Spontaneous hepatitis B surface antigen clearance in a long-term follow-up study of patients with chronic type B hepatitis. Lack of correlation with hepatitis C and D virus superinfection Authors
Liver, Pancreas, and Biliary Tract
Received: 14 August 1995 Accepted: 06 February 1996 DOI:
Cite this article as: Da Silva, L.C., De Assis Madruga, C.L., Carrilho, F.J. et al. J Gastroenterol (1996) 31: 696. doi:10.1007/BF02347619 Abstract
We investigated the frequency of HBsAg clearance and the possible role of viral superinfection in a long-term follow-up of 184 patients with chronic hepatitis B (CHB). Our subjects were 184 patients with chronic hepatitis B and the follow-up was 12–216 months (mean 66.2±53.7 months). The investigative methods used were: immunoenzymatic assays for HBV, HCV, HDV, and HIV markers; polymerase chain reaction (PCR) for HBV DNA; and liver biopsy and immunoperoxidase. During the follow-up, 20 of the 184 patients cleared serum HBsAg. A comparison of patients with persistent HBsAg (group I) and of those who cleared this marker (group II) showed a significant difference in mortality (
P=0.002) between the two groups and a tendency to a more severe exacerbation (flare) in group II ( P=0.07). Antibodies to hepatitis C and D virus as well as antibodies to HIV were equally distributed in both groups. Thirteen patients (7.9%) from group I, but none from group II, subsequently developed hepatocellular carcinoma. These results suggest that the frequency of spontaneous clearance of HBsAg during chronic HBV infection is low. No determinant factor for the clearance was found, including the presence of liver cirrhosis. Serum HBV DNA was undetectable by PCR after clearance in 16 out of 17 patients. Key words hepatitis B chronic hepatitis B spontaneous HBsAg clearance
Some of these findings were presented at the Biennial Scientific Meeting of the International Association for the Study of the Liver, held in Brighton, UK, in June 1992.
Hoofnagle JH, Seeff LB. Natural history of chronic type B hepatitis. In: Popper H, Schaffner F (eds) Progress in liver diseases, vol. 7. New York: Grune and Straton, 1982; 469–479.
Liaw Y-F, Sheen I-S, Chen T-J, et al. Incidence, determinants and significance of delayed clearance of serum HBsAg on chronic hepatitis B virus infection: A prospective study. Hepatology 1991;13:627–631.
Sampliner RE, Hamilton FA, Iseri OA, et al. The liver histology and frequency of clearance of the hepatitis B surface antigen (HBsAg) in chronic carriers. Am J Med Sci 1979; 277:17–22.
Wu TT, Hsu HC, Chen DS, et al. Clearance of hepatitis B surface antigen (HBsAg) after surgical resection of hepatocellular carcinoma. J Hepatol 1987;4:45–51.
Viola LA, Coleman JC, Fluker JL, et al. Natural history of liver disease in chronic hepatitis B surface antigen carriers. Survey of 100 patients from Great Britain. Lancet 1981; II:1156–1159.
Poralla T, Manns M, Hutteroth TH, et al. HBsAg clearance in patients with long-standing chronic active hepatitis B and hepatitis B virus-induced liver cirrhosis. Digestion 1986;33:53–60.
Liaw Y-F, Lin S-M, Sheen I-S, et al. Acute hepatitis C virus superinfection followed by spontaneous HBeAg seronconversion and HBsAg elimination. Infection 1991;19:250–251.
Sheen I-S, Liaw I-F, Chu C-M, et al. Role of hepatitis C virus infection in spontaneous hepatitis B surface antigen clearance during chronic hepatitis B virus infection. J Infect Dis 1992; 165:831–834.
Pinho JRR, Fonseca LEP, Miyamoto Y, et al. Comparison of serum hepatitis B virus replication markers in patients with chronic hepatitis B: Studies on HBeAg/anti-HBe system, viral DNA polymerase and HBV-DNA. Rev Inst Med Trop S Paulo 1989;31:328–325.
Kaneko S, Miller RH, Feinstone SM, et al. Detection of serum hepatitis B virus DNA in patients with chronic hepatitis using the polymerase chain reaction assay. Proc Natl Acad Sci USA 1989;86:312–316.
Kwok S, Higuchi R. Avoiding false positives with PCR. Nature 1989;239:237–238.
Lok ASF, Lai CL, Wu PC, et al. Spontaneous hepatitis B e antigen to antibody seroconversion and reversion in Chinese patients with chronic hepatitis B virus infection. Gastroenterology 1987; 92:1839–1843.
Stemberger LA, Hardy Jr PH, Cuculis JJ, et al. The unlabeled antibody enzyme method of immunohistochemistry. Preparation and properties of soluble antigen—antibody complex (PAP) and its use in identification of spirochetes. J Histochem Cytochem 1970;8:315–334.
Rosner B. Fundamentals of biostatistics. 2nd ed. Boston: PWS Publishers, 1982;288–293.
Alward WLM, McMahon BJ, Hall DB, et al. The long-term serological course of asymptomatic hepatitis B virus carriers and the development of primary hepatocellular carcinoma. J Infect Dis 1985;151:604–609.
Dooley JS, Davis GL, Peters M, et al. Pilot study of recombinant human alpha-interferon for chronic type B hepatitis. Gastroenterology 1986;90:150–157.
Realdi G, Alberti A, Rugge M, et al. Seroconversion from hepatitis B e antigen to anti-HBe in chronic hepatitis B virus infection. Gastroenterology 1980;79:195–199.
Bortolotti F, Cadrobbi F, Crivellaro C, et al. Chronic hepatitis type B in childhood: longitudinal study of 35 cases. Gut 1981; 22:499–504.
Dormeyer HH, Arnod W, Schonborn H, et al. The significance of serologic, histologic, and immunohistologic findings in the prognosis of 88 asymptomatic carriers of hepatitis B surface antigen. J Infect Dis 1981;144:33–37.
Sánchez-Tapias JM, Vilar HJ, Hosta J, et al. Natural history of chronic persistent hepatitis B. Relationship between hepatitis B virus replication and the course of the disease. J Hepatol 1984;1:15–27.
Liaw Y-F, Sheen I-S, Chen T-J, et al. Incidence, determinants and significance of delayed clearance of serum HBsAg in chronic hepatitis B virus infection: A prospective study. Hepatology 1991;13:627–631.
Morgan TR, Redeker AG, Yamada S, et al. HBsAg clearance in chronic active hepatitis B. A possible cause of cryptogenic cirrhosis. Dig Dis Sci 1986;31:700–704.
Draelos M, Morgan T, Schifman RB, et al. Significance of isolated antibody to hepatitis B core antigen determined by immune response to hepatitis B vaccination. JAMA 1987;258:1193–1195.
Baker BL, Di Bisceglie AM, Kaneko S, et al. Determination of hepatitis B virus DNA in serum using the polymerase chain reaction: Clinical significance and correlation with serological and biochemical markers. Hepatology 1991;13:632–636.
Koremman J, Backer B, Waggoner, J, et al. Long-term remission of chronic hepatitis B after alpha-interferon therapy. Ann Int Med 1991;114:629–634.
Hsu H-Y, Chang M-H, Lee C-Y, et al. Spontaneous loss of HBsAg in children with chronic hepatitis B virus infection. Hepatology 1992;15:382–386.
Adachi H, Kaneko S, Matsushits E, et al. Clearance of HBsAg in seven patients with chronic hepatitis B. Hepatology 1992;16:1334–1337.
Fong TL, Di Bisceglie AM, Waggoner JG, et al. The significance of antibody to hepatitis C virus in patients with chronic hepatitis B. Hepatology 1991;14:264–267.
Fong TL, Di Bisceglie AM, Feinstone SM, et al. Persistent hepatic HBV-DNA after clearance of HBsAg from serum of patients with chronic hepatitis B. Hepatology 1991;14:130A.
Kuhns M, McNamara A, Mason A, et al. Serum and liver hepatitis B virus DNA in chronic hepatitis B after sustained loss of surface antigen. Gastroenterology 1992;103:1649–1656.
Marcellin P, Martinot-Peignoux M, Loriot M-A, et al. Persistence of hepatitis B virus DNA demonstrated by polymerase chain reation in serum and liver after loss of HBsAg induced by antiviral therapy. Ann Int Med 1990;112:227–228.
Mason A, Yoffe B, Noonan C, et al. Hepatitis B virus DNA in peripheral blood mononuclear cells in chronic hepatitis B after HBsAg clearance. Hepatology 1992;16:36–41.
Hadchouel M, Pasquinelli C, Fournier JG, et al. Detection of mononuclear cells expressing hepatitis B virus in peripheral blood from HBsAg positive and negative patients by in situ hybridization. J Med Virol 1988;24:27–32.
Pasquinelli C, Laure F, Chatenoud L, et al. Hepatitis B virus DNA in mononuclear blood cells. J Hepatol 1986;3:95–103.
Laure F, Zagury D, Saimot AG, et al. Hepatitis B virus DNA sequences in lymphoid cells from patients with AIDS and AIDS-related complex. Science 1985;229:561–563.
Laure F, Chatenoud L, Pasquinelli C, et al. Frequent lymphocyte infection by hepatitis B virus in haemophiliacs. Br J Haematol 1987;65:181–185.
Lie-Injo LE, Balase-Garam M, Lopez C, et al. Hepatitis B DNA in liver and white blood cells of patients with hepatima DNA cells. Biology 1983;2:301–308.