TAF (Tenofovir Alafenamide) for Preventing Progression of Liver Disease in Non-cirrhotic Chronic HBV Infection With Normal ALT and Low Viral Load.

TAF (Tenofovir Alafenamide) for Preventing Progression of Liver Disease in Non-cirrhotic Chronic HBV Infection With Normal ALT and Low Viral Load - a Randomized Controlled Trial

The main goal of therapy for patients with chronic HBV infection with no significant liver disease is to improve survival and quality of life by preventing disease progression, development of liver cirrhosis and consequently HCC development. The likelihood of achieving these goals depends on the timing of therapy during the natural course of the infection but also on the stage of the disease and the patients' age when treatment is started. The inhibition of viral replication and normalization of ALT by antiviral treatment has been shown to achieve the elimination of chronic HBV-induced necroinflammatory activity and progressive fibrotic liver progression in the vast majority of patients, in turn reducing the risk of HCC. Even in HBeAg positive patients, treatment-induced HBeAg loss and seroconversion to antiHBe characterizes the induction of a partial immune control often leading to a low replicative phase of the chronic HBV infection and good outcomes.

Treatment in chronic HBV infection is indicated in - presence of advanced fibrosis/cirrhosis (LSM >11 KPA) or patients with significant fibrosis (LSM >8 or APRI >1.5 or >F2 on liver biopsy) with high viral load (>2000 IU/ml) or significantly elevated ALT (x2 ULN). Presence of any of these factors is known to increase the risk of development of cirrhosis and hepatocellular carcinoma. TAF in non-cirrhotic patients (LSM <8 KPA) with normal ALT and low viral load (HBV DNA <2000 IU/ml) (currently treatment ineligible) as compared to delayed initiation (on demand) might reduce HCC risk, progression of liver fibrosis and reduction in HBsAg levels. As TAF is known to have favorable effects on the overall long-term outcome, the main clinical challenge is to identify the patients at risk of HCC and cirrhosis who warrant early antiviral therapy.

Study Overview

• Status: Recruiting
• Conditions: Non-cirrhotic, Chronic Hepatitis B
• Intervention / Treatment: Drug: Tenofovir alafenamide fumarate

Detailed Description

Aim and Objective - To study the safety and efficacy of TAF as compared to initiation based on current criteria in patients with non-cirrhotic chronic HBV infection and normal ALT and low viral load.

Methodology:

Study population: The study will be conducted on the treatment naïve consecutive patients having non-cirrhotic chronic HBV infection and normal ALT and low viral load seen at the outpatient clinics/wards of Department of Hepatology, ILBS, New Delhi.

Study design:

• A prospective, randomized, single center open label study.

Study period: 5 years from the last patient enrollment

Sample size with justification: All consecutive cases consenting to be a participant in this study and meeting inclusion and exclusion criteria will be enrolled. Considering the incidence of 20% for the composite end-point in patients without TAF and 5% for patients on TAF, with power of 80% and alpha error of 5%, 176 patients (88 patients in each arm) need to be enrolled. Considering the attrition rate of ~15%, we decide to enroll 100 patients in each arm.

Intervention

• TAF 25 mg OD vs no treatment x 5 years and beyond
• Tests - Baseline - USG abdomen, ALT, Creatinine, DEXA, HBVDNA, HBeAg, HBsAg (quant), Fibroscan
• 6 monthly - ALT
• 1 yearly - USG abdomen, ALT, Creatinine, DEXA, HBVDNA, HBeAg, HBsAg (quant), Fibroscan
• No liver biopsy

Statistical Analysis:

Data will be reported as mean + SD. Categorical variables will be compared using the chi-square test or Fisher exact test. Normal continuous variables will be compared using the Student's t test Non normal continuous variables will be compared using the Mann Whitney rank-sum test (unpaired data) or the Wilcoxon test (paired data). The actuarial probability of survival will be calculated by the Kaplan-Meier method and compared using the log-rank test. A Cox regression analysis will be performed to identify independent prognostic factors for survival. Univariate and multivariate analysis will be used whenever applicable.

Adverse effects:

Most common- headache, nausea, and fatigue; (1% to 10%): Abdominal pain, nausea, diarrhea, dyspepsia, elevated serum amylase, vomiting, flatulence, abdominal distension; Common (1% to 10%): Rash, pruritus, elevated ALT; Uncommon (0.1% to 1%): Treatment ALT flares.

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Dr Ankur Jindal, DM; Phone Number: 01146300000; Email: ankur.jindal3@gmail.com

Study Locations

• India
  • Delhi
    • New Delhi, Delhi, India, 110070
      • Recruiting
      • Institute of Liver & Biliary Sciences (ILBS)
      • Contact: Dr Ankur Jindal, DM; Phone Number: 01146300000; Email: ankur.jindal3@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

- HBsAg+

• Persistent normal ALT 3-6m apart (<30 IU/ml in male and <20 IU/ml in female)
• HBV DNA < 2000 IU/ml
• LSM <8 Kpa

Exclusion Criteria:

• Prior NUC/IFN exposure
• Renal dysfunction (Serum Creatinine >1.5 mg/dl)
• Known liver cirrhosis/ esophageal varices
• Any clinical decompensation (CD)
• Pre-existing hepatocellular carcinoma
• Pregnancy
• Healthcare workers (HCW)
• Post transplant, patients with advance malignancy or on chemotherapy
• Co-infections - Hepatitis C, Hepatitis D, Human immunodeficiency virus

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: Tenofovir Alafenamide Fumarate; • TAF 25 mg OD vs no treatment x 5 years and beyond	Drug: Tenofovir alafenamide fumarate; • TAF 25 mg OD vs no treatment x 5 years and beyond
No Intervention: No Treatment Arm; No treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients with HBV DNA <2000 IU/ml, normal ALT and no significant fibrosis (as per APASL 2015).	Any two of the following -; Significant fibrosis (LSM >8 Kpa or APRI >1.5); Persistently elevated ALT (2 consecutive ALT >30 U/ml 3-6m apart); HBV DNA >2000 IU/ml	upto 5 Years

Secondary Outcome Measures

Outcome Measure	Time Frame
Incidence of HCC	upto 3 years
Incidence of HCC	upto 5 years
Percentage of patients with LSM >8 Kpa	upto 5 Years
Percentage of patients with LSM >11 Kpa	upto 5 Years
Number of subjects with no progression of fibrosis	upto 5 Years
Percentage of patients with APRI score >1.5 and >2	upto 5 Years
Percentage of patients with HBV DNA >2000 IU/ml	upto 5 Years
Percentage of patients with undetectable HBV DNA	upto 5 Years
Percentage of patients with HBsAg loss and HBsAg seroconversion	upto 5 Years
Log HBsAg reduction	upto 5 Years
Percentage of patients with HBeAg loss and HBeAg seroconversion in HBeAg+ chronic hepatitis B	upto 5 Years
Percentage of patients with ALT > ULN, >2 times and 5 times ULN	upto 5 Years
Treatment related adverse effects of TAF	upto 5 Years
Non-compliant to treatment or monitoring	upto 5 years
Death	upto 5 years
Treatment related severe adverse effects	upto 5 years

Collaborators and Investigators

• Sponsor: Institute of Liver and Biliary Sciences, India

Study record dates

Study Major Dates

• Study Start (Actual): February 23, 2022
• Primary Completion (Anticipated): December 31, 2027
• Study Completion (Anticipated): December 31, 2027

Study Registration Dates

• First Submitted: January 4, 2022
• First Submitted That Met QC Criteria: January 4, 2022
• First Posted (Actual): January 19, 2022

Study Record Updates

• Last Update Posted (Actual): February 28, 2022
• Last Update Submitted That Met QC Criteria: February 23, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Hepatitis, Chronic; Hepatitis; Liver Diseases; Hepatitis B; Hepatitis B, 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
• Other Study ID Numbers: ILBS-HBV-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No