Loss of Hepatitis B e Antigen (HBeAg) during Nucleos(t)Ide (NUC) Therapy Is Associated with Greater Improvement in Liver Fibrosis

Abstract

Background: The role of HBeAg in hepatic inflammation and fibrosis is not well understood. The intrahepatic production of HBeAg may contribute to inflammation in NUC-treated patients and it follows that conversion to HBeAg negative status may reduce intrahepatic inflammation and potentially a reduction in fibrosis. The aim of this investigation was to evaluate the effects of HBeAg loss during long-term NUC therapy on liver fibrosis regression in a well characterized study population.

Methods: Viremic HBeAg+ CHB patients randomized in an ongoing Phase 3 study (GS-US-320-0110) to TAF or TDF once daily for up to 8 years. Available data through Week (WK) 144 was pooled across treatment arms. Serum HBeAg was evaluated qualitatively at Baseline (BSL) and every 12 WKs. FibroTest scores (FT) were generated at BSL and every 48 WKs by central laboratory. Descriptive statistics of absolute and change from BSL at WKs 48, 96, and 144 in FT scores and categorical changes in FT were compared between patients with and without HBeAg loss by WK 96. FT categories (Metavir fibrosis scores) were: <0.49 (F0-F1), 0.49 to <0.75 (F2-F3), and ≥0.75 (F4). ALT normal levels defined as <19 U/L female and <30 U/L male.

Results: 770 HBeAg+ patients had HBeAg results at WK 96: 517 were randomized to TAF and 253 to TDF. Rates of HBeAg loss at WKs 48, 96 and 144 were: 106 (14%), 174 (23%), and 193 (27%), respectively. The rate of HBeAg loss by WK 96 was similar by treatment (24% TAF vs 20% TDF). A higher rate of ALT normalization by WK 96 was observed in patients with vs without HBeAg loss: 121 (70%) vs 295 (50%). In patients with HBeAg loss by WK 96, a higher rate of ALT normalization was observed in TAF vs TDF treated patients (75% TAF vs 57% TDF). Key BSL characteristics and change from BSL in FT are presented by HBeAg status at WK 96 in the Table. Majority of patients were Asian (82%), male (65%), non-cirrhotic by medical history (90%), GT C (54%), and NUC-naïve (74%). Patients with HBeAg loss by WK 96 were older, non-obese, had lower HBV DNA and higher ALT levels, and were more likely to have FT ≥0.75 (13% vs 6% in HBeAg+) at BSL. Mean decline from BSL in FT was observed in patients with and without HBeAg loss; however, HBeAg loss patients had a greater decline at WK 144 (Table). The difference observed in the mean (SD) decline from BSL in FT between patients with and without HBeAg loss remained when viremic patients (HBV DNA ≥29 IU/mL at Week 96) were excluded from the analysis (WK 144 of -0.08 [0.17] HBeAg loss vs -0.05 [0.14] HBeAg+). A higher proportion of patients with vs without HBeAg loss had ≥1 categorical improvement in FT: 21% vs 10%, 17% vs 10%, and 16% vs 9%, at WKs 48, 96, and 144, respectively.

Conclusion: By serum FT, improvement in liver fibrosis was observed in CHB patients during NUC therapy regardless of HBeAg status. However, patients with HBeAg loss by Week 96 had a greater improvement in FT scores then those that remained HBeAg+ suggesting a possible role for HBeAg loss in reducing fibrogenesis.