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Journal of Clinical Microbiology, May 2003, p. 2144-2146, Vol. 41, No. 5
0095-1137/03/$08.00+0     DOI: 10.1128/JCM.41.5.2144-2146.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Kinetics and Significance of Serum Hepatitis C Virus Core Antigen in Patients with Acute Hepatitis C

Agostino Cividini,^1,2 Antonella Cerino,¹ Alba Muzzi,² Milena Furione,³ Chiara Rebucci,² Laura Segagni,¹ Marta Gatti,³ Vincenzo Barnaba,⁴ and Mario U. Mondelli^1,2*

Laboratori di Ricerca-Area Infettivologica,¹ Dipartimento di Malattie Infettive,² Servizio di Virologia, IRCCS Policlinico, San Matteo, and University of Pavia, Pavia,³ Laboratorio di Immunologia Cellulare e Molecolare, Fondazione A. Cesalpino, Policlinico Umberto I, and University of Roma "La Sapienza," Rome, Italy⁴

Received 16 September 2002/ Returned for modification 8 December 2002/ Accepted 17 February 2003

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An immunoassay detecting hepatitis C virus core antigen was evaluated for its ability to predict clinical outcome in a series of patients with acute hepatitis C. In subjects who cleared the virus, core antigen was no longer detectable within 16 weeks of onset, whereas considerable fluctuations were noted among patients progressing to chronic hepatitis, one of whom showed consistently negative values despite the intermittent presence of viral RNA.

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Acute infection with hepatitis C virus (HCV) is characterized by a disturbingly high propensity to progress to chronic hepatitis which, in a proportion of cases, may evolve into cirrhosis and hepatocellular carcinoma (1, 4). Attempts to identify predictive markers of progression to chronic infection have been largely unsuccessful, and the persistently or intermittently positive identification of HCV RNA by PCR is currently accepted as evidence of chronic evolution even when liver enzymes, such as alanine aminotransferase (ALT), return to within the normal range after acute onset (2). Recently, a new immunoassay for the detection of circulating HCV core antigen has been developed that may be useful for identifying acute HCV infection earlier than anti-HCV seroconversion, which is occasionally delayed by several weeks after onset (5, 11). The assay performance seems excellent, with a 99.9% specificity and a sensitivity relative to nucleic acid testing (NAT) of 98.6% (7) and with a statistically significant positive correlation with HCV RNA levels (9). Recent studies suggest that alpha interferon treatment of patients with acute hepatitis C may dramatically reduce progression to chronic liver disease (6). However, no information is yet available on the use of HCV core antigen assay to predict progression to chronic hepatitis, which could avoid prolonged and unnecessary treatment in recovering patients, who may account for up to 45% of infected subjects (10). In the present study we prospectively evaluated the significance and kinetics of serum HCV core antigen relative to NAT by using a recently released immunoassay in a well-characterized group of patients presenting with acute hepatitis C.

Nine patients (five males and four females; median age, 39 years [range, 21 to 84 years]) with acute HCV infection were considered for prospective analysis of serum HCV core protein concentration. The patients were enrolled and monitored between June 1998 and January 2002. At the initial consultation, all patients presented with positive anti-HCV serology and/or HCV RNA by an in-house nested-PCR assay (8) and grossly elevated ALT values in serum (i.e., >15 times the upper normal limit). Two HCV RNA-positive patients seroconverted to anti-HCV during follow-up. There was no evidence of prior liver disease of any cause in their past medical history. HCV RNA levels were determined by a quantitative signal amplification technique (Versant HCV RNA 3.0 bDNA [Bayer Corp., Tarrytown, N.Y.], detection limit of 615 IU/ml) and qualitatively by nested PCR as for a baseline workup. The sensitivity of our "in-house" nested-PCR assay was 365 IU/ml according to a European Quality Control Panel, a value significantly lower than that of the commercial quantitative assay. The HCV genotypes determined by using INNO-LiPA, HCV II (Bayer), were 1b in four patients, 1a in two patients, 3a in two patients, and 2a/c in one patient. None of the patients had serological markers of current or past hepatitis B virus infection and all were human immunodeficiency virus negative. The median follow-up period was 26 months (range, 7 to 48 months) in seven patients, whereas two patients, one of whom died of carcinoma of Vater's papilla, were lost to follow-up 2 and 3 months after acute onset: their serum HCV RNA was still positive and their ALT values were still grossly abnormal when last observed in the clinic. Sera were stored frozen at -80°C until used.

Circulating HCV core antigen was detected by a commercially available enzyme immunoassay (Ortho Trak-C assay; Ortho Clinical Diagnostics, Raritan, N.J.). The assay was carried out exactly as described by the manufacturer. The lower detection limit was defined at 1.5 pg/ml. The upper detection limit was 100 pg/ml. Sera showing values exceeding this limit were diluted to obtain values comprised within the curve, and the data were extrapolated. Samples were tested in triplicates to ensure accuracy and intratest reproducibility.

HCV core protein levels in sera were minimally or grossly elevated at presentation, ranging from 3.4 to 2,058 pg/ml in all patients irrespective of the clinical outcome, and generally parallelled those of HCV RNA. There was no correlation between baseline HCV RNA or core protein levels and clinical evolution. Of the seven patients for whom a sufficient duration of follow-up was available, three made a complete clinical and virological recovery and were still HCV RNA negative with normal ALT levels at 26, 34, and 37 months after clinical presentation. The viral genotypes were 1b in two subjects and 3a in one patient. HCV RNA and core antigen concentrations in serum rapidly declined, reaching stably negative values by 16, 5, and 4 weeks after presentation, respectively (Fig. 1A to C). However, one of the patients (patient A) remained HCV RNA positive as determined by nested PCR for additional 2 months after HCV core disappeared from the serum. Interestingly, patient C showed weakly positive core antigen at the same time that the PCR data were still positive. Four patients remained instead HCV RNA positive and developed chronic infection with persistently elevated ALT in the serum in three patients. Their current median duration of follow-up was 18 months (range, 7 to 48 months). As shown in Fig. 1D to G, the dynamics of core antigen concentrations in serum differed substantially among patients. Indeed, patient D showed fluctuating core levels reproducibly above the detection limit throughout the follow-up period, and patient E showed an abrupt decrease in core antigen concentration together with the decrease in ALT with occasional fluctuations above the positive detection level. One patient (patient F) showed low but unequivocally increased core values at onset; these values subsequently declined to below the detection limit and again reached a high concentration in parallel with an increase in HCV RNA titers and ALT. HCV core antigenemia rapidly declined from high values at onset to undetectable levels in patient G and remained negative after several months of follow-up. Patient G still showed intermittently positive PCR assays and persistently normal ALT at 48 months after presenting with acute disease. The HCV core levels in the two patients lost to follow-up were positive at presentation and declined to below the detection limit within 2 months (data not shown). There were no differences in serial HCV core evaluations according to viral genotype.

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FIG. 1. Kinetics of serum HCV RNA, core antigen, and ALT in patients A to G who recovered from acute hepatitis C (A to C) or instead evolved to chronic infection (D to G). The viral genotype is indicated next to the patient letter. Qualitative PCR data (+ or -) are indicated at the top of each panel. Notice that qualitative PCR tested positive, whereas quantitative HCV RNA was below the detection limit (<615 IU/ml) on a number of occasions during follow-up of patient A (3 months), patient C (4 weeks), patient E (10 weeks), patient F (from months 2 to 8), and patient G (several points). There was only one positive HCV RNA result determined by the commercial assay that tested negative by the "in-house" qualitative PCR assay (patient G, 3 months after onset).

Patients presenting with clinically overt acute hepatitis C are exceedingly rare, and therefore this prospectively observed cohort represents a unique opportunity to investigate viral predictors of outcome. We confirm here that serum HCV core can be used as a surrogate marker of HCV replication since a good correlation was found with HCV RNA titers of >10,000 IU/ml, as determined by a signal amplification technique, as shown in several previous studies (3, 5, 7, 9). However, in the setting of acute HCV infection, determination of HCV core antigen showed some limitations as a predictor of clinical outcome. Indeed, at low levels of HCV RNA, such as those noted in patient G, the assay gave consistently negative values, as in recovered patients during long-term follow-up. Indeed, molecular assays allow a better distinction between resolved and persistent infections and, to this end, repeatedly negative PCR data must therefore be considered indicative of virological recovery. However, in selected cases it was possible to demonstrate a coordinated increase of HCV core and RNA levels, attesting to the value of the former as a surrogate marker of viral replication (patients D and F).

In conclusion, the currently available HCV core antigen assay is highly specific, useful, and likely to replace NAT for several clinical applications, including antiviral treatment monitoring; however, its value as a marker of chronically evolving HCV infection is currently limited by its low sensitivity relative to PCR-based assays.

 
We thank Ortho Clinical Diagnostics Italy for providing us with the HCV core antigen kit. We thank Lara Firmo for editorial assistance.

This work was supported by Ministero dell'Università e della Ricerca Scientifica (COFIN-MIUR prot. MM06261448_003) and Ministero della Salute (no. 015RFM/00/01, no. 08920401, and no. 103).

 
* Corresponding author. Mailing address: Laboratori di Ricerca-Area Infettivologica, IRCCS Policlinico San Matteo, via Taramelli 5, 27100 Pavia, Italy. Phone: 39-0382-502636. Fax: 39-0382-526450. E-mail: m.mondelli{at}smatteo.pv.it.

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1
1. Alberti, A., L. Chemello, and L. Benvegnù. 1999. Natural history of hepatitis C. J. Hepatol. 31(Suppl. 1):17-24.
2
2. Alter, M. J., H. S. Margolis, K. Krawczynski, F. N. Judson, A. Mares, W. J. Alexander, P. Y. Hu, J. K. Miller, M. A. Gerber, R. E. Sampler, et al. 1992. The natural history of community-acquired hepatitis C in the United States. N. Engl. J. Med. 327:1899-1905.[Abstract]
3
3. Bouvier-Alias, M., K. Patel, H. Dahari, S. Beaucourt, P. Larderie, L. Blatt, C. Hezode, G. Picchio, D. Dhumeaux, A. U. Neumann, J. G. McHutchison, and J.-M. Pawlotsky. 2002. Clinical utility of total HCV core antigen quantification: a new indirect marker of HCV replication. Hepatology 36:211-218.[CrossRef][Medline]
4
4. Di Bisceglie, A. M. 2000. Natural history of hepatitis C: its impact on clinical management. Hepatology 31:1014-1018.[CrossRef][Medline]
5
5. Icardi, G., F. Ansaldi, B. M. Bruzzone, P. Durando, S. Lee, C. de Luigi, and P. Crovari. 2001. Novel approach to reduce the hepatitis C virus (HCV) window period: clinical evaluation of a new enzyme-linked immunosorbent assay for HCV core antigen. J. Clin. Microbiol. 39:3110-3114.[Abstract/Free Full Text]
6
6. Jaeckel, E., M. Cornberg, H. Wedemeyer, T. Santantonio, J. Mayer, M. Zankel, G. Pastore, M. Dietrich, C. Trautwein, and M. P. Manns. 2001. Treatment of acute hepatitis C with interferon alfa-2b. N. Engl. J. Med. 345:1452-1457.[Abstract/Free Full Text]
7
7. Muerhoff, A. S., L. Jiang, D. O. Shah, R. A. Gutierrez, J. Patel, C. Garolis, C. R. Kyrk, G. Leckie, A. Frank, J. L. Stewart, and G. J. Dawson. 2002. Detection of HCV core antigen in human serum and plasma with an automated chemiluminescent immunoassay. Transfusion 42:349-356.[CrossRef][Medline]
8
8. Silini, E. M., F. Bono, A. Cerino, V. Piazza, E. Solcia, and M. U. Mondelli. 1993. Virological features of HCV infection in hemodialysis patients. J. Clin. Microbiol. 31:2913-2917.[Abstract/Free Full Text]
9
9. Tanaka, E., C. Ohue, K. Aoyagi, K. Yamaguchi, S. Yagi, K. Kiyosawa, and H. J. Alter. 2000. Evaluation of a new enzyme immunoassay for hepatitis C virus (HCV) core antigen with clinical sensitivity approximating that of genomic amplification of HCV RNA. Hepatology 32:388-393.[CrossRef][Medline]
10
10. Vogt, M., T. Lang, G. Frösner, C. Klingler, A. F. Sendl, A. Zeller, B. Wiebecke, B. Langer, H. Meisner, and J. Hess. 1999. Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening. N. Engl. J. Med. 341:866-870.[Abstract/Free Full Text]
11
11. Widell, A., V. Molnegren, F. Pieksma, M. Calmann, J. Peterson, and S. Lee. 2002. Detection of hepatitis C core antigen in serum or plasma as a marker of hepatitis C viraemia in the serological window-phase. Transfus. Med. 12:107-113.[CrossRef][Medline]

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Journal of Clinical Microbiology, May 2003, p. 2144-2146, Vol. 41, No. 5
0095-1137/03/$08.00+0     DOI: 10.1128/JCM.41.5.2144-2146.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

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• Krajden, M., Shivji, R., Gunadasa, K., Mak, A., McNabb, G., Friesenhahn, M., Hendricks, D., Comanor, L. (2004). Evaluation of the Core Antigen Assay as a Second-Line Supplemental Test for Diagnosis of Active Hepatitis C Virus Infection. J. Clin. Microbiol. 42: 4054-4059 [Abstract] [Full Text]  
• Rebucci, C., Cerino, A., Cividini, A., Timo, L., Furione, M., Mondelli, M. U. (2003). Monitoring Response to Antiviral Therapy for Patients with Chronic Hepatitis C Virus Infection by a Core-Antigen Assay. J. Clin. Microbiol. 41: 3881-3884 [Abstract] [Full Text]  

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cividini, A. Articles by Mondelli, M. U. Search for Related Content PubMed PubMed Citation Articles by Cividini, A. Articles by Mondelli, M. U.