Changes of Serum Levels of Keratin-18 Fragments in Hepatitis B E Antigen-Negative Chronic Hepatitis B Patients under Oral Antiviral Therapy

Abstract

The effect of chronic hepatitis B (CHB) treatment on hepatocyte apoptosis has not been evaluated. We investigated the changes in serum levels of the apoptotic caspase-generated fragments of keratin-18 (K-18) in hepatitis B e antigen (HBeAg)-negative CHB patients under nucleoside/nucleotide analogue(s). We included 46 patients with HBeAg-negative CHB who had received lamivudine or adefovir monotherapy for ≥12 months. Of the 42 lamivudine treated patients, 23 developed virological breakthroughs and received add-on adefovir therapy for ≥12 months. Levels of K-18 fragments were measured blindly in stored serum samples using the M30-Apoptosense(®) ELISA Kit (PEVIVA, Alexis, Grünwald, Germany). During initial therapy, the median serum K-18 fragment levels were significantly reduced from baseline (280 U/l [149-2,461]) to 6 months (164 U/l [110-454]; P<0.001) and from 6 to 12 months (145 U/l [113-280]; P=0.031). K-18 fragment levels increased at breakthroughs (187 U/l [137-1,063]) compared to last previous visits (145 U/l [118-389]; P=0.015) but remained lower than baseline (P=0.036). Changes of K-18 fragment levels correlated positively with changes of alanine aminotransferase (ALT) and HBV DNA from baseline to 6 or 12 months of initial therapy. In patients with breakthroughs, K-18 fragment levels had only a trend towards a decrease from adefovir addition (198 U/l [124-1,219]) to 6 months (170 U/l [122-1,576]; P=0.109) and mainly to 12 months (156 U/l [122-878]; P=0.055). Serum levels of K-18 fragments decrease significantly during oral antiviral therapy in HBeAg-negative CHB in parallel with the improvements in ALT and HBV DNA levels. They increased again during breakthroughs and improved after an effective rescue therapy, perhaps at a slower rate compared to the initial therapy.