Finite Versus Continuous Nucleos(t)Ide Analogues for Chronic Hepatitis B

Chronic hepatitis B virus (HBV) infection imposes a serious threat to global public health, affecting more than 250 million individuals around the world. In the management of patients with chronic hepatitis B (CHB), treatment with nucleos(t)ide analog (Nuc) has been shown to improve clinical outcomes including occurrence and recurrence of hepatocellular carcinoma (HCC), liver-related mortality, and overall mortality. Nuc therapy, however, cannot exterminate HBV and so continuous treatment is usually required to sustain viral inhibition. Seroclearance of hepatitis B surface antigen (HBsAg) predicts durable remission off Nuc and may serve as the treatment endpoint, but it rarely occurs with current regimen. Therefore, long-term to indefinite treatment is currently recommended.

In view of various concerns such as drug exposure, adherence, and expense for a treatment course that could be lifelong, a finite strategy of Nuc therapy was proposed to allow treatment withdrawal prior to HBsAg seroclearance. Another major reason for the finite strategy is a higher chance of HBsAg seroclearance following treatment cessation. Nevertheless, viral replication almost always reactivates and often leads to clinical flares. While an episode of acute flare might be self-limited or even conducive to HBsAg seroclearance, it could progress to acute on chronic liver failure with fatal consequences. Risks of these serious outcomes following treatment withdrawal need to be accurately quantified in order to inform the practice of finite Nuc therapy.

Existent literature on the efficacy and safety of finite Nuc therapy remained very limited, as recently shown in a systematic review and meta-analysis by Hall and colleagues. In order to close the gaps in current knowledge, the investigators conduct this multicenter randomized controlled trial to examine if cessation of Nuc is safe and conducive to HBsAg seroclearance.

Inclusion criteria

• Age ≥ 20 years
• Chronic hepatitis B virus infection (defined as positive HBsAg for ≥ 6 months)
• Entecavir or tenofovir (either tenofovir disoproxil fumarate or tenofovir alafenamide) for at least two years and still on therapy at screening for this trial.
• Fulfillment of the stopping rules recommended by the Asian-Pacific guidelines 2016:

• For patients with positive HBeAg prior to their antiviral treatment, HBeAg seroconversion needs to be documented and followed by consolidation treatment for at least one year). Besides, serum ALT is within normal limits and HBV DNA is undetectable.
• For those with negative HBeAg prior to the antiviral therapy, undetectable HBV DNA documented on three separate occasions (at least 6 months apart)
• At screening for this study, HBsAg serology is positive, HBeAg negative, and HBV DNA undetectable in serum.

Exclusion criteria

• Liver cirrhosis (either clinical or pathological diagnosis) at screening
• Serious underlying disease (with valid certification of catastrophic illness) at screening
• Manifestations and concerns of hepatic decompensation, including serum bilirubin >2mg/dL and/or prolongation of prothrombin time > 3 seconds at screening
• Hepatitis C virus (if anti-HCV serology is positive, confirmation with detectable HCV RNA is required), human immunodeficiency virus (HIV) or hepatitis delta virus (HDV) coinfection at screening.
• Prior history of any malignancy including liver cancer
• Prior history of any organ transplantation
• Prior history of drug resistance to any Nuc agent
• Any patient condition that the treating physician deems inappropriate for enrollment in this trial