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. 1992 May;30(5):1111–1119. doi: 10.1128/jcm.30.5.1111-1119.1992

New assays for quantitative determination of viral markers in management of chronic hepatitis B virus infection.

F Zoulim 1, L Mimms 1, M Floreani 1, C Pichoud 1, I Chemin 1, A Kay 1, L Vitvitski 1, C Trepo 1
PMCID: PMC265234  PMID: 1583107

Abstract

We performed a quantitative study of serum hepatitis B virus (HBV) markers, including new parameters such as pre-S1 antigen (Ag), pre-S2 Ag, and anti-HBx, in 88 chronic hepatitis B surface antigen (HBsAg) carriers. New IMx assays for HBsAg and immunoglobulin M (IgM) anti-HBc detection were also used. The population studied was composed of 65 chronic hepatitis cases (40 positive for hepatitis B antigen [HBeAg] and 25 positive for anti-HBe) and 23 anti-HBe-positive, asymptomatic HBsAg carriers. Serum HBsAg levels detected by IMx were higher in HBeAg-positive than in anti-HBe-positive HBsAg carriers (all patient subgroups included) and correlated with the serum HBV DNA level (P = 0.0001). Both pre-S1 and pre-S2 Ags were detected by enzyme immunoassays in almost all HBsAg carriers. Both pre-S1 and pre-S2 Ag titers correlated positively with the serum HBsAg concentration (P = 0.0001), but only the pre-S1 Ag titer correlated with the level of serum HBV DNA (P = 0.02). The detection of low levels of IgM anti-hepatitis B core (anti-HBc) antibodies by IMx was associated with the presence of liver disease (P = 0.05) but not with the level of viral replication. The prevalence of anti-HBx antibodies detected by the enzyme immunoassay was slightly, although not significantly, higher in patients with high levels of HBV DNA (greater than 100 pg/ml) than in patients without detectable HBV DNA (P = 0.16). In anti-HBe-positive chronic HBsAg carriers, the quantitative detection of serum HBV DNA, pre-S Ag titers, and IgM anti HBc allowed us to predict which patients suffered from chronic liver disease and/or supported viral replication (P < 0.05). In a follow-up study of eight patients undergoing antiviral therapy, the clearance of both pre-S1 Ag and HBV DNA was associated with a subsequent clearance of HBV. Therefore, the quantitative determination of HBV DNA, pre-S Ags, IgM anti-HBc may prove useful for the decision to use and the monitoring of antiviral therapy, especially in anti-HBe-positive HBsAg carriers.

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Selected References

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  1. Baker B. L., Di Bisceglie A. M., Kaneko S., Miller R., Feinstone S. M., Waggoner J. G., Hoofnagle J. H. Determination of hepatitis B virus DNA in serum using the polymerase chain reaction: clinical significance and correlation with serological and biochemical markers. Hepatology. 1991 Apr;13(4):632–636. [PubMed] [Google Scholar]
  2. Bonino F., Rosina F., Rizzetto M., Rizzi R., Chiaberge E., Tardanico R., Callea F., Verme G. Chronic hepatitis in HBsAg carriers with serum HBV-DNA and anti-HBe. Gastroenterology. 1986 May;90(5 Pt 1):1268–1273. doi: 10.1016/0016-5085(86)90395-1. [DOI] [PubMed] [Google Scholar]
  3. Brahm J., Alexander G. J., Fagan E. A., Smith H. M., Daniels H. M., Eddleston A. L., Williams R. Clearance of pre-S2 antigen: a marker of successful interferon therapy in hepatitis B virus infection. J Med Virol. 1988 Apr;24(4):453–459. doi: 10.1002/jmv.1890240412. [DOI] [PubMed] [Google Scholar]
  4. Brechot C., Hadchouel M., Scotto J., Degos F., Charnay P., Trepo C., Tiollais P. Detection of hepatitis B virus DNA in liver and serum: a direct appraisal of the chronic carrier state. Lancet. 1981 Oct 10;2(8250):765–768. doi: 10.1016/s0140-6736(81)90182-3. [DOI] [PubMed] [Google Scholar]
  5. Budkowska A., Dubreuil P., Gerlich W. H., Lazizi Y., Pillot J. Occurrence of pre-S1 antigen in viremic and nonviremic carriers of hepatitis B surface antigen. J Med Virol. 1988 Oct;26(2):217–225. doi: 10.1002/jmv.1890260213. [DOI] [PubMed] [Google Scholar]
  6. Bänninger P., Altorfer J., Frösner G. G., Pirovino M., Gudat F., Bianchi L., Grob P. J., Schmid M. Prevalence and significance of anti-HBc IgM (radioimmunoassay) in acute and chronic hepatitis B and in blood donors. Hepatology. 1983 May-Jun;3(3):337–342. doi: 10.1002/hep.1840030310. [DOI] [PubMed] [Google Scholar]
  7. Carman W. F., Jacyna M. R., Hadziyannis S., Karayiannis P., McGarvey M. J., Makris A., Thomas H. C. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet. 1989 Sep 9;2(8663):588–591. doi: 10.1016/s0140-6736(89)90713-7. [DOI] [PubMed] [Google Scholar]
  8. Chemin I., Baginski I., Petit M. A., Zoulim F., Pichoud C., Capel F., Hantz O., Trepo C. Correlation between HBV DNA detection by polymerase chain reaction and Pre-S1 antigenemia in symptomatic and asymptomatic hepatitis B virus infections. J Med Virol. 1991 Jan;33(1):51–57. doi: 10.1002/jmv.1890330111. [DOI] [PubMed] [Google Scholar]
  9. Eble K., Clemens J., Krenc C., Rynning M., Stojak J., Stuckmann J., Hutten P., Nelson L., DuCharme L., Hojvat S. Differential diagnosis of acute viral hepatitis using rapid, fully automated immunoassays. J Med Virol. 1991 Mar;33(3):139–150. doi: 10.1002/jmv.1890330302. [DOI] [PubMed] [Google Scholar]
  10. Fattovich G., Brollo L., Alberti A., Pontisso P., Giustina G., Realdi G. Long-term follow-up of anti-HBe-positive chronic active hepatitis B. Hepatology. 1988 Nov-Dec;8(6):1651–1654. doi: 10.1002/hep.1840080630. [DOI] [PubMed] [Google Scholar]
  11. Feitelson M. A., Clayton M. M. X antigen/antibody markers in hepadnavirus infections. Antibodies to the X gene product(s). Gastroenterology. 1990 Aug;99(2):500–507. doi: 10.1016/0016-5085(90)91033-3. [DOI] [PubMed] [Google Scholar]
  12. Gerken G., Paterlini P., Manns M., Housset C., Terre S., Dienes H. P., Hess G., Gerlich W. H., Berthelot P., Meyer zum Büschenfelde K. H. Assay of hepatitis B virus DNA by polymerase chain reaction and its relationship to pre-S- and S-encoded viral surface antigens. Hepatology. 1991 Jan;13(1):158–166. [PubMed] [Google Scholar]
  13. Hadziyannis S. J., Lieberman H. M., Karvountzis G. G., Shafritz D. A. Analysis of liver disease, nuclear HBcAg, viral replication, and hepatitis B virus DNA in liver and serum of HBeAg Vs. anti-HBe positive carriers of hepatitis B virus. Hepatology. 1983 Sep-Oct;3(5):656–662. doi: 10.1002/hep.1840030505. [DOI] [PubMed] [Google Scholar]
  14. Hadziyannis S., Raimondo G., Papaioannou C., Anastassakos C., Wong D., Sninsky J., Shafritz D. Expression of pre-S gene-encoded proteins in liver and serum during chronic hepatitis B virus infection in comparison to other markers of active virus replication. J Hepatol. 1987 Dec;5(3):253–259. doi: 10.1016/s0168-8278(87)80029-6. [DOI] [PubMed] [Google Scholar]
  15. Hess G., Gerlich W., Gerken G., Manns M., Hütteroth T. H., Meyer zum Büschenfelde K. H. The effect of recombinant alpha-interferon treatment on serum levels of hepatitis B virus-encoded proteins in man. Hepatology. 1987 Jul-Aug;7(4):704–708. doi: 10.1002/hep.1840070414. [DOI] [PubMed] [Google Scholar]
  16. Hoofnagle J. H., Dusheiko G. M., Seeff L. B., Jones E. A., Waggoner J. G., Bales Z. B. Seroconversion from hepatitis B e antigen to antibody in chronic type B hepatitis. Ann Intern Med. 1981 Jun;94(6):744–748. doi: 10.7326/0003-4819-94-6-744. [DOI] [PubMed] [Google Scholar]
  17. Hoofnagle J. H., Shafritz D. A., Popper H. Chronic type B hepatitis and the "healthy" HBsAg carrier state. Hepatology. 1987 Jul-Aug;7(4):758–763. doi: 10.1002/hep.1840070424. [DOI] [PubMed] [Google Scholar]
  18. Hu P. S., Carithers R. L., Jr, Fiorenza V., Peterson D. L. Quantitative studies of the hepatitis B viral pre-S proteins: lack of correlation with the HBeAg status. J Virol Methods. 1987 May;16(1-2):97–114. doi: 10.1016/0166-0934(87)90035-8. [DOI] [PubMed] [Google Scholar]
  19. Kakumu S., Arao M., Mizokami M., Orido E., Yamamoto M., Sakamoto N. Pre-S proteins in chronic hepatitis B virus infection: markers of active viral infection. Am J Gastroenterol. 1989 Oct;84(10):1250–1254. [PubMed] [Google Scholar]
  20. Kaneko S., Miller R. H., Di Bisceglie A. M., Feinstone S. M., Hoofnagle J. H., Purcell R. H. Detection of hepatitis B virus DNA in serum by polymerase chain reaction. Application for clinical diagnosis. Gastroenterology. 1990 Sep;99(3):799–804. doi: 10.1016/0016-5085(90)90971-3. [DOI] [PubMed] [Google Scholar]
  21. Kay A., Dupont de Dinechin S., Vitvitski-Trépo L., Mandart E., Shamoon B. M., Galibert F. Recognition of the N-terminal, C-terminal, and interior portions of HBx by sera from patients with hepatitis B. J Med Virol. 1991 Apr;33(4):228–235. doi: 10.1002/jmv.1890330404. [DOI] [PubMed] [Google Scholar]
  22. Kuhns M. C., McNamara A. L., Perrillo R. P., Cabal C. M., Campbel C. R. Quantitation of hepatitis B viral DNA by solution hybridization: comparison with DNA polymerase and hepatitis B e antigen during antiviral therapy. J Med Virol. 1989 Apr;27(4):274–281. doi: 10.1002/jmv.1890270404. [DOI] [PubMed] [Google Scholar]
  23. Lai M. C., Tong M. J., Nowicki M. J., Lee S. D. Is anti-HBc IgM a useful clinical test in patients with HBsAg-positive chronic hepatitis or primary hepatocellular carcinoma? Hepatology. 1988 May-Jun;8(3):514–517. doi: 10.1002/hep.1840080314. [DOI] [PubMed] [Google Scholar]
  24. Levrero M., Stemler M., Pasquinelli C., Alberti A., Jean-Jean O., Franco A., Balsano C., Diop D., Brechot C., Melegari M. Significance of anti-HBx antibodies in hepatitis B virus infection. Hepatology. 1991 Jan;13(1):143–149. [PubMed] [Google Scholar]
  25. Li J., Tong S., Vitvitski L., Zoulim F., Trépo C. Rapid detection and further characterization of infection with hepatitis B virus variants containing a stop codon in the distal pre-C region. J Gen Virol. 1990 Sep;71(Pt 9):1993–1998. doi: 10.1099/0022-1317-71-9-1993. [DOI] [PubMed] [Google Scholar]
  26. Mimms L. T., Floreani M., Tyner J., Whitters E., Rosenlof R., Wray L., Goetze A., Sarin V., Eble K. Discrimination of hepatitis B virus (HBV) subtypes using monoclonal antibodies to the PreS1 and PreS2 domains of the viral envelope. Virology. 1990 Jun;176(2):604–619. doi: 10.1016/0042-6822(90)90031-l. [DOI] [PubMed] [Google Scholar]
  27. Petit M. A., Zoulim F., Capel F., Dubanchet S., Dauguet C., Trepo C. Variable expression of preS1 antigen in serum during chronic hepatitis B virus infection: an accurate marker for the level of hepatitis B virus replication. Hepatology. 1990 May;11(5):809–814. doi: 10.1002/hep.1840110515. [DOI] [PubMed] [Google Scholar]
  28. Scotto J., Hadchouel M., Hery C., Yvart J., Tiollais P., Brechot C. Detection of hepatitis B virus DNA in serum by a simple spot hybridization technique: comparison with results for other viral markers. Hepatology. 1983 May-Jun;3(3):279–284. doi: 10.1002/hep.1840030301. [DOI] [PubMed] [Google Scholar]
  29. Theilmann L., Klinkert M. Q., Gmelin K., Salfeld J., Schaller H., Pfaff E. Detection of pre-S1 proteins in serum and liver of HBsAg-positive patients: a new marker for hepatitis B virus infection. Hepatology. 1986 Mar-Apr;6(2):186–190. doi: 10.1002/hep.1840060206. [DOI] [PubMed] [Google Scholar]
  30. Theilmann L., Salfeld J., Kommerell B., Pfaff E. Detection of antibodies to proteins encoded by the X-region of hepatitis B virus (HBV) in sera of patients with chronic HBV infection: correlation with other HBV markers. Hepatogastroenterology. 1988 Jun;35(3):104–106. [PubMed] [Google Scholar]
  31. Tong S. P., Diot C., Gripon P., Li J., Vitvitski L., Trépo C., Guguen-Guillouzo C. In vitro replication competence of a cloned hepatitis B virus variant with a nonsense mutation in the distal pre-C region. Virology. 1991 Apr;181(2):733–737. doi: 10.1016/0042-6822(91)90908-t. [DOI] [PubMed] [Google Scholar]
  32. Trepo C. G., Magnius L. O., Schaefer R. A., Prince A. M. Detection of e antigen and antibody: correlations with hapatitis B surface and hepatitis B core antigens, liver disease, and outcome in hepatitis B infections. Gastroenterology. 1976 Nov;71(5):804–808. [PubMed] [Google Scholar]
  33. Vitvitski-Trépo L., Kay A., Pichoud C., Chevallier P., de Dinechin S., Shamoon B. M., Mandart E., Trépo C., Galibert F. Early and frequent detection of HBxAg and/or anti-HBx in hepatitis B virus infection. Hepatology. 1990 Dec;12(6):1278–1283. doi: 10.1002/hep.1840120605. [DOI] [PubMed] [Google Scholar]
  34. Yuki N., Hayashi N., Katayama K., Kasahara A., Ueda K., Fusamoto H., Sato N., Kamada T. Quantitative analysis of pre-S1 and pre-S2 in relation to HBsAg expression. Hepatology. 1990 Jan;11(1):38–43. doi: 10.1002/hep.1840110108. [DOI] [PubMed] [Google Scholar]

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