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Fibronectin Predicts Seroclearance in Chronic Hepatitis B

Fibronectin may be a potential marker for hepatitis B surface antigen (HBsAg) seroclearance, according to study results published in The Journal of Infectious Diseases.

A potentially achievable treatment end point for chronic hepatitis B viral (HBV) infection is seroclearance of HBsAg. Achieving this reflects a functional cure by indicating successful immune control of the infection. Although the kinetics of HBsAg serum and HBV DNA levels have been shown to be associated with HBsAg seroclearance, the clinicopathologic mechanisms leading to HBsAg seroclearance, and whether certain plasma proteins promote seroclearance is still uncertain. Therefore, the study aimed to apply isobaric tags for relative and absolute quantification-based quantitative proteomics to reveal protein profiles associated with HbsAg seroclearance, followed by validation and prediction of identified proteins in patient cohorts.

The study design included 3 stages: (1) isobaric tags-based proteomic analysis, (2) prospective validation in a separate cohort of 90 patients, and (3) an assessment of predictive values of identified plasma proteins for HBsAg seroclearance (n=164). For the first 2 stages, patients with chronic HBV infection who have never received treatment and prior HBsAg-positivity for at least 6 months were recruited for the study. These patients were either in the experimental group, which included patients with spontaneous HBsAg seroclearance, or the control group, which included patients with persistent HBsAg-positivity. HBsAg seroclearance was defined as serum HBsAg-negative results on 2 occasions that were at least 6 months apart and remaining negative up to the last visit. The experimental and control groups were age- and gender-matched.

In the first stage, proteomic analysis identified 487 plasma proteins, in which 97 of the proteins showed altered expression. Of these, 88 were upregulated and 9 were down-regulated. The 4 proteins that were most associated with immunologic response were fibronectin, CD44, aldolase A, and S100 calcium-binding protein A9.

In the second stage, 90 patients (45 in both the experimental and control groups) were studied. Median fibronectin levels were higher in patients achieving HBsAg seroclearance compared with HBsAg-positive control patients (P =.009). However, there were no significant differences in median levels of CD44, aldolase A, and S100 calcium-binding protein A9.

In the third stage, 164 patients (82 in both the experimental and control groups) had archived plasma at the 3 specific time points examined. Results showed that median fibronectin levels were higher in patients with HBsAg compared with control participants at Year −1 and Year 0 (both P <.001); however there was no significant difference at Year 3. Further, in the experimental group, there was no difference between median fibronectin levels across all 3 time points (P =.667), while a significant difference was observed in the control group (P <.001).

The predictive value of fibronectin was assessed at 3 years, 1 year before the time of HBsAg seroclearance (Year −1), and at the time of HbsAg seroclearance (Year 0).  In a subgroup of patients with annual HBsAg log reduction >0.5 (n=60), the addition of plasma fibronectin level at Year −1 achieved the highest predictive value (area under the receiving operating characteristic, 0.884; P =.0003). The optimal cutoff fibronectin level was 122.03 µg/mL, with a positive predictive value of 98.2% and a negative predictive value of 75.0%. Therefore, plasma fibronectin level was associated with HBsAG seroclearance and shows potential to be a predictor of “functional cure.”

Overall, the study authors concluded that, “Future studies should explore the mechanistic nature between fibronectin and HBsAg seroclearance, as well as its application in clinical prognostication of [chronic hepatitis B].”

By Zahra Masoud


Liu F, Seto W, Wong DK, et al. Plasma fibronectin levels identified via quantitative profiling predicts hepatitis B surface antigen seroclearance in chronic hepatitis B [published online May 6, 2019]. Journ Inf Dis. doi:10.1093/infdis/jiz223/5485908


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