Clinical trial NCT05965388: Predictive Value of HBV pgRNA on Long-term Outcomes in Hepatitis B Patients Treated With Antiviral Therapy
Official title: Predictive Value of HBV pgRNA on Long-term Outcomes in Hepatitis B Patients Treated With Antiviral Therapy
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: HBV
HCC
Lead sponsor: Huashan Hospital
Sponsor class: OTHER
Collaborators: name: Shandong Provincial Hospital
name: First Affiliated Hospital Xi'an Jiaotong University
name: The Affiliated Hospital of Xuzhou Medical University
name: First Affiliated Hospital of Fujian Medical University
name: The Third People's Hospital of Taiyuan
name: The First People's Hospital of Yunnan
name: The First Affiliated Hospital of Anhui Medical University
name: Wuhan Union Hospital, China
name: The First Affiliated Hospital with Nanjing Medical University
First posted: 2023-07-28
Enrollment: 5000
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with chronic hepatitis B who have been determined by clinicians to start, or have already taken the first-line treatment {including pegylated interferon \[IFN\] monotherapy, a potent nucleos(t)ide analogue \[NA\] monotherapy, two different potent NAs combination therapy, or NA plus IFN combination therapy

Brief summary: The goal of this prospective, exploratory, non-intervention, multi-center, real-world study is to investigate the predictive value of HBV pgRNA in the occurrence of long-term outcomes under antiviral therapy in patients with chronic hepatitis B.

Participants will take the necessary clinical examination and blood draw during the patient's treatment and follow-up, and all the treatment is determined by clinicians.

Detailed description: This study is a prospective, exploratory, multi-center, real-world study, with Huashan Hospital as the leading unit. The study includes patients with chronic hepatitis B who have been determined by clinicians to start, or have already taken the first-line treatment { including pegylated interferon \[IFN\] monotherapy, a potent nucleos(t)ide analogue \[NA\] monotherapy, two different potent NAs combination therapy, or NA plus IFN combination therapy. The study only collects clinical data and serum samples, without imposing any additional intervention measures or affecting any relevant clinical decisions. The clinical data is collected from the patient's clinical follow-up examination data, without additional visits and auxiliary examinations. Sample collection During the necessary clinical examination and blood draw during the patient's treatment and follow-up, one additional serum separation tube (3ml) was drawn, without additional invasive examination for the patient. The study will follow up with patients for 5 years to explore the relationship between the serum HBV pgRNA level and the endpoint event at different time points.

Eligibility criteria: Inclusion Criteria:

* CHB defined as positive hepatitis B surface antigen at least 6 months, or HBV-related histological changes within 1 year if HBsAg positive less than 6 months;
* Age between 18-80 years, gender is not limited；
* Patients with chronic hepatitis B who have been determined by clinicians to start, or have already taken the first-line treatment {including pegylated interferon \[IFN\] monotherapy, a potent nucleos(t)ide analogue \[NA\] monotherapy, two different potent NAs combination therapy, or NA plus IFN combination therapy;
* Patient who reads and signs informed consent.

Exclusion Criteria:

* Patients with malignancies other than hepatocellular carcinoma.

Primary outcomes:
measure: Number of Participants with Diagnosis of hepatocellular carcinoma during the observation period
timeFrame: 5 years
Secondary outcomes:
measure: Number of Participants with Diagnosis of participants with decompensation cirrhosis during the observation period
timeFrame: Week 4, Week 12, Week24, Week36, Week48, Week72, Week96, Week120, Week144, Week168, Week192, Week216 and Week240
measure: Number of Participants with Diagnosis of participants with liver transplantation during the observation period
timeFrame: Week 4, Week 12, Week24, Week36, Week48, Week72, Week96, Week120, Week144, Week168, Week192, Week216 and Week240
measure: Number of Participants with Diagnosis of participants with fibrosis regression and progression during the observation period
timeFrame: Week 4, Week 12, Week24, Week36, Week48, Week72, Week96, Week120, Week144, Week168, Week192, Week216 and Week240
measure: Number of Participants with Diagnosis of participants with serological response during the observation period
timeFrame: Week 4, Week 12, Week24, Week36, Week48, Week72, Week96, Week120, Week144, Week168, Week192, Week216 and Week240
Other outcomes:
Locations:
city: Hefei
country: China
facility: The First Affiliated Hospital of Anhui Medical University
state: Anhui
city: Fuzhou
country: China
facility: The First Affiliated Hospital of Fujian Medical University
state: Fujian
city: Wuhan
country: China
facility: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
state: Hubei
city: Nanjing
country: China
facility: Jiangsu Province Hospital
state: Jiangsu
city: Xuzhou
country: China
facility: the Affiliated Hosptial of Xuzhou Medical University
state: Jiangsu
city: Jinan
country: China
facility: Shandong Provincial Hospital of Shandong University
state: Shandong
city: Taiyuan
country: China
facility: The Third People's Hospital of Taiyuan
state: Shanxi
city: Xi'an
country: China
facility: First Affiliated Hospital Xi'an Jiaotong University
state: Shanxi
city: Kunming
country: China
facility: The First People's Hospital Of YunNan
state: Yunnan
city: Shanghai
country: China
facility: Huashan Hospital
Study officials:
References:
citation: Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015 Oct 17;386(10003):1546-55. doi: 10.1016/S0140-6736(15)61412-X. Epub 2015 Jul 28.
citation: Chinese Society of Infectious Diseases, Chinese Medical Association; Chinese Society of Hepatology, Chinese Medical Association. [The guidelines of prevention and treatment for chronic hepatitis B (2019 version)]. Zhonghua Gan Zang Bing Za Zhi. 2019 Dec 20;27(12):938-961. doi: 10.3760/cma.j.issn.1007-3418.2019.12.007. Chinese.
citation: Jung MC, Pape GR. Immunology of hepatitis B infection. Lancet Infect Dis. 2002 Jan;2(1):43-50. doi: 10.1016/s1473-3099(01)00172-4.
citation: Shin EC, Sung PS, Park SH. Immune responses and immunopathology in acute and chronic viral hepatitis. Nat Rev Immunol. 2016 Aug;16(8):509-23. doi: 10.1038/nri.2016.69. Epub 2016 Jul 4.
citation: Nassal M. HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B. Gut. 2015 Dec;64(12):1972-84. doi: 10.1136/gutjnl-2015-309809. Epub 2015 Jun 5.
citation: Pollicino T, Belloni L, Raffa G, Pediconi N, Squadrito G, Raimondo G, Levrero M. Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 histones. Gastroenterology. 2006 Mar;130(3):823-37. doi: 10.1053/j.gastro.2006.01.001.
citation: Ko C, Chakraborty A, Chou WM, Hasreiter J, Wettengel JM, Stadler D, Bester R, Asen T, Zhang K, Wisskirchen K, McKeating JA, Ryu WS, Protzer U. Hepatitis B virus genome recycling and de novo secondary infection events maintain stable cccDNA levels. J Hepatol. 2018 Dec;69(6):1231-1241. doi: 10.1016/j.jhep.2018.08.012. Epub 2018 Aug 22.
citation: Tang LSY, Covert E, Wilson E, Kottilil S. Chronic Hepatitis B Infection: A Review. JAMA. 2018 May 1;319(17):1802-1813. doi: 10.1001/jama.2018.3795.
citation: Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH, Wong JB. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018 Apr;67(4):1560-1599. doi: 10.1002/hep.29800. No abstract available.
citation: European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017 Aug;67(2):370-398. doi: 10.1016/j.jhep.2017.03.021. Epub 2017 Apr 18.
citation: Omata M, Cheng AL, Kokudo N, Kudo M, Lee JM, Jia J, Tateishi R, Han KH, Chawla YK, Shiina S, Jafri W, Payawal DA, Ohki T, Ogasawara S, Chen PJ, Lesmana CRA, Lesmana LA, Gani RA, Obi S, Dokmeci AK, Sarin SK. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int. 2017 Jul;11(4):317-370. doi: 10.1007/s12072-017-9799-9. Epub 2017 Jun 15.
citation: Kim GA, Lim YS, An J, Lee D, Shim JH, Kim KM, Lee HC, Chung YH, Lee YS, Suh DJ. HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability. Gut. 2014 Aug;63(8):1325-32. doi: 10.1136/gutjnl-2013-305517. Epub 2013 Oct 25.
citation: Lim TH, Gane E, Moyes C, Borman B, Cunningham C. HBsAg loss in a New Zealand community study with 28-year follow-up: rates, predictors and long-term outcomes. Hepatol Int. 2016 Sep;10(5):829-37. doi: 10.1007/s12072-016-9709-6. Epub 2016 Mar 8.
citation: Wang YX, Niklasch M, Liu T, Wang Y, Shi B, Yuan W, Baumert TF, Yuan Z, Tong S, Nassal M, Wen YM. Interferon-inducible MX2 is a host restriction factor of hepatitis B virus replication. J Hepatol. 2020 May;72(5):865-876. doi: 10.1016/j.jhep.2019.12.009. Epub 2019 Dec 18.
citation: Tan G, Yi Z, Song H, Xu F, Li F, Aliyari R, Zhang H, Du P, Ding Y, Niu J, Wang X, Su L, Qin FX, Cheng G. Type-I-IFN-Stimulated Gene TRIM5gamma Inhibits HBV Replication by Promoting HBx Degradation. Cell Rep. 2019 Dec 10;29(11):3551-3563.e3. doi: 10.1016/j.celrep.2019.11.041.
citation: Sadler AJ, Williams BR. Interferon-inducible antiviral effectors. Nat Rev Immunol. 2008 Jul;8(7):559-68. doi: 10.1038/nri2314.
citation: Marcellin P, Ahn SH, Ma X, Caruntu FA, Tak WY, Elkashab M, Chuang WL, Lim SG, Tabak F, Mehta R, Petersen J, Foster GR, Lou L, Martins EB, Dinh P, Lin L, Corsa A, Charuworn P, Subramanian GM, Reiser H, Reesink HW, Fung S, Strasser SI, Trinh H, Buti M, Gaeta GB, Hui AJ, Papatheodoridis G, Flisiak R, Chan HL; Study 149 Investigators. Combination of Tenofovir Disoproxil Fumarate and Peginterferon alpha-2a Increases Loss of Hepatitis B Surface Antigen in Patients With Chronic Hepatitis B. Gastroenterology. 2016 Jan;150(1):134-144.e10. doi: 10.1053/j.gastro.2015.09.043. Epub 2015 Oct 8.
citation: Reijnders JG, Rijckborst V, Sonneveld MJ, Scherbeijn SM, Boucher CA, Hansen BE, Janssen HL. Kinetics of hepatitis B surface antigen differ between treatment with peginterferon and entecavir. J Hepatol. 2011 Mar;54(3):449-54. doi: 10.1016/j.jhep.2010.07.046. Epub 2010 Nov 5.
citation: Wursthorn K, Lutgehetmann M, Dandri M, Volz T, Buggisch P, Zollner B, Longerich T, Schirmacher P, Metzler F, Zankel M, Fischer C, Currie G, Brosgart C, Petersen J. Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B. Hepatology. 2006 Sep;44(3):675-84. doi: 10.1002/hep.21282.
citation: van Bommel F, van Bommel A, Krauel A, Wat C, Pavlovic V, Yang L, Deichsel D, Berg T, Bohm S. Serum HBV RNA as a Predictor of Peginterferon Alfa-2a Response in Patients With HBeAg-Positive Chronic Hepatitis B. J Infect Dis. 2018 Aug 24;218(7):1066-1074. doi: 10.1093/infdis/jiy270.
citation: Huang YW, Takahashi S, Tsuge M, Chen CL, Wang TC, Abe H, Hu JT, Chen DS, Yang SS, Chayama K, Kao JH. On-treatment low serum HBV RNA level predicts initial virological response in chronic hepatitis B patients receiving nucleoside analogue therapy. Antivir Ther. 2015;20(4):369-75. doi: 10.3851/IMP2777. Epub 2014 Apr 16.
citation: Jansen L, Kootstra NA, van Dort KA, Takkenberg RB, Reesink HW, Zaaijer HL. Hepatitis B Virus Pregenomic RNA Is Present in Virions in Plasma and Is Associated With a Response to Pegylated Interferon Alfa-2a and Nucleos(t)ide Analogues. J Infect Dis. 2016 Jan 15;213(2):224-32. doi: 10.1093/infdis/jiv397. Epub 2015 Jul 27.
citation: Tsuge M, Murakami E, Imamura M, Abe H, Miki D, Hiraga N, Takahashi S, Ochi H, Nelson Hayes C, Ginba H, Matsuyama K, Kawakami H, Chayama K. Serum HBV RNA and HBeAg are useful markers for the safe discontinuation of nucleotide analogue treatments in chronic hepatitis B patients. J Gastroenterol. 2013 Oct;48(10):1188-204. doi: 10.1007/s00535-012-0737-2. Epub 2013 Feb 9.
citation: Serum hepatitis B virus RNA levels as an early predictor of hepatitis B envelope antigen seroconversion during treatment with polymerase inhibitors. Hepatology. 2016 Jan;63(1):349. doi: 10.1002/hep.28349. No abstract available.
citation: Department of Medical Administration, National Health and Health Commission of the People's Republic of China. [Guidelines for diagnosis and treatment of primary liver cancer in China (2019 edition)]. Zhonghua Gan Zang Bing Za Zhi. 2020 Feb 20;28(2):112-128. doi: 10.3760/cma.j.issn.1007-3418.2020.02.004. No abstract available. Chinese.
citation: Chinese Society of Hepatology,Chinese Medical Association. [Chinese guidelines on the management of liver cirrhosis]. Zhonghua Gan Zang Bing Za Zhi. 2019 Nov 20;27(11):846-865. doi: 10.3760/cma.j.issn.1007-3418.2019.11.008. Chinese.