JourdofHepuro~ogy, 1991; 13(Suppl. 4): S116-X18 @ 1991 Elsevier Science Publishers B.V. All rightsreserved.0168.8278191/$03.50
Slid HEPAT 01075
Hepatitis
ta virus (
) infe&ons
Epidetiologkaland clinical heterogeneity Mario Rizzetto and Marilena Institute of internal Medicine, University of Torino, T&no,
IhzIy
Heterogeneity is a feature of all aspects of HDV infection and biology. Epidemiological studies indicate wide variations
in the global distribution of the virus, often with different and bizarre rates of prevalence within apparently homogeneous populations. The medical expression of the infection is likewise manifold, ranging from the asymptomatic carrier of HDV to terminal cirrhosis. The clinical variability is matched at the biological level by extensive molecular heterogeneities, as expected with a small RNA virus such as the HDV.
Egide
c heterogeneities
Although the epidemiology of HDV resembles the epidemiology of the HBV, modes of transmission differ in the relative efficiency by which they can transmit the two viruses and the geographical prevalence of HDV overlaps but does not coincide with that of HBV. The elusive and often delayed response to acute hepatitis D (which requires serial blood samples to be tested over 2 to 6 months after the onset of acute hepatitis in order to establish HDV coinfection (1)) and sampling errors caused by screening of healthy blood donors instead of carriers with liver disease (HDV is most often pathogenic and infected patients are more likely to be sick than healthy (2)) explain, in part, the epidemiological discrepancies reported in the literature. Comparison of the prevalence of HDV infection in HBsAg carriers with chronic liver disease indicates, nevertheless, genuine world-wide differences, according to which three epidemiologic patterns of HDV can be defined (3): (i) of high endemicity (accompanied by high HBV endemicity); (ii) of intermediate endemicity (accompanied by intermediate or high HBV endemicity); (iii) of low endemicity (accompanied by low, intermediate or high HBV endemicity). In areas of tropical Africa and of the Amazon Basin the ratio of HDV infection in HBV-infected individuals is very high, often exceeding 60% (4), while it is low in South East of
Asia (5) and among Alaskan Eskimos (6), where HBV
infections are nevertheless hyperendemic. Remarkable differences also occur in areas with similar intermediate HBV rates, such as the Mediterranean Basin and Japan; infection is noted in 20% to 30% of chronic HBsAgpositive hepatitis in Greece (7) and Italy (8) but in less than 3% of Japanese carriers of the HBsAg with similar clinical characteristics (9). In high endemicity areas, hepatitis D is usually caused by HDV superinfection within the context of high HBV endemicity (10). HDV infection occurs as a secondary event in children and adolescents infected by HBV in infancy. In low endemicity areas HDV infection is confmed predominantly to groups at risk for parenteral exposure to the HBV, such as the drug users and the haemophiliacs (11). In drug-abusing communities HDV is acquired predominantly by coinfection, with most persons contracting the virus from other patients with coinfection rather than from chronic carriers of HBV and HDV. Thus, spreading occurs from acute case to acute case through the continuous recruitment of new drug users rather than from a few isolated primary cases serving as the reservoir of the virus. In areas where the prevalence of HDV is low, but the prevalence of HBV is high, such as the Far East, the
Correspond~ce:M. RiuettO, Instituteof InternalMedicine, University of Torino, CO~SOBramante, 88, Torino, Italy.
infection occurs sporadically in chronic forms acquired by superinfection (12), but it might expect from modern patt tions and the facilita of a large number 0 susceptible carriers o
infection is composite, resulting from ern in the general population and an e demic pattern withi ell-defined categories of persons at risk of contractin V, among which the intravenous drug addicts account for the largest risk group in urban areas. Interestingly sexual transmission does occur but DV infection rates h sexuals at high risk of ual activity (13). In the general ~opulatiQR the endemicity of maintained by transmission of the virus thro infection from carrier to carrier 0f spreading from acute case to acute case; secondary sporadic extension of the virus from the carriers reservoir to the normal population is relatively rare.
The association between liver disease and HDV shown in clinical studies conducted in the last decade led to the conclusion that HDV is highly pathogenic and invariably creates or aggravates disease in infected persons. This conclusion, however, has been challenged by the observation that in Rhodes, Greece many HBV carriers with anti-HD had no biochemical or histologic sign of liver damage (14). Important differences in disease expression were also noted between Nauru, Melanesia and AmeriBV is endemic; amican Samoa, Polynesia, where notransferases were elevated in as many as 30% of Nauruans but were abnormal only in 7% of Samoans exposed to HDV (15); among Samoans the rate of liver disease was similar in HDV-infected and non-infected carriers of #B&g, but among Nauruans enzyme abnormalities were 3-times more frequent in HDV-infected than in the non-infected. The lack of liver damage in a consistent number of carriers with serologic evidence of HDV infection in different parts of the world raises the possibility that the natural history of HDV infection may differ from its medical history, the former remaining largely unexplored because attention has been drawn only to the clinical tip of the HDV iceberg. This hypothesis is supported by the recognition that low grade replication of HDV has continued without significant liver damage in 54% of the
The medical expression of minor forms of chronic pers’ is and hepatocellular carcinoma; the consists of a wide range of symptoms, none of which is sufficiently specific to provide a diagnosis. areas disease occurs often in si;;g outbreaks of severe and fu causing chronic liver epatitis in the tropics ttern, consisting of bling viral hepatitis with the addition of which there is microvesicular fatty infll ntigen can be localize e course of hepatitis addicts, as in these communities V infection is often associated with severe and fuIm t hepatitis (20-22) _ The pathological findings differ from those of f~~rni~a~t hepatitis D in the Tropics, usually lacking the distinct microvesicular steatosis; this aspect has been observed only occassionally in fulminant hepatitis D in developed countries (23). In intermediate endemicity areas the course of disease is more often chronic study of 176 Italian patients with chronic (24) has shown a bimodal progression of tbe disease with disease running a rapidly progressive course to liver failure within l-2 years in about 15% of cases and evolving slowly over one to two decades in about 70% of cases; remissions were noted in 15% of cases.
The factors influencing the various clinical expressions of HDV are not understood. Apparently asymptomatic cases or !ow-grade disease predominantes in communities where the circulation of HDV is relatively slow, whereas severe disease predominates in populations where the circulation of the virus is rapid. Although a consistent proportion of drug addicts at’e also positive at the test HCV infection does not predominate i with severe HDV hepatitis; therefore represent an adventitious cause that increases morbidity and mortality of hepatitis D. In addicts, illness severity may correlate with the larger size of infectious inocula that are transmitted parenterally or to an increase i?
5118 of HDV through adaptation during multiple transfers, in analogy with the increasing pathogenic effect exerted by the virus during serial passaging in chimpanzees (251, The consistent geographical differences noted in the expression of HDV disease might result from genetic differences in the infecting HDV strain. Like all RNA viruses HDV exhibits large genetic heterogeneities and extensive sequence variations have been noted among various published isolates of HDV-RNA (26-28). Although the genetic diversities might encode for a wide range of phenotypes, the functions of HDV virulence
References 1 Aragona M. Macagno S. Caredda F, et al. Serological response to the hepatitis delta virus in hepatitis D. Lancet 1987: i: 47880. 2 Riuetto M. The Delta agent. Hepatology 1983; 3: 7X2-37. 3 Riwetto M, Hadziyannis S, Hansson BG. Toukan A, Just I. Hepatitis Delta Virus Infection in the developed world: epidemiologic and clinical expression. Gastroenterol Int 1991; in press. 4 Bensabath G, Hadler SC, Soares P, et al. Hepatitis Delta Virus Infection and Labrea hepatitis. Prevalence and role in fulminant hepatitis in the Amazon Basin. JAMA 1987; 2.58: 479-83. 5 Rizzetto M, Ponzetto A, Forzani I. Epidemiology of hepatitis delta virus. In: Gerin JL, Purcell RH, Rizzetto M, eds. The Hepatitis Delta Virus. New York: Wiley-Liss, 1991: l-20. 6 Ratman S, Head CB, Butler RW. Lack of evidence of hepatitis D (delta) infection in Newfoundland and Labrador. Can Med Assoc J 1986; 134: 905-7. 7 Papaevangelou G. Benign and fulminant HDV hepatitis in Greece. Prog Clin Biol Res 1987; 234: 395-402. 8 Smedile A. Lavarini C. Farci P, et al. Epidemiologic patterns of infection with the hepatitis B virus-associated delta agent in Italy. Am J Epidemiol 1983: 117: 223-9. 9 Tamura I, Ichimura H, Itoh Y, Kurimura 0. Kurimura T. Prevalence of antibody to delta antigen among HBV carriers in Japan. J Med Viral 1987; 22: 217-21. 10 Hadler SC, De Monzon M, Ponzetto A, et al. An epidemic of severe hepatitis due to delta virus infection in Yupca Indians of Venezuela. Ann Int Med 1984; 100: 339-49. 11 Raimondo G, Smedile A, Gallo L, Balbo A, Ponzetto A, Rizzetto M. Multicentre study of HDV-associated delta infection and liver disease in drug addicts. Lancet 1982; i: 245-X. 12 Omata M, Ito Y, Imazeki F, et al. Infection with delta agent in Japan. Hepato-Gastroenterology 1985; 32: 220-3. 13 Hess G, Bienzle U. Slusarczyk J. Hepatitis B virus and delta infection in male homosexuals. Liver 1986; 6: 13-6. 14 HadziyannisSJ, Papaioannou C, Alexopulou A. The role of hepatitis delta virus in acute hepatitis and in chronic liver disease in Greece. In: Gerin JL, Purcell RH, Rizzetto M. eds. The Hepatitis DeIta Virus. New York: Wiley-Liss, 1991; 51-62. 15 Hadler S, de Monzon MA, Bensabath G, et al. Epidemiology of hepatitis delta virus infection in less developed countries. In: Gerin JL, Purcell RH, Rizzetto M. eds. The Hepatitis Delta virus. New York: Wiley-Liss, 1991; 21-31. 16 Negro E Bergmann KF, Baroudy BM, et al. Chronic hepatitis D virus (HDV) infection in hepatitis B virus carrier chimpanzees experimentally superinfected with HDV. J Infect Dis 1988; 158: 151-9. 17 Gttobrelli A, Manano A, Smedile A, et al. Patterns of hepatitis delta virus reinfection and disease in liver transplantation. Gas-
M. RIZZETTO
AND M. DURAZZO
genes and the significance of inter- and intra-species
variations are not understood. Strain differences in the helper HBV might also be relevant, as rates of HDV synthesis are greater in patients with active HBV infections and HBeAg in serum compared to the synthesis of HDV in carriers with antiHBe (29). The recent recognition of geographical variations in mutants of HBV which lack the ability of express the HBeAg (30-32) raises the question of whether these mutants may support HDV less efficiently than the wild-type virus, thus explaining, at least in part, the bizzarre epidemiology of
troenterology 1991; in press. 18 Saracco G. Macagno S. Rosina F, Rizzetto M. Serologic Markers with fulminant hepatitis in persons positive for hepatitis B surface antigen. A worldwide epidemiologic and clinical survey. Ann Intern Med 1988; 106: 380. 19 Fonseca JCE Gayotto LCC, Ferreira LCL, et al. Labrea hepatitis-hepatitis B and delta antigen expression in liver tissue: report of three autopsy cases. Revista do Institute de Medicina tropical de Sao Paul0 1985; 27: 224-7. 20 Ponzetto A, Seeff LB, Buskell-Bales Z. et al. Hepatitis B markers in United States drug addicts with special emphasis on the delta hepatitis virus. Hepatology 1984; 4: 1111-5. 21 Shattock AG, Kelly MG, Fielding J, Arthurs Y. Epidemic hep atitis B with delta antigenemia among Dublin drug-abusers. Irish J Med Sci 1982: 151: 334-S. 22 Lee SD, Wang JY, Wu JC, Chiang YT, Tsai YT. Lo KJ. Hepatitis B and D virus infection among drug abusers in Taiwan. J Med Viral 1986; 20: 247-52. 23 Lefkowitch JH. Goldstein H. Yatto R, Gerber M. Cytopathic liver injury in acute delta virus hepatitis. Gastroenterology 1987; 92: 1262-6. 24 Bonino F. Negro F, Baldi M, et al. The natural history of chronic delta hepatitis. Prog Clin Biol Res 1987; 234: 145-52. 25 Ponzetto A. Negro F, Popper H, et al. Serial passage of hepatitis Delta in chronic hepatitis B virus carrier chimpanzees. Hepatology 1988; 8: 1655-61. 26 Wang KS, Choo QL, Weiner AJ, et al. Structures, sequence and expression of the hepatic delta viral genome. Nature 1986; 323: 508-14. 27 Makino S, Chang MF, Shieh CK, et al. Molecular Cloning and sequencing of a human hepatitis delta virus RNA. Nature 1987; 329: 343-6. 28 Kuo MYP, Goldberg J, Coates L, Mason W, Gerin JL, Taylor J. Molecular cloniug of hepatitis delta virus RNA from an infected woodchuck liver: sequence, structure, and applications. J Virol 1988; 62: 1855-61. 29 Negro F, Baldi M, Bonino F, et al. Chronic HDV (hepatitis delta virus) hepatitis: intrahepatic expression of delta antigen, histologic activity and outcome of liver disease. J Hepatol 1988; 6: 8-14. 30 Brunetto MR, Stemler M. Schodel F, et al. Identification of HBV variants which cannot produce precore derived HBeAg and may be responsible for severe hepatitis. Ital J Gastroenterol 1989; 21: 151-4. 31 Carman WF, Jacyna MR, Hadziyannis S, et al. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet 1989; ii: 588-90. 32 Bnmetto MR, Stemler M, Bonino F, et al. A new hepatitis B virus strain in patients with severe antiHbe positive chronic hepatitis B. J Hepatol 1990; 10: 258-61.
Slid HEPAT 01075
Hepatitis
ta virus (
) infe&ons
Epidetiologkaland clinical heterogeneity Mario Rizzetto and Marilena Institute of internal Medicine, University of Torino, T&no,
IhzIy
Heterogeneity is a feature of all aspects of HDV infection and biology. Epidemiological studies indicate wide variations
in the global distribution of the virus, often with different and bizarre rates of prevalence within apparently homogeneous populations. The medical expression of the infection is likewise manifold, ranging from the asymptomatic carrier of HDV to terminal cirrhosis. The clinical variability is matched at the biological level by extensive molecular heterogeneities, as expected with a small RNA virus such as the HDV.
Egide
c heterogeneities
Although the epidemiology of HDV resembles the epidemiology of the HBV, modes of transmission differ in the relative efficiency by which they can transmit the two viruses and the geographical prevalence of HDV overlaps but does not coincide with that of HBV. The elusive and often delayed response to acute hepatitis D (which requires serial blood samples to be tested over 2 to 6 months after the onset of acute hepatitis in order to establish HDV coinfection (1)) and sampling errors caused by screening of healthy blood donors instead of carriers with liver disease (HDV is most often pathogenic and infected patients are more likely to be sick than healthy (2)) explain, in part, the epidemiological discrepancies reported in the literature. Comparison of the prevalence of HDV infection in HBsAg carriers with chronic liver disease indicates, nevertheless, genuine world-wide differences, according to which three epidemiologic patterns of HDV can be defined (3): (i) of high endemicity (accompanied by high HBV endemicity); (ii) of intermediate endemicity (accompanied by intermediate or high HBV endemicity); (iii) of low endemicity (accompanied by low, intermediate or high HBV endemicity). In areas of tropical Africa and of the Amazon Basin the ratio of HDV infection in HBV-infected individuals is very high, often exceeding 60% (4), while it is low in South East of
Asia (5) and among Alaskan Eskimos (6), where HBV
infections are nevertheless hyperendemic. Remarkable differences also occur in areas with similar intermediate HBV rates, such as the Mediterranean Basin and Japan; infection is noted in 20% to 30% of chronic HBsAgpositive hepatitis in Greece (7) and Italy (8) but in less than 3% of Japanese carriers of the HBsAg with similar clinical characteristics (9). In high endemicity areas, hepatitis D is usually caused by HDV superinfection within the context of high HBV endemicity (10). HDV infection occurs as a secondary event in children and adolescents infected by HBV in infancy. In low endemicity areas HDV infection is confmed predominantly to groups at risk for parenteral exposure to the HBV, such as the drug users and the haemophiliacs (11). In drug-abusing communities HDV is acquired predominantly by coinfection, with most persons contracting the virus from other patients with coinfection rather than from chronic carriers of HBV and HDV. Thus, spreading occurs from acute case to acute case through the continuous recruitment of new drug users rather than from a few isolated primary cases serving as the reservoir of the virus. In areas where the prevalence of HDV is low, but the prevalence of HBV is high, such as the Far East, the
Correspond~ce:M. RiuettO, Instituteof InternalMedicine, University of Torino, CO~SOBramante, 88, Torino, Italy.
infection occurs sporadically in chronic forms acquired by superinfection (12), but it might expect from modern patt tions and the facilita of a large number 0 susceptible carriers o
infection is composite, resulting from ern in the general population and an e demic pattern withi ell-defined categories of persons at risk of contractin V, among which the intravenous drug addicts account for the largest risk group in urban areas. Interestingly sexual transmission does occur but DV infection rates h sexuals at high risk of ual activity (13). In the general ~opulatiQR the endemicity of maintained by transmission of the virus thro infection from carrier to carrier 0f spreading from acute case to acute case; secondary sporadic extension of the virus from the carriers reservoir to the normal population is relatively rare.
The association between liver disease and HDV shown in clinical studies conducted in the last decade led to the conclusion that HDV is highly pathogenic and invariably creates or aggravates disease in infected persons. This conclusion, however, has been challenged by the observation that in Rhodes, Greece many HBV carriers with anti-HD had no biochemical or histologic sign of liver damage (14). Important differences in disease expression were also noted between Nauru, Melanesia and AmeriBV is endemic; amican Samoa, Polynesia, where notransferases were elevated in as many as 30% of Nauruans but were abnormal only in 7% of Samoans exposed to HDV (15); among Samoans the rate of liver disease was similar in HDV-infected and non-infected carriers of #B&g, but among Nauruans enzyme abnormalities were 3-times more frequent in HDV-infected than in the non-infected. The lack of liver damage in a consistent number of carriers with serologic evidence of HDV infection in different parts of the world raises the possibility that the natural history of HDV infection may differ from its medical history, the former remaining largely unexplored because attention has been drawn only to the clinical tip of the HDV iceberg. This hypothesis is supported by the recognition that low grade replication of HDV has continued without significant liver damage in 54% of the
The medical expression of minor forms of chronic pers’ is and hepatocellular carcinoma; the consists of a wide range of symptoms, none of which is sufficiently specific to provide a diagnosis. areas disease occurs often in si;;g outbreaks of severe and fu causing chronic liver epatitis in the tropics ttern, consisting of bling viral hepatitis with the addition of which there is microvesicular fatty infll ntigen can be localize e course of hepatitis addicts, as in these communities V infection is often associated with severe and fuIm t hepatitis (20-22) _ The pathological findings differ from those of f~~rni~a~t hepatitis D in the Tropics, usually lacking the distinct microvesicular steatosis; this aspect has been observed only occassionally in fulminant hepatitis D in developed countries (23). In intermediate endemicity areas the course of disease is more often chronic study of 176 Italian patients with chronic (24) has shown a bimodal progression of tbe disease with disease running a rapidly progressive course to liver failure within l-2 years in about 15% of cases and evolving slowly over one to two decades in about 70% of cases; remissions were noted in 15% of cases.
The factors influencing the various clinical expressions of HDV are not understood. Apparently asymptomatic cases or !ow-grade disease predominantes in communities where the circulation of HDV is relatively slow, whereas severe disease predominates in populations where the circulation of the virus is rapid. Although a consistent proportion of drug addicts at’e also positive at the test HCV infection does not predominate i with severe HDV hepatitis; therefore represent an adventitious cause that increases morbidity and mortality of hepatitis D. In addicts, illness severity may correlate with the larger size of infectious inocula that are transmitted parenterally or to an increase i?
5118 of HDV through adaptation during multiple transfers, in analogy with the increasing pathogenic effect exerted by the virus during serial passaging in chimpanzees (251, The consistent geographical differences noted in the expression of HDV disease might result from genetic differences in the infecting HDV strain. Like all RNA viruses HDV exhibits large genetic heterogeneities and extensive sequence variations have been noted among various published isolates of HDV-RNA (26-28). Although the genetic diversities might encode for a wide range of phenotypes, the functions of HDV virulence
References 1 Aragona M. Macagno S. Caredda F, et al. Serological response to the hepatitis delta virus in hepatitis D. Lancet 1987: i: 47880. 2 Riuetto M. The Delta agent. Hepatology 1983; 3: 7X2-37. 3 Riwetto M, Hadziyannis S, Hansson BG. Toukan A, Just I. Hepatitis Delta Virus Infection in the developed world: epidemiologic and clinical expression. Gastroenterol Int 1991; in press. 4 Bensabath G, Hadler SC, Soares P, et al. Hepatitis Delta Virus Infection and Labrea hepatitis. Prevalence and role in fulminant hepatitis in the Amazon Basin. JAMA 1987; 2.58: 479-83. 5 Rizzetto M, Ponzetto A, Forzani I. Epidemiology of hepatitis delta virus. In: Gerin JL, Purcell RH, Rizzetto M, eds. The Hepatitis Delta Virus. New York: Wiley-Liss, 1991: l-20. 6 Ratman S, Head CB, Butler RW. Lack of evidence of hepatitis D (delta) infection in Newfoundland and Labrador. Can Med Assoc J 1986; 134: 905-7. 7 Papaevangelou G. Benign and fulminant HDV hepatitis in Greece. Prog Clin Biol Res 1987; 234: 395-402. 8 Smedile A. Lavarini C. Farci P, et al. Epidemiologic patterns of infection with the hepatitis B virus-associated delta agent in Italy. Am J Epidemiol 1983: 117: 223-9. 9 Tamura I, Ichimura H, Itoh Y, Kurimura 0. Kurimura T. Prevalence of antibody to delta antigen among HBV carriers in Japan. J Med Viral 1987; 22: 217-21. 10 Hadler SC, De Monzon M, Ponzetto A, et al. An epidemic of severe hepatitis due to delta virus infection in Yupca Indians of Venezuela. Ann Int Med 1984; 100: 339-49. 11 Raimondo G, Smedile A, Gallo L, Balbo A, Ponzetto A, Rizzetto M. Multicentre study of HDV-associated delta infection and liver disease in drug addicts. Lancet 1982; i: 245-X. 12 Omata M, Ito Y, Imazeki F, et al. Infection with delta agent in Japan. Hepato-Gastroenterology 1985; 32: 220-3. 13 Hess G, Bienzle U. Slusarczyk J. Hepatitis B virus and delta infection in male homosexuals. Liver 1986; 6: 13-6. 14 HadziyannisSJ, Papaioannou C, Alexopulou A. The role of hepatitis delta virus in acute hepatitis and in chronic liver disease in Greece. In: Gerin JL, Purcell RH, Rizzetto M. eds. The Hepatitis DeIta Virus. New York: Wiley-Liss, 1991; 51-62. 15 Hadler S, de Monzon MA, Bensabath G, et al. Epidemiology of hepatitis delta virus infection in less developed countries. In: Gerin JL, Purcell RH, Rizzetto M. eds. The Hepatitis Delta virus. New York: Wiley-Liss, 1991; 21-31. 16 Negro E Bergmann KF, Baroudy BM, et al. Chronic hepatitis D virus (HDV) infection in hepatitis B virus carrier chimpanzees experimentally superinfected with HDV. J Infect Dis 1988; 158: 151-9. 17 Gttobrelli A, Manano A, Smedile A, et al. Patterns of hepatitis delta virus reinfection and disease in liver transplantation. Gas-
M. RIZZETTO
AND M. DURAZZO
genes and the significance of inter- and intra-species
variations are not understood. Strain differences in the helper HBV might also be relevant, as rates of HDV synthesis are greater in patients with active HBV infections and HBeAg in serum compared to the synthesis of HDV in carriers with antiHBe (29). The recent recognition of geographical variations in mutants of HBV which lack the ability of express the HBeAg (30-32) raises the question of whether these mutants may support HDV less efficiently than the wild-type virus, thus explaining, at least in part, the bizzarre epidemiology of
troenterology 1991; in press. 18 Saracco G. Macagno S. Rosina F, Rizzetto M. Serologic Markers with fulminant hepatitis in persons positive for hepatitis B surface antigen. A worldwide epidemiologic and clinical survey. Ann Intern Med 1988; 106: 380. 19 Fonseca JCE Gayotto LCC, Ferreira LCL, et al. Labrea hepatitis-hepatitis B and delta antigen expression in liver tissue: report of three autopsy cases. Revista do Institute de Medicina tropical de Sao Paul0 1985; 27: 224-7. 20 Ponzetto A, Seeff LB, Buskell-Bales Z. et al. Hepatitis B markers in United States drug addicts with special emphasis on the delta hepatitis virus. Hepatology 1984; 4: 1111-5. 21 Shattock AG, Kelly MG, Fielding J, Arthurs Y. Epidemic hep atitis B with delta antigenemia among Dublin drug-abusers. Irish J Med Sci 1982: 151: 334-S. 22 Lee SD, Wang JY, Wu JC, Chiang YT, Tsai YT. Lo KJ. Hepatitis B and D virus infection among drug abusers in Taiwan. J Med Viral 1986; 20: 247-52. 23 Lefkowitch JH. Goldstein H. Yatto R, Gerber M. Cytopathic liver injury in acute delta virus hepatitis. Gastroenterology 1987; 92: 1262-6. 24 Bonino F. Negro F, Baldi M, et al. The natural history of chronic delta hepatitis. Prog Clin Biol Res 1987; 234: 145-52. 25 Ponzetto A. Negro F, Popper H, et al. Serial passage of hepatitis Delta in chronic hepatitis B virus carrier chimpanzees. Hepatology 1988; 8: 1655-61. 26 Wang KS, Choo QL, Weiner AJ, et al. Structures, sequence and expression of the hepatic delta viral genome. Nature 1986; 323: 508-14. 27 Makino S, Chang MF, Shieh CK, et al. Molecular Cloning and sequencing of a human hepatitis delta virus RNA. Nature 1987; 329: 343-6. 28 Kuo MYP, Goldberg J, Coates L, Mason W, Gerin JL, Taylor J. Molecular cloniug of hepatitis delta virus RNA from an infected woodchuck liver: sequence, structure, and applications. J Virol 1988; 62: 1855-61. 29 Negro F, Baldi M, Bonino F, et al. Chronic HDV (hepatitis delta virus) hepatitis: intrahepatic expression of delta antigen, histologic activity and outcome of liver disease. J Hepatol 1988; 6: 8-14. 30 Brunetto MR, Stemler M. Schodel F, et al. Identification of HBV variants which cannot produce precore derived HBeAg and may be responsible for severe hepatitis. Ital J Gastroenterol 1989; 21: 151-4. 31 Carman WF, Jacyna MR, Hadziyannis S, et al. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet 1989; ii: 588-90. 32 Bnmetto MR, Stemler M, Bonino F, et al. A new hepatitis B virus strain in patients with severe antiHbe positive chronic hepatitis B. J Hepatol 1990; 10: 258-61.
![[Detection of hepatitis delta virus (HDV) markers in HBV carriers].](/assets/img/hold.png)
