Abstract
Non invasive immunologic markers of virus-induced liver disease are unmet needs. We tested the clinical significance of quantitative total and IgM-anti-HBc in well characterized chronic-HBsAg-carriers. Sera (212) were obtained from 111 HBsAg-carriers followed-up for 52 months (28-216) during different phases of chronic-HBV-genotype-D-infection: 10 HBeAg-positive, 25 inactive-carriers (HBV-DNA≤2000IU/ml, ALT<30U/L), 66 HBeAg-negative-CHB-patients and 10 with HDV-super-infection. In 35 patients treated with Peg-IFN±nucleos(t)ide-analogues (NUCs) sera were obtained at baseline, end-of-therapy and week-24-off-therapy and in 22 treated with NUCs (for 60 months, 42-134m) at baseline and end-of-follow-up. HBsAg and IgM-anti-HBc were measured by Architect-assays (Abbott, USA); total-anti-HBc by double-antigen-sandwich-immune-assay (Wantai, China); HBV-DNA by COBAS-TaqMan (Roche, Germany). Total-anti-HBc were detectable in all sera with lower levels in HBsAg-carriers without CHB (immune-tolerant, inactive and HDV-superinfected, median 3.26, range 2.26-4.49 Log10 IU/ml) versus untreated-CHB (median 4.68, range 2.76-5.54 Log10 IU/ml), p<0.0001. IgM-anti-HBc positive using the chronic-hepatitis-cut-off" (0.130-S/CO) were positive in 102 of 212 sera (48.1%). Overall total-anti-HBc and IgM-anti-HBc correlated significantly (p<0.001, r=0.417). Total-anti-HBc declined significantly in CHB patients with response to Peg-IFN (p<0.001) and in NUC-treated patients (p<0.001); the lowest levels (median 2.68, range 2.12-3.08 Log10 IU/ml) were found in long-term responders who cleared HBsAg subsequently. During spontaneous and therapy-induced fluctuations of CHB (remissions and reactivations) total- and IgM-anti-HBc correlated with ALT (p<0.001, r=0.351 and p=0.008, r=0.185 respectively). Total-anti-HBc qualifies as a useful marker of HBV-induced-liver-disease that might help to discriminate major phases of chronic HBV infection and to predict sustained response to antivirals.
Highlights
Hepatitis-B-Virus (HBV) infection elicits a prominent immune response against hepatitis-Bcore-antigen (HBcAg) [1,2,3,4,5]: IgG-antibodies against HBcAg persist lifelong in HBV exposed individuals whereas IgM-antibodies decline becoming undetectable after recovery from hepatitis-B [4,6,7,8]
The dynamic quantification range of the new total-anti-HBc assay allows to distinguish chronic-HBV-infection associated with HBV-induced liver disease, namely chronic-hepatitisB (CHB), from chronic HBV infection without HBV-induced liver damage, namely noninflammatory HBeAg-positive and inactive HBeAg-negative phases, independently from HBV-genotypes
Comparing the kinetics of the different HBV-markers according to response to Peg-IFN we found (Fig 3) that the decline of total-anti-HBc during therapy parallels that of HBV-DNA and this may be useful in clinical practice to confirm the effectiveness of Peg-IFN antiviral activity
Summary
Hepatitis-B-Virus (HBV) infection elicits a prominent immune response against hepatitis-Bcore-antigen (HBcAg) [1,2,3,4,5]: IgG-antibodies against HBcAg (anti-HBc) persist lifelong in HBV exposed individuals whereas IgM-antibodies decline becoming undetectable after recovery from hepatitis-B [4,6,7,8]. A new assay based on double antigen sandwich method that detects total (IgG and IgM) anti-HBc was developed and proposed to monitor patients, chronically infected with genotype B and C HBV undergoing antiviral therapy [21,22,23,24]. We tested this assay in a validation study on a panel of sera from well characterized genotype D, HBsAg carriers
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