liver disease the usual natural course. However, when treated early, about 80% of such cases may be cured with interferon.' The important problem in future is to understand the natural history of other types of hepatitis C so that effective treatment strategies can be designed. The present study and treatment of hepatitis C are based on HCV antibody tests. Detection of HCV-RNA by PCR methods is now becoming widely used as a method to test for the presence of HCV. An outstanding question is whether HCV-RNA estimation truly detects replicative HCV. The novel method of testing by a DNA probe (which does not require amplification of HCV-RNA) is currently being developed. If this method of antigen detection has practical application, the results will further progress the study of HCV. Development of the study of hepatitis C has relied on remarkable developments in the application of molecular biology. However, discovery and analysis of the HCV particle itself may be required to
more fully elucidate the state of infection and its relationship to liver disease caused by hepatitis C.
REFERENCES 1. YANOM., YATSUHASHI H., INOUE 0. & KOGAM. Epidemiol-
2. 3.
4.
5.
ogy of hepatitis C virus in Japan. Role in chronic liver disease and hepatocellular carcinoma. J. Gastroenterol. Hepatol. 1991; 6: 31-4. KUHNL P., SEIDLS., STANGEL W. ef al. Antibody to hepatitis C virus in German blood donors. Lancet 1989; 334 324. AWADA. S., AHMED M. A., ABDULMOHSIN A. R. et al. Hepatitis C virus infection in Egyptian volunteer blood donors in Riyadh. Lancet 1991; 338: 459-60. CHANG. C. B., LIN W. & YEOHE. K. Prevalence of hepatitis C infection in Hong Kong. J. Gastroenterol. Hepatol. 1992; 7 : 117-20. BRUXJ., BARRERA J. M., CALVET X. et al. Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet
1989; 334 1004-6. 6. KEWM. C., HOUGHTON M., CHOOQ. L. & Kuo G. Hepatitis
C virus antibodies in southern African blacks with hepatocellular carcinoma. Lancet 1990; 335: 873-4. 7. FOLLETTE. A., Dow B. C., MCOMISHF. et al. HCV confirmatory testing of blood donors. Lancet 1991;
338: 1024. M., FOUNG S. K. H. et al. Antibodies 8. Hsu H. H., GONZALEZ to hepatitis C virus in low-risk blood donors: Implications for counseling positive donors. Gastroenterology 199 1; 101: 1724-7. 9. OMATA M., YOKOSUKA O., TAKANO S. et al. Resolution of
acute hepatitis C after therapy with natural beta interferon. Lancet 1991; 338:914-15. 10. LIN R., SCHOEMAN M. N., CRAIGP. I. et al. Can the response to interferon treatment be predicted in patients with chronic active hepatitis C? Aust. N.Z. J. Med. 1991; 21: 387-92. P., BOYER N., GIOSTRA E. et al. Recombinant 11. MARCELLIN
human a-interferon in patients with chronic non-A, non-B hepatitis: multicenter randomized controlled trial from France. Hepatology 1991; 13: 393-7.
EDITORIAL COMMENT
Advances in hepatitis C: Sero-epidemiology and natural history MICHITAMI YANO
WHO Collaborating Centre for Viral Hepatitis and Institute for Clinical Research, Nagasaki Chuo National Hospital, Ku bara, Nagasaki, Japan
T h e study of the hepatitis C virus (HCV) has greatly advanced the understanding of liver diseases. There are several reasons for this. First, persistent HCV infection, even with minor necro-inflammatory change in the liver may ultimately progress to liver cirrhosis which is closely connected with the development of hepatocellular carcinoma. There are few cases of chronic HCV infection which show spontaneous improvement during the clinical course; a major difference from the natural history of hepatitis B virus (HBV) infection in which the outcome is transformed by seroconversion of hepatitis Be antigen (HBeAg).' Second, the course of HCV can be changed by treatment with interferon which occasionally leads to cure of the infection. Next, the development of detection and assay systems for HCV antigens and antibodies are dramatic models of the development and application of molecular biology to clinical practice. The application of diagnostic tests for HCV infection during the past 2 years, has provided an increasingly clear picture of the epidemiology, diagnosis and pathogenesis of HCV. Several epidemiological reports about the geographic incidence of HCV infection indicate positive rates of HCV antibody from 0.2 to 1.9% of the total In relation to the association of HCV with hepatocellular carcinoma, which is the final stage of liver disease, positive rates are from 16 to 7 2 9 ' 0 . ~Moreover, ~~ the epidemiology of HCV infection is quite different from that of HBV infection which is also a blood-borne infectious disease. In particular, the proportion of people infected with HCV is low in several high-risk places of HBV infection, including China, Africa and several other countries. Is it possible, from these facts, to guess the infectious routes by which HCV is transmitted? Blood transfusion, medical accident, sexual intercourse, drug abuse and tattooing are usually considered to be the infectious routes of HCV. In several countries, however, there are many people in whom the route of infection is not clear. This is particularly the case for countries in which the prevalence of HCV infection is known to be high. In Japan for instance, it is clear that age is an important determinant of prevalence.' Thus, the antiHCV positive rate of people aged over 50 years is more than 10 times that of those aged under 20 years. It has been suggested that the main reason for the higher
prevalence in older people is dissemination caused by past medical treatment. Conversely, it has been proposed that the lower positivity of anti-HCV in younger people is accounted for by the introduction of disposable syringes and needles during the past 30 years.' A significant problem in elucidating the epidemiology of hepatitis C is that early tests for HCV antibodies lacked sensitivity and specificity. T h e original enzyme-linked immunosorbance assay (ELISA- 1) was developed using ClOO (a non-structural epitope of HCV) as the target antigen. It has been replaced by a second generation antibody test (ELISA-2) in which various epitopes from the HCV core and non-structural regions are combined. A problem arises from reports which mix the results of assays performed by the past (ELISA-1) and present (ELISA-2) kits. In epidemiological studies of normal populations the anti-HCV positive rate can be almost 30%higher if the second generation test kit is used than if the first generation test kit is used. For exam le, in blood donor screening or mass population studies.?' Moreover, the result of HCV antibody tests by the ELISA-1 method has a higher false-positive rate than the passive haemoagglutination (PHA), radio-immunoassay method, and recombinant immunoblot assays (RIBA). This makes the evaluation of epidemiological studies difficult. Epidemiological studies using PHA, RIA or RIBA assays have low rates of false-positive results and are a significant improvement over the EIA methods.',' T h e significance of various antibodies in anti-HCV positive individuals needs to be clarified. Judging from the clinical course, antibodies to both core and nonstructural (NS) regions are positive during the active period of hepatitis C. Non-structural region antibodies, especially those against NS3 and NS4 region sensitively reflect the replication of HCV. On the other hand, the presence of antibodies against the core region with no antibodies against the NS region is a frequent finding among cases who have normal liver function tests who are detected from mass examination or blood donor screening tests. Such cases probably have inactive infection with HCV, an assertion supported by HCV-RNA testing which shows no evidence for HCV replication. T h e majority of the cases whose antibody is positive only for core region are found in those who are normal for liver function tests from mass examination and blood donor screening.
Correspondence: M. Yano, Director, Institute for Clinical Research, Nagasaki Chuo National Hospital, Kubara 2-1001 Omura City, Kubara 856, Japan. Accepted for publication 15 April 1992.
M. Yano
5 50
The biological significance of anti-HCV positive cases requires further investigation. For instance, does antibody positive only for the HCV core region reflect an immune response to past infection or does the possibility remain of future transition to more active forms of hepatitis C? The widespread use of HCV antibody screening with second generation tests together with longitudinal studies of marker-positive cases will allow the qualitative significance of these findings to be elucidated. An outstanding problem of clinical research in hepatitis C is to link precisely the stage of HCV infection with the natural course of the associated liver disease, such as development to chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. In post-transfusion hepatitis C, for example, many cases continue to experience the symptoms of severe acute hepatitis for several weeks, following which liver function gradually normalizes. Then, after 5-10 years, patients may exhibit severe clinical symptoms of chronic hepatitis. As for the effects of treatment with interferon in various stages of infection with HCV, such as acute hepatitis C, chronic hepatitis C, liver cirrhosis C, it is becoming apparent that the earlier the stage the better is the effect of treatment.'-'' This is particularly so for the cure rate. More than 60% of post-transfusional hepatitis C becomes prolonged with chronic liver disease the usual natural course. However, when treated early, about 80% of such cases may be cured with interferon.' The important problem in future is to understand the natural history of other types of hepatitis C so that effective treatment strategies can be designed. The present study and treatment of hepatitis C are based on HCV antibody tests. Detection of HCV-RNA by PCR methods is now becoming widely used as a method to test for the presence of HCV. An outstanding question is whether HCV-RNA estimation truly detects replicative HCV. The novel method of testing by a DNA probe (which does not require amplification of HCV-RNA) is currently being developed. If this method of antigen detection has practical application, the results will further progress the study of HCV. Development of the study of hepatitis C has relied on remarkable developments in the application of molecular biology. However, discovery and analysis of the HCV particle itself may be required to
more fully elucidate the state of infection and its relationship to liver disease caused by hepatitis C.
REFERENCES 1. YANOM., YATSUHASHI H., INOUE 0. & KOGAM. Epidemiol-
2. 3.
4.
5.
ogy of hepatitis C virus in Japan. Role in chronic liver disease and hepatocellular carcinoma. J. Gastroenterol. Hepatol. 1991; 6: 31-4. KUHNL P., SEIDLS., STANGEL W. ef al. Antibody to hepatitis C virus in German blood donors. Lancet 1989; 334 324. AWADA. S., AHMED M. A., ABDULMOHSIN A. R. et al. Hepatitis C virus infection in Egyptian volunteer blood donors in Riyadh. Lancet 1991; 338: 459-60. CHANG. C. B., LIN W. & YEOHE. K. Prevalence of hepatitis C infection in Hong Kong. J. Gastroenterol. Hepatol. 1992; 7 : 117-20. BRUXJ., BARRERA J. M., CALVET X. et al. Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet
1989; 334 1004-6. 6. KEWM. C., HOUGHTON M., CHOOQ. L. & Kuo G. Hepatitis
C virus antibodies in southern African blacks with hepatocellular carcinoma. Lancet 1990; 335: 873-4. 7. FOLLETTE. A., Dow B. C., MCOMISHF. et al. HCV confirmatory testing of blood donors. Lancet 1991;
338: 1024. M., FOUNG S. K. H. et al. Antibodies 8. Hsu H. H., GONZALEZ to hepatitis C virus in low-risk blood donors: Implications for counseling positive donors. Gastroenterology 199 1; 101: 1724-7. 9. OMATA M., YOKOSUKA O., TAKANO S. et al. Resolution of
acute hepatitis C after therapy with natural beta interferon. Lancet 1991; 338:914-15. 10. LIN R., SCHOEMAN M. N., CRAIGP. I. et al. Can the response to interferon treatment be predicted in patients with chronic active hepatitis C? Aust. N.Z. J. Med. 1991; 21: 387-92. P., BOYER N., GIOSTRA E. et al. Recombinant 11. MARCELLIN
human a-interferon in patients with chronic non-A, non-B hepatitis: multicenter randomized controlled trial from France. Hepatology 1991; 13: 393-7.
