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

Safety and Efficacy of Finite Versus Continuous Nucleos(t)Ide Analogues Therapy in Patients With Chronic Hepatitis B: A Multicenter Randomized Controlled Trial

BACKGROUND: Finite nucleos(t)ide analogue (Nuc) therapy was proposed as an alternative strategy in the management of chronic hepatitis B (CHB) but there remained not data from randomized controlled trials to clarify safety and efficacy of this treatment strategy. AIMS: The investigators aimed to evaluate the safety and efficacy of finite Nuc therapy versus continuous treatment in CHB patients without liver cirrhosis and also to identify factors that may predict therapeutic responses and clinical outcomes after withdrawal of Nuc treatment for CHB MATERIAL AND METHODS: This is a multicenter randomized controlled trial conducted in Taiwan. Eligible patients are adults (age≥20 years) with CHB (chronic infection ≥ 6 months) who fulfill the APASL guideline 2016 to stop NA therapy. Those with cirrhosis, malignancy, organ transplant, autoimmune disorder, or serious underlying diseases including renal impairment were excluded. A total of 360 patients will be enrolled. Enrolled patients are randomly allocated with a 1:1 ratio to continue viral suppression with entecavir (0.5mg once daily) or tenofovir disoproxil fumarate (300mg once daily) or stop the treatment. All patients will be followed up according to the protocol recommended by a panel of APASL experts. The primary analysis for study outcomes is scheduled at 3 years after randomization and the primary outcome is seroclearance of HBsAg. There will be interim analyses scheduled at one- and two-years following randomization of the first 200 patients, and also one-and two years following randomization of the planned 360 patients, to determine whether early termination of the trial may be justified by attainment of the efficacy endpoint (10% vs 1% of HBsAg seroclearance) or concerns of the safety outcomes (significant between-group difference in mortality, acute on chronic liver failure, or acute flares with hepatic decompensation).

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.

Continuation of oral Nuc monotherapy using entecavir (0.5mg/tab, once per day), tenofovir disoproxil fumarate (300mg/tab, once per day), or tenofovir alafenamide (25mg/tab, once per day) for 3 years

Eligible patients are randomly allocated with a 1:1 ratio to continue viral suppression or stop the treatment (entecavir or tenofovir). Patients will be followed up for 3 years. For patients who are assigned to the finite Nuc therapy, they should be monitored monthly for the initial 3 months and then every 3-6 months thereafter for relapse.

Serum alanine aminotransferase > 5 times the upper limit of normal with either serum bilirubin ≥2mg/dL or prolongation of prothrombin time ≥3 seconds, in the presence of serum HBV DNA >2000 IU/mL

Serum alanine aminotransferase > 2 times the upper limit of normal in the presence of serum HBV DNA >2000 IU/mL

Chinese version of the Short-form 36. Responses in each domain are transformed into a 0-100 scale, with a higher score indicating better health or functioning.

Chinese version of the questionnaire. The total score can range from 0 to 21, with a higher score indicating more severe anxiety

Chinese version of the questionnaire. The total score can range from 0 to 56, with a higher score indicating a higher level of perceived stress.

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

Data collected during this trial, including de-identified individual participant data and data dictionaries defining fields in the datasets will be available to access. Documents that include the study protocol, statistical analysis plan, and informed consent form will also be available. Data access will be provided to investigators for academic research after a proposal has been approved by the study committee identified for this purpose. The investigator will sign a data access agreement on how to collaborate with consideration of potential overlaps between the proposal and ongoing efforts. Data will be available beginning with full publication of this Article. Proposals should be directed to the Principal Investigator (Dr. Yao-Chun Hsu), and the de-identified database will be transferred by email.

Data will become available beginning with full publication of the study results in an academic peer-reviewed journal and for at least a year.

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