Long-term Clinical Outcomes and Risk of Hepatocellular Carcinoma in Chronic Hepatitis B Patients with HBsAg Seroclearance

Transcription

1 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

2 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 Lok AS. Hepatology 2009;50: Buster EH. Gastroenterology 2008;135: Moucari R. Journal of Hepatology 2009;50: Yuen MF. Gastroenterology 2008;135:1192-9

3 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% % Little is known about whether surveillance for HCC is worthwhile in patients with HBsAg seroclearance. 1 Bruix J. Hepatology 2011;53: Yuen MF. Gastroenterology 2008;135: Arase Y. Am J Med 2006;119:71 4 Tong MJ Gastroenterol Hepatol 2009;7:

4 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

5 Methods (1) 5 Design Retrospective cohort study Chronic HBV-infected patients with HBsAg seroclearance , 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

6 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)

7 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)

8 Clinical characteristics 8 Characteristics All patients (n=829) Non-cirrhosis (n=731) Cirrhosis (n=98) P Age (years)* 52 ± 9 52 ± ± 7 <0.001 Male 575 (69%) 504(69%) 71 (72%) 0.48 HBeAg-positive HBV DNA-positive 24 (2.9%) 16 (2.2%) 8 (8.2%) ALT, IU/L 20 (14-29) 20 (14-28) 23 (16-33) 0.57 Albumin*, g/dl 4.2 ± ± ± Bilirubin*, mg/dl 1.1 ± ± ± 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 ( ) 4.1 ( ) 3.5 ( ) *mean ± standard deviation (SD), median (interquartile range, IQR) The information of family history and alcohol consumption were obtained in 624 patients

9 Cumulative Incidence of Hepatocellular Carcinoma (%) Cumulative Incidence of Death or Transplantation (%) Clinical outcomes 9 (A) HCC (B) Death or transplantation P<0.001 Cirrhotic Non-cirrhotic P<0.001 Cirrhotic Non-cirrhotic % 14.1% % 25.4% 0 0.5% 3.8% 0 1.5% 3.4% Number at risk Years After HBsAg Seroclearance Years After HBsAg Seroclearance Non-cirrhosis Cirrhosis

10 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 ( ) 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)

11 Predictive factors for Hepatocellular carcinoma 11 Univariate analysis Multivariable analysis Variable HR (95% CI) p HR (95% CI) p Age of HBsAg seroclearance ( ) < ( ) 0.02 Gender (Male) 6.97 ( ) ( ) 0.04 ALT (> 1 x ULN) 2.22 ( ) 0.12 Albumin 0.49 ( ) 0.33 Cirrhosis ( ) < ( ) <0.001 Previous antiviral treatment 1.30 ( ) 0.73 Family history of HCC 1.07 ( ) 0.92 Alcohol consumption 1.92 ( ) 0.19 Cox proportional hazard model was used for all analyses. * Total number of patients, 829; number of events, 19.

12 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 ( ) ( ) ( ) Gender Male ( ) ( ) ( ) Female ( ) ( ) Age of HBsAg seroclearance ( ) ( ) ( ) < ( ) ( )

13 Sensitivity Sensitivity Performance of CU-HCC score 13 (A) AUC (5-Year) (B) AUC (10-Year) Area under the ROC curve 0.85 ( ) 0.2 Area under the ROC curve 0.74 ( ) 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

14 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 Sensitivity, % Specificity, % Positive predictive value, % Negative predictive value, % Positive likelihood ratio Negative likelihood ratio

15 Cumulative Incidence of Hepatocellular Carcinoma (%) Cumulative rates of HCC according to CU-HCC score P<0.001 CU-HCC 5 CU-HCC < Years After HBsAg Seroclearance

16 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%)

17 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%

18 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.

19 Thank you for your attention.