대한소화기학회지 2010;56:365-372 DOI: 10.4166/kjg.2010.56.6.365 HBeAg 양성만성 B 형간염환자에서, 및 의초치료효과 동아대학교의과대학소화기내과학교실 배숙향ㆍ백양현ㆍ이성욱ㆍ한상영 Treatment Efficacy of, and in Treatment-naive Patients with HBeAg-Positive Chronic Hepatitis B Suk Hyang Bae, M.D., Yang-Hyun Baek, M.D., Ph.D., Sung-Wook Lee, M.D., Ph.D., and Sang Young Han, M.D., Ph.D. Department of Gastroenterology, Dong-A University College of Medicine, Busan, Korea Background/Aims: is a potent antiviral agent that has demonstrated efficacy in patients with chronic hepatitis B. This study compared the efficacy of clevudine (C), entecavir (E) and lamivudine (L) in treatment-naive patient with HBeAg-positive chronic hepatitis B. Methods: A total of 146 treatment-naive patients with HBeAg-positive chronic hepatitis B received clevudine, entecavir or lamivudine. C group (n=39) received 30 mg of clevudine, E group (n=39) received 0.5 mg of entecavir and L group (n=68) received 100 mg of lamivudine once a day for more than 48 weeks. The efficacy analysis estimated the mean changes of the HBV DNA levels as a virologic response, the normalization of the ALT levels (less than 35 IU/L) as a biochemical response and loss of HBeAg or seroconversion as a serologic response. The serum HBV DNA level was quantified by hybrid capture and real-time PCR assay. Results: Before the administration of clevudine, entecavir and lamivudine, the mean HBV DNA and ALT levels and the gender and age were well balanced among the three groups (p>0.05). For the virologic response at 48 weeks, the mean changes of the HBV DNA levels from baseline of the C, E and L groups were 3.8±2.2, 4.5±1.9 and 2.5±2.1 log copies/ml. C and E group showed superior antiviral activity compared to that of L group (p<0.0001), but no significant differences in antiviral response were noted between C and E groups. For the biochemical response at 48 weeks, the normalization of the ALT levels (less than 35 IU/L) among the C, E and L groups was 82%, 74% and 71%, respectively (p=0.46). The rates of undetectable serum HBV DNA (less than 300 copies/ml) of the C, E and L groups were 39%, 69% and 27%, respectively (p<0.0001). For the serologic response at 48 weeks, the loss of HBeAg was 13%, 31% and 24% and the seroconversion was 10%, 23% and 17%, respectively. There was no difference of efficacy among the three groups regarding ALT normalization or serologic response (p>0.05). Viral breakthrough in C group was noted at 24 weeks (5%) and 48 weeks (21%), but no biochemical breakthrough was noted. The elevation of the serum CK level was noted in only 1 patient of group C at 48 weeks (2.56%) after therapy. For the patients without or with liver cirrhosis (LC), C and E group showed superior antiviral activity compared to 접수 : 2010 년 4 월 19 일, 승인 : 2010 년 7 월 18 일연락처 : 한상영, 602-715, 부산시서구동대신동 3-1 동아대학교의과대학소화기내과학교실 Tel: (051) 248-1510, Fax: (051) 240-2861 E-mail: syhan@dau.ac.kr Correspondence to: Sang Young Han, M.D. Department of Gastroenterology, Dong-A University College of Medicine, 3-1, Dongdaeshin-dong, Seo-gu, Busan 602-715, Korea Tel: +82-51-248-1510, Fax: +82-51-240-2861 E-mail: syhan@dau.ac.kr
366 대한소화기학회지 : 제 56 권제 6 호, 2010 that of the L group, but the antiviral activity was more effective in non- LC group than LC group (p<0.0001 vs p=0.036). Conclusions: therapy compared with lamivudine for 48 weeks showed significantly potent antiviral efficacy in treatment-naive patients with HBeAg-positive chronic hepatitis B, and especially in the non-lc patients. However, the antiviral efficacy of clevudine was similar to that of entecavir even though taking into account relatively short follow up period and retrospective study. (Korean J Gastroenterol 2010;56:365-372) Key Words: ; ; ; Chronic hepatitis B 서론혈청 HBV DNA가지속적으로높은만성 B형간염환자들은진행성간질환, 간경변, 간암발병및간질환으로인한사망위험률이높다. 1-4 따라서만성 B형간염의치료목적은 HBV DNA 복제를억제하여간세포의괴사성염증반응을감소시키고간질환의진행을막는것이다. 5 경구용뉴클레오시드제제로바이러스를지속적으로억제시키면간의조직학적호전을가져올수있다. 6 또한혈청 ALT의정상화를유지하는것은간질환의진행과간암발생률을감소시켜생존율을향상시킨다. 7 만성 B형간염의유지요법으로서 lamivudine 치료는 HBV 바이러스를지속적으로억제시키고간의조직학적소견을호전시켜간질환의진행을막을수있었고 1년간치료후 HBeAg의혈청전환율이 16-17%, 조직학적호전율이 52-56% 에달하였다. 8-10 비교적근래에사용되기시작한 entecavir는조직학적반응, 바이러스반응, 생화학적반응률에서 lamivudine에비하여효과가우수함이검증되었다. 11,12 특히 lamivudine 투여중내성변이가생긴환자에서 1년간치료시 HBV DNA 소실률이 21%, ALT 정상화율은 65% 를보여주었다. 13 한편국내에서처음으로개발된경구용 L-뉴클레오시드인 clevudine은임상시험에서강력한항바이러스효과가입증되었다. HBV DNA 음전화율이 HBeAg 양성군에서 82%, HBeAg 음성군에서 100% 로서우수한항바이러스효과를보이고있으며, entecavir가투여를중단하면바이러스의재출현이자주발생하는것과는상대적으로 clevudine은약제중단후에도항바이러스효과가장기간지속되는장점을갖고있다. 이번연구는이전치료경험이없는만성 B형간염환자들중 HBeAg 양성환자에있어서 clevudine의치료효과에대하여 entecavir 및 lamivudine과비교하여알아보고자약제에대한바이러스반응, 생화학적반응, 혈청학적반응을 48주간후향적으로분석하였다. 대상및방법 2006년 1월부터 2008년 6월까지동아대학교병원소화기 내과를방문한만성B형간염환자들중이전항바이러스제를사용한경험이없는 HBeAg 양성인환자들을대상으로하였다. 환자들은초치료제로서 clevudine, entecavir, lamivudine을각각 30 mg/ 일, 0.5 mg/ 일, 100 mg/ 일을 1년이상복용하였다. 복수, 황달, 간뇌증, 정맥류출혈등의증상을보이지않는대상성간경변환자를포함하였고, C형또는 D형간염, HIV 등두가지이상의바이러스감염이혼재해있거나, 비대상성간경변환자, 간암환자, 임산부, 만성신질환자, 악성종양및스테로이드사용환자, 1년이내약제를변경한환자, 1년이상추적관찰에실패한환자는대상에서제외하였다. 치료효과의분석은 HBV DNA 감소율로바이러스반응 (virologic response), ALT의정상화율로생화학반응 (biochemical response), HBeAg 혈청소실및혈청전환으로혈청반응 (serologic response) 을측정하였다. 또한대상성간경변환자군과비간경변환자군에서약물간치료효과를 DNA 감소율로비교하였다. 먼저 HBV DNA 음전화는 HBV DNA 가 300 copies/ml 미만인값으로정하였다. Hybrid capture법, real-time PCR법을통하여 HBV DNA 값을측정하였고 1 IU/mL를 5 copies/ml로변환하였다. 또한 ALT 값의정상화를 35 IU/L이하로정하여 3개월단위로평균 ALT값을측정하였고 HBeAg 혈청소실률과혈청전환율을확인하였다. 약물치료도중 3개월마다확인한검사실검사에서정상화되었던 ALT가다시정상상한치이상으로측정될때 생화학적돌파 로정의하여이를평가하였고, 약물치료도중 3 개월마다확인한평균 HBV DNA 값이최저치의 10배이상증가시에 (1 log HBV DNA level above nadir) 바이러스돌파 로정의하여내성에대한평가를하였다. 대상환자의인구통계학적자료및건강상태를범주형자료인경우빈도와백분율로, 계량형자료인경우평균, 표준편차로요약하였다. 세약제간비율차이검정을위해 Fisher의정확검정을이용하였으며, baseline에서 12주까지추적된환자에서 HBV DNA level과 serum ALT level을각시점별로세약제간비교를위해일원분산분석과 Tukey-Kramer 사후검정을사용하였다. 뿐만아니라, 평균 ±95% 신뢰구간그래프를이용해 baseline에대한 12주차 HBV DNA level과 serum ALT level의차이를표시하였다. 유의수준 0.05 하에서가설검정
배숙향외 3 인. HBeAg 양성만성 B 형간염환자에서, 및 의초치료효과 367 을실시하였으며, 모든통계분석은 SAS 9.1.3과 R 2.9.1 통계소프트웨어를이용해수행하였다. 결과만성 B형간염초치료대상자 597명중 HBeAg 양성인환자를대상으로간암, 바이러스혼합감염, 비대상성간경변, 임산부, 만성신질환, 간암이외기타악성종양및스테로이드사용자, 1년이내약제를변경한환자, 1년이상추적관찰에실패한환자를제외하여 clevudine 투약군 (C) 39명, entecavir 투약군 (E) 39명, lamivudine 투약군 (L) 68명이었다 (Fig. 1). 치료약물투여군의평균연령은각각 45±11, 46± 11, 43±14세였고남성이각각 29명 (74%), 27명 (69%), 39명 (57%) 으로여성보다많았다. 치료전평균 HBV DNA 값은 7.0±1.5, 6.9±1.4, 7.3±1.3 log copies/ml으로 lamivudine 투약군에서비교적높았고평균 ALT 값은 112.6±117.8, 163.1± 172.6, 150.9±228.5 IU/L였다. C, E, L 군에대상성간경변환자가각각 18명 (46%), 17명 (44%), 33명 (49%) 포함되었으며투여군간에통계적유의한차이는없었다 (Table 1). 바이러스반응으로서 HBV DNA 평균감소율을비교하였을때치료 48주째C, E, L군의평균 HBV DNA 감소는각각 3.8 ±2.2, 4.5±1.9, 2.5±2.1 log copies/ml 였으며 C, E군에서 L군에비하여유의하게 HBV DNA 평균감소율이우수하였다 (p<0.001). 그러나 C군과 E군에서 HBV DNA 평균감소율의차이는통계적으로유의하지않았다 (p>0.05) (Table 2, Fig. 2). 생화학적반응으로서 ALT의평균값은치료 48주째 C, E, L군에서각각정상화를보였으며세군간의유의한차이가보이지않았다 (p=0.35) (Table 3, Fig. 3). HBV DNA Fig. 1. Schema of study population though 48 weeks. HCC, hepatocelluar carcinoma; LC, liver cirrhosis. Table 1. Baseline Characteristics of the Patients Total (n=146) (n=39) (n=39) (n=68) Male (%) 95 (65) 29 (74) 27 (69) 39 (57) 0.18 Age (year) Mean±SD 44±12 45±11 46±11 43±14 0.47 Median (range) 45 (13-75) 47 (24-75) 46 (19-68) 44 (13-68) Serum HBV DNA (log copies/ml) Mean±SD 7.1±1.4 7.0±1.5 6.9±1.4 7.3±1.3 0.34 Median (range) 7.3 (2.6-10.3) 7.1 (3.4-9.8) 7.1 (4.2-9.1) 7.5 (2.6-10.3) ALT (IU/L) Mean±SD 143.9±189.4 112.6±117.8 163.1±172.6 150.9±228.5 0.46 Median (range) 88.5 (10-1368) 70 (10-514) 107 (17-699) 88.5 (18-1368) LC (compensated) 68 (47) 18 (46) 17 (44) 33 (49) 0.89 SD, standard deviation.
368 The Korean Journal of Gastroenterology: Vol. 56, No. 6, 2010 Table 2. Changes of HBV DNA Level (log copies/ml) from Baseline HBV DNA (log copies/ml) (n=39) (n=39) (n=68) At baseline 7.0±1.5 6.9±1.4 7.3±1.3 0.34 Change from baseline 12 weeks 3.7±1.2* 3.5±1.7* 2.3±1.5 <.0001 24 weeks 4.3±1.5* 4.3±1.5* 2.7±1.6 <.0001 36 weeks 4.2±1.6* 4.5±1.4* 2.6±2.1 <.0001 48 weeks 3.8±2.2* 4.5±1.9* 2.5±2.1 <.0001 * The mean±sd, values (*) are different from another scripts ( ) (p<0.05). The mean±sd, values ( ) are different from another scripts (*) (p<0.05). Table 3. Changes of Serum ALT Level (IU/L) from Baseline Serum ALT (IU/L) (n=39) (n=39) (n=68) At baseline 112.6±117.8 163.1±172.6 150.9±228.5 0.46 Change from baseline 12 weeks 73.2±118.6 128.1±170.4 86.2±227.2 0.41 24 weeks 87.4±121.8 125.6±164.4 117.0±191.3 0.58 36 weeks 88.1±120.0 126.6±160.9 141.7±257.8 0.43 48 weeks 77.6±98.8 137.2±173.3 121.2±230.6 0.35 Fig. 2. Changes of HBV DNA level (log copies/ml) from baseline through the 48 weeks. Mean±95% confidence interval plot of HBV DNA level (log copies/ml) according to PCR through 48 weeks by groups treated with clevudine, entecavir and lamivudine. s were derived from ANOVA for the comparison of change from baseline by groups. Fig. 3. Changes of serum ALT level (IU/L) from baseline through the 48 weeks. Mean±95% confidence interval plot of serum ALT level (IU/L) through 48 weeks by groups treated with clevudine, entecavir and lamivudine. s were derived from ANOVA for the comparison of change from baseline by groups. 음전화율 (300 copies/ml 이하 ) 을비교하였을때치료 48주째 E군이 C, L군에비하여유의하게 HBV DNA 음전화율이높았다 (p<0.001). ALT 정상화율, HBeAg 소실률, 혈청전환율은 C군과 L군에서통계적유의한차이가없었고 C군과 E군에서도차이가없었다 (Table 4). 간경변 (LC) 및비간경변 (non-lc) 환자군에서치료 48주째 HBV DNA 평균감소율을각각비교하였을때 C, E군에서 L군에비하여유의하게 HBV DNA 평균감소율이우수하였다. 그리고이러한항바 이러스효과는 LC군에비하여 non-lc군에서보다강력한것으로보인다 (LC vs. non-lc, p=0.036 vs. p<0.001). 한편 C 군과 E군간 HBV DNA 평균감소율의차이는통계적으로유의하지않았다 (Table 5). ALT의평균값의변화는 LC 및 non-lc군에서세군간의유의한차이가보이지않았다 (Table 6). 치료 48주째바이러스돌파현상이 C군에서 8명 (21%), E군에서는 1명 (3%), L군에서는 17명 (25%) 에서나타났다 (Table 7). 그러나생화학적돌파현상은 C, E, L군모두
Bae SH, et al. Treatment Efficacy of, and in HBeAg-Positive Chronic Hepatitis B 369 Table 4. Virologic, Biochemical, and Serologic Response at 48 Weeks Variable (n=39) (n=39) (n=68) HBV DNA <300 (copies/ml) (%) 14 (39)* 20 (69) 18 (27)* <.0001 ALT <35 (IU/L) 32 (82) 28 (74) 48 (71) 0.46 Loss of HBeAg 5 (13) 12 (31) 16 (24) 0.15 Seroconversion 4 (10) 9 (23) 11 (17) 0.32 * Rates of undetectable serum HBV DNA, value (*) is different from another script ( ) (p<0.0001). Rates of undetectable serum HBV DNA, value ( ) is different from another script (*) (p<0.0001). Fisher s chi square test was employed for comparison between groups (*, ). Table 5. Changes of HBV DNA (log copies/ml) from Baseline HBV DNA (log copies/ml) (n=21) (n=22) Non-LC (n=35) (n=18) (n=17) LC (n=33) At baseline 8.0±1.2* 7.0±1.6 7.8±1.1* 0.042 5.9±1.2 6.7±1.1 6.8±1.3 0.058 Change from baseline 12 weeks 4.3±1.0* 3.7±2.0* 2.5±1.7 0.0010 3.1±1.0* 3.3±1.1* 2.0±1.3 0.0013 24 weeks 5.0±1.1* 4.5±1.5* 2.9±1.6 <0.0001 3.4±1.4* 3.9±1.4* 2.6±1.6 0.015 36 weeks 5.0±1.1* 4.8±1.4* 2.7±2.3 <0.0001 3.2±1.6 4.0±1.4 2.6±1.9 0.070 48 weeks 4.±1.2* 4.8±2.3* 2.5±2.2 <0.0001 2.5±2.6* 4.2±1.2* 2.5±2.0 0.036 * Mean changes of the HBV DNA levels from baseline, values (*) are different from another scripts ( ). Mean changes of the HBV DNA levels from baseline, values ( ) are different from another scripts (*). Table 6. Changes of Serum ALT (IU/L) from Baseline Serum ALT (IU/L) (n=21) Non-LC (n=22) (n=35) (n=18) LC (n=17) (n=33) At baseline 140.8±117.6 229.2±200.6 198.7±271.2 0.41 79.6±112.3 77.6±58.0 100.3±161.4 0.79 Change from baseline 12 weeks 94.0±121.9 183.7±200.3 103.3±264.4 0.32 50.1±113.6 50.2±64.3 67.3±180.3 0.89 48 weeks 113.0±118.5 204.1±298.0 172.7±270.8 0.39 36.4±44.0 45.2±60.0 66.6±165.7 0.67 Table 7. Viral Breakthrough Viral breakthrough (n=39) (n=39) (n=68) 12 weeks 0 (0) 1 (3) 0 (0) 0.53 24 weeks 2 (5) 0 (0) 2 (3) 0.38 36 weeks 3 (8) 0 (0) 7 (10) 0.10 48 weeks 8 (21)* 1 (3) 17 (25)* 0.0060 * Patient suffered from viral breakthrough, value (*) is different from another script ( ) (p<0.0060). Patient suffered from viral breakthrough, value ( ) is different from another script (*) (p<0.0060). Fisher s chi square test was employed for comparison between groups (*, ). 에서나타나지않았다. 치료 48주째에 C군에서 creatine kinase (CK) 상승및근육병증을보인환자가 1명 (2.56%) 있었다. 그외 C, E, L 군에서특이한부작용은보이지않았다. 비록본연구가후향적연구로서부작용이나효과를비교하기에는대상환자수가적고탈락률이많으며추적기간이짧다는한계점을가지고있으나, 48주간추적한초치료대상자들에대하여 clevudine은 lamivudine에비하여강력한항바이러스효과를나타내었고 entecavir와는유의한차이가없었으며이는간경변으로진행되기전만성 B형간염환자에서더욱효과적인것으로나타났다.
370 대한소화기학회지 : 제 56 권제 6 호, 2010 고찰 치료는간의조직학적소견을호전시키고간경변의 Child-Pugh 점수를감소시키며간암의발생을줄일수있다고알려져있다. 이것은 B형간염바이러스를효과적으로억제시켜간의괴사성염증과섬유화를막기때문이다. 그러나 lamivudine에대한약제내성은치료기간과비례하여그출현빈도가점차증가하는데, 1년투여시약 14-32% 발생하고점차그빈도가증가하여 3년투여시에는 50% 이상에서내성이발생되었다. 8-10 한편 entecarvir는 lamivudine에비하여훨씬더효과적으로바이러스복제를억제하고내성변이가없으며부작용이적어만성 B형간염환자에서 1차치료제로고려되었다. 그러나투여종료후에는간염의악화가빈번하다고보고하였다. 11,12 은국내에서처음으로개발된경구용 L-뉴클레오시드로서임상연구를거쳐위약군에비하여만성 B형간염에서강력한항바이러스효과가검증되었고약물투여종료 6개월후에도치료효과가일정부분지속되는항바이러스제로보고된바있다. 14-17 의 12개월평균 HBV DNA 감소정도가 4.4 log 10 copies/ml였고 18 아직까지 clevudine과 lamivudine의바이러스증식억제효과를비교한논문은없었다. 본연구에서 HBeAg 양성환자에서살펴보았을때 clevudine의바이러스증식억제효과가 lamivudine에비하여우수하였고 clevudine과 entecavir 간의효과는차이가없었다. 가 lamivudine에비하여 ALT 정상화율에서우수하다는보고가있었으나 12 이번연구에서는 C, E, L군의 ALT 정상화효과가모두우수하였고 C, E, L군간의차이는통계적으로유의하지않았다. HBeAg 소실율과혈청전환율에서도세군간의유의한차이는보이지않았다. 이것은이전의연구에서 clevudine 1년치료후 HBeAg 혈청전환율 16% 18 에비하여이연구에서는 10% 를보였는데이는바이러스돌파율의차이로인한결과일것으로보인다 (10.0% 18 vs. 21%). 바이러스돌파현상은 C군에서 24주째 2명 (5%), 36주째 3명 (8%), 48주째 8명 (21%) 에서나타났다. 내성이생기면바이러스돌파현상이먼저생기고대부분그이후에 ALT가상승하며일부심한간염의악화를동반할수있는데, 1 이번연구에서는비록 C군에서바이러스돌파현상이나타났으나 drug related mutation이생기지않았고 ALT 증가도없었다. 바이러스돌파의원인으로는약물의복용량, 환자들의순응도및아직밝혀지지않은돌연변이가능성을생각해볼수있겠다. 48주동안생화학적돌파현상은 C, E, L군모두에서일어나지않았고 clevudine 48주치료에서내성은나타나지않았다. 그러나 C군에서 HBV DNA 감소율이 36-48주째에줄어들고있으므로 (Table 2, Fig. 2) clevudine 투약이 48주 이상장기간지속된다면내성출현및생화학적돌파현상이가능할수있다. 을장기간사용하면미토콘드리아 DNA 복제와관련있는 DNA polymerase를억제하기때문에결과적으로미토콘드리아 DNA를고갈시켜근육괴사를동반한근육병증을유발한다는보고가있었다. 19 이번연구에서 clevudine 투약 48주째에계단오르기가힘들정도의근육통을동반하고 CK 상승 ( 정상상한가 3배이상 ) 환자가 1명 (2.56%) 있었고, 근육관련증상이없고운동과무관한 CK 상승 ( 정상상한가 3배이상 ) 환자가 1명 (2.56%) 있었다. 모두약제중단 2-4주후증상과 CK값은정상화되었다. 치료 48 주째비간경변환자군에서 clevudine은 lamivudine에비하여유의하게 HBV DNA 평균감소율이우수하였고 (p<0.001) 간경변환자군에서도유의하게 HBV DNA 평균감소율의차이를보였다 (p=0.036). 그러나이번연구에서 lamivudine에비하여 clevudine의항바이러스효과는간경변으로진행된환자군보다비간경변환자군에서더욱뚜렷하게나타났다 (p <0.001 vs. p=0.036). 따라서만성 B형간염환자에서다른항바이러스제와마찬가지로간섬유화가진행되기전에 clevudine을사용하는것이좋겠다. HBeAg 양성만성 B형간염환자들에서 clevudine의 48주초치료효과는 lamivudine 과비교하여강력한항바이러스효과를보이며 entecavir와유의한차이는없었다. 또한내성및부작용의빈도가낮아 entecavir와함께만성 B형간염환자의항바이러스제로서 1 차치료제로고려된다. 그러나일부에서투약 48주이후근육병증의부작용을보였다. 이번연구는후향연구로서부작용이나효과를비교하기에는대상환자수가적고탈락률이많으며추적기간이짧다. 따라서장기간의치료효과, 투여용량결정, 내성발현과부작용에대한다기관연구가지속적으로이루어져야할것으로생각된다. 또한이번연구에서비대상성간경변환자또는간암환자의탈락률이높으므로이에대한항바이러스약제의효과에대하여장기간다기관연구가필요할것으로생각된다. 요약목적 : 만성 B형간염환자에서 clevudine 치료는임상시험을통해강력한항바이러스효과가입증되었다. 이번연구는치료경험이없는만성 B형간염환자에서 clevudine (C) 의치료효과를 entecavir (E) 및 lamivudine (L) 과비교하여후향적으로분석해보고자하였다. 대상및방법 : 동아대학교병원에내원하여초치료로 clevudine, entecavir, lamivudine을각각복용한 HBeAg 양성만성 B형간염환자 146명을대상으로하였다. 환자군은 C군 (39명), E군 (39명), L군 (68 명 ) 으로분류하여각각 clevudine 30 mg/ 일, entecavir 0.5 mg/ 일, lamivudine 100 mg/ 일을 48주이상지속적으로투약하였
배숙향외 3 인. HBeAg 양성만성 B 형간염환자에서, 및 의초치료효과 371 다. 치료효과의분석은치료약제의바이러스반응으로서 HBV DNA 감소, 생화학적반응으로서 ALT의정상화, 혈청학적반응으로서 HBeAg 소실및혈청전환율을측정하였다. HBV DNA는 hybrid capture법, real-time PCR법을사용하여측정하였다. 결과 : 치료전 C, E, L 투약군의평균 HBV DNA, ALT, 나이, 성별의차이는없었다 (p>0.05). HBV DNA 음전화는 HBV DNA가 300 copies/ml 미만으로감소한경우로하였고 ALT 정상화는 35 IU/L 미만으로감소한경우로하였다. 치료 48주째 C, E, L군의평균 HBV DNA 감소는각각 3.8±2.2, 4.5±1.9, 2.5±2.1 log copies/ml이었으며 C와 E군에서 L군에비하여강력한항바이러스효과를보였고 C, E군간의유의한차이는없었다. 치료 48주째 ALT의평균값은 C, E, L군에서각각정상화를보였으며세군간의유의한차이가보이지않았다. 치료 48주째 DNA 음전화율은 E군에서 C, L군에비하여유의하게높았고 ALT 정상화율, HBeAg 소실율, 혈청전환율은 C, E, L군에서통계적유의한차이가없었다. C군에서투약 24주째 5%, 48주째 21% 에서바이러스돌파현상이나타났으나생화학적돌파현상은없었다. C군에서치료 48주째 CK 상승및근육통을보인환자가 1명 (2.56%) 있었다. 비간경변환자군과대상성간경변환자군간치료 48주째평균 DNA 감소율을비교하였을때, lamivudine에비하여 clevudine의항바이러스효과는간경변으로진행된환자군보다비간경변환자군에서더욱뚜렷하게나타났다 (p<0.001 vs p=0.036). 결론 : HBeAg 양성인만성 B형간염환자들에서초치료제로서 clevudine 은 48주간 lamivudine과비교하여강력한항바이러스효과를보이며이는간경변환자와비교하여비간경변환자에서더욱뚜렷하다. 비록효과나부작용을비교하기에추적기간이짧은후향분석이나 clevudine과 entecavir의항바이러스효과는차이가없었다. 색인단어 : 클레부딘, 엔테카비어, 라미부딘, 만성 B형간염참고문헌 1. Cheong JY. Management of chronic hepatitis B in treatment-naive patients. Korean J Gastroenterol 2008;51:338-345. 2. Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006;130:678-686. 3. 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;295:65-73. 4. Chen G, Lin WY, Shen FM, Iloeje UH, London WT, Evans AA. Viral load as a predictor of mortality from hepatocellular carcinoma and chronic liver disease in chronic hepatitis B infection. Abstract 477. 40th EASL. April 13-17, 2005. Paris, France. 5. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007;45:507-539. 6. Mommeja-Marin H, Mondou E, Blum MR, Rousseau F. Serum HBV DNA as a marker of efficacy during therapy for chronic HBV infection: analysis and review of the literature. Hepatology 2003;37:1309-1319. 7. Di Marco V, Lo Iacono O, Cammà C, et al. The long-term course of chronic hepatitis B. Hepatology 1999;30:257-264. 8. Dienstag JL, Goldin RD, Heathcote EJ, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology 2003;124:105-117. 9. Leung NW, Lai CL, Chang TT, et al. Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy. Hepatology 2001;33:1527-1532. 10. Dienstag JL, Schiff ER, Wright TL, et al. as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341:1256-1263. 11. 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;354:1001-1010. 12. Lai CL, Shouval D, Lok AS, et al. versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2006;354:1011-1020. 13. Sherman M, Yurdaydin C, Simek H, et al. therapy for lamivudine-refractory chronic hepatitis B: improved virologic, biochemical, and serology outcomes through 96 weeks. Hepatology 2008;48:99-108. 14. Lim SG, Leung N, Hann HW, et al. Clinical trial: a phase II, randomized study evaluating the safety, pharmacokinetics and anti-viral activity of clevudine for 12 weeks in patients with chronic hepatitis B. Aliment Pharmacol Ther 2008;27:1282-1292. 15. Lee KS, Byun KS, Chung YH, et al. therapy for 24 weeks further reduced serum hepatitis B virus DNA levels and increased ALT normalization rates without emergence of viral breakthrough than 12 weeks of clevudine therapy. Intervirology 2007;50:296-302. 16. Yoo BC, Kim JH, Chung YH, et al. Twenty-four-week clevudine therapy showed potent and sustained antiviral activity in HBeAg-positive chronic hepatitis B. Hepatology 2007;45: 1172-1178. 17. Yoo BC, Kim JH, Kim TH, et al. is highly efficacious in hepatitis B e antigen-negative chronic hepatitis B
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