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).

Study Overview

• Status: Active, not recruiting
• Conditions: Chronic Hepatitis b
• Intervention / Treatment: Other: Nuc Discontinuation; Drug: Entecavir or Tenofovir

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 360
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Taiwan
  • Chiayi City, Taiwan
    • Chia-Yi Christian Hospital
  • Kaohsiung, Taiwan, 824
    • E-DA Hospital
  • Taichung, Taiwan
    • Taichung Veterans General Hospital
  • Taipei, Taiwan
    • Fu-Jen Catholic University Hospital
  • Taitung, Taiwan
    • Taitung MacKay Memorial Hospital
  • Yilan, Taiwan
    • Lotung Poh-Ai Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 20 years
2. Chronic hepatitis B virus infection (defined as positive HBsAg for ≥ 6 months)
3. Entecavir or tenofovir (either tenofovir disoproxil fumarate or tenofovir alafenamide) for at least two years and still on therapy at screening for this trial.

4. 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)
5. At screening for this study, HBsAg serology is positive, HBeAg negative, and HBV DNA undetectable in serum.

Exclusion Criteria:

1. Liver cirrhosis (either clinical or pathological diagnosis) at screening
2. Serious underlying disease (with valid certification of catastrophic illness) at screening
3. Manifestations and concerns of hepatic decompensation, including serum bilirubin >2mg/dL and/or prolongation of prothrombin time > 3 seconds at screening
4. 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.
5. Prior history of any malignancy including liver cancer
6. Prior history of any organ transplantation
7. Prior history of drug resistance to any Nuc agent
8. Any patient condition that the treating physician deems inappropriate for enrollment in this trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Finite Therapy; Discontinuation of nucleos(t)ide analog (Nuc) therapy	Other: Nuc Discontinuation; 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.
Active Comparator: Continuous Therapy; 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	Drug: Entecavir or Tenofovir; Continuation of either entecavir or tenofovir treatment for 3 years

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with seroclearance of HBsAg	Serology of HBsAg was negative by the laboratory report	The time from randomization to seroclearance of HBsAg, up to 3 years after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with liver-related mortality or liver transplantation	Death from liver failure or liver transplantation because of liver failure	The time from randomization to this secondary outcome, up to 3 years after randomization
Number of Participants with acute on chronic liver failure	According to the definition of Asian-Pacific Association for the Study of Liver Diseases	The time from randomization to this secondary outcome, up to 3 years after randomization
Number of Participants with severe acute exacerbation of chronic hepatitis B	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	The time from randomization to this secondary outcome, up to 3 years after randomization
Number of Participants with clinical relapse of active hepatitis B	Serum alanine aminotransferase > 2 times the upper limit of normal in the presence of serum HBV DNA >2000 IU/mL	The time from randomization to this secondary outcome, up to 3 years after randomization
Number of Participants with incident hepatocellular carcinoma	Diagnosis of hepatocellular carcinoma after randomization	The time from randomization to this secondary outcome, up to 3 years after randomization
Changes in the FIB4 index from baseline	The formula for FIB-4 is: Age ([yr] x AST [U/L]) / ((PLT [10(9)/L]) x (ALT [U/L])(1/2)).	At three years after randomization
Changes in serum concentration of quantitative HBsAg from the baseline at randomization	Quantitative HBsAg measured in log IU/mL	At three years after randomization
Changes in serum concentration of HBcrAg from the baseline at randomization	Quantitative HBcrAg measured in log U/mL	At three years after randomization
Changes in the quality of life as measured by Short Form-36 Inventory from the baseline	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.	At each follow-up visit during the study period, up to 3 years after randomization
Changes in the scores measured by the General Anxiety Disorder-7 from baseline	Chinese version of the questionnaire. The total score can range from 0 to 21, with a higher score indicating more severe anxiety	At each follow-up visit during the study period, up to 3 years after randomization
Direct expenditure on healthcare	Money (measured in US dollars) that is paid for all sort of healthcare	At three years after randomization
Changes in the scores measured by the Perceived Stress Scale - 14 from baseline	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.	At each follow-up visit during the study period, up to 3 years after randomization

Collaborators and Investigators

• Sponsor: E-DA Hospital
• Investigators: Principal Investigator: Yao-Chun Hsu, MD, PhD, E-Da Hospital/I-Shou University

Publications and helpful links

General Publications

• Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, Chen DS, Chen HL, Chen PJ, Chien RN, Dokmeci AK, Gane E, Hou JL, Jafri W, Jia J, Kim JH, Lai CL, Lee HC, Lim SG, Liu CJ, Locarnini S, Al Mahtab M, Mohamed R, Omata M, Park J, Piratvisuth T, Sharma BC, Sollano J, Wang FS, Wei L, Yuen MF, Zheng SS, Kao JH. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016 Jan;10(1):1-98. doi: 10.1007/s12072-015-9675-4. Epub 2015 Nov 13.
• Kao JH, Jeng WJ, Ning Q, Su TH, Tseng TC, Ueno Y, Yuen MF. APASL guidance on stopping nucleos(t)ide analogues in chronic hepatitis B patients. Hepatol Int. 2021 Aug;15(4):833-851. doi: 10.1007/s12072-021-10223-5. Epub 2021 Jul 23.
• Hsu YC, Yeh ML, Wong GL, Chen CH, Peng CY, Buti M, Enomoto M, Xie Q, Trinh H, Preda C, Liu L, Cheung KS, Yeo YH, Hoang J, Huang CF, Riveiro-Barciela M, Kozuka R, Istratescu D, Tsai PC, Accarino EV, Lee DH, Wu JL, Huang JF, Dai CY, Cheung R, Chuang WL, Yuen MF, Wong VW, Yu ML, Nguyen MH. Incidences and Determinants of Functional Cure During Entecavir or Tenofovir Disoproxil Fumarate for Chronic Hepatitis B. J Infect Dis. 2021 Dec 1;224(11):1890-1899. doi: 10.1093/infdis/jiab241.
• Berg T, Simon KG, Mauss S, Schott E, Heyne R, Klass DM, Eisenbach C, Welzel TM, Zachoval R, Felten G, Schulze-Zur-Wiesch J, Cornberg M, Op den Brouw ML, Jump B, Reiser H, Gallo L, Warger T, Petersen J; FINITE CHB study investigators [First investigation in stopping TDF treatment after long-term virological suppression in HBeAg-negative chronic hepatitis B]. Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients - FINITE study. J Hepatol. 2017 Nov;67(5):918-924. doi: 10.1016/j.jhep.2017.07.012. Epub 2017 Jul 21.
• Jeng WJ, Chen YC, Chien RN, Sheen IS, Liaw YF. Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B. Hepatology. 2018 Aug;68(2):425-434. doi: 10.1002/hep.29640. Epub 2018 May 6.
• Hall SAL, Vogrin S, Wawryk O, Burns GS, Visvanathan K, Sundararajan V, Thompson A. Discontinuation of nucleot(s)ide analogue therapy in HBeAg-negative chronic hepatitis B: a meta-analysis. Gut. 2022 Aug;71(8):1629-1641. doi: 10.1136/gutjnl-2020-323979. Epub 2021 Sep 7.

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2022
• Primary Completion (Anticipated): December 1, 2025
• Study Completion (Anticipated): December 1, 2026

Study Registration Dates

• First Submitted: December 19, 2022
• First Submitted That Met QC Criteria: March 30, 2023
• First Posted (Actual): March 31, 2023

Study Record Updates

• Last Update Posted (Actual): March 31, 2023
• Last Update Submitted That Met QC Criteria: March 30, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: randomized trial; antiviral therapy; hepatitis b virus infection
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis B, Chronic; Hepatitis, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Tenofovir; Entecavir
• Other Study ID Numbers: EMRP26111N

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.
• IPD Sharing Time Frame: Data will become available beginning with full publication of the study results in an academic peer-reviewed journal and for at least a year.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No