Impact of Hepatitis B Immunoglobulins in Patients With Chronic Hepatitis B on Hepatocellular Carcinoma - a Proof of Concept Study

Hepatocellular Carcinoma Clinical Trial

— HBIG  

Official title:

Impact of Hepatitis B Immunoglobulins in Patients With Chronic Hepatitis B on Hepatocellular Carcinoma

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05293158
• Other study ID #: HBIG
• Status: Not yet recruiting
• Phase: N/A
• Start date: November 2024
• Est. completion date: June 2026

Study information

• Verified date: January 2024
• Source: Medical University of Graz
• Contact: Peter Schemmer, Univ.-Prof. DDr. MBA FACS
• Phone: +43 316 385 84094
• Email: peter.schemmer[@]medunigraz.at
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

In the current literature, infection with the hepatitis B virus (HBV) is described as one of the main risk factors for the development of hepatocellular carcinoma (HCC).

According to the current study situation, the Hepatitis B surface antigen (HBsAg) is considered as an important marker, since low levels and sero-clearance of HBsAg are both correlated with a lower risk of HCC development / recurrence.Currently there is no treatment option available that efficiently targets HBsAg. Besides neutralizing infectious HBV virions, Hepatitis B immunoglobulins (HBIG) can directly bind and neutralize extracellular HBsAg/SVPs, and even intracellular HBsAg targeting is reported. In addition, HBIGs can initiate effector-cell attack (via antibody-dependent cellular cytotoxicity, ADCC) towards infected hepatocytes.

The potential benefit of HBIGs in the HCC context is further underlined by recent evidence for the ability of HBIGs to reduce the viability, proliferation, and self-renewal of tumor-initiating cells (TICs) - isolated from HBV-HCC patients - accompanied by downregulation of stemness markers, e.g., OCT-4.According to the current study situation, the use of HBIGs significantly reduces the risk of HBV reinfection after transplantation and improves the results of liver transplantation in patients with chronic HBV infection. The potential benefit of treating HBV-HCC patients on the LTx (liver transplantation) waiting list with hepatitis B immunoglobulin is the possible stop or inhibition of tumor progression while waiting for an LTx. So far there is no clinical evidence of this.

Mechanistically, hepatitis B immunoglobulin could occur through neutralization of circulating HBsAg, which is an important driver of an immunosuppressive environment in HBV patients, and possibly through direct effects against HBV HCC tumor cells (through antibody-dependent cellular cytotoxicity, ADCC). Therefore, the idea behind preoperative HBIG administration before liver transplantation is to reduce the rate of patients in whom a transplantation would no longer have been possible due to tumor progression. Thus, due to tumor progression in HBV-positive HCC-patients there is a monthly drop-out from the waiting list of about 4%.

The basic idea behind the treatment of HBV-HCC patients before tumor resection with hepatitis B immunoglobulin is to potentially stop or positively influence tumor progression through the effects mentioned above, in the time between diagnosis and resection.

Zhou et al. (2015) have shown a connection between HBsAg levels and HCC relapses after resection, although the exact role of HBsAg is still unclear. In no case will the treatment postpone the time of tumor resection, as only patients are considered who, for clinical reasons, can expect a certain time until resection. The present proof of concept study aims to quantify HBsAg reduction due to preoperative administration of HBIGs in HBV-positive HCC-patients and serve as a template for future multicentre clinical trials.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 5
• Est. completion date: June 2026
• Est. primary completion date: June 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years to 80 Years

Eligibility

Inclusion Criteria:

• Patients = 19 years and = 80 of age

• HBsAg-positive HCC-patients scheduled for resection in =6 weeks or HBsAg-positive HCC- patients listed for LT

• Ability of subjects to understand character and individual consequences of the clinical trial

• Written informed consent must be available before enrolment in the trial

Exclusion Criteria:

• Clinically significant illness (other than HBV) or any other major medical disorder that, in the opinion of the investigator, may interfere with subject treatment

• No eligibility for resection / LT

• Concurrent any other malignancy

• Co-infection with hepatitis C virus (defined as HCV RNA positive, HCV RNA-negative/anti-HCV-positive patients can be included) and/or human immunodeficiency virus (HIV)

• Clinical hepatic decompensation

• Allergy to HBIG

• Pregnant, lactating patients

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• HBV
• Hepatitis
• Hepatitis B
• Hepatitis B, Chronic
• Hepatocellular Carcinoma

Intervention

Drug:
• Hepatect CP 50 I.E./ml infusion solution
Application of i.v. (intravenously) HBIGs for =6-weeks: Day (D) 0-7: 10.000 IU D14 until end-of-treatment: 10.000 IU once per week HBIGs will be given until LT/liver resection.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Medical University of Graz

References & Publications (24)

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Chang TS, Chen CL, Wu YC, Liu JJ, Kuo YC, Lee KF, Lin SY, Lin SE, Tung SY, Kuo LM, Tsai YH, Huang YH. Inflammation Promotes Expression of Stemness-Related Properties in HBV-Related Hepatocellular Carcinoma. PLoS One. 2016 Feb 26;11(2):e0149897. doi: 10.1371/journal.pone.0149897. eCollection 2016. Erratum In: PLoS One. 2017 Jan 26;12 (1):e0171176. — View Citation

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Lee EC, Kim SH, Lee SD, Park H, Lee SA, Park SJ. High-dose hepatitis B immunoglobulin therapy in hepatocellular carcinoma with hepatitis B virus-DNA/hepatitis B e antigen-positive patients after living donor liver transplantation. World J Gastroenterol. 2016 Apr 14;22(14):3803-12. doi: 10.3748/wjg.v22.i14.3803. — View Citation

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Liu H, Xu J, Zhou L, Yun X, Chen L, Wang S, Sun L, Wen Y, Gu J. Hepatitis B virus large surface antigen promotes liver carcinogenesis by activating the Src/PI3K/Akt pathway. Cancer Res. 2011 Dec 15;71(24):7547-57. doi: 10.1158/0008-5472.CAN-11-2260. Epub 2011 Oct 12. — View Citation

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Liu WR, Tian MX, Jin L, Yang LX, Ding ZB, Shen YH, Peng YF, Zhou J, Qiu SJ, Dai Z, Fan J, Shi YH. High levels of hepatitis B surface antigen are associated with poorer survival and early recurrence of hepatocellular carcinoma in patients with low hepatitis B viral loads. Ann Surg Oncol. 2015 Mar;22(3):843-50. doi: 10.1245/s10434-014-4043-5. Epub 2014 Oct 1. — View Citation

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Salpini R, Surdo M, Warner N, Cortese MF, Colledge D, Soppe S, Bellocchi MC, Armenia D, Carioti L, Continenza F, Di Carlo D, Saccomandi P, Mirabelli C, Pollicita M, Longo R, Romano S, Cappiello G, Spano A, Trimoulet P, Fleury H, Vecchiet J, Iapadre N, Barlattani A, Bertoli A, Mari T, Pasquazzi C, Missale G, Sarrecchia C, Orecchini E, Michienzi A, Andreoni M, Francioso S, Angelico M, Verheyen J, Ceccherini-Silberstein F, Locarnini S, Perno CF, Svicher V. Novel HBsAg mutations correlate with hepatocellular carcinoma, hamper HBsAg secretion and promote cell proliferation in vitro. Oncotarget. 2017 Feb 28;8(9):15704-15715. doi: 10.18632/oncotarget.14944. — View Citation

Schilling R, Ijaz S, Davidoff M, Lee JY, Locarnini S, Williams R, Naoumov NV. Endocytosis of hepatitis B immune globulin into hepatocytes inhibits the secretion of hepatitis B virus surface antigen and virions. J Virol. 2003 Aug;77(16):8882-92. doi: 10.1128/jvi.77.16.8882-8892.2003. — View Citation

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Thi Vo T, Poovorawan K, Charoen P, Soonthornworasiri N, Nontprasert A, Kittitrakul C, Phumratanaprapin W, Tangkijvanich P. Association between Hepatitis B Surface Antigen Levels and the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Infection: Systematic Review and Meta-Analysis. Asian Pac J Cancer Prev. 2019 Aug 1;20(8):2239-2246. doi: 10.31557/APJCP.2019.20.8.2239. — View Citation

Tseng TC, Liu CJ, Yang HC, Su TH, Wang CC, Chen CL, Kuo SF, Liu CH, Chen PJ, Chen DS, Kao JH. High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology. 2012 May;142(5):1140-1149.e3; quiz e13-4. doi: 10.1053/j.gastro.2012.02.007. Epub 2012 Feb 11. — View Citation

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* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	HBsAg change from baseline to week 6	Quantification of the magnitude of the effect of =6-week; unit: IU/ml treatment with Hepatitis B immunoglobulins in patients with chronic hepatitis B and HCC, determined by the HBsAg reduction after week 6; Evaluation of the safety and tolerability of Hepatitis B immunoglobulins administered for =6-weeks in patients with chronic hepatitis B and HCC	=6-weeks
Secondary	Change of HBsAg at different time points during treatment	unit: IU/ml	baseline and weekly during the treatment period and during the follow-up at 2 weeks, 4 weeks, 6 weeks, and 8 weeks after treatment stop.
Secondary	Change of HCC response to treatment	Tumor size (cm) will be investigated via MR Primovist (RECIST) or alternatively via CT (RECIST).	Tumor material will be measured at baseline and at end of treatment (on average =6-weeks)
Secondary	Change of Biochemical response (B cells)	Immune responses during HBIG treatment (analysis of B cells); unit 10^9/l	baseline and weekly during the treatment period and during the follow-up at 2 weeks, 4 weeks, 6 weeks, and 8 weeks after treatment stop.
Secondary	Change of Biochemical response (NK cells)	Immune responses during HBIG treatment (analysis of NK cells); unit 10^9/l	baseline and weekly during the treatment period and during the follow-up at 2 weeks, 4 weeks, 6 weeks, and 8 weeks after treatment stop.
Secondary	Change of Biochemical response (T cells)	Immune responses during HBIG treatment (analysis of T cells); unit 10^9/l	baseline and weekly during the treatment period and during the follow-up at 2 weeks, 4 weeks, 6 weeks, and 8 weeks after treatment stop.
Secondary	Change of Cellular response (CD3)	Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (CD3); unit:10^9/L	Tumor material will be collected at baseline and end-of-treatment (on average =6-weeks) via liver biopsies and will be analysed by immune histochemistry
Secondary	Change of Cellular response (CD4)	Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (CD4); unit:10^9/L	Tumor material will be collected at baseline and end-of-treatment (on average =6-weeks) via liver biopsies and will be analysed by immune histochemistry
Secondary	Change of Cellular response (CD8)	Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (CD8); unit:10^9/L	Tumor material will be collected at baseline and end-of-treatment (on average =6-weeks) via liver biopsies and will be analysed by immune histochemistry
Secondary	Change of Cellular response (CD25)	Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (CD25); unit:10^9/L	Tumor material will be collected at baseline and end-of-treatment (on average =6-weeks) via liver biopsies and will be analysed by immune histochemistry
Secondary	Change of Cellular response (CD34)	Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (CD34); unit:10^9/L	Tumor material will be collected at baseline and end-of-treatment (on average =6-weeks) via liver biopsies and will be analysed by immune histochemistry
Secondary	Change of Cellular response (CD133)	Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (CD133); unit:10^9/L	Tumor material will be collected at baseline and end-of-treatment (on average =6-weeks) via liver biopsies and will be analysed by immune histochemistry
Secondary	Change of Cellular response (CD19)	Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (CD19); unit:10^9/L	Tumor material will be collected at baseline and end-of-treatment (on average =6-weeks) via liver biopsies and will be analysed by immune histochemistry
Secondary	Change of Cellular response (CD56)	Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (CD56); unit:10^9/L	Tumor material will be collected at baseline and end-of-treatment (on average =6-weeks) via liver biopsies and will be analysed by immune histochemistry
Secondary	Change of Cellular response (CD49f)	Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (CD49f); unit:10^9/L	Tumor material will be collected at baseline and end-of-treatment (on average =6-weeks) via liver biopsies and will be analysed by immune histochemistry
Secondary	Change of Cellular response (FoxP3)	Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (FoxP3) unit: µg/ml	Tumor material will be collected at baseline and end-of-treatment (on average =6-weeks) via liver biopsies and will be analysed by immune histochemistry
Secondary	Change of Cellular response (Ki67)	Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (Ki67) unit: %	Tumor material will be collected at baseline and end-of-treatment (on average =6-weeks) via liver biopsies and will be analysed by immune histochemistry
Secondary	Change of Cellular response (HLA-DR)	Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (HLA-DR) unit: %	Tumor material will be collected at baseline and end-of-treatment (on average =6-weeks) via liver biopsies and will be analysed by immune histochemistry
Secondary	Change of Cellular response (IFN gamma)	Tumor material will be collected via liver biopsies and will be analysed by immune histochemistry (IFN gamma) unit: IU/ml	Tumor material will be collected at baseline and end-of-treatment (on average =6-weeks) via liver biopsies and will be analysed by immune histochemistry