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1 대한내과학회지 : 제 85 권제 2 호 초치료만성 B형간염환자에서엔테카비어의장기치료효과및그예측인자 충남대학교의학전문대학원내과학교실 김범희 윤범용 박대화 이엄석 김석현 이병석 이헌영 Clinical Efficacy of Entecavir and Factors Predicting Long-Term Treatment Response in Nucleoside-Naïve Patients with Chronic Hepatitis B Beom Hee Kim, Beom Yong Yoon, Dae Wha Park, Eaum Seok Lee, Seok Hyun Kim, Byung Seok Lee, and Heon Young Lee Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea Background/Aims: The aims of this study were to characterize the treatment response to entecavir and to examine factors affecting that response. Methods: A total of 77 nucleoside-naïve patients with chronic hepatitis B who had received entecavir (0.5 mg daily) for at least 48 weeks were consecutively enrolled between March 2007 and March The rates of virological response (hepatitis B virus [HBV] DNA < 116 copies/ml), biochemical response (alanine aminotransferase upper limit of normal), hepatitis B e antigen (HBeAg) loss, and seroconversion were retrospectively analyzed. Results: The cumulative rates of virological response at 12, 24, 48, 96, and 144 weeks were 59.7%, 82%, 88.3%, 89.6%, and 93.1%, respectively; biochemical response rates were 51.9%, 74%, 84.4%, 94.8%, and 98.3%, respectively; HBeAg loss rates were 10.5%, 18.4%, 28.9%, 36.8%, and 47.4%, respectively; and HBeAg seroconversion rates were 7.9%, 18.4%, 21.1%, 28.9%, and 39.5%, respectively. In multivariate analysis, independent predictors associated with HBV DNA polymerase chain reaction (PCR) negativity were the absence of HBeAg at baseline (p = 0.006) and early virological response (HBV DNA < 2,000 copies/ml after 12 weeks of therapy; p = 0.027). In univariate analysis, early virological response was an independent factor predicting HBeAg loss (p = 0.001). Conclusions: Entecavir induced excellent biochemical and virological responses in nucleoside-naïve patients with chronic hepatitis B. Early virological response was an independent factor predicting HBV PCR negativity and HBeAg loss, and can be used to predict long-term treatment response to entecavir. (Korean J Med 2013;85: ) Keywords: Hepatitis B; Entecavir; Clinical prediction rule Received: Revised: Accepted: Correspondence to Byung Seok Lee, M.D. Department of Internal Medicine, Chungnam National University School of Medicine, 33 Munhwa-ro, Jung-gu, Daejeon , Korea Tel: , Fax: , gie001@cnuh.co.kr Copyright c 2013 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - The Korean Journal of Medicine: Vol. 85, No. 2, 서론전세계적으로약 20억명이만성 B형간염에감염되어있고 3억 6천만명이만성 B형간염에의한만성간질환을갖고있으며, 해마다 60만명이 HBV와관련된간질환으로사망한다 [1]. 우리나라에서는 10세이상에서 3.7% 로남자의약 4.3%, 여자의약 3.2% 가 HBV에만성감염되어있다 [2]. 혈청 B형간염바이러스 (hepatitis B virus, HBV) DNA 수치는만성 B형간염과관련된간질환의자연경과와연관되어있으며치료하지않은만성 B형간염환자를 11년동안관찰한연구에서혈청 HBV DNA 치가 10 6 copies/ml 이상인환자의 36.2% 가간경변증으로진행한반면, 300 copies/ml 미만인환자에서는 4.5% 에서만이간경변증이발생하였다고보고되어있다 [3]. 또한혈청 HBV DNA가상승되어있는경우 ( 10,000 copies/ml) 에는 B형간염 e항원 (hepatitis e antigen, HBeAg) 양성만성간염환자, 혈청아스파르테이트아미노전이효소 (aspartate aminotransferase, AST) 및알라닌아미노전이효소 (alanine aminotransferase, ALT) 수치가증가한환자, 간경변증을동반한환자들에서독립적으로간세포암종의발생위험이높다고보고되어있다 [4]. 만성 B형간염의치료목표는장기간바이러스의증식을억제함으로써간경변증이나간암으로의진행을막고합병증과사망률을감소시키며삶의질을향상시키는데있다. 엔테카비어는 HBV DNA polymerase 의강력한억제제로서엔테카비어와라미부딘의치료효과를비교한연구에서 48주후 HBV DNA 음전율 (67% vs. 36%) 이유의하게높았으며조직학적호전 (72% vs. 62%) 및 ALT 정상화율 (68% vs. 60%) 도라미부딘보다우수하였다 [5]. 아데포비어와의비교연구에서도엔테카비어는강력한초기바이러스억제효과가있었고치료 52주후혈청 HBV DNA의감소효과가아데포비어보다우수하였다 [6]. 또한뉴클레오사이드유사체치료경험이없는환자를대상으로 5년동안엔테카비어를투여한해외연구에서엔테카비어에대한누적내성률은약 1% 였고 HBV DNA가검출한계미만으로유지된환자는 93% 였다 [7]. 라미부딘내성이치료 1년후 16-32%, 치료 4년후 71% 까지나타나는것을고려할때 [8] 엔테카비어는강력한항바이러스효과와함께낮은내성발생률을보이므로만성 B형간염환자에서초치료약제로서권장되고있으나, 국내에서는아직엔테카비어의사용기간이충분하지않아이에대한연구가부족한실정이다. 이에본연구 의저자들은과거항바이러스제치료경험이없고엔테카비어 0.5 mg을최소 48주이상투여받은초치료만성 B형간염환자들을대상으로엔테카비어의장기간치료효과와치료반응과관련된예측인자에대해알아보고내성발생률을평가하고자하였다. 대상및방법대상환자 2007년 3월부터 2012년 3월까지충남대학교병원에내원한과거항바이러스제치료경험이없는만성 B형간염환자로서엔테카비어 0.5 mg 을매일최소 48주이상복용한 96명에대하여후향적으로분석하였다. 엔테카비어는 2007년만성 B형간염의치료에대한대한간학회가이드라인에따라간질환의진행정도가만성간염의단계에있는환자는혈청 HBV DNA가일정수준 (HBeAg 양성의경우 20,000 IU/mL, HBeAg 음성의경우 2,000 IU/mL) 이상증가해있고혈청 AST 또는 ALT치가정상상한치의두배이상이거나두배미만이지만간생검에서중등도이상의염증괴사소견이나문맥주변부섬유화단계이상의간섬유화를보이는경우치료를시작하였다. 대상성간경변증환자는 HBeAg 유무에관계없이혈청 HBV DNA가 2,000 IU/mL ( 11,200 copies/ml) 이며혈청 AST, ALT치가정상상한치이상인경우치료를시작하였고혈청 AST, ALT치가정상인경우환자의상태에따라치료를결정하였다. 비대상성간경변증환자는혈청 HBV DNA가양성인경우치료를시작하였다 [9]. 간경변증은임상적으로진단하였으며간의비대상성정도 ( 복수, 간성혼수유무, 황달및상부위장관출혈 ) 등과영상검사결과합당한소견이있는경우, 상부소화관내시경검사에서식도정맥류나위정맥류등의문맥고혈압의증거또는말초혈액검사에서혈소판수 < 100,000/mm 3 등비장기능항진증의증거가있는경우로하였다. C형간염환자, 알코올간염환자, 자가면역간염환자, 그리고이전에인터페론이나라미부딘, 또는아데포비어치료를받은과거력이있는환자등은본연구의대상군에서제외하였다. 치료효과의평가선정기준에적합한환자의의무기록을후향적으로분석하였고, 투여개시전이학적검사, 간기능검사, 혈청 HBeAg,

3 - Beom Hee Kim, et al. Efficacy of entecavir and factors predicting long-term treatment response - anti-hbe, HBV DNA 정량검사를시행하였으며이후 3개월간격으로추적관찰하였다. 혈청 HBV DNA의정량은 COBAS AmpliPrep/COBAS TaqMan을이용해 real-time PCR로측정하였으며검출한계는 ,400,000 copies/ml (20-170,000,000 IU/mL) 였다. 혈청 HBV DNA는상용로그값으로변환 (1 IU/mL = 5.82 copies/ml) 하여사용하였으며따라서 HBV DNA가검출한계의상한치를넘는경우는 8 log 10 copies/ml로하한치이하인경우는 116 copies/ml 로산정하여분석하였다. 엔테카비어의치료효과에대한평가는엔테카비어투여중혈청 HBV DNA치가 116 copies/ml 이하로감소하여검출되지않는경우를바이러스반응 (virologic response, VR) 으로혈청 ALT치의정상화를생화학적반응 (biochemical response) 으로정의하였고 HBeAg 의혈청소실과혈청전환을평가하였다. 초기바이러스반응 (early virologic response, EVR) 은엔테카비어치료 12주에혈청 HBV DNA가 2,000 copies/ml 미만으로감소한경우로, 부분바이러스반응 (partial virologic response, PVR) 은치료 48주에혈청 HBV DNA가 real-time PCR 검사에서 2 log 10 IU/mL 이상감소하였지만지속적으로검출되는경우로정의하였다. 일차치료실패 (primary non- responder) 는엔테카비어를 24주동안투여후에도혈청 HBV DNA가치료전에비해 2 log 10 이상감소하지않는경우로정의하였고바이러스돌파 (virologic breakthrough) 는치료중바이러스반응을보였으나이후혈청 HBV DNA가 2번의연속 된검사에서이전검사결과 ( 최저치, nadir) 보다 1 log 10 이상증가하는경우로정의하였다. 통계분석부분바이러스반응군 (PVR) 과바이러스반응군 (VR), 혈청 HBeAg 양성군과음성군의치료전임상양상들을비교하기위해연속형변수는 Student s t-test를이용하였고범주형변수는 chi-square test를이용하였다. 또한바이러스반응, 생화학적반응, HBeAg 혈청소실및혈청전환의시간에대한누적비율을구하기위해 Kaplan-Meier법을이용하였고각각의인자에대해서는 log rank법을이용하여비교하였다. 치료반응에독립적인예측인자를조사하기위하여먼저단변량분석에서유의한변수들을대상으로다시다변량로지스틱회귀분석을시행하였다. p 값이 0.05 미만인경우를통계적으로유의한것으로판정하였고모든분석은 SPSS 18 (SPSS Inc., Chicago, IL, USA) 을이용하였다. 결과엔테카비어투여전대상환자의특징 2007년 3월부터 2011년 5월까지본원에내원한과거항바이러스제치료경험이없는만성 B형간염환자로서매일엔테카비어 0.5 mg을최소 48주이상복용한총 96명의환자 Table 1. Baseline characteristics of 77 nucleoside-naïve patients with chronic hepatitis B who received entecavir therapy Characteristics Total subjects (n = 77) Age (yr), mean ± SD 43.5 ± 11.7 Male, n (%) 48 (62.3) HBeAg positive, n (%) 38 (49.4) Serum AST (IU/L), median (range) mean ± SD 78.0 (19-750) ± Serum ALT (IU/L), median (range) mean ± SD ( ) ± Serum Albumin (g/dl), median (range) mean ± SD 4.3 ( ) 4.2 ± 0.5 Platelet (10 8 /m 2 ), median (range) mean ± SD (29-330) ± 63.5 Serum HBV DNA (log 10 copies/ml), median (range) mean ± SD 6.38 ( ) 6.25 ± 1.27 Serum HBB DNA > 8 log 10 copies/ml, n (%) 2 (2.6) Serum HBV DNA 8 log 10 copies/ml, n (%) 75 (97.4) Liver cirrhosis, n (%) 24 (31.2) Follow-up duration (wk), mean ± SD (range) ± 22.7 (64-180) SD, standard deviation; HBeAg, hepatitis B e antigen; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HBV, hepatitis B virus

4 - 대한내과학회지 : 제 85 권제 2 호통권제 636 호 중추적관찰이소실되거나사망한환자를제외한나머지 77 명을본연구에포함시켰다. 대상환자군의평균연령은 43.5세였고그중남자는 48명 (62.3%), 치료전혈청 HBeAg 양성인환자는 38명 (49.4%), 간경변증을동반한환자는 24명 (31.2%) 이었다. 엔테카비어치료전혈청 AST의중앙값은 78 IU/L, 혈청 ALT의중앙값은 121 IU/L, 혈청알부민의중앙값은 4.3 g/dl, 혈소판의중앙값은 /mm 3, 그리고혈청 HBV DNA의중앙값은 6.38 log 10 copies/ml 였다. 치료전혈청 HBV DNA가 > 8 log 10 copies/ml 인환자는 2명 (2.6%) 이었고, 8 log 10 copies/ml인환자는나머지 75명 (97.4%) 이었다. 평균추적관찰기간은 133.7주였으며관찰기간이가장짧은환자는 64주, 최장기간은 180주였다 (Table 1). 엔테카비어투여기간에따른치료효과엔테카비어치료전혈청 HBeAg 양성인 38명의환자중 HBeAg 혈청전환은 24주에 7명 /38명(18.4%), 48주에 8명 /38 명 (21.1%) 에서관찰되었고, HBeAg 혈청소실은각각 7명 /38 명 (18.4%), 11명 /38명(28.9%) 에서관찰되었다. 96주까지엔테카비어를투여한경우 HBeAg 혈청전환은 11명 /38명(28.9%), 혈청소실은 14명 /38명(36.8%) 에서관찰되었다. 엔테카비어투여후 HBV DNA 음전 (< 116 copies/ml) 은치료 24주, 48주, 96주에각각 54명 (70.1%), 59명 (76.6%), 63명 (86.3%) 에서관 찰되었다. 엔테카비어투여후혈청 ALT치가정상화된환자는치료 24주, 48주, 96주에각각 55명 (71.4%), 63명 (81.8%), 70명 (95.9%) 이었다. 엔테카비어치료기간동안일차치료실패는없었고바이러스돌파현상은 6명에서일어났다. 엔테카비어치료를받은 77명의환자중 71명이바이러스반응 (VR) 을보였으며누적바이러스반응률은 12주에 59.7%, 24주에 82%, 48주에 88.3%, 96주에 89.6%, 144주에 93.1% 였다 (Fig. 1). 77명의환자중 75명이생화학적반응을보였으며, 누적생화학적반응률은 12주에 51.9%, 24주에 74%, 48주에 84.4%, 96주에 94.8%, 144주에 98.3% 였다 (Fig. 2). 치료시작당시혈청 HBeAg 양성반응을보인 38명의누적 HBeAg 혈청소실률은 12주에 10.5%, 24주에 18.4%, 48주에 28.9%, 96주에 36.8%, 144주에 47.4% 였고 (Fig. 3), 누적 HBeAg 혈청전환율은 12주에 7.9%, 24주에 18.4%, 48주에 21.1%, 96주에 28.9%, 144주에 39.5% 였다 (Fig. 4). 엔테카비어치료 48주에부분바이러스반응군과바이러스반응군의대상환자의특징비교엔테카비어치료 48주에부분바이러스반응군 (PVR, n = 9) 과바이러스반응군 (VR, n = 68) 에서두군간의치료전나이, 성별, 혈청 HBeAg 의유무, 혈청 AST 및 ALT치, 알부민치, 혈소판치, 혈청 HBV DNA, 간경변증의동반유무그리고추 Figure 1. Cumulative rates of virological response during entecavir therapy (59.7%, 82%, 88.3%, 89.6%, and 93.1% at weeks 12, 24, 48, 96, and 144, respectively). Figure 2. Cumulative rates of biochemical response during entecavir therapy (51.9%, 74%, 84.4%, 94.8%, and 98.3% at weeks 12, 24, 48, 96, and 144, respectively)

5 - 김범희외 6 인. 만성 B 형간염환자에서엔테카비어치료 - Figure 3. Cumulative rates of hepatitis B e antigen (HBeAg) loss during entecavir therapy (10.5%, 18.4%, 28.9%, 36.8%, and 47.4% at weeks 12, 24, 48, 96, and 144, respectively). Figure 4. Cumulative rates of hepatitis B e antigen (HBeAg) seroconversion during entecavir therapy (7.9%, 18.4%, 21.1%, 28.9%, and 39.5% at weeks 12, 24, 48, 96 and 144, respectively). Table 2. Comparison of baseline characteristics between partial virological responders (PVRs) and virological responders (VRs) at week 48 Characteristics PVR (n = 9) VR (n = 68) p value Age (yr), mean ± SD 33.4 ± ± Male, n (%) 6 (66.7) 42 (61.8) HBeAg positive, n (%) 29 (31.0) 9 (13.2) Serum AST (IU/L), mean ± SD ± ± Serum ALT (IU/L), mean ± SD ± ± Serum Albumin (g/dl), mean ± SD 4.4 ± ± Platelet (10 9 /m 3 ), mean ± SD ± ± Serum HBV DNA (log 10 copies/ml), mean ± SD 7.1 ± ± Liver cirrhosis, n (%) 0 (0) 24 (35.3) Follow-up duration (wk), mean ± SD ± ± SD, standard deviation; HBeAg, hepatitis B e antigen; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HBV, hepatitis B virus. 적관찰기간을비교하였다. 바이러스반응군에서부분바이러스반응군에비해치료전평균나이가유의하게많았다 (p = 0.006). 또한치료전혈청 HBeAg 양성률이부분바이러스반응군에서는 31.0%, 바이러스반응군에서는 13.2% 로바이러스반응군에서의혈청 HBeAg 양성률이유의하게낮았다 (p = 0.001). 치료전혈소판의평균값은바이러스반응군에서더낮았으며역시유의한차이를보였다 ( /mm 3 vs /mm 3, p = 0.026). 치료전간경변증을동반한환자는바이러스반응군에서 24명 (35.3%) 으로유의하게높았다 (p = 0.032). 치료전혈청 HBV DNA의평균값은부분바이러스반응군에서 7.1 log 10 copies/ml 였고바이러스반응군에서 6.1 log 10 copies/ml 로바이러스반응군에서유의하게낮았다 (p = 0.041). 그외성별, 혈청 AST 및 ALT치, 알부민치그리고추적관찰기간은두군간에의미있는차이를보

6 - The Korean Journal of Medicine: Vol. 85, No. 2, 이지않았다 (Table 2). 치료전혈청 HBeAg 유무에따른대상환자의특징및엔테카비어치료효과의비교치료전혈청 HBeAg 양성군의평균연령은 40.5세 ( 표준편차 = 13.0) 로 HBeAg 음성군의평균연령 46.4세 ( 표준편차 = 9.7) 보다유의하게낮았으며 (p = 0.027), HBeAg 양성군의치료전혈청 HBV DNA값은평균 6.8 log 10 copies/ml 로 HBeAg 음성군의평균 5.7 log 10 copies/ml 보다유의하게높았다 (p = 0.000). 간경변증을동반한환자는 HBeAg 양성군에서 6명 (15.8%) 으로 HBeAg 음성군의 18명 (46.2%) 보다유의하게낮았으며 (p = 0.004), 초기바이러스반응 (EVR) 은 HBeAg 양성군에서 18명 (47.4%) 으로 HBeAg 음성군의 32명 (82.1%) 보다유의하게낮았다 (p = 0.001). 혈소판치의평균값은 HBeAg 음성군은 /mm 3 이고, HBeAg 양성군은 /mm 3 로 HBeAg 음성군에서더낮은수치를보였으나통 Table 3. Comparison of baseline characteristics between hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients Characteristics HBeAg positive (n = 38) HBeAg negative (n = 39) p value Age (yr), mean ± SD 40.5 ± ± Male, n (%) 23 (60.5) 25 (64.1) Serum AST (IU/L), mean ± SD ± ± Serum ALT (IU/L), mean ± SD ± ± Serum Albumin (g/dl), mean ± SD 4.2 ± ± Platelet (10 9 /m 3 ), mean ± SD ± ± Serum HBV DNA (log 10 copies/ml), mean ± SD 6.8 ± ± Liver cirrhosis, n (%) 6 (15.8) 18 (46.2) Follow-up duration (wk), mean ± SD ± ± Early virologic response (EVR), n (%) 18 (47.4) 32 (82.1) SD, standard deviation; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HBV, hepatitis B virus. Figure 5. Comparison of virological responses in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. The cumulative virological response rates at weeks 12, 24, 48, 96, and 144 were 42.1%, 68.4%, 81.6%, 84.2%, and 92.1%, respectively, in HBeAg-positive patients and those at weeks 12 and 24 were 76.9% and 94.9%, respectively, in HBeAg-negative patients (p = 0.008). Figure 6. Comparison of biochemical responses in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. The cumulative biochemical response rates at weeks 12, 24, 48, and 96 were 44.7%, 68.4%, 81.6%, and 92.1%, respectively, in HBeAg-positive patients and 59%, 79.5%, 87.2%, and 97.4%, respectively, in HBeAg-negative patients (p = 0.296)

7 - Beom Hee Kim, et al. Efficacy of entecavir and factors predicting long-term treatment response - Table 4. Factors associated with hepatitis B virus (HBV) DNA negativity after 48 weeks of entecavir therapy, as determined by polymerase chain reaction (PCR) Variables Univariate analysis Multivariate analysis PCR (-), n = 59 PCR (+), n = 18 p value OR (Odds ratio) 95% CI p value Age (yr), mean ± SD 45.4 ± ± Male, n (%) 33 (55.9) 15 (83.3) Serum AST (IU/L), mean ± SD ± ± Serum ALT (IU/L), mean ± SD ± ± Serum Albumin (g/dl), mean ± SD 4.1 ± ± Platelet (10 9 /m 3 ), mean ± SD ± ± Liver cirrhosis, n (%) 20 (33.9) 4 (22.2) HBeAg-negative, n (%) 37 (62.7) 2 (11.1) Serum HBV DNA (log 10 copies/ml), mean ± SD 6.0 ± ± Early virologic response (EVR), n (%) 45 (76.3) 5 (27.8) OR, odds ratio; CI, confidence interval; SD, standard deviation; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus. Table 5. Factors associated with hepatitis B e antigen (HBeAg) loss after 48 weeks of entecavir therapy in 38 HBeAg-positive patients Characteristics HBeAg loss (+), n = 11 HBeAg loss (-), n = 27 p value Age (yr), mean ± SD 34.5 ± ± Male, n (%) 7 (63.6) 16(59.3) Serum AST (IU/L), mean ± SD ± ± Serum ALT (IU/L), mean ± SD ± ± Serum Albumin (g/dl), mean ± SD 4.0 ± ± Platelet (10 9 /m 3 ), mean ± SD ± ± Liver cirrhosis, n (%) 2 (18.2) 4 (14.8) Serum HBV DNA (log 10 copies/ml), mean ± SD 6.8 ± ± Early virologic response (EVR), n (%) 10 (90.9) 8 (29.6) SD, standard deviation; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HBV, hepatitis B virus. 계학적유의성은없었다 (p = 0.173). 그외성별, 치료전혈청 AST 및 ALT치, 알부민치그리고추적관찰기간은두군간에의미있는차이를보이지않았다 (Table 3). 치료전혈청 HBeAg 양성군의누적바이러스반응률은 12주에 42.1%, 24주에 68.4%, 48주에 81.6%, 96주에 84.2%, 144주에 92.1% 였고, HBeAg 음성군의누적바이러스반응률은 12주에 76.9%, 24주에 94.9% 로 HBeAg 음성군의누적바이러스반응률이유의하게높았다 (p = 0.008, Fig. 5). 누적생화학적반응률은 HBeAg 양성군에서 12주에 44.7%, 24주에 68.4%, 48주에 81.6%, 96주에 92.1% 였고 HBeAg 음성군에서 12주에 59%, 24주에 79.5%, 48주에 87.2%, 96주에 97.4% 로 HBeAg 음성군의누적생화학적반응률이더높았으나통계 적인의의는없었다 (p = 0.296, Fig. 6). 엔테카비어치료효과에대한예측인자엔테카비어치료 48주후혈청 HBV DNA 음전에영향을준인자들에대하여로지스틱회귀분석을시행하였다. 단변량분석 (univariate analysis) 결과환자의평균나이가많은경우 (p = 0.007), 남자인경우 (p = 0.036), 치료전혈소판치가낮은경우 (p = 0.013), 치료전 HBeAg 음성만성간염 (p = 0.000) 인경우, 초기바이러스반응 (EVR) 이일어난경우 (p = 0.000) 에혈청 HBV DNA 음전이유의하게많았다. HBV DNA 음전이일어난군에서치료전혈청 HBV DNA 평균값이더낮은 (6.0 vs. 7.0 log 10 copies/ml, p = 0.002) 경향을보였으

8 - 대한내과학회지 : 제 85 권제 2 호통권제 636 호 나다변량분석에서통계적유의성은없었다 (p = 0.214). 다변량분석 (multivariate analysis) 결과치료전혈청 HBeAg 음성 [p = 0.006, odd ratio(or) (95% CI) = ( )] 과초기바이러스반응 (EVR) [p = 0.027, odd ratio(or) (95% CI) = ( )] 이엔테카비어치료 48주에 HBV DNA 음전을예측할수있는독립적인인자였다 (Table 4). 마찬가지로엔테카비어치료 48주후 HBeAg 혈청소실에영향을준인자들에대하여비모수검정분석을시행하였다. 단변량분석 (univariate analysis) 결과초기바이러스반응 (EVR) 이일어난경우 (p = 0.001) 에만 HBeAg 혈청소실이혈청전환이유의하게많아서 HbeAg 혈청소실에대한독립적인예측인자였다 (Table 5). 고찰본연구에서는총 77명의만성 B형간염환자에게엔테카비어초치료를시행한결과혈청 HBV DNA 음전 (< 116 copies/ml), 혈청 ALT치의정상화, HBeAg 의혈청소실및혈청전환이치료 48주에각각 88.3%, 84.4%, 28.9%, 21.1% 로나타났으며 144주까지치료받은 31명의환자에서는각각 93.1%, 98.3%, 47.4%, 39.5% 로관찰되어치료기간이길어질수록엔테카비어의바이러스반응, 생화학적반응그리고 HBeAg 혈청반응률이증가하는것을확인할수있었다. 국내에서는 Song 등 [10] 이 97명의혈청 HBeAg 양성만성간염환자를대상으로한연구에서평균 60주의엔테카비어치료후, 혈청 ALT치의정상화율은 83.5%, 바이러스반응은 75.3%, HBeAg 혈청소실은 27.8% 로보고하였다. 296명의 HBeAg 음성환자만을대상으로엔테카비어의효과를조사한연구에서혈청 ALT치의정상화율과 HBV DNA 음전율이치료 48 주후각각 78%, 90% 였고 24개월째는각각 89%, 94% 로 HBeAg 양성환자에비하여양호한결과를보고하였다 [11]. 이와마찬가지로본연구에서도치료 48주후혈청 HBV DNA 음전율이 HBeAg 음성환자에서는 94.9%, 양성환자에서는 57.9% 로엔테카비어치료전혈청 HBeAg 음성인환자에서바이러스반응 (VR) 이유의하게높았다. 본연구에서는엔테카비어치료 48주에부분바이러스반응군 (PVR) 과바이러스반응군 (VR) 을비교한결과바이러스반응군에서대상환자의평균연령이높았고 (p = 0.006), 치료전혈청 HBeAg 양성률 (p = 0.001) 및혈소판수치 (p = 0.026), 혈청 HBV DNA 수치 (p = 0.041) 가더낮았으며간경변증을동반하고있는경우가더많았다 (p = 0.032). 치료 48 주에 HBeAg 음성군은 94.9% 의누적바이러스반응률을보여 HBeAg 양성군의누적바이러스반응률인 81.6% 보다유의하게높았는데 (p = 0.008) 이는기존의연구결과와부합하는것으로이들환자군의치료전혈청 HBV DNA가유의하게낮음과관련되는현상이라생각된다 [5]. 또한치료 48 주에혈청 HBV DNA 음전율이 HBeAg 음성군에서 94.9%, 양성환자에서는 57.9% 로, HBeAg 음성군에서바이러스반응이유의하게높았던결과와도일치하였다. HBeAg 혈청전환을예측할수있는인자로인터페론치료의경우에는높은 ALT치, 조직의염증정도가심한경우, 낮은혈청 HBV DNA, 간염유전자 A와 B형이보고되고있으며 [12-14] 라미부딘치료시에는 ALT치가높을수록 HBeAg 혈청전환이증가하는것으로보고되어있다 [15]. 아데포비어의경우유전자형에따른혈청전환율의차이는없으나 [16] ALT치가높거나 HBeAg 음성인환자에서치료반응이양호하였다는보고가있다 [17]. 본연구에서는엔테카비어치료시 HBeAg 양성군에비해 HBeAg 음성군의평균연령이유의하게높았고 (p = 0.027) 간경변증의동반도유의하게높았으며 (p = 0.004) 치료전혈청 HBV DNA 값은낮았고 (p = 0.000) 초기바이러스반응 (EVR) 은더높게일어났는데 (p = 0.001) 이것또한일반적으로알려진바와일치하였다 [18-20]. 단변량분석을통해엔테카비어투여전혈소판수치가낮은경우, 간경변증을동반한경우, 초기바이러스반응 (EVR) 이있는경우에 HBeAg 의혈청소실또는혈청전환율이높을것으로예측할수있었다. 또한엔테카비어치료 48 주에혈청 HBV DNA 음전의예측인자들에대하여단변량분석을시행한결과환자의평균나이가많을수록, 남성인경우치료전혈소판수치가낮은경우, 혈청 HBeAg 음성인경우, 초기바이러스반응 (EVR) 이있는경우가높은 HBV DNA 음전을예측할수있는유의한인자로판명되었다. 단변량분석결과치료전혈청 HBeAg 음성인경우와초기바이러스반응 (EVR) 이있는경우가치료 48주후 HBV DNA 음전에대한독립적인예측인자였다. 치료 12주후바이러스반응인초기바이러스반응 (EVR) 은단변량분석에서 HBeAg 의혈청소실의독립적예측인자였으며특히치료 48주후 HBV DNA 음전의독립적예측인자로도확인되어치료중초기바이러스반응 (EVR) 이장기적인치료반응을예측하

9 - 김범희외 6 인. 만성 B 형간염환자에서엔테카비어치료 - 는데유용할것이다. 한편, 이번연구에서엔테카비어유전자형내성 (genotypic resistance) 은바이러스돌파현상 (viral breakthrough) 을보인환자 6명중 B형간염바이러스의유전자형내성검사를시행한오직 1명에서만발견되었으며발생한변이는 rtt184, rts202였다. 이러한변이는엔테카비어에대한유전자형내성중약제감수성을감소시키는데가장큰역할을하는염기서열의돌연변이로알려져있다 [21]. Tenney 등 [7] 은라미부딘에내성을보이는환자에게엔테카비어를투여할경우바이러스돌파현상의누적발생률이 1, 2, 3, 4, 5년에 1.4%, 10.0%, 27.0%, 39.5%, 43.0%, 유전자형내성의누적발생률은 1, 2, 3, 4, 5년에 6%, 15%, 36%, 46%, 51% 로유전자형내성이바이러스돌파현상보다치료기간에따라 배더많이발생했으며대부분유전자형내성이발생한환자에서바이러스돌파현상이발생했다고보고하였다. 다른연구들에서도약제순응도가좋은데도불구하고발생한바이러스돌파현상의원인은유전자형내성이그원인이라고보고하고있다 [22,23]. 따라서현재치료경과중약제내성을발견하기위해혈청 HBV DNA값으로바이러스돌파현상을모니터링하고있는데바이러스돌파현상발견시환자는이미유전자형내성을가지고있다고보아도무방하다고생각된다. 본연구에서는엔테카비어초치료시바이러스돌파현상의누적발생률이 1년, 2년, 3년에 1.3%, 11.5%, 16.1% 였다. 이는이전에라미부딘이나아데포비어등의항바이러스제치료를받지않고엔테카비어를초치료로시행한환자들을대상으로했다는점과평균추적기간이 133.7주로짧다는점에서지금까지연구결과의내성발생률과는큰차이를보이는것으로생각된다. 향후더많은환자들을대상으로추적기간을더길게보았을때는다른결과가나올수있을것으로예상된다. 본연구의한계점은단일기관의후향연구라는점, 추적관찰간격이환자마다차이가있어특정시점에서혈청 HBV DNA의감소폭을정확하게파악할수없었고바이러스반응을평가하는추적관찰기간이짧아내성발생에대한분석에한계가있다는점등으로생각한다. 또한우리나라의엔테카비어의도입시기가 2007년 3월로그기간이길지않아치료기간이 48주에서 96주인환자들이다수포함되었으며이로인해결과의해석에혼란이있을것으로생각한다. 비만은만성 B형간염이없는사람에서도간수치상승과연 관이있고비만과관련된비알콜성지방간이만성 B형간염환자에서도동반될수있으나 [24,25] 본연구에서는비만과연관된체질량지수 (BMI) 에대해서는파악하지못하였다. 비만이엔테카비어의치료효과에미치는영향에대하여추후더많은연구가필요할것으로생각한다. 결론적으로엔테카비어는초치료만성 B형간염환자에서우수한치료효과를보이며치료기간이길어질수록엔테카비어의생화학적반응, 바이러스반응및혈청반응률이증가하는것을확인할수있었다. 치료 12주후바이러스반응인초기바이러스반응 (EVR) 은 HBeAg 의혈청소실이나혈청전환의독립적예측인자였으며특히혈청 HBV DNA 음전의독립적예측인자로도확인되어치료중초기바이러스반응 (EVR) 이엔테카비어의장기적인치료반응을예측하는데유용할것으로생각한다. 요약목적 : 초치료만성 B형간염환자들에서엔테카비어의치료효과와그예측인자에대해분석하였다. 방법 : 2007년 3월부터 2011년 5월까지과거항바이러스제치료경험이없는만성 B형간염환자로서엔테카비어 0.5 mg을매일최소 48주이상복용한환자 77명을후향적으로조사하였다. 엔테카비어투여중혈청 HBV DNA치가 116 copies/ml 이하로감소하여검출되지않는경우인바이러스반응과혈청 ALT치의정상화되는경우인생화학적반응, HBeAg 의혈청소실과혈청전환을각각평가하였다. 결과 : 치료 12, 24, 48, 96, 144주에대한누적바이러스반응률은각각 59.7%, 82%, 88.3%, 89.6%, 93.1% 였다 ; 누적생화학적반응률은각각 51.9%, 74%, 84.4%, 94.8%, 98.3% 였다 ; HBeAg 의누적혈청소실률은 10.5%, 18.4%, 28.9%, 36.8, 47.4% 였다 ; 누적 HBeAg 혈청전환율은 7.9%, 18.4%, 21.1%, 28.9%, 39.5% 였다. 다변량분석을시행한결과혈청 HBV DNA 음전과관련된독립적예측인자는기저 HBeAg 음성 (p = 0.006) 과치료 12주후바이러스반응인초기바이러스반응 (p = 0.027) 이었다. 또한 HBeAg 혈청소실과관련된독립적예측인자도초기바이러스반응 (p = 0.001) 이었다. 결론 : 엔테카비어는초치료만성 B형간염환자에서뛰어난생화학적반응과바이러스반응을보였다. 초기바이러스반응은혈청 HBV DNA 음전과 HBeAg 혈청소실을예측할

10 - The Korean Journal of Medicine: Vol. 85, No. 2, 수있는독립적인자로확인되어치료중초기바이러스반응이엔테카비어의장기적인치료반응을예측하는데유용할것으로생각된다. 중심단어 : 만성 B 형간염 ; 엔테카비어 ; 치료효과 ; 예측인자 REFERENCES 1. Shepard CW, Simard EP, Finelli L, Fiore AE, Bell BP. Hepatitis B virus infection: epidemiology and vaccination. Epidemiol Rev 2006;28: Korea centers for disease control and prevention: the fourth Korea National Health and Nutrition Examination Survey Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006;130: Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;295: Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006;354: Leung N, Peng CY, Hann HW, et al. Early hepatitis B virus DNA reduction in hepatitis B e antigen-positive patients with chronic hepatitis B: a randomized international study of entecavir versus adefovir. Hepatology 2009;49: Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy. Hepatology 2009;49: Lok AS, Lai CL, Leung N, et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology 2003;125: The Korean Association for the Study of the Liver (KASL). KASL Clinical Practice Guidelines: management of chronic hepatitis B. Clin Mol Hepatol 2012;18: Song BC, Chae HB, Kim YN, Lee BS, Cho YK. Pretreatment levels of HBV DNA and early virological response during entecavir therapy predicts HBeAg loss in HBeAgpositive chronic hepatitis B patients. Korean J Hepatol 2009;15(Supp1 3):S Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2006;354: Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 2005;365: Perrillo RP, Schiff ER, Davis GL, et al. A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B: the Hepatitis Interventional Therapy Group. N Engl J Med 1990;323: Lok AS, Wu PC, Lai CL, et al. A controlled trial of interferon with or without prednisone priming for chronic hepatitis B. Gastroenterology 1992;102: Tseng TC, Liu CJ, Wang CC, et al. A higher alanine aminotransferase level correlates with earlier hepatitis B e antigen seroconversion in lamivudine-treated chronic hepatitis B patients. Liver Int 2008;28: Westland C, Delaney W 4th, Yang H, et al. Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil1. Gastroenterology 2003;125: Fung SK, Chae HB, Fontana RJ, et al. Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol 2006;44: Hadziyannis SJ, Papatheodoridis GV. Hepatitis B e antigen-negative chronic hepatitis B: natural history and treatment. Semin Liver Dis 2006;26: Papatheodoridis GV, Dimou E, Dimakopoulos K, et al. Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine. Hepatology 2005;42: Zarski JP, Marcellin P, Cohard M, Lutz JM, Bouche C, Rais A. Comparison of anti-hbe-positive and HBe-antigenpositive chronic hepatitis B in France: French Multicentre Group. J Hepatol 1994;20: Tenney DJ, Levine SM, Rose RE, et al. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to Lamivudine. Antimicrob Agents Chemother 2004;48: Degertekin B, Lok AS. Monitoring antiviral resistance in patients receiving nucleos(t)ide analog therapies for hepatitis B: which method should be used? J Hepatol 2008;48: Lok AS, Zoulim F, Locarnini S, et al. Antiviral drugresistant HBV: standardization of nomenclature and assays and recommendations for management. Hepatology 2007; 46: Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003;98: Adams LA, Knuiman MW, Divitini ML, Olynyk JK. Body mass index is a stronger predictor of alanine aminotransaminase levels than alcohol consumption. J Gastroenterol Hepatol 2008;23(7 Pt 1):