Korean J Gastroenterol Vol. 65 No. 1, 35-42 http://dx.doi.org/10.4166/kjg.2015.65.1.35 pissn 1598-9992 eissn 2233-6869 ORIGINAL ARTICLE 약제내성만성 B 형간염환자에서테노포비어를포함한구원치료의효과 최강혁 *, 이한민 *, 전백규, 이세환, 김홍수, 김상균 1, 김영석 1, 김부성 1, 정승원 2, 장재영 2, 김영돈 3, 천갑진 3 순천향대학교의과대학천안병원, 부천병원 1, 서울병원 2, 울산대학교의과대학강릉아산병원 3 내과학교실 Efficacy of Tenofovir-based Rescue Therapy for Patients with Drug-resistant Chronic Hepatitis B Kanghyug Choi*, Han Min Lee*, Baek Gyu Jun, Sae Hwan Lee, Hong Soo Kim, Sang Gyune Kim 1, Young Seok Kim 1, Boo Sung Kim 1, Soung Won Jeong 2, Jae Young Jang 2, Young Don Kim 3 and Gab Jin Cheon 3 Departments of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Bucheon Hospital, Bucheon 1, Seoul Hospital, Seoul 2, Soonchunhyang University College of Medicine, Department of Internal Medicine, University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung 3, Korea Background/Aims: Tenofovir disoproxil fumarate (TDF) plays a pivotal role in the management of drug-resistant chronic hepatitis B. However, it remains unclear whether TDF-nucleoside analogue combination therapy provides better outcomes than TDF monotherapy. This study aimed to compare the efficacy of TDF monotherapy with that of TDF-nucleoside analogue combination therapy in patients with drug-resistant chronic hepatitis B. Methods: This retrospective cohort study included 76 patients receiving TDF-based rescue therapy for more than 12 months. Suboptimal response was defined as serum HBV-DNA level of >60 IU/mL during prior rescue therapy. Multi-drug resistance was defined as the presence of two or more drug resistance-related mutations confirmed by mutation detection assay. The relationship between baseline characteristics and virologic response (HBV DNA <20 IU/mL) at 12 months were evaluated using logistic regression analysis. Results: Fifty-five patients (72.4%) were suboptimal responders to prior rescue therapy, and 26 (34.2%) had multi-drug resistance. Forty-two patients (55.3%) received combination therapy with nucleoside analogues. Virologic response at 12 months was not significantly different between the TDF monotherapy group and TDF-nucleoside analogue combination therapy group (p=0.098). The serum HBV DNA level was reduced to 4.49±1.67 log 10 IU/mL in the TDF monotherapy group and to 3.97±1.69 log 10 IU/mL in the TDF-nucleoside analogue combination therapy group at 12 months (p=0.18). In multivariate analysis, female sex (p=0.032), low baseline HBV-DNA level (p=0.013), and TDF monotherapy (p=0.046) were predictive factors for virologic response at 12 months. Conclusions: TDF monotherapy showed similar efficacy to that of TDF-nucleoside analogue combination therapy in patients with drug-resistant chronic hepatitis B. (Korean J Gastroenterol 2015;65:35-42) Key Words: Hepatitis B; Drug resistance; Tenofovir; Virologic response Received August 24, 2014. Revised October 7, 2014. Accepted October 31, 2014. CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright 2015. Korean Society of Gastroenterology. *These two authors have equally contributed to this work. 교신저자 : 이세환, 330-721, 천안시동남구순천향 6길 31, 순천향대학교천안병원간클리닉 Correspondence to: Sae Hwan Lee, Liver Clinic, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 330-903, Korea. Tel: +82-41-570-3692, Fax: +82-41-574-5762, E-mail: stevesh@sch.ac.kr Financial support: This work was supported by the Soonchunhyang University Research Fund. Conflict of interest: None. Korean J Gastroenterol, Vol. 65 No. 1, January 2015 www.kjg.or.kr
36 최강혁등. 약제내성시테노포비어의효과 서론 B형간염바이러스감염자는세계적으로약 4억명가량으로파악되며우리나라의경우 10세이상인구에서 B형간염항원양성률은약 3.7% 로조사되었다. 1,2 만성 B형간염은간경변증및간세포암종과같이치명적인질환을유발할수있어사회경제적인문제가된다. 3,4 라미부딘은 B형간염바이러스의증식을억제하는항바이러스제로우리나라에서는약 15 년전만성 B형간염환자의치료에도입되었으며만성간염뿐만아니라간경변증을동반한경우에도항바이러스효과와생존율향상이입증되었으나장기투여시약제내성변이바이러스의출현과이로인한바이러스돌파가임상적인문제로대두되었다. 5-7 이후출시된아데포비어와텔비부딘도 2년치료시약 17-25% 정도의환자에서약제내성변이바이러스의출현을경험하고있어장기치료시약제내성발생에서자유롭지못하다. 8,9 현재이러한약제내성치료의원칙은서로다른계열의약제를병합하여교차내성의발생을예방하는것이권유되고있지만라미부딘내성구원치료가도입되던시기에는아데포비어혹은엔테카비어단독요법이시도되었으며이로인한순차내성혹은다약제내성발생이문제가되고있다. 10-12 최근만성 B형간염치료제로서허가를받은테노포비어는강력한항바이러스효과와함께장기간치료에도약제내성발생이없는것으로알려져있다. 13,14 또한, 항바이러스제내성변이바이러스에도우수한증식억제효과를나타내어구원치료로서의유용성이인정되었으나테노포비어단독요법과테노포비어와 nucleoside 유사체병합요법간의장기적인효과에대한논란은지속되고있으며단독요법과병합요법사이의항바이러스효과를비교한연구들에서는서로상이한결과들을보고하고있다. 15,16 더욱이테노포비어와같은 nucleotide 유사체로분류되는아데포비어내성변이가있는환자에서테노포비어단독요법이장기간치료시교차내성발생의가능성을높일것인가에대한연구는부족한실정이다. 이에저자들은약제내성만성 B형간염환자에서테노포비어단독요법과테노포비어-nucleoside 유사체병합요법간의항바이러스효과를비교하고자하였으며이차적으로약제내성변이바이러스종류에따른바이러스반응의차이를평가하고자하였다. 대상및방법 1. 연구설계및대상이연구는다기관연구로순천향대학교천안병원, 순천향대학교부천병원, 순천향대학교서울병원및아산재단강릉아 산병원에서바이러스돌파와함께약제내성변이가확인된후구원치료에불충분한바이러스반응을보이거나바이러스돌파와함께새로이약제내성변이가확인된환자들중에서 2012년 6월부터 2013년 6월까지테노포비어 (300 mg/day) 가포함된구원치료로변경되거나새로이테노포비어포함구원치료를받은환자들의의무기록을후향적으로조사하였다. 총 153명의환자중테노포비어도입시약제내성변이가확인되지않았거나 (26명) 테노포비어가포함된구원치료의기간이 12개월미만인환자들 (51명) 은제외한후최종 76명을대상으로분석하였다. 임상연구시행전각참여병원연구윤리심의위원회의승인을받았다. 2. 연구방법및정의대상환자들의인구학적변수와이전구원치료의유무및종류를조사하였으며테노포비어구원치료시작시의혈청생화학검사, HBeAg, anti-hbe, 혈청 HBV DNA 수치및약제내성변이의종류를조사하였다. 이후추적기간중 3-6개월간격으로시행된혈청생화학검사와바이러스검사결과를 12 개월까지조사하였다. 혈청 HBV DNA 수치는중합효소연쇄반응법 (PCR) 정량 (Amplicor HBV Monitor; Roche Diagnostics, Mannheim, Germany) 으로측정하였고최소검출한도는 20 IU/mL였다. 약제내성변이검출을위한검사는순천향대학교천안병원에서는제한효소절편질량다형법 (restriction fragment mass polymorphism assay) 을이용하였고순천향대학교부천병원, 순천향대학교서울병원, 아산재단강릉아산병원에서는직접염기서열분석법 (direct sequencing) 을이용하였다. 바이러스돌파는항바이러스치료중가장낮게측정된혈청 HBV DNA보다 1 log 10 IU/mL 이상증가하였을경우로정의하였으며불충분한바이러스반응은 12개월이상의구원치료유지에도불구하고혈청 HBV DNA가지속적으로검출 (>60 IU/mL) 되는경우로하였다. 다약제내성은서로다른계열의두가지이상약제에대한내성변이를동시에나타내는경우로정의하였다. 17 완전바이러스반응은혈청 HBV DNA 음전 (<20 IU/mL) 으로정의하였으며생화학반응은혈청알라닌아미노전달효소가 40 IU/L 이하로감소됨으로하였다. 일차변수는테노포비어가포함된구원치료 12개월후의완전바이러스반응달성여부였으며이차변수로치료기간중평균 HBV DNA 감소율의차이를조사하였다. 3. 통계분석방법범주형자료인경우에는각범주의피험자수와전체피험자를기준으로한백분율을제시하고, chi-square test ( 또는 Fisher s exact test) 를이용하여두군을비교하였다. 연속형자료는평균, 표준편차, 최소, 최대치등의기술통계량을구하 The Korean Journal of Gastroenterology
Choi K, et al. Tenofovir for Drug-resistant Chronic Hepatitis B 37 Table 1. Baseline Characteristics of the Study Population Characteristic Total (n=76) TDF monotherapy (n=34) TDF-nucleoside analogues combination therapy (n=42) p-value Age (yr) 50 (20-74) 48 (33-65) 50 (22-74) 0.988 Male 56 (73) 23 (41) 33 (58) 0.282 Antiviral agents in naïve state Lamivudine 54 (71) 22 (65) 32 (76) 0.273 Clevudine 7 (9) 2 (6) 5 (12) Telbivudine 5 (5) 3 (9) 2 (5) Entecavir 7 (9) 5 (14) 2 (5) Adefovir dipivoxil 3 (4) 2 (6) 1 (2) Prior rescue therapy 55 (72) 23 (67) 32 (76) 0.408 Cirrhosis 14 (18) 8 (23) 6 (14) 0.301 ALT (IU/L) 31 (13-417) 32 (13-332) 30 (15-417) 0.645 Creatinine (mg/dl) 0.9 (0.3-1.3) 0.9 (0.3-1.3) 1 (0.5-1.3) 0.327 HBeAg-positivity 62 (81) 26 (42) 36 (58) 0.432 HBV DNA (log 10 IU/mL) a 4.4 (1.8-7.9) 4.76±1.7 4.54±1.76 0.224 Values are presented as median (range), n (%), or mean±sd. TDF, tenofovir disoproxil fumarate. 고, 각변수의분포의특성에따라독립 t-검정또는 Wilcoxon rank sum test로두군간의통계적유의성을분석하였다. 12개월째바이러스반응에영향을주는결과변수를확인하기위해서 logistic regression analysis를이용하였다. 유의수준 0.05 미만에서가설검정을실시하였으며모든통계분석은 SPSS version 14.0 (SPSS Inc., Chicago, IL, USA) 을이용해수행하였다. 결과 1. 대상환자의특성대상환자총 76명의초치료약제의분포는라미부딘 54명, 클레부딘 7명, 텔비부딘 5명, 엔테카비어 7명, 아데포비어 3 명이었다. 이전에다른구원치료를받은환자는 55명 (72.3%) 이었고이중 22명은 2종류이상의구원치료를경험하였다. 이전모든구원치료의기간은 50개월 (12-102개월) 이었다. 테노포비어가포함된구원치료이전의마지막구원치료의종류는아데포비어단독요법이 11명, 엔테카비어단독요법이 19명, 라미부딘과아데포비어병합요법이 9명, 텔비부딘과아데포비어병합요법이 3명, 엔테카비어와아데포비어병합요법이 13명이었다 (Table 1). 테노포비어-nucleoside 유사체병합요법을받은환자들은 42명 (55.3%) 이었으며 nucleoside 유사체의종류는엔테카비어 (1 mg/day) 26명, 라미부딘 (100 mg/day) 8명, 텔비부딘 (600 mg/day) 7명, 클레부딘 (30 mg/day) 1명이었다. 테노포비어가포함된구원치료를시작할때의기저약제내성은라미부딘내성이 38명 (50.0%), 아데포비어내성이 12명 (15.8%) 이었고다약제내성으로분류할수있었던환자는라미부딘과아데포비어동시내성 5명 Table 2. Baseline Mutation Patterns and Virologic Response Drug resistance Genotypic mutations n VR12 LAM, 38 (50.0) rt180 4 30 (78.9) rt204i 11 rt180+rt204i 5 rt180+rt204v 13 rt180+rt204i/v 5 ADV, 12 (15.8) rt181a 4 9 (75.0) rt181a+rt236t 8 LAM-ADV, 5 (6.6) LAM-ETV, 17 (22.4) LAM-ADV-ETV, 4 (5.3) rt180+rt181a 1 3 (60.0) rt180+rt181a+rt204v 3 rt181a+rt204i 1 rt204i+rtt184 1 12 (70.6) rt204vvrtt184 1 rt180+rt204v+rtt184 3 rt180+rt204i/v+rtt184 1 rt180+rt204i/v+rti169 1 rt180+rt204v+rtt184+rti169 3 rt180+rt204v+rts202 7 rt181a+rt204i+rtt184 2 4 (100) rt180+rt181a+rt204i/v+ 1 rtt184 rt180+rt181a+rt204v+ 1 rt236t+rts202+rtm250 Values are presented as n only or n (%). LAM, lamivudine; ADV, adefovir dipivoxil; ETV, entecavir; VR12, virological response at month 12. (6.6%), 라미부딘과엔테카비어동시내성 17명 (22.4%), 라미부딘, 아데포비어, 엔테카비어세가지약제모두에내성유전자돌연변이를가지고있던 4명 (5.0%) 이었다 (Table 2). 테노포비어단독요법군과테노포비어-nucleoside 유사체병합요법군에서라미부딘내성은각각 18명과 20명 (p=0.646), 아데포비어내성은 7명과 5명 (p=0.3), 라미부딘과아데포비어동 Vol. 65 No. 1, January 2015
38 최강혁등. 약제내성시테노포비어의효과 Table 3. Predictive Factors for Virological Response at 12 Months Factor Univariate Multivariate OR (95% CI) p-value OR (95% CI) p-value Age (>50 yr) 1.93 (0.65-5.69) 0.231 Gender (male) 0.12 (0.02-0.97) 0.047 0.08 (0.01-0.81) 0.032 Cirrhosis 4.91 (0.59-40.47) 0.139 6.64 (0.63-69.4) 0.114 Prior rescue therapy 0.44 (0.11-1.72) 0.242 Combination with nucleoside 0.38 (0.12-1.21) 0.104 0.23 (0.05-0.97) 0.046 Presence of adefovir dipivoxil 0.99 (0.31-3.22) 0.987 resistance-associated mutations Mutation on rt236 2.33 (0.26-20.3) 0.443 Multi-drug resistance 0.76 (0.25-2.28) 0.632 HBeAg-positive 0.24 (0.02-1.99) 0.186 0.21 (0.02-2.14) 0.186 HBV DNA (<4.3 log 10 IU/mL) 4.62 (1.35-15.7) 0.014 6.05 (1.47-24.9) 0.013 Fig. 1. Mean (95% CI) changes in serum HBV DNA levels between TDF monotherapy group and TDF-nucleoside analogue combination therapy group. Fig. 2. Mean (95% CI) changes in serum HBV DNA levels according to adefovir dipivoxil resistance-associated mutations. ADV-R, adefovir dipivoxil resistance-associate mutation. 시내성은테노포비어-nucleoside 유사체병합군에서만 5명, 라미부딘과엔테카비어동시내성 7명과 10명 (p=0.74), 세가지약제동시내성은각각 2명이었다. 대상환자모두테노포비어포함구원치료시작후분석이가능하였던 12개월까지 nucleoside의추가및중단혹은종류의변경은없었다. 2. Nucleoside 유사체병합여부에따른바이러스반응구원치료시작시기저약제내성에따른 12개월완전바이러스반응달성률은라미부딘내성에서 78.9%, 아데포비어내성에서 75.0%, 다약제내성에서는 73.1% 였다 (Table 2). 테노포비어단독요법군과테노포비어-nucleoside 유사체병합요법군의 12개월완전바이러스반응률을비교하였고테노포비어단독요법군에서는 85.2%, 테노포비어-necleoside 유사체병합요법군에서는 69.0% 로두군간에유의한차이를보이지않았다 (p=0.098, Table 3). 구원치료기간중테노포비어단독요법과테노포비어-necleoside 병합요법간의평균혈청 HBV DNA 감소를 Fig. 1에나타냈으며 12개월째평균 HBV DNA 감소는테노포비어단독요법군에서 4.49±1.67 log 10 IU/mL, 테노포비어-necleoside 병합요법군에서는 3.97±1.69 log 10 IU/mL로유의한차이는없었다 (p=0.18). 3. 아데포비어내성변이유무에따른바이러스반응전체대상환자를아데포비어내성변이의유무에따라나누어기저특성을비교하였으며성별 (p=0.759), HBeAg 양성여부 (p=0.807), 혈청 HBV DNA 수치 (p=0.977) 는각각에서유의한차이가없었다. 아데포비어내성유전자돌연변이유무에따른 12개월완전바이러스반응을비교하였고아데포비어내성이없는군에서 76.4% (42/55), 아데포비어내성군에서도 76.2% (16/21) 로차이가없었다 (p=0.987). 구원치료기간중아데포비어내성변이유무에따른평균혈청 HBV DNA 감소를 Fig. 2에나타내었으며 12개월째평균 HBV DNA 감소는아데포비어내성변이가없는군에서 4.18±1.74 log 10 The Korean Journal of Gastroenterology
Choi K, et al. Tenofovir for Drug-resistant Chronic Hepatitis B 39 IU/mL, 내성변이가있는군에서는 4.26±1.58 log 10 IU/mL로차이가없었다 (p=0.847). 아데포비어내성변이바이러스가검출된환자 21명을대상으로테노포비어단독요법 (9명) 과테노포비어-necleoside 병합요법 (12명) 의 12개월완전바이러스반응을비교하였을때테노포비어단독요법군에서는 9명모두, 테노포비어-necleoside 병합요법군에서는 7 명에서완전바이러스반응이달성되었으며 (p=0.027), 3개월과 6개월째평균 HBV DNA 감소는테노포비어단독요법군에서각각 3.31±1.29와 4.03±1.09, 테노포비어-necleo- side 병합요법군에서각각 2.89±1.05와 3.79±1.65로통계적으로유의한차이를보이지않았다 (p=0.434, p=0.647). 4. 임상변수와바이러스반응과의관계연령, 성별, 간경변증동반여부, 이전구원치료의유무, nucleoside 병합여부, 아데포비어내성변이유무, rt236 변이유무, 다약제내성유무, HBeAg 양성여부, 테노포비어포함구원치료도입시혈청 HBV DNA 수치를변수로하여 12개월완전바이러스반응달성과의연관성을찾기위한단변량분석결과여자 (p=0.047), 낮은혈청 HBV DNA 수치 (p=0.014) 가바이러스반응달성과연관이있었다. 다변량분석을위한변수의선택을위해서유의수준 0.2 미만 (p<0.2) 의변수를포함시켰으며여자 (p=0.032), 테노포비어단독요법 (p=0.046), 낮은혈청 HBV DNA 수치 (p=0.013) 가독립적인예측인자였다 (Table 3). 고찰 우리나라의경우과거라미부딘으로초치료를시작한환자들이축적되어있으며라미부딘의높은약제내성변이발생률로인해다양한구원치료를경험한환자들이많다. 그중아데포비어혹은엔테카비어단독요법후순차내성발생으로다약제내성을획득한경우가적지않고라미부딘과아데포비어의병합요법도완전바이러스반응을유도하려면장기간의치료가필요하다. 18-20 약제내성환자들을대상으로한이번연구에서테노포비어가포함된구원치료의 12개월누적바이러스반응은 76.3% 였으며 nucleoside 유사체병합여부나기저약제내성변이의종류및다약제내성여부와관계없이비교적좋은바이러스반응을얻을수있었다. 최근약제내성만성 B형간염환자들에대한구원치료나이전항바이러스제에부분바이러스반응을보인환자들을대상으로테노포비어가포함된구원치료의효과에대한전향연구들이발표되었다. 15,21,22 이들연구에서공통적으로치료후 12개월째바이러스반응획득은 70% 를상회하였으며이는초치료환자들이대상이었던연구의치료의도자분석 (intention to treat analysis) 결과와크게다르지않았다. 23 항바이러스제를경험한환자들에서의이러한결과는테노포비어의강력한항바이러스효과와높은유전자장벽으로설명할수있다. 다양한연구들에서약제내성만성 B형간염환자에서테노포비어단독요법과테노포비어-necleoside 병합요법의바이러스반응을비교한결과들이보고되었다. 홍콩에서시행된전향코호트연구에서는테노포비어단독요법이테노포비어 -necleoside 병합요법에비해서 3년누적바이러스반응달성률이저조하였다. 16 하지만다른무작위배정전향연구들에서는테노포비어단독요법과테노포비어-necleoside 병합요법사이에바이러스반응달성률은차이가없었다. 15,21 금번연구에서테노포비어단독요법의 12개월바이러스반응달성률은테노포비어-necleoside 병합요법에비해오히려더높은것으로나타났으나통계적으로유의한차이는없었다. 테노포비어의사용이불가능하였던시기에약제내성만성 B형간염의구원치료의중추적인역할을담당하였던아데포비어는임상용량에서는바이러스증식억제효과에제한이있어종국에는교차내성의발생이문제가되었다. 24 이를막기위해다른계열인 nucleoside 유사체병합요법이추천되어왔고이로인해교차내성발생률은획기적으로감소하였으나병합된 nucleoside 유사체가지속적인선택압력으로작용하여내성변이바이러스의지속적인검출을유도하고장기간의치료에도불구하고부분바이러스반응의유지를초래하는원인중한가지였다. 25,26 테노포비어의경우여러연구들에서입증되었듯이약제내성환자에서도초기혈청 HBV DNA를효과적으로감소시키며장기간치료시에도완전바이러스반응달성과함께지속적인유지가가능하여약제내성만성 B형간염의구원치료로아데포비어만사용할수있었던때와는다른전략적접근이가능하겠으며테노포비어단독구원치료의효용성이인정된다. 테노포비어는항바이러스기전및내성획득의특성이아데포비어와매우유사하다고알려져있다. 이전항바이러스제를경험한환자들을대상으로테노포비어단독요법의효과에대한후향코호트연구결과테노포비어와같은 nucleotide 유사체인아데포비어내성환자들에서는라미부딘내성환자에비해바이러스반응달성률이통계적으로유의하게감소하였다는보고가있었다. 27 이후비슷한환자들을대상으로테노포비어가포함된구원치료의효과에대한연구들에서는아데포비어내성변이가있는경우에도장기누적바이러스반응달성률은유의한차이가없었지만치료초기, 6-12개월간의바이러스반응달성률은통계적으로유의하게감소하였다. 16,28 이러한초기치료반응의임상적유용성이여러연구들을통해강조되어왔으며이에따른치료전략의수정을고려할수있는데특히낮은유전자장벽을가지고있는라미부딘, 텔비부 Vol. 65 No. 1, January 2015
40 최강혁등. 약제내성시테노포비어의효과 딘과같은경우에는 24주째부분바이러스반응을보일경우약물의교체를감안할수있다. 29 또한여러연구들을통해서약제내성만성 B형간염의구원치료시에도초기치료반응의중요성이입증되었는데라미부딘내성환자들을대상으로한연구들에서아데포비어단독혹은병합요법의구원치료시작후 24주째바이러스반응의유무가장기바이러스반응달성의강력한예측인자라는것이알려졌다. 30,31 그러나높은유전자장벽을가진엔테카비어와테노포비어의경우에는초치료환자의경우 48주째부분바이러스반응의유무를판단하도록권고되고있으며최근한코호트연구결과비록일차무반응을보인경우에도엔테카비어지속투여시장기누적바이러스반응이일반적인좋은반응을보였던군과차이가없었다는보고가있었다. 32,33 이번연구에서도대상환자수가적어그결과의해석에제한이있지만아데포비어내성변이가있는환자들에서치료초기혈청 HBV DNA 감소율은테노포비어단독요법군과테노포비어-necleoside 병합요법군간에차이가없었으며 12개월완전바이러스반응달성률은테노포비어단독요법군에서통계적으로유의하게높았다. 더욱이최근아데포비어를경험한환자들을대상으로테노포비어단독요법과테노포비어와엠트리시타빈병합요법의효과를비교한무작위배정전향연구에서는아데포비어내성변이유무에따른누적바이러스반응달성률이나구원치료초기혈청 HBV DNA 감소율은차이가없었으며임상시험기간중단독요법군에서교차내성의발생도없었다. 22 이를종합해보면아데포비어내성변이가존재하는경우에도테노포비어단독요법이효과적인바이러스반응유지와함께교차내성발생에서자유로울가능성이크지만대규모전향연구들의결과가필요하다. 이번연구에서는약제내성유전자돌연변이가확인된환자들만을대상으로연구를진행하였고이전연구에서아데포비어내성변이중 rt236 변이가존재하는경우테노포비어구원치료의효과가감소한다는보고가있었으나금번연구에서는 12개월바이러스반응달성에는차이가없었다. 21 또한다변량분석결과 rt236 변이유무와다약제내성여부는 12 개월바이러스반응달성에영향을미치지못하였다. 이는이번연구에포함된다약제내성환자의 65.3% 가 nucleoside 유사체인라미부딘과엔테카비어내성환자들로테노포비어에투여시내성변이바이러스들을효과적으로억제할수있었던경우였던것이중요한이유로생각된다. 구원치료시작시높은혈청 HBV DNA 수치가 12개월바이러스반응을예측하는중요한인자로나타났으나앞서언급된전향연구들의결과를고려해보면강력하고높은유전자장벽을지닌테노포비어가포함된구원치료를유지할경우혈청 HBV DNA 수치에관계없이장기바이러스반응은유도될것으로생각된다. 또한단변량분석에서 p값이비교적낮았던 (0.2 이하 ) 변 수들을모두다변량분석에포함시켜분석한결과 nucleoside 유사체병합여부가완전바이러스반응달성예측의독립적인예측인자로확인되었으나이는두군의기저특성의차이 (HBeAg 양성환자의분포 ) 가다변량분석시영향을미쳤을가능성이있으며대상환자의수가적었던것과도연관있을것으로판단되어주의깊은해석이필요하다. 이번연구의제한점은후향연구로약제순응도평가가이루어지지못한것이며대상환자의수가적은것이다. 테노포비어가포함된구원치료시작시의내성변이를모두확인하여변이종류에따른바이러스반응달성유무를분석하고자하였으나대상환자가적고내성변이가매우다양하여각내성변이에따른치료효과의분석에한계가있었다. 마지막으로대상환자들의초치료약제의종류, 이전구원치료의종류와기간, 그리고테노포비어와병합된 necleoside의종류가매우다양하였던것도제한점이다. 결론으로약제내성만성 B형간염에서테노포비어가포함된구원치료의 12개월바이러스반응은우수하였다. 테노포비어단독요법은테노포비어-necleoside 병합요법에비해바이러스반응달성및혈청 HBV DNA 감소에차이가없었으며기저아데포비어내성변이의존재유무도바이러스억제에영향을미치지못했다. 향후테노포비어단독요법과아데포비어내성환자들에서의장기성적및교차내성발생여부에대한지속적인관찰이필요하다. 요약 목적 : 최근약제내성만성 B형간염의구조치료로테노포비어가중요한역할을하고있다. 하지만테노포비어-nucleoside 유사체병합요법이테노포비어단독요법보다더좋은효과를유도하는지는분명하지않다. 이연구는약제내성변이가확인된만성 B형간염환자들의구원치료로서테노포비어단독요법과테노포비어-nucleoside 유사체병합요법의효과를비교해보고자하였다. 대상및방법 : 이연구는 12개월이상테노포비어가포함된구원치료를받은 76명의환자들의의무기록을후향적으로조사하였다. 불충분한바이러스반응은이전구원치료유지에도불구하고혈청 HBV DNA가지속적으로검출 (>60 IU/mL) 되는경우로하였으며다약제내성은서로다른계열의두가지이상약제에대한내성변이가동시에검출되는경우로정의하였다. 환자의기저특성과 12개월완전바이러스반응 (HBV DNA <20 IU/ ml) 을 logistic regression analysis를이용하여분석하였다. 결과 : 대상환자총 76명중 55명 (72.4%) 의환자가이전구원치료에불충분한바이러스반응을보인경우였으며 26명 The Korean Journal of Gastroenterology
Choi K, et al. Tenofovir for Drug-resistant Chronic Hepatitis B 41 (34.2%) 의환자가다약제내성을가지고있었다. 테노포비어와 nucleoside 유사체병합요법을받은환자들은 42명 (55.3%) 이었다. 테노포비어단독요법과테노포비어-nucleo- side 유사체병합요법의 12개월완전바이러스반응률은두군간에유의한차이를보이지않았다 (p=0.098). 12개월혈청 HBV DNA 수치의감소는테노포비어단독요법군에서 4.49±1.67 log 10 IU/mL이었으며테노포비어-nucledoside 유사체병합요법군에서는 3.97±1.69 log 10 IU/mL였다 (p=0.18). 다변량분석에서는여성 (p=0.032), 낮은기저 HBV DNA 수치 (p=0.013), 그리고테노포비어단독요법 (p=0.046) 이 12개월바이러스반응의예측인자였다. 결론 : 약제내성만성 B형간염환자에서테노포비어단독요법은테노포비어-nucleoside 유사체병합요법과비슷한효과를보였다. 색인단어 : B형간염 ; 약제내성 ; 테노포비어 ; 바이러스반응 REFERENCES 1. Lee WM. Hepatitis B virus infection. N Engl J Med 1997; 337:1733-1745. 2. Ministry of Helalth & Welfare, Korea Centers for Disease Control and Prevention. The third Korea national health and nutrition examination survey (KNHANES III), 2005: health examination. Sejong: Ministry of Helalth & Welfare, 2006:68. 3. Schiff ER. Prevention of mortality from hepatitis B and hepatitis C. Lancet 2006;368:896-897. 4. Chu CM. 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