Comparison of HBV Reactivation Between Patients With High HBV-DNA and Low HBV-DNA Loads Undergoing ICI and Concurrent Antiviral Prophylaxis: a Prospective Observational Study

Comparison of Hepatitis B Virus Reactivation Between Patients With High HBV-DNA and Low HBV-DNA Loads Undergoing Immune Checkpoint Inhibitor and Concurrent Antiviral Prophylaxis: a Prospective Observational Study

Immune checkpoint inhibitor (ICI), including programmed cell death protein-1 (PD-1) inhibitor or programmed cell death-Ligand 1 (PD-L1) inhibitor , is recommended to treat advanced hepatocellular carcinoma (HCC). However, the safety of ICI in patients with a high HBV-DNA load is unknown because of the potential risk of hepatitis B virus (HBV) reactivation. This study was to compare the HBV reactivation between patients with low HBV-DNA loads and high HBV-DNA loads undergoing antiviral prophylaxis and ICI.

Study Overview

• Status: Recruiting
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Drug: ICI; Drug: Antiviral Prophylaxis

• Study Type: Observational
• Enrollment (Estimated): 800

Contacts and Locations

Study Locations

• China
  • Zhongshan, China
    • Recruiting
    • ZhongShan People 's Hospital
    • Contact: Peng Peng; Phone Number: 13501509619; Email: 1547463629@qq.com
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Recruiting
      • Cancer Center Sun Yat-sen University
      • Contact: Ming Shi, MD; Phone Number: 8620-87343115; Email: shiming@mail.sysu.edu.cn
    • Guangzhou, Guangdong, China, 510620
      • Recruiting
      • Guangzhou Twelfth People 's Hospital
      • Contact: Yuanmin Zhou, MD; Phone Number: 15521278919; Email: 13430288977@139.com
      • Principal Investigator: Jinghua Chen, MD
    • Kaiping, Guangdong, China, 529300
      • Recruiting
      • Kaiping Central Hospital
      • Contact: Shijie Zhang, MD; Phone Number: 13717287622; Email: Shijie_9262511@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Eligible patients were divided into low HBV-DNA group (low group, ≤500 IU/ml) and high HBV-DNA group (high group, >500 IU/ml) according to baseline HBV-DNA level. Baseline HBV-DNA was the HBV-DNA level within 2 weeks prior to initial ICI therapy. For patients who had prior experience with antiviral therapy, the antiviral therapy would be continued. For patients who did not have prior experience with antiviral therapy, antiviral therapy would be administered after patients was confirmed with positive HBsAg or positive HBV-DNA level. Prior use of antiviral therapy was defined that patients have taken antiviral therapy for a period of time before they received ICI therapy. Antiviral prophylaxis was defined as anti-HBV treatment administered before and during ICI therapy. Antiviral treatment was continued even though ICI therapy was terminated.

Description

Inclusion Criteria:

• The diagnosis of HCC was based on the diagnostic criteria for HCC used by the European Association for the Study of the Liver (EASL)
• Seropositive for hepatitis B surface antigen (HBsAg)
• Received concurrent antiviral prophylaxis and at least one cycle of ICI treatment. Prior use of antiviral therapy was allowed
• Adherence to antiviral therapy
• A life expectancy of 3 months or more
• An Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2

Exclusion Criteria:

• other positive viral markers, including IgM antibodies to hepatitis A virus, the hepatitis C virus viral load, IgG antibodies to hepatitis D virus, IgM antibodies to hepatitis E virus
• Antibodies to human immunodeficiency virus,
• A lack of HBV DNA and liver function testing before the first immunotherapy and during the follow-up period.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
high HBV-DNA group; patients with HBV-DNA >500 IU/ml	Drug: ICI; Patients received ICI, including PD-1 inhibitor (pembrolizumab, toripalimab, nivolumab, sintilimab, camrelizumab) or PD-L1 inhibitor (atezolizumab); Drug: Antiviral Prophylaxis; Patient received concurrent antiviral prophylaxis, such as tenofovir, entecavir
low HBV-DNA group; patients with HBV-DNA≤500 IU/ml	Drug: ICI; Patients received ICI, including PD-1 inhibitor (pembrolizumab, toripalimab, nivolumab, sintilimab, camrelizumab) or PD-L1 inhibitor (atezolizumab); Drug: Antiviral Prophylaxis; Patient received concurrent antiviral prophylaxis, such as tenofovir, entecavir

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HBV Reactivation rate	HBV Reactivation rate was defined as one of the following according to the American Association for the Study of Liver Diseases (AASLD) 2018 hepatitis B guidelines: (i) a ≥2 log (100-fold) increase in HBV DNA compared to the baseline level, (ii) HBV DNA ≥3 log (1,000) IU/mL in a patient with previously undetectable level (since HBV DNA levels fluctuate)	2 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
overall survival		12 months
HBV-associated hepatitis	HBV-associated hepatitis was defined as HBV Reactivation plus an ALT increase to ≥3 times the baseline level and >100 U/L according to the AASLD 2018 Hepatitis B Guidance	2 months
PD-1 inhibitor disruption due to hepatitis	PD-1 inhibitor disruption due to hepatitis was defined as either premature termination or a delay of at least 7 days between PD-1 inhibitor cycles because of hepatitis.	2 months
adverse event		30 Days after ICI

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Collaborators: Guangzhou No.12 People's Hospital; Kaiping Central Hospital; ZhongShan People 's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 25, 2020
• Primary Completion (Estimated): December 31, 2023
• Study Completion (Estimated): December 31, 2023

Study Registration Dates

• First Submitted: December 17, 2020
• First Submitted That Met QC Criteria: December 22, 2020
• First Posted (Actual): December 23, 2020

Study Record Updates

• Last Update Posted (Actual): August 2, 2023
• Last Update Submitted That Met QC Criteria: August 1, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma, Hepatocellular; Anti-Infective Agents; Antiviral Agents
• Other Study ID Numbers: SH003

Drug and device information, study documents

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