Long-term Clinical Outcomes and Risk of Hepatocellular Carcinoma in Chronic Hepatitis B Patients with HBsAg Seroclearance Gi-Ae Kim, Han Chu Lee *, Danbi Lee, Ju Hyun Shim, Kang Mo Kim, Young-Suk Lim, Young-Hwa Chung, Yung Sang Lee, Jung Yeoun Hyun, Young-Joo Yang Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine Seoul, Republic of Korea
Introduction (1) 2 Hepatitis B surface antigen (HBsAg) seroclearance One of the most important end point of chronic hepatitis B virus (HBV) infection. 1 Spontaneous or therapy-induced HBsAg seroclearance Associated with a lower risk of hepatocellular carcinoma (HCC) and prolonged survivals. 2-4 Risk of HCC after HBsAg seroclearance still exists. 2-4 1 Lok AS. Hepatology 2009;50:661-2 2 Buster EH. Gastroenterology 2008;135:459-67 3 Moucari R. Journal of Hepatology 2009;50:1084-92 4 Yuen MF. Gastroenterology 2008;135:1192-9
Introduction (2) 3 Threshold incidence for efficacy of surveillance 1 0.2%/year in non-cirrhotic patients 1.5%/year in cirrhotic patients HBsAg seroclearance 2-4 Reported HCC incidence: 0% - 30.7% Little is known about whether surveillance for HCC is worthwhile in patients with HBsAg seroclearance. 1 Bruix J. Hepatology 2011;53:1020-2.. 2 Yuen MF. Gastroenterology 2008;135:1192-9 3 Arase Y. Am J Med 2006;119:71 4 Tong MJ Gastroenterol Hepatol 2009;7:889-93.
Aim 4 To evaluate incidence rates of HCC and associated risk factors after HBsAg seroclerance To validate the HCC prediction score (CU-HCC) based on data at the time of HBsAg clearance
Methods (1) 5 Design Retrospective cohort study Chronic HBV-infected patients with HBsAg seroclearance 1997-2011, At Asan Medical Center, Seoul, Korea Inclusion criteria Detection of HBsAg for more than 6 months Patients with HBsAg clearance (Loss of HBsAg detectability at least twice and until last follow-up) No evidence of co-infection with HCV, HDV, or HIV No evidence of HCC or other malignancy
Methods (2) 6 Clinical outcomes HCC Death or transplantation Follow-up duration for HCC Interval between HBsAg seroclearance and HCC development or last imaging test Serum assays HBsAg: Architect assay (Abbott Laboratories) HBV DNA: hybrid capture assay (LLOD, 20,000 IU/mL) or real-time PCR assay (Abbott Laboratories, LLOD, 15 IU/mL)
Study subjects 7 Chronic HBV-infected patients with HBsAg seroclearance between 1997 and 2012 (N = 1,588) Patients recruited for analysis (n = 829) Excluded (Total = 759) 97 HCC development before HBsAg clearance or within 6 months of HBsAg clearance 23 Prior cirrhosis-related complications 81 Prior immunosuppressive therapy 555 Refusal to follow-up 3 Lost to follow-up and revisited hospital after HCC development Non-cirrhosis (n = 731) Cirrhosis (n = 98)
Clinical characteristics 8 Characteristics All patients (n=829) Non-cirrhosis (n=731) Cirrhosis (n=98) P Age (years)* 52 ± 9 52 ± 10 55 ± 7 <0.001 Male 575 (69%) 504(69%) 71 (72%) 0.48 HBeAg-positive 0 0 0 - HBV DNA-positive 24 (2.9%) 16 (2.2%) 8 (8.2%) 0.001 ALT, IU/L 20 (14-29) 20 (14-28) 23 (16-33) 0.57 Albumin*, g/dl 4.2 ± 0.3 4.2 ± 0.3 4.1 ± 0.4 0.001 Bilirubin*, mg/dl 1.1 ± 0.4 1.1 ± 0.4 1.3 ± 0.5 <0.001 Family history of HCC 77 (12.3%) 72 (13.1%) 5 (6.8%) 0.30 Alcohol 121 (19.4%) 108 (19.6%) 13 (17.6%) 0.85 Prior antiviral therapy 105 (12.7%) 77 (10.5%) 28 (28.6%) <0.001 Duration of follow-up (years) 4.1 (2.2-7.4) 4.1 (2.2-7.6) 3.5 (2.1-5.9) 0.004 *mean ± standard deviation (SD), median (interquartile range, IQR) The information of family history and alcohol consumption were obtained in 624 patients
Cumulative Incidence of Hepatocellular Carcinoma (%) Cumulative Incidence of Death or Transplantation (%) Clinical outcomes 9 (A) HCC (B) Death or transplantation 100 100 80 80 60 40 P<0.001 Cirrhotic Non-cirrhotic 60 40 P<0.001 Cirrhotic Non-cirrhotic 20 10.1% 14.1% 20 4.6% 25.4% 0 0.5% 3.8% 0 1.5% 3.4% Number at risk 0 2 4 6 8 10 12 Years After HBsAg Seroclearance 0 2 4 6 8 10 12 Years After HBsAg Seroclearance Non-cirrhosis 731 523 305 202 106 49 14 731 591 376 252 158 82 37 Cirrhosis 98 66 35 16 7 4 2 98 77 41 23 12 5 2
Characteristics of Hepatocellular carcinoma 10 Characteristics HCC (n=19) Age at the time of HCC diagnosis (years)* 63 ± 8 Gender (male) 18 (95%) Cirrhosis 10 (53%) Tumor size 2.0 (1.7-3.0) BCLC stage Very early (0) 8 (42%) Early (A) 10 (53%) Intermediate (B) 1 (5%) Initial treatment Surgical resection 7 (37%) Radiofrequency ablation 3 (16%) Liver transplantation 2 (10%) Transarterial chemoembolization 7 (37%) *mean ± standard deviation (SD), median (interquartile range, IQR)
Predictive factors for Hepatocellular carcinoma 11 Univariate analysis Multivariable analysis Variable HR (95% CI) p HR (95% CI) p Age of HBsAg seroclearance 50 14.92 (1.99-112.1) <0.001 12.14 (1.61-91.6) 0.02 Gender (Male) 6.97 (0.93-52.31) 0.05 8.96 (1.17-68.8) 0.04 ALT (> 1 x ULN) 2.22 (0.84-5.86) 0.12 Albumin 0.49 (0.18-2.06) 0.33 Cirrhosis 11.44 (4.61-28.4) <0.001 10.80 (4.25-27.4) <0.001 Previous antiviral treatment 1.30 (0.30-5.74) 0.73 Family history of HCC 1.07 (0.31-3.69) 0.92 Alcohol consumption 1.92 (0.73-5.06) 0.19 Cox proportional hazard model was used for all analyses. * Total number of patients, 829; number of events, 19.
Annual Incidence of Hepatocellular carcinoma 12 Group Overall Non-cirrhosis Cirrhosis Patients -years No. of events Annual rate Patients -years No. of events Annual rate Patientsyears No. of events Annual rate Overall 3464 19 0.55 (0.33-0.86) 3113 9 0.29 (0.13-0.55) 351 10 2.85 (1.37-5.24) Gender Male 2480 18 0.73(0.43-1.15) 2229 9 0.40 (0.19-0.77) 251 9 3.58 (1.64-6.79) Female 984 1 0.10 (0.01-0.57) 884 0 0 100 1 1.00 (0.03-5.61) Age of HBsAg seroclearance 50 2029 18 0.89 (0.53-1.40) 1777 8 0.45 (0.19-0.89) 252 10 3.96 (1.90-7.29) <50 1435 1 0.07 (0.01-0.39) 1336 1 0.07(0.01-0.42) 99 0 0
Sensitivity Sensitivity Performance of CU-HCC score 13 (A) AUC (5-Year) 1.0 1.0 (B) AUC (10-Year) 0.8 0.8 0.6 0.6 0.4 0.4 0.2 Area under the ROC curve 0.85 (0.73 0.97) 0.2 Area under the ROC curve 0.74 (0.58 0.89) 0.0 0.0 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 1-Specificity 1-Specificity CU-HCC score: Age, albumin, bilirubin, HBV DNA, cirrhosis (0-44.5) 1 1 Wong VW. J Clin Oncol 2010;28:1660-5
Performance of CU-HCC score 14 Variable 5-Year Prediction 10-Year Prediction Value 95% CI Value 95% CI Cutoff value 5 5 Time-dependent AUC 0.85 0.73-0.97 0.74 0.58-0.89 Sensitivity, % 73.0 41.0-100.0 49.8 21.2-78.5 Specificity, % 87.8 85.5-90.2 89.6 86.4-92.8 Positive predictive value, % 85.7 73.8-91.5 82.7 60.9-91.6 Negative predictive value, % 76.5 59.2-100.0 64.1 52.3-81.2 Positive likelihood ratio 5.99 2.82-10.72 4.79 1.56-10.91 Negative likelihood ratio 0.31 0.01-0.69 0.56 0.23-9.12
Cumulative Incidence of Hepatocellular Carcinoma (%) Cumulative rates of HCC according to CU-HCC score 15 100 80 60 40 P<0.001 CU-HCC 5 CU-HCC < 5 20 0 0 2 4 6 8 10 12 Years After HBsAg Seroclearance
Summary (1) 16 Clinical outcomes after HBsAg seroclearance HCC; 19/829 patients (3,464 patient-years); 0.55%/year Death or transplantation; 15/829 patients; 0.36%/year Predictive factors for HCC Cirrhosis, male gender, age of HBsAg seroclearance 50years Characteristics of HCC BCLC stage 0-A; 18 patients (95%)
Summary (2) 17 Estimated annual incidence of HCC Cirrhosis; 2.85% Non-cirrhosis; 0.29% - Male; 0.40%, Female; 0% - Age of HBsAg seroclearance 50; 0.45%, <50; 0.07% The performance of CU-HCC score 5-Year; TD-AUC 0.85, sensitivity 73.0%, specificity 87.8% 10-Year; TD-AUC 0.74, sensitivity 49.8%, specificity 89.6%
Conclusion 18 Among chronic HBV-infected patients with HBsAg seroclearance, surveillance for HCC should be continued for cirrhotic patients and non-cirrhotic male patients. HBsAg seroclearance at age 50 years was also independent predictor for HCC. The performance of CU-HCC score seems accurate to predict HCC development in our cohort.
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