Effectiveness of TAF in Reducing Clinical Events in CHB Patients Beyond Treatment Indications by Current Guidelines (ATTENTION)

Effectiveness of TAF in Reducing Clinical Events in CHB Patients Beyond Treatment Indications by Current Guidelines

A Multinational, Multicenter, Open-label, Randomized Controlled Trial to Investigate the Effectiveness of Tenofovir Alafenamide in Reducing Clinical Events in Chronic Hepatitis B Patients Beyond Treatment Indications by Current Guidelines

Samsung Medical Center, Kyunghee University Medical Center, Chung-Ang University Hosptial, Chung-Ang University College of Medicine, Seoul National University Hospital, Ulsan University Hospital, Konkuk University Medical Center, Kyungpook National University Hospital, Korea University Guro Hospital, Seoul St. Mary's Hospital, Kaohsiung Medical University, Chang Gung Memorial Hospital, E-DA Hospital, Taitung Mackay Memorial Hospital, National Cheng-Kung University Hospital, Chi Mei Medical Hospital, Chiayi Christian Hospital, St. Martin De Porress Hospital, Dalin Tzu Chi General Hospital, Taichung Veterans General Hospital, China Medical University Hospital

Treatment with Tenofovir Alafenamide(TAF) in Chronic Hepatitis B (CHB) patients classified as beyond treatment indication of current international guidelines (e.g. aged more than 40 years old and 4 ≤ log HBV-DNA IU/mL < 8) is expected to bring improvement in long-term clinical outcomes. This expected result may expand the treatment indications in patients with CHB based on age and HBV-DNA in contrast to current international guidelines of CHB.

Study objectives: To investigate whether TAF treatment reduce clinical events (HCC, death, liver decompensation, portal hypertensive complications, and liver transplantation) in CHB patients beyond treatment indications by current guidelines Study procedure: 780 subjects will be randomized in a 1:1 ratio (A:B) either to receive TAF 25 mg QD or to receive best supportive care after stratification according to the HBeAg status. The duration of maintaining both arms is 8 years. During treatment period, among treatment arm B, subjects who are indicated for antiviral treatment will be treated with TAF as follows: Based on the AASLD 2018 Guidelines of CHB (ALT 70≥ for male, 50≥ for female) 40≤ALT levels<70 IU/L (males) or 40≤ ALT levels<50 IU/L (females) with evidence of significant fibrosis(F2; ≥7.2 kPa) as measured by either liver biopsy, Fibroscan or MR elastograpy performed within 3 months. If they were clinically judged to have cirrhosis by investigators and confirmed with Fibroscan (≥ 12.0 kPa). Treatment Arm A: 390 subjects administered TAF 25 mg once daily Treatment Arm B: 390 subjects received best supportive care The primary analysis will occur at Year 4 with the primary endpoint being cumulative incidence rate of clinical events

390 subjects received best supportive care During treatment period, among treatment arm B, subjects who are indicated for antiviral treatment will be treated with TAF as follows: Based on the AASLD 2018 Guidelines of CHB (ALT 70≥ for male, 50≥ for female) 40≤ALT levels<70 IU/L (males) or 40≤ ALT levels<50 IU/L (females) with evidence of significant fibrosis(F2; ≥7.2 kPa) as measured by either liver biopsy, Fibroscan or MR elastograpy performed within 3 months. If they were clinically judged to have cirrhosis by investigators and confirmed with Fibroscan (≥ 12.0 kPa).

Cumulative rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC)

Cumulative rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC)

Rate of receiving nucleos(t)ide analogue by meeting reimbursement criteria of treatment among Treatment ARM B subjects

Rate of receiving nucleos(t)ide analogue by meeting reimbursement criteria of treatment among Treatment ARM B subjects

Cumulative and annual incidence rate of portal hypertensive complications among HBeAg-positive or HBeAg-negative

Cumulative and annual incidence rate of HCC among subjects according to baseline ALT level (normal ALT and elevated ALT)

Cumulative incidence rate of HCC amongsubjects according to baseline ALT level (normal ALT and elevated ALT)

Cumulative and annual incidence rate of liver transplantation among subjects according to baseline ALT level (normal ALT and elevated ALT)

Cumulative incidence rate of liver transplantation among subjects according to baseline ALT level (normal ALT and elevated ALT)

Cumulative and annual incidence rate of liver decompensation among subjects according to baseline ALT level (normal ALT and elevated ALT)

Cumulative incidence rate of liver decompensation among subjects according to baseline ALT level (normal ALT and elevated ALT)

Cumulative and annual incidence rate of portal hypertensive complications among subjects according to baseline ALT level (normal ALT and elevated ALT)

Cumulative incidence rate of portal hypertensive complications among subjects according to baseline ALT level (normal ALT and elevated ALT)

Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) after excluding patients who occurrs clinical events within 6 months of enrollment

Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) after excluding patients who occurrs clinical events within 12 months of enrollment

Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) in patients with normal ALT (<40 U/L) at the time of enrollment, after excluding patients who occurrs clinical events within 6 months of enrollment

Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) in patients with normal ALT (<40 U/L) at the time of enrollment, after excluding patients who occurrs clinical events within 12 months of enrollment

Inclusion Criteria: Patients must meet all of the following criteria to be eligible to participate in the study Patient must have the ability to understand and sign a written informed consent form; consent must be obtained prior to initiation of study procedures Male or female, 40 to 80 years of age Positive for HBsAg or HBV DNA for at least 6 months or more HBeAg positive or negative No evidence of liver cirrhosis (platelet count ≥100,000/mm3) serum HBV DNA ≥ 4 log10 IU/mL and ≤ 8 log10 IU/mL Serum ALT level <70 if male, <50 if female Estimated creatinine clearance ≥ 30 ml/min based on serum creatinine as measured at the screening evaluation Patient is willing and able to comply with all study requirements Exclusion Criteria: Patients who meet any of the following exclusion criteria are not to be enrolled in this study Co-infection with HCV, HDV, HIV (Confirmed by nucleic acid tests) Abusing alcohol (more than 60 g/day) or illicit drugs Patients with history of hepatic decompensation (e.g., ascites, encephalopathy or variceal hemorrhage) 4-1) Evidence of cirrhosis, including any of follows: Platelet count <100,000/mm3 Esophagogastric varices on endoscopy Evidence of clinically significant portal hypertension Fibroscan ≥ 12.0 kPa (If the test was done in 3 months before the time of screening.) and confirmed to have liver cirrhosis by an investigator 4-2) 40≤ALT levels<70 IU/L (males) or 40≤ ALT levels<50 IU/L (females) with evidence of significant fibrosis(F2; ≥7.2 kPa) as measured by either liver biopsy, Fibroscan or MR elastograpy performed within 3 months. 5. Received interferon or other immunomodulatory treatment for HBV infection in the 12 months before screening for this study 6. Medical condition that requires concurrent use of systemic corticosteroid or other immunosuppressive agents 7. Received solid organ or bone marrow transplant 8. Known hypersensitivity to study drugs, metabolites, or formulation excipients 9. Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the patient unsuitable for the study or unable to comply with dosing requirements 10. Use of investigational agents within 6 months of screening, unless allowed by the Sponsor or Investigator 11. Significant renal, cardiovascular, pulmonary, or neurological disease in the opinion of the Investigator 12. Any malignant tumor in the preceding five years. However, a history of treated malignancy (other than HCC) is allowable if the patient's malignancy has been in complete remission, off chemotherapy and without additional surgical intervention, during the preceding three years 13. Pregnant or breastfeeding or willing to be pregnant 14. Participating in other clinical trials to administer medication. However, it is possible to participate if it is not an antiviral agent or immunosuppressant related clinical trial.

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.

European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; 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.

Tseng TC, Kao JH. Treating Immune-tolerant Hepatitis B. J Viral Hepat. 2015 Feb;22(2):77-84. doi: 10.1111/jvh.12370. Epub 2014 Nov 25.

Andreani T, Serfaty L, Mohand D, Dernaika S, Wendum D, Chazouilleres O, Poupon R. Chronic hepatitis B virus carriers in the immunotolerant phase of infection: histologic findings and outcome. Clin Gastroenterol Hepatol. 2007 May;5(5):636-41. doi: 10.1016/j.cgh.2007.01.005. Epub 2007 Apr 11.

Hui CK, Leung N, Yuen ST, Zhang HY, Leung KW, Lu L, Cheung SK, Wong WM, Lau GK; Hong Kong Liver Fibrosis Study Group. Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase. Hepatology. 2007 Aug;46(2):395-401. doi: 10.1002/hep.21724.

Kennedy PTF, Sandalova E, Jo J, Gill U, Ushiro-Lumb I, Tan AT, Naik S, Foster GR, Bertoletti A. Preserved T-cell function in children and young adults with immune-tolerant chronic hepatitis B. Gastroenterology. 2012 Sep;143(3):637-645. doi: 10.1053/j.gastro.2012.06.009. Epub 2012 Jun 15.

Lai M, Hyatt BJ, Nasser I, Curry M, Afdhal NH. The clinical significance of persistently normal ALT in chronic hepatitis B infection. J Hepatol. 2007 Dec;47(6):760-7. doi: 10.1016/j.jhep.2007.07.022. Epub 2007 Sep 24.

Kumar M, Sarin SK, Hissar S, Pande C, Sakhuja P, Sharma BC, Chauhan R, Bose S. Virologic and histologic features of chronic hepatitis B virus-infected asymptomatic patients with persistently normal ALT. Gastroenterology. 2008 May;134(5):1376-84. doi: 10.1053/j.gastro.2008.02.075. Epub 2008 Feb 29.

Kim GA, Lim YS, Han S, Choi J, Shim JH, Kim KM, Lee HC, Lee YS. High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B. Gut. 2018 May;67(5):945-952. doi: 10.1136/gutjnl-2017-314904. Epub 2017 Oct 21.

Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, Huang GT, Iloeje UH; REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006 Jan 4;295(1):65-73. doi: 10.1001/jama.295.1.65.

Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ; Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-In HBV (the REVEAL-HBV) Study Group. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006 Mar;130(3):678-86. doi: 10.1053/j.gastro.2005.11.016.

Lin ZH, Xin YN, Dong QJ, Wang Q, Jiang XJ, Zhan SH, Sun Y, Xuan SY. Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis. Hepatology. 2011 Mar;53(3):726-36. doi: 10.1002/hep.24105. Epub 2011 Feb 11.

Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, S Sulkowski M, Torriani FJ, Dieterich DT, Thomas DL, Messinger D, Nelson M; APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006 Jun;43(6):1317-25. doi: 10.1002/hep.21178.