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1 Korean J Gastroenterol Vol. 63 No. 6, pissn eissn REVIEW ARTICLE 만성 B 형간염에서 B 형간염표면항원정량의임상적의의 연종은 고려대학교의과대학내과학교실 Clinical Significance of Hepatitis B Surface Antigen Quantification in Chronic Hepatitis B Jong Eun Yeon Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea Since the discovery of HBsAg in the early 1960s, presence of HBsAg in serum has only served to diagnose hepatitis B. Recent development in the quantitative measurement of serum HBsAg has enabled us to improve our understanding on the management of chronic hepatitis B. The surface antigen (sag) level is at its highest in immune tolerance phase and decreases to the lowest level in immune control/inactive phase when HBeAg is cleared from the serum. Combination of serum sag titer less than 1,000 IU/mL and serum HBV DNA less than 2,000 IU/mL can identify true inactive carrier from e antigen (eag) negative hepatitis with diagnostic accuracy of 95%. During the natural course of chronic hepatitis B, changes or absolute level of sag less than certain level can predict spontaneous sero-clearance of HBsAg. Although the decline of sag is very slow in interferon (IFN)/pegylated interferon (PEG-IFN) or oral nucleos(-t)ide treated patients, interferon based therapy results in a greater decrease of sag level and sag loss. Lack of any decline in sag titer during PEG-IFN therapy could identify the group of patients who do not response to IFN/PEG-IFN therapy. With the aid of serum HBV DNA, quantitative measurement of serum HBsAg level can be used to optimize the management of chronic hepatitis B in our daily practice. (Korean J Gastroenterol 2014;63: ) Key Words: Hepatitis B surface antigen; Hepatitis B virus; Interferons; Antiviral; Phase 서론 1960년대초 B형간염바이러스발견이후약 40여년간 B형간염바이러스 (HBV) 표면항원단백 (surface antigen, sag) 의존재는간염의원인을알기위한진단적의미외에는별다른주목을받지못하였다. 과거연구에서혈청내의상대적인역가가 e항원 (e antigen, eag) 양성과 eag 음성만성간염에서다르다는보고도있었지만, 혈액에서 sag의양을측정하는것은기술적인문제로임상에서응용하기어려웠기때문에질환의경과를반영하거나치료반응을예측할수있는간접적인인자로서추가적인연구는거의없는실정이었다. 이에반해혈청 HBV DNA는최근분자생물학적기법의발달 로극히적은농도도정량이가능하여, 여러연구에서항바이러스제치료반응, 간경변증및간세포암발생과밀접한관련이있다고보고된바있다. 1 그러나혈청 HBV DNA는한개체내에서도변화하며, 일회성의농도측정으로는질환의경과및치료에대한반응을완벽하게반영할수없는데이는혈청 HBV DNA가바이러스증식만을반영하며실제간세포에서 HBV 증식의 template가되는 cccdna (covalently closed circular DNA) 의변화를직접적으로반영하지못한다는단점이있기때문이다. 2007년이후로개발된혈청 sag의정량은간내 cccdna 의변화를간접적으로대변할수있다는연구결과 2 를뒷받침으로최근에는만성 B형간염의자연경과, 치료반응예측인자, CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 교신저자 : 연종은, , 서울시구로구구로동로 148, 고려대학교구로병원내과 Correspondence to: Jong Eun Yeon, Department of Internal Medicine, Korea University College of Medicine, 148 Gurodong-ro, Guro-gu, Seoul , Korea. Tel: , Fax: , jeyyeon@hotmail.com Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 63 No. 6, June

2 336 연종은. 만성 B 형간염에서 HBsAg 정량의임상적의의 Fig. 1. Hepatitis B surface antigen (HBsAg) production. ER, endoplasmic reticulum; cccdna, covalently closed circular DNA. HBV DNA가낮은환자에서의간세포암발생의예측인자등여러부가적인정보를제공할수있는수단으로서이에관한임상적인연구가폭발적으로증가하고있다. 본론 1. HBV surface antigen production sag의생성은 1) transcriptionally active한 cccdna가증식의 template로작용하면서생성되는경로와 2) host genome에 integration한 HBV DNA sequence로부터 translation되는경로가있다 (Fig. 1). 3 sag는감염력이있는 complete virion에비해 spheres/filament 형의 non-infectious particle로생성되는형태가약 배만큼많다. 바이러스증식에가장중요한간조직의 cccdna를정량하는것이실제감염된간세포를가장정확하게반영할수있는수단이지만, 조직을이용해야한다는문제와기술적인한계로임상에서쉽게이용할수없다는단점이있다. 최근연구에의하면혈청 sag titer는간내 cccdna, intrahepatic total HBV DNA 등과양적상관관계가있다는보고 2 가있어혈청 sag titer를측정하면조직을얻지않고도간세포의 cccdna의변화를간접적으로모니터할수있다는장점이있다. 또한혈청 HBV DNA의정량은 viral replication을반영하지만, sag titer는 cccdna에서의능동적인전사나숙주세포에통합된유전자로부터합성된정도를나타내기때문에그임상적의의가다르다고할수있다. 2. HBsAg titer의측정혈액에서 sag titer를측정하는상용화된 kit로는 Architec HBsAg QT (chemi luminescence microparticle immunoassay; Abbot Laboratories, North Chicago, IL, USA), Elecsys HBsAg II quant (electrochemiluminescence; Roche Diagnostics, Basel, Switzerland), Liaison XL murex HBsAg Quant assay (chemiluminescence; Diasorin, Saluggia, Italy) 등이있으며 sensitivity는동일하게 0.05 IU/mL이다. 희석하지않은혈청으로측정가능한범위는 Architec HBsAg QT IU/mL, Elecsys HBsAg II quant IU/mL, Liaison XL murex HBsAg Quant assay IU/mL이며최종측정의범위는각각 ,000 IU/mL, ,000 IU/mL, ,000 IU/mL이다. Elecsys HBsAg II는자동화된희석배수 1:100 or 1: 400을선택할수있으며, Architec HBsAg QT는수작업으로희석하여오류가있을수있다는한계가있었으나최근 on board automatic dilution 1:500을사용자가선택할수있게되었다. Liaison XL assay도자동화된희석을사용자가선택할수있다. 4 각각의 kit 간의변이는 10% 미만으로상관관계가좋으며 5 Architec과 Elecsys 간의상관계수는모든유전형에대해 r=0.96으로, YMDD mutant에서는 r=0.94로보고되었다. 역가가 0.5 log 10 IU/mL 이상차이가나는경우는약 6% 에불과하여 in vitro mutagenesis로유발된 surface gene의 T123A 변이는 Architec에서, P142S, P142L, The Korean Journal of Gastroenterology

3 Yeon JE. Clinical Significance of HBsAg Quantification in Chronic Hepatitis B 337 G145K는 Elecsys에서낮게측정된다는보고가있다 만성 B형간염의자연경과 1) 자연경과에따른 sag titer의변화만성 B형간염의자연경과는 1) immune tolerance phase, 2) immune clearance phase, 3) immune control/inactive phase, 4) reactivation/hbeag negative hepatitis와같이크게 4개의 phase로나눌수있다. 모든환자가 4개의 phase 를순차적으로경험하는것은아니며 phase 간이동이가능하다. 각 phase의특징을보면 immune tolerance phase는 active HBV replication이있으며 HBeAg 양성이지만, ALT 는정상혹은거의정상으로조직손상이거의없거나미미한정도이다. Immune clearance phase는 HBV DNA가다소감소하면서 HBeAg 양성이며, ALT가증가하고조직손상을동반한다. Immune control/inactive phase는 low replicative phase로 eag 음성, e항체양성이며염증이호전되는시기이다. Inactive carrier는후일재활성화되거나약 20-30% 에서 HBeAg negative hepatitis phase로진행할수있다. 6 연구마다그역가가차이가있으며유전형에따라다르지만혈청 HBV DNA와혈청 sag titer가만성 B형간염의경과에따라다르게변화하는양상은약유전형에도동일하게관찰되는데, immune tolerance phase에가장높고 immune clearance phase로갈수록점점감소하여 inactive phase에가장낮다 (Table 1). 6,7 2) sag의자연소실예측인자만성 B형간염의자연경과중 sag의자연소실은연간약 % 로, 8 이를 clinical remission으로간주할수있는데 HCV/HDV와같은바이러스의중복감염이없고, 간경변증이동반되지않으며, sag 소실이 50세이전에일어난경우, 간세포암발생이현저히감소하는등양호한임상경과를밟기때문이다. 7,9,10 sag 소실과관련된인자로혈청 HBV DNA보다혈청 sag titer가더중요하다고알려져있는데약 688명의 eag 음성환자중 HBV DNA가 2,000 IU/mL 미만인환자를 11.6년추적하여연간약 1.6% 의 sag 소실을관찰한연구 11 에서는 sag level이 10 IU/mL 미만인경우 sag 1,000 IU/mL 이상인경우에비해 sag 소실이더욱잘발생하여연간약 7% 에서 sag의소실이있었다고보고하였다 (hazard ratio [HR], 13.2; 95% CI, ). 자연적인경과중의 sag 의감소는성공적인면역조절을의미하여경과중 sag titer 가 1 log 10 IU/mL 이상감소한환자에서 sag 소실이효과적으로일어났다고보고된바있다. 12 3) sag titer; inactive carrier phase 진단의유용성혈청 sag titer는 true inactive carrier와 HBeAg negative hepatitis를감별하는데도도움을줄수있는데, 실제 2개의 phase 모두 eag 음성이며 HBeAg negative hepatitis도일시적으로 HBV DNA가매우낮고 ALT가정상인경우가있어연속적으로측정하여변화를관찰하지않는다면양군을구별하는것은쉽지않기때문이다. 양군을감별해야하는임상적인중요성은 true inactive carrier와달리 eag negative hepatitis는적극적인치료를고려해야하며간세포암의발생및합병증에대한추적도주의관찰할필요가있기때문이다. Brunetto 등 13 은 209명의만성 B형간염보유자를추적하여 1회성의 sag IU/mL 미만, HBV DNA IU/mL 미만인경우 3-year inactive carrier state를 94.3% 의정확도로진단이가능하다고보고하였다. 비록기준이되는혈청 HBV DNA와 sag titer에대한이견은있으나 sag는 IU/mL 미만, HBV DNA는 IU/mL 미만을기준으로하면 inactive carrier를 % 의정확도로감별할수있다. 4) 간암발생의예측인자로서혈청 sag titer의의의간경변증이없는 2,688명의대만환자를추적하여 sag titer와간세포암발생과의연관관계를살펴본연구 14 를보면 HBsAg titer, HBV DNA titer 모두추적기간동안간암의발생과연관이있었지만 HBV DNA가좀더우월한인자로생각되었고이중 1,068명이 eag 음성이며 HBV DNA 2,000 IU/mL 미만인환자에서 sag titer가 1,000 IU/mL 이상인경우는그미만에비하여간암발생의 HR이 13.7로, sag level 만이유일한간암발생의위험인자인것으로 (95% CI, ) 로보고하였다. Table 1. HBsAg Levels in Different Phases of Chronic Hepatitis B Variable Immune tolerance Immune clearance Inactive carrier Reactivation HBeAg negative hepatitis HBeAg + + Anti-HBe antibody + + HBV DNA (log 10 IU/mL) ALT Normal Elevated Normal Elevated Histology None/mild Moderate Mild to liver cirrhosis Moderate HBsAg (log 10 IU/mL) Vol. 63 No. 6, June 2014

4 338 연종은. 만성 B 형간염에서 HBsAg 정량의임상적의의 4. 치료반응만성 B형간염치료제로 interferon (IFN) 과같은주사제와경구용항바이러스제 ( 라미부딘, 텔비부딘, 아데포비어, 엔테카비어, 테노포비어및우리나라의경우클레부딘포함 ) 가있으며경구용항바이러스제보다는 IFN/pegylated IFN (PEG-IFN) 에서 sag titer의감소가현저하다 (Table 2) IFN/PEG-IFN 치료는 eag 양성및음성군에서각각 30%, 15% 의제한된반응을보이고약제부작용이발생할수있기때문에, 반응이좋을것으로예측되는환자에서는계속적인치료를하도록유도하고반응이떨어질것으로생각되는환자는조기에치료종료를고려한다면효과와부작용, 비용적인측면에서환자와의사에게모두도움이될수있다. 1) 인터페론 / 페그인터페론 sag titer의변화가치료반응을예측할수있는인자로쓰일수있는가 라는관점에서현재까지발표된연구를보면, 202명의 PEG-IFN2b로치료받은 eag 양성환자에서 19 반응군에서비반응군에비해 sag 감소가현저하였다는 (52주, 3.3 vs. 0.7 log 10 IU/mL), (78주, 3.4 vs log 10 IU/mL, p<0.001) 보고가있다. Chan 등 20 의연구에서도 3개월째 sag titer <1,500 IU/mL, 6개월째 sag titer <300 IU/mL 가치료종료 12개월의반응을예측할수있다고 ( 각각양성예측률 46%, 62%) 하였다. 치료 12주 sag titer <1,500 IU/mL 인환자는종료 6개월후 HBeAg 혈청전환을예측할수있는양성예측률이 33% 라는보고도있다. 21 eag 음성환자에서치료 48주째 sag titer는 <10 IU/mL이며치료중 sag titer가 1.1 log 10 IU/mL 이상감소한환자에서치료 3년째 sag 소실의 HR는각각 22.8, 10.8을보였다. 15 치료중각각 12주, 24 주에 sag titer가 0.5, 1.0 log 10 IU/mL 감소한경우 12주, 24주의양성예측률은각각 89%, 92% 였다는보고가있다. 22 혈청 HBV DNA는 relapse와 responder group에서모두감소하였기때문에 HBV DNA보다는 sag titer의변화를관찰하는것이지속적바이러스반응을예측하는데좀더유용하다고보고하였다. sag titer가치료에대한무반응을예측할수있는인자로 쓰일수있는가? 이를위해서는 sag titer의역가혹은변화가치료에높은음성예측률을가져야할것이다. 202명의 genotype A/D 환자에서 12주의 PEG-IFN 치료중 sag titer 변화를살펴본연구를보면어떠한 sag titer의감소도보이지않는경우의 NPV는 97% 로보고하였다. 19 치료 3개월 sag titer가 1,500 IU/mL 미만인경우의음성예측률이 86% 로보고된바있다. 21 HBeAg 음성만성간염에서치료 12주 sag decline 0.5 log 10 IU/mL, 24주 1 log 10 IU/mL의음성예측률은각각 90%, 97% 로보고하였고, 22 genotype D 환자에서 12 주 sag decline과 HBV DNA 2 log 10 IU/mL의조합이음성예측률 100% 를관찰할수있다고보고하였다. 23 2) 경구용항바이러스제경구용항바이러스제에서의 sag titer 감소는대부분 eag 양성환자에서관찰되며 17 1년의엔테카비어치료중 sag titer가 1 log 10 IU/mL 이상감소한환자에서는 eag 소실이의미있게관찰되었다는보고가있다 (80% vs. 30%, p=0.034). 24 텔비부딘치료중 1 log 10 IU/mL 이상현저한 sag 감소를보이는환자에서 (8/32) 그렇지않은환자에비해 (0/56) 3년 sag 소실이의미있게관찰되었다는보고가있다. 25 치료 104 주, sag titer가 2 log 10 IU/mL 미만인경우 sustained off treatment response를성공적으로예측할수있다는보고도있다 ( 양성예측률 93%, 음성예측률 100%). 26 경구용항바이러스제치료반응에대한 sag titer의변화를참고하더라도 27,28 IFN과같은정도의유의성을보이지는못하여, 같은 stopping rule을적용할수있을지는추가적인연구가필요하다. 결론 과거에는오직정성검사로간염의원인을알기위해측정했던 HBsAg는 2000년대들어여러측면에서새로운조명을받고있다. 혈청 sag titer의변화를관측하는것이간내 cccdna의변화를간접적으로반영하기때문에만성간염의자연경과나치료에대한반응을예측하고 eag 음성만성간염과같이적극적인치료대상을찾는데보조적인정보를제 Table 2. Decline of Serum HBsAg Levels during Antiviral Treatment HBeAg PEG-IFN Oral nucleos(-t)ide Positive Negative PEG-IFN, wk 48, 0.94 log 10 IU/mL PEG-IFN, wk 78, 0.90 log 10 IU/mL PEG-IFN, wk 48, 0.56, log 10 IU/mL PEG-IFN, wk 48, 0.71, log 10 IU/mL PEG-IFN+LMV, wk 48, 0.67 log 10 IU/mL ETV, 0.38 log 10 IU/mL TDF, wk 144, 0.63 log 10 IU/mL LdT, wk 48, 0.5 log 10 IU/mL ETV, 0.01 log 10 IU/mL LMV, wk 48, 0.02 log 10 IU/mL PEG-IFN, pegylated interferon; ETV, entecavir; TDF, tenofovir; LdT, telbivudine; LMV, lamivudine. The Korean Journal of Gastroenterology

5 Yeon JE. Clinical Significance of HBsAg Quantification in Chronic Hepatitis B 339 공할수있다. 그러나임상에서이를실제로응용할수있도록의미를찾으려면 sag kinetics에대한추가적인연구와, kit 간의표준화, 치료반응에대한공통적인정의와함께측정시점과역가에대한합의가도출되어야할것이다. 또한 sag titer 단독으로는임상적인의미를제공할수없고비용적인측면에서도제한점이있기때문에유일무이의절대적인기준이라기보다는생화학적간기능검사결과와혈청 HBV DNA 및 HBeAg 등의기존검사에추가적인정보를제공하는의미가있겠다. REFERENCES 1. Chen CJ, Yang HI, Su J, et al; REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;295: Werle-Lapostolle B, Bowden S, Locarnini S, et al. Persistence of cccdna during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology 2004; 126: Liaw YF. Clinical utility of hepatitis B surface antigen quantitation in patients with chronic hepatitis B: a review. Hepatology 2011; 54:E1-E9. 4. Hadziyannis E, Hadziyannis SJ. Hepatitis B surface antigen quantification in chronic hepatitis B and its clinical utility. 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6 340 연종은. 만성 B 형간염에서 HBsAg 정량의임상적의의 response to entecavir. Hepatology 2011;53: Seto WK, Liu K, Wong DK, et al. Patterns of hepatitis B surface antigen decline and HBV DNA suppression in Asian treatment-experienced chronic hepatitis B patients after three years of tenofovir treatment. J Hepatol 2013;59: The Korean Journal of Gastroenterology

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<30322E535453BABBB9AE2DC6EDC1FD2E687770> 탁원영 HBsAg 정량검사의임상적의의 HBsAg 정량검사의임상적의의 Clinical Significance of Serum HBsAg Titer 경북대학교의학전문대학원내과학교실 탁원영 Since its discovery in 1965, hepatitis B virus surface antigen (HBsAg) is used as the hallmarker of