Abstract

Background: This study extends the follow-up of participants who completed a randomized placebo-controlled trial evaluating the safety and efficacy of tenofovir disoproxil fumarate (TDF) in reducing the risk of histological progression in patients with chronic hepatitis B (CHB) characterized by high viral load and minimally raised serum alanine aminotransferase (ALT) levels. We report herein the outcomes of patients who received three years of open-label TDF treatment after completing a randomized trial

Methods: This open-label study enrolled participants who had completed a three-year trial of TDF vs. placebo for CHB patients with serum HBV DNA exceeding 2000 IU/mL and ALT levels between one to two times the upper limit of normal (ULN). Exclusion criteria included malignancy, cirrhosis, hepatic insufficiency, renal failure, pregnancy, or viral coinfections. Upon completing the randomized trial, eligible patients were all rolled over to receive three years of open-label TDF treatment, followed by a liver biopsy to evaluate histological changes. The severity of fibrosis was evaluated using the Ishak scoring system, and necroinflammation was assessed using the Knodell system (ClinicalTrials.gov Identifier: NCT02463019).

Results: A total of 146 patients (median age of 47 years, IQR: 41-57 years, 80.8% male) were enrolled in the study. At baseline, 18.5% (n=27) of patients were HBeAg-positive, and 47.9% (n=70) had undetectable HBV DNA. Moderate to severe liver fibrosis or cirrhosis (Ishak ≥ 3 points) was present in 33.3% (n=42) of patients. During the 3-year period, 23 patients withdrew from the study, including 5 who developed hepatocellular carcinoma (3 initially assigned to placebo, 2 to TDF). Among the remaining 123 patients with paired liver biopsies, severity of liver fibrosis significantly improved after 3 years of open-label TDF treatment (p<0.0001, Stuart-Maxwell test), with the proportion of patients with an Ishak score of liver fibrosis ≥ 3 points decreasing to 9.8% (12 patients, Figure 1). Furthermore, viral remission (defined as undetectable HBV DNA) and ALT normalization were achieved in 82.2% and 69.0% of patients, respectively. There were no serious adverse events attributable to the study medication.

Conclusion: In this open-label rollover study following a three-year randomized trial, we found that continued use of TDF in CHB patients with high viral load and mild ALT elevation led to significant improvement in liver fibrosis.