HCC risk in inactive HBV carrier 안녕하십니까. 목요세미나 발표를 맡은 3년차 이철형입니다. 금일 준비한 논문은 2014년, 2018년 우리나라 3차병원에서 만성 간염 환자를 대상으로 시행한 retrospective cohort study를 준비했습니다. 정숙향 선생님께서 지도해 주셨습니다. 2018. 11. 01. R3 이철형 / Pf. 정숙향

Introduction HBV infection is a major health problem with 350 million chronic carriers worldwide In the context of HCC, chronic HBV infection constitutes major proportion, with other risk factors also identified HBV viral load, HBeAg positivity, HBV genotype, HCV coinfection Male, aflatoxin, alcohol 대한간학회 진료 가이드라인, 2018 B형 간염은 전세계적으로 3억 5000만 명이 감염되어 있는 의료 문제입니다. HCC나 LC로의 진행을 막는 것이 임상적으로 중요하며, 선행 연구에서 몇 가지 위험인자들이 밝혀져 있으며 다음과 같습니다. 바이러스의 요소로 BV viral load, HBeAg+, BV genotype, CV coinfection 여부가 있으며 남성, 고령, aflatoxin, alcohol 섭취 등이 잘 알려져 있습니다. HCC와 관련된 사망자 수는 다른 암종과 다르게 지속 증가추세에 있으며, 경제가능 연령 중 암 사망률 1위로 사회 경제적으로 중요한 측면이 있습ㄴ디ㅏ. Sleisenger and Fordtran’s GI and liver disease, 10th ed.

Introduction Precise mechanism of HCC carcinogenesis by HBV is not known Viral DNA integration to host chromosome induces downstream signal activation (MAPK, JAK/STAT pathway) Chronic necroinflammatory hepatocyte injury BV의 carcinogenesis의 정확한 원인은 밝혀져 있지 않으나, histology 및 임상적인 연구를 통해 다음과 같은 요소들이 관여할 것으로 제시되어 왔습니다. 만성 감염은 주로 수직감염에 의한 면역 관용기, 이후 HBeAg의 seroconversion이 일어나는 immune clearance phase를 거쳐 inactive carrier phase로 넘어가게 됩니다. 대한간학회에서는 만성간염의 치료에 있어 eAg positivity, DNA titer 및 tissue의 necroinflammatory marker를 참고하게 되며, nucleoside analog로 치료를 권고하고 있습니다. BV treatment 기준: BV DNA titer, cirrhosis 여부, ALT, HBeAg, necroinflammatory activity

Introduction Purpose of study Advent of NUCs and gaining virological response has been associated with decreased incidence of HCC by inducing status similar to inactive CHB Patients with inactive stage CHB have the lowest risk of HCC in the spectrum of CHB infection (Lok AS, 2007) However, long-term prognosis of patients with CHB undergoing NUCs versus inactive carrier remains controversial Purpose of study Compare the long-term risk of HCC in patients treated with NUCs with inactive CHB NUC의 개발 및 바이러스 치료는 HCC의 발생률 감소와 관련이 있습니다. 만성 간염의 cycle에서 inactive stage의 B형 간염이 HCC risk가 가장 낮은 것으로 알려져 있습니다. 하지만 실제 NUC로 치료받은 만성 간염군과 inactive carrier 의 장기 예후에 대해서는 알려진 바가 많지 않습니다. 본 두 연구에서는 NUC로 치료받은 간염군과 inactive CHB에서 간암 발생을 비교하고자 했습니다.

Materials & Methods Retrospective, cohort study 2007 ~ 2012, Samsung medical center Tx naïve patients, HBsAg+ >6month NUC group (n=1378) NUC-CR/IR (n=1132/246) Inactive CHB (n=1014) HBeAg- ALT <40 BV DNA <2000 IU/mL Retrospective cohort study, BV를 치료받은 group, inactive group으로 나누었고, inactive group의 경우 HBeAg-, 정상 ALT level, BV DNA가 지속 2000이하로 유지된 경우 포함시켰으며, NUC group의 경우 지속 BV titer가 <2000 미만으로 유지된 CR group과 virological response를 획득하지 못한 Incomplete responder group으로 나누었음.

Materials & Methods Exclusion criteria HCV coinfection, NUC Tx <24wks, Dx’ed HCC within 6month antiviral Tx according to KASL guideline Entecavir (73%), lamivudine, clevudine… NUC group (n=1378) NUC-CR/IR (n=1132/246) Inactive CHB (n=1014) HBeAg- ALT <40 BV DNA <2000 IU/mL

Assessment 3- to 6- month interval : blood test and imaging studies (CT, MRI) Virological response : reduction in BV DNA <2000IU/mL Liver cirrhosis Bx (n=17, 3.4%), imaging modalities (irregular surface, morphological abn, portal HTN) Primary endpoint: development of HCC NUC-CR vs inactive carrier

Result : Baseline characteristics 42.4 month follow-up NUC vs inactive : 106 (7.7%) vs 11 (1.1%)

NUC CR vs inactive CHB d Predominance of men and liver cirrhosis in the NUC CR group was not noticed for patients with HCC. NUC-CR vs inactive : 70 (6.2%) vs 11 (1.1%)

NUC CR vs inactive CHB (cumulative incidence) 2.3%/yr vs 0.3%/yr 7.2%/5yr vs 0.8%/5yr 17.4%/5yr vs 6.0%/5yr

HBeAg- NUC CR vs inactive CHB d -LC patients 15.3%/5yr vs 6.0%/5yr -without LC 6.9%/5yr vs 0.8%/5yr

NUC-CR vs NUC-IR -LC patients : 17.4%/5yr vs 38.7%/5yr (p=0.004) -without LC : 11.1%/5yr vs 7.2%/5yr (p=0.212)

Risk predictors for HCC (NUC-CR) In multivariate analysis, NUC-CR group (HR=10.1), male gender, age, baseline LC (HR=1.94) had greater incidence of HCC development

Discussion Despite long-term NUC treatment, cumulative incidence of HCC development is still higher than inactive CHB Annual incidence 2.3%/yr vs 0.3%/yr Subgroup analysis with baseline liver cirrhosis shows consistent result HBeAg- NUC-CR group also shows higher incidence of HCC Other known risk factors : age, male gender, HBeAg status, BV-DNA level, genotype C HBV In the previous REVEAL study, the population was treatment naïve.

Discussion Achieving virological response and HCC development, conflicting data has been reported. May need different surveillance strategy Limitations Retrospective design Relative short follow up period * Persistent inflammation present before the treatment of NUCs (elevated ALT levels) NUC-CR 군에서 지속 incidence가 높았던 이유 *

“VR” : also achieve biochemical response (normal ALT) Materials & Methods Retrospective, cohort study 2006 ~ 2015, Severance hospital VR group treated with NUCs: lamivudine(31.5%), entecavir (39.7%), telbivudine, clevudine, adefovir… NUC-VR group (n=1291) “VR” : also achieve biochemical response (normal ALT) HBeAg+ 639 (49.5%) ICHBP (n=741) HBeAg- ALT <40 BV DNA <2000 IU/mL

Materials & Methods “Fibrotic burden” Exclusion criteria In addition to assess cirrhosis via ultrasonographic method, liver stiffness (LS) was assessed using transient elastography at “VR” Reliability : 10 valid measures, >60% succsess rate, IQR<30% Exclusion criteria Fail to LS measurement Hx of HCC, hepatic decompensation, liver TPL Newly Dx’ed HCC within 6months after enrollment HCV coinfection Significant medical illness CTP class B or C, only Child A included Serum ALT >300

Materials & Methods Primary endpoint : development of HCC or comprehensive LRE (HCC, decompensation, ascites, SBP, variceal bleeding and mortality) Statistical analysis using propensity score mathcing (age, gender, diabetes, PLT count, albumin, bilirubin), US cirrhosis (Same as above), LS value at VR (same as above), both LS value and US findings

Result : Baseline characteristics Median f/u : 41.4 months 82 cases of HCC, 111LREs developed

Clinical outcomes of entire population Supplementary table 1. Comparison between patients who developed HCC and those who did not Group Patients who developed HCC (n=82, 4.0%) Patients who did not develop HCC (n=1,950, 96.0%) P value   Demographic variables Age 62 ± 8 54 ± 11 <0.001 Male gender 63 (76.8) 1157 (59.3) 0.002 Diabetes mellitus 18 (22.0) 203 (10.4) 0.001 Laboratory variables HBeAg positivity 33 (40.2) 606 (31.1) 0.080 HBV-DNA (log10 IU/mL) 2.723 ± 0.873 2.524 ± 0.925 0.053 Alanine aminotransferase (IU/mL) 30 ± 10 24 ± 10 Total bilirubin (mg/dL) 1.0 ± 0.4 0.8 ± 0.4 Serum albumin (g/dL) 4.2 ± 0.5 4.4 ± 0.4 Prothrombin time (INR) 1.06 ± 0.10 1.01 ± 0.10 Platelet count (x103/mm3) 123.2 ± 50.4 181.2 ± 66.3 Imaging variables Ultrasonographic cirrhosis 73 (89.0) 555 (28.5) Liver stiffness (kPa) 15.3 ± 8.4 7.9 ± 5.5 Variables are expressed as n (%) or mean ± SD. HCC, hepatocellular carcinoma; HBeAg, hepatitis B e antigen; INR, international normalized ratio; kPa, kilopascal.

NUC-VR vs ICHBP 9.4%/7yr vs 3.3%/7yr P<0.001 13.0%/7yr vs 4.7%/7yr

NUC-VR vs ICHBP

NUC-VR vs ICHBP (stratified according to US cirrhosis) Without cirrhosis 1.2%/7yr vs 2.5%/7yr (P=0.674)

NUC-VR vs ICHBP (stratified according to US cirrhosis) 21.1%/7yr vs 20.0%/7yr (P=0.980)

Model B Model C PSM analysis Model A

Statistical analysis using propensity score mathcing (age, gender, diabetes, PLT count, albumin, bilirubin), US cirrhosis (Same as above), LS value at VR (same as above), both LS value and US findings

Discussion Adjusting heavier hepatic fibrosis burden in NUC-VR group, overall clinical outcomes are comparable to inactive carrier phase group. The first study to adjust for fibrotic burden using quantitative scale between two groups (NUC treatment and HBV inactive carrier) Including biochemical response (e.g. normal ALT) to virological response, the study could minimize confounding effect of other liver diseases

Discussion Shortcomings Retrospective design Relative short-term follow-up period Histological information could confer more information, if possible Confined to HBV genotype C Result of single large tertiary hospital

Critical Appraisal Upcoming potent antiviral therapy drug era, it is meaningful to estimate the effect of CHB treatment with NUCs. Prospective, community/multicenter design with uniform use of NUCs. Discrepancy between two studies The importance of biochemical markers to the incidence of HCC cirrhosis 21.1%/7yr vs 20.0%/7yr (P=0.980)

Critical Appraisal For the second study, follow up fibroscan would be useful whether improvement of fibrotic burden could influence the incidence of HCC Predicting the risk of HCC of CHB patients? Virological response + fibrosis score + biochemical measures

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