Predicting HBsAg clearance in genotype A chronic hepatitis B using HBsAg epitope profiling: A biomarker for functional cure

Abstract

Background and Aim Functional cure is the major goal of chronic hepatitis B (CHB) therapy though few biomarkers predict this outcome. HBsAg epitope occupancy can be influenced by therapeutic and immune pressure. The aim of this study was to map the HBsAg epitope profiles during long‐term nucleos(t)ide analogue therapy in patients with genotype A CHB, in the context of HBsAg loss (SL)/seroconversion. Methods We evaluated 25 genotype A CHB patients in the GS‐US‐174‐0103 trial of HBeAg‐positive CHB patients treated with tenofovir or adefovir for 4 years, 14 who achieved SL whilst 11 had no change. We epitope mapped the major domains of HBsAg to identify those patients with HBsAg clearance profile (CP) (loss of binding at both loops 1 and 2 epitopes of the ‘a’ determinant) vs non‐clearance profile (no change in epitope recognition, or loss of epitope binding at one loop only), correlating this to on‐treatment HBsAg responses. Complexed anti‐HBs was also measured. Results Analysis of the HBsAg epitope profiles of the 25 patients at baseline identified no predictive correlation with SL. In contrast, analysis at week 48 and end of study (week 192) or prior to SL identified significant predictive associations between development of HBsAg CPs and outcome of functional cure. The detection of a CP also correlated with the development of an alanine aminotransferase flare and detection of anti‐HBs complexed with HBsAg. Conclusion The detection of HBsAg CPs by epitope mapping represents a novel viral biomarker, reflecting an emerging anti‐HBs selection pressure prior to functional cure.

Advances in treatment and prevention of hepatitis B

“…Biomarkers for HBV functional cure include HBsAg clearance profile (CPs, defined by loss of binding at both loops 1 and 2 epitopes of the 'a' determinant)[ 15 ]. A 48th week and 192 nd week HBsAg CPs analysis of genotype A CHB patients on either tenofovir or adefovir for at least four years prior revealed its positive association with HBsAg loss (SL), seroconversion, and response to treatment[ 15 ].…”

The Role of Hepatitis B Surface Antibodies in Hbv infection, Disease and Clearance

“…Further support for the role of anti-HBs in HBV clearance comes from a study of individuals who cleared HBV infection during adefovir/tenofovir therapy. Using a 19-plex epitope mapping approach across the HBsAg antigenic 'a' determinant, occupancy of epitopes in loop 1 and loop 2 of the 'a' determinant was detected in those patients who went on to achieve a functional cure, suggesting that anti-HB responses across these regions are required for clearance [37].…”

“…As introduced above, it has been suggested that anti-HBs could be depleted by the large number of circulating SVPs that greatly outnumber virions. In support of this suggestion is the finding that complexes of anti-HBs with circulating HBsAg are not recognized by current diagnostic assays, but can be detected in chronically infected patients using more highly sensitive immunoassays [37,38]. However, alternative explanations have been provided to understand this apparent lack of anti-HBs as an HBsAg-specific B-cell dysfunction.…”

Defining the specificity and function of a human neutralizing antibody for Hepatitis B virus

“…The S region contains the “a” determinant spanning from residues 99 to 160 and is thought to be the major anti-HBs epitope binding domain 11 . Antibodies targeting the “a” determinant have been reported to be potent neutralizers making them ideal candidates for testing as prophylactic or therapeutic reagents 12 .…”