Microsoft Word HBVGuideline

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1 2014 대한간학회 만성 B 형간염진료가이드라인업데이트 : 약제내성의치료 대한간학회

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3 2014 대한간학회만성 B 형간염진료가이드라인업데이트 : 약제내성의치료 [ 권고사항 ] 라미부딘내성 1. 테노포비어단독또는뉴클레오시드유사체에테노포비어를병합치료한다 (A1). 2. 테노포비어를사용할수없는경우에는라미부딘과아데포비어를병합치료한다 (A2). 이외에아데포비어에엔테카비어또는다른뉴클레오시드유사체의병합치료를고려할수있다 (B2). 3. 대상성간기능을가진환자에서는라미부딘을중단하고페그인터페론투여를고려할수있다 (B2). 텔비부딘, 클레부딘내성 라미부딘내성에준하여치료할수있다 (B2). 아데포비어내성 1. 라미부딘에내성을보여아데포비어를사용했던경우 1) 테노포비어단독또는테노포비어와엔테카비어병합치료를고려한다 (B1). 2) 테노포비어와다른뉴클레오시드유사체의병합치료를고려할수있다 (B2). 3) 테노포비어를사용할수없는경우에는아데포비어와엔테카비어병합치료를고려할수있다 (B2). 2. 초치료로아데포비어를사용했던경우 1) 테노포비어단독또는테노포비어와엔테카비어병합치료를고려한다 (B1). 2) 테노포비어와다른뉴클레오시드유사체의병합치료를고려할수있다 (B2). 3) 테노포비어를사용할수없는경우에는아데포비어와엔테카비어또는다른뉴클레오시드유사체의병합치료를고려할수있다 (B2). 엔테카비어내성 1 테노포비어단독또는테노포비어와엔테카비어병합치료를고려한다 (B1). 2 테노포비어를사용할수없는경우에는아데포비어와엔테카비어병합치료를고려할수있다 (B2). 1

4 다약제내성 1. 테노포비어단독또는테노포비어와엔테카비어병합치료를고려한다 (B1). 2. 테노포비어를사용할수없는경우에는아데포비어와엔테카비어병합치료를고려할수있다 (B2). 1. 라미부딘내성 가. 테노포비어 : 테노포비어는라미부딘내성변이 B형간염바이러스 (HBV) 에대하여강력한증식억제효과를나타낸다. 1-4 야생형및라미부딘내성변이에대한테노포비어효과를비교한후향적연구를보면모두 197명의환자가포함되었는데 ( 초치료환자 105명 ), 테노포비어단독치료또는라미부딘과병합치료는항바이러스제초치료군과라미부딘내성군에서치료 36개월째 HBV 불검출률 (HBV DNA <20 IU/mL) 이 HBeAg(e항원 ) 음성에서각각 94%, 96%, e항원양성에서각각 67%, 83% 로양군간의의미있는차이는없었다. 2 HIV와동시감염된라미부딘내성환자를대상으로아데포비어와테노포비어의항바이러스효과를비교한연구에서 HBV DNA 감소가 10 5 copies/ml 이하인경우는아데포비어와테노포비어군에서치료 48주째각각 44%, 100% 로유의한차이를보였다. 1 테노포비어단독치료와테노포비어와 nucleoside( 뉴클레오시드 ) 유사체인엠트리시타빈병합치료를비교한연구에서는라미부딘내성환자 280명이포함되었는데 96주째 HBV DNA 불검출률 (HBV DNA <69 IU/mL) 은각각 85.8% 와 83.5% 으로양군간의유의한차이는없었으며양군모두에서테노포비어내성은검출되지않았다. 4 라미부딘내성환자를대상으로테노포비어단독치료와테노포비어와라미부딘병합치료를비교한전향적연구는없으나항바이러스제의치료경험이있는 125명의환자에서테노포비어단독치료 (n=71) 와테노포비어와라미부딘병합치료 (n=54) 를후향적으로분석한연구에서는 HBV DNA 누적불검출률 (HBV DNA <20 IU/mL) 이투약 3년째각각 90.7% 와 96.0% 로통계학적으로의미있는차이를보였다. 3 나. 아데포비어 : 아데포비어는라미부딘내성변이바이러스에증식억제효과를나타낸다. 라미부딘내성에대한아데포비어와라미부딘병합치료는아데포비어단독치료에비해장기간추적시아데포비어내성발현이의미있게낮았다. 5,6 뉴클레오시드유사체와아데포비어병합치료효과를테노포비어와비교한연구는없다. 그러나라미부딘내성치료중추가적인약제내성발생이보고되어있지않은테노포비어에비해서, 라미부딘와아데포비어병합치료는평균 5.4년 3.0% 7, 48주 2.2%, 8 24개월 13.3% 9 및 5년 10.2% 10 등으로다양한아데포비어내성발생이보고되었다. 라미부딘내성에서아데포비어를근간으로하고라미부딘대신에다른뉴클레오시드유사체인엔테카비어, 텔비부딘혹은클레부딘을병합치료하는것에대한추가연구는많지않으며대상환자수도적다. 라미부딘내성환자 91명을대상으로아데포비어단독치료 (n=29), 아데포비 2

5 어와라미부딘병합치료 (n=30), 및아데포비어와엔테카비어 1.0 mg 병합치료 (n=32) 를후향적으로비교한연구에서는, 9 HBV DNA 불검출률 (HBV DNA <60 IU/mL) 이 24개월째각각 48.2%, 76.7%, 87.5% 로통계적으로는의미가없다고보고하였으나아데포비어내성발현율은각각 27.6%, 13.3%, 0% 로의미있는차이를보였다. 아데포비어와텔비부딘병합치료 (n=21) 를아데포비어단독치료 (n=21) 와비교한소규모전향적연구에서 11 HBV DNA 불검출률 (HBV DNA <300 copies/ml) 은치료 96주째각각 38.5%, 0% 였으며아데포비어단독치료군에서는 9.6% 에서아데포비어내성바이러스가검출되었다. 11 두개의소규모전향적연구에서는아데포비어와텔비부딘병합치료군에서아데포비어와라미부딘병합치료군에비해 HBV DNA 감소정도가유의하게높다고보고하였다. 12,13 다. 엔테카비어 : 라미부딘내성변이에서엔테카비어 1.0 mg을사용하였을때내성변이종에대한증식억제효과가있다는보고가있다. 14,15 라미부딘내성변이바이러스에대한엔테카비어 1.0 mg과아데포비어와라미부딘병합치료의효과를비교한연구를보면항바이러스효과는두군에서다양하게보고되었으나, 엔테카비어 1.0 mg 군에서아데포비어와라미부딘병합치료보다유의한바이러스돌파현상을보였다 ( 각각 17.6%, 2.0%). 8,16-18 라미부딘내성에서아데포비어와엔테카비어 1.0 mg 병합치료에대한두개의후향적연구에따르면 96주치료시내성발생률은 0-2.6% 로기존의아데포비어를근간으로하는병합치료나엔테카비어 1.0 mg 단독치료에비해의미있게낮았다. 9,19 라. 페그인터페론알파 : 대상성간기능을가진라미부딘내성 e항원양성환자에서페그인터페론알파 48주간투여 (n=155) 와아데포비어 72주간단독투여 (n=80) 를비교한연구에따르면 HBV DNA 불검출률 (HBV DNA <80 IU/mL) 은페그인터페론과아데포비어군에서각각 10.6%, 22.5% 로페그인터페론군에서낮았으나 e항원혈청전환율은각각 14.8%, 3.8% 로페그인터페론군에서유의하게높았다. 20 더불어야생형바이러스와라미부딘내성변이바이러스환자에서의페그인터페론알파효과를비교한또다른연구에서 e항원혈청전환율과 HBV DNA 불검출률은두군간의미있는차이를보이지않았다. 21 [ 권고사항 ] 1. 테노포비어단독또는뉴클레오시드유사체에테노포비어를병합치료한다 (A1). 2. 테노포비어를사용할수없는경우에는라미부딘과아데포비어를병합치료한다 (A2). 이외에 아데포비어에엔테카비어또는다른뉴클레오시드유사체의병합치료를고려할수있다 (B2). 3. 대상성간기능을가진환자에서는라미부딘을중단하고페그인터페론투여를고려할수있다 (B2). 3

6 2. 텔비부딘내성 텔비부딘내성발생후치료에관한자료는매우부족하다. 텔비부딘에내성이생겼거나유전자표현형내성은발견되지않았어도바이러스돌파현상이생긴 68명의환자에게아데포비어를추가하고 12개월후분석한결과 70% 이상의환자에서 HBV DNA 300 copies/ml 이하로검출되었다는보고가있다. 22 그러나또다른뉴클레오시드유사체인라미부딘내성변이바이러스에서테노포비어를근간으로한치료가효과적인것으로보고된것과대조적으로, 텔비부딘내성에서의테노포비어를근간으로하는치료성적에대한보고는매우부족하다. 따라서일반적인치료원칙은라미부딘내성의치료를참고하도록한다. [ 권고사항 ] 라미부딘내성에준하여치료할수있다 (B2). 3. 클레부딘내성 클레부딘내성발생후치료에대한연구는매우부족하다. 따라서현재클레부딘내성의일반적 인치료원칙은라미부딘내성의치료를참고하도록한다. [ 권고사항 ] 라미부딘내성에준하여치료할수있다 (B2). 4. 아데포비어내성 아데포비어에대한내성변이는 rtn236t나 rta181t/v이다. 23,24 rta181t는아데포비어뿐아니라라미부딘치료시에도관찰할수있다 rtn236t 변이의아데포비어에대한저항성은야생종의 7-10배수준이며 rta181v/t는이보다낮은 1.2-5배의저항성을보인다. 27,29 반면, rtn236t와 rta181v/t가함께있는경우, 아데포비어에대한저항성이 배로더높게나타난다. 27 아데포비어에대한내성발현은바이러스돌파와이로인한간염의악화를유발할수있으며, 심 지어는비대상간부전으로진행할수있다. 30 아데포비어내성은아데포비어치료전에라미부딘 을사용하였거나라미부딘에대한내성이있는경우발생이증가한다고알려져있다. 4

7 초치료환자에서의아데포비어내성은 e 항원양성환자에서 5 년간 20% 로보고되었고, 31 e 항원음 성환자에서는 5 년의누적발생률이 29% 로알려져있다. 23 항바이러스제초치료환자와라미부딘내성환자에서아데포비어투약 48주째아데포비어내성발생을비교한연구를보면각각 0%, 18% 로양군간의미있는차이를보였으며, 32 라미부딘내성환자에서아데포비어단독치료시 2년간 22-25% 에서아데포비어내성이발현되었다는보고가있다. 33,34 가. 라미부딘 : rtn236t 변이는라미부딘에대한감수성이있지만 rta181t/v의경우에는감수성이저하된다. 27 아데포비어초치료환자에서아데포비어내성발생시라미부딘, 클레부딘또는텔비부딘을단독또는아데포비어와병합치료한임상연구는극히제한적이다. e항원양성환자 58 명중아데포비어내성 (n=41) 혹은바이러스돌파 (n=17) 가확인된환자를텔비부딘과아데포비어병합치료또는엔테카비어 0.5 mg 단독치료하여전향적으로비교한연구를보면 35 HBV DNA 불검출률 (HBV DNA <1000 copies/ml) 은 73.3%, 57.1% 로통계적으로유의한차이는없었으나 e항원혈청전환은 20%, 0% 로차이가있었다. 라미부딘내성이동반된환자에서의아데포비어단독치료중아데포비어내성이발생한경우, 다시아데포비어와라미부딘을병합치료하면 1년내에 7.3% 에서바이러스돌파현상이발생하며, 일차무반응환자 ( 치료 6개월째 HBV DNA 감소 < 1 log 10 IU/mL) 가 51.2% 까지나타나고, 1년치료후에도 HBV DNA 불검출률 (HBV DNA <60 IU/mL) 이 12.2% 로매우낮다. 36 나. 엔테카비어 : 아데포비어내성변이에대하여엔테카비어는교차내성이없다. 27 그러나, 라미부딘을경험하였거나라미부딘내성이있는환자에서아데포비어치료중발생한아데포비어내성또는불완전반응의치료를위해엔테카비어단독치료를하는경우 37 치료반응은아데포비어초치료환자에서의엔테카비어치료효과보다더낮고 (42% vs. 75%) 엔테카비어내성발생도높다 (17% vs. 0%). 라미부딘과아데포비어순차치료를받은환자에서엔테카비어단독치료로교체한경우, 교체전아데포비어와라미부딘모두에내성을가진환자는라미부딘에만내성을가진환자에비해치료반응이낮으며 (42% vs. 75%), 일차무반응이 30% 에이른다고보고되었다. 38 라미부딘을경험한환자에서아데포비어치료에불완전반응을보이는경우아데포비어와엔테카비어병합치료와엔테카비어단독치료를비교한연구를보면투약 1년째 HBV DNA 불검출률 (HBV DNA <20 IU/mL) 은 31.1%, 29.9%, 2년째에 44.7%, 34.5% 로양군의차이는없었지만매우낮았으며, 바이러스돌파현상은 1년에 0%, 17.4%, 2년에 2.6%, 44.8% 로의미있는차이를보였다. 19 다. 테노포비어 : 테노포비어는아데포비어와같은 nucleotide( 뉴클레오티드 ) 계열의약제로아데포비어의내성 rtn236t 변이에 3-4배의감수성저하가있다고보고되었다. 27,39 라미부딘에대한내성발생후아데포비어를사용한환자에서적절한항바이러스반응을얻지못하거나아데포비어에대한동시내성이있었던경우테노포비어를사용하여효과적으로바이러스증식을억제할수 5

8 있다는연구도있다. 40,41 특히, 아데포비어에내성을가지거나효과가없는환자에서테노포비어단독치료와테노포비어와엠트리시타빈병합치료의전향적무작위연구에서는투약 3.5년째 HBV DNA 불검출률 (HBV DNA <69 IU/mL) 이각각 82%, 84% 로양군의차이가없다고보고하였다. 42 또한, 아데포비어내성이있거나적절한효과가없는환자에서테노포비어단독치료와테노포비어와라미부딘병합치료의전향적코호트연구에서도 48주치료후 HBV DNA가 69 IU/mL 이하로감소한환자가 81% 였다고보고하고있어 43 테노포비어와뉴클레오시드유사체의병합치료도효과적일수있다. 그러나이들연구에서아데포비어의유전적내성변이가확인된예는 27.6% 과 42 48% 에 43 불과하여해석에제한점을가진다. 다양한항바이러스제에불완전반응을보인 57명의환자에서테노포비어와엔테카비어병합치료의효과에대한연구에서는 32.5% 의아데포비어내성환자가포함되어있었는데, 투약 6개월째 89.4% 의환자에서 HBV DNA 가 80 IU/mL 이하로감소하였으며아데포비어내성은치료반응과무관하다고보고하였다. 44 최근, 아데포비어내성이확인된환자에서시행한국내의전향적무작위연구에서 48주후에 HBV DNA가 60 IU/mL 이하로감소하는환자가테노포비어단독치료에서 74%, 테노포비어와엔테카비어병합치료에서 78.8% 로유사한효과를보였다. 45 다만, 이연구는 48주간의상대적으로짧은관찰기간을가졌으며, rtn236t와 rta181t/v 변이를모두가진환자에서는테노포비어와엔테카비어병합치료군이테노포비어단독치료군에비해 HBV DNA 감소가통계적인유의성은없었으나차이가있어 (-3.45 log 10 IU/mL % vs log 10 IU/mL, p=0.09) 추후장기간의추적관찰이필요하다. [ 권고사항 ] 1. 라미부딘에내성을보여아데포비어를사용했던경우 1) 테노포비어단독또는테노포비어와엔테카비어병합치료를고려한다 (B1). 2) 테노포비어와다른뉴클레오시드유사체의병합치료를고려할수있다 (B2). 3) 테노포비어를사용할수없는경우에는아데포비어와엔테카비어병합치료를고려할수있다 (B2). 2. 초치료로아데포비어를사용했던경우 1) 테노포비어단독또는테노포비어와엔테카비어병합치료를고려한다 (B1). 2) 테노포비어와다른뉴클레오시드유사체의병합치료를고려할수있다 (B2). 3) 테노포비어를사용할수없는경우에는아데포비어와엔테카비어또는다른뉴클레오시드유 6

9 사체의병합치료를고려할수있다 (B2). 5. 엔테카비어내성 엔테카비어내성돌연변이 (rtt184a/c/f/g/i/l/s, rts202g, rtm250l/v) 는필수적으로라미부딘내성돌연변이 (rtm204v/i) 를기반으로발생한다. 따라서, 엔테카비어내성이있는환자는모든뉴클레오시드유사체에교차내성이발현될것으로예상된다. 그러므로, 약제의구조와 in vitro 연구결과를고려할때, 27,28,46,47 엔테카비어내성바이러스에대한증식억제효과를기대할수있는약제는뉴클레오티드유사체인아데포비어와테노포비어뿐이다. 이들약제를엔테카비어내성환자들에서단독치료또는뉴클레오시드유사체와의병합치료로사용한임상연구결과는수편에불과하며, 대부분은후향적코호트연구였다. 44,48-51 이환자들을대상으로수행된전향적연구는최근에엔테카비어내성및다약제내성환자들을대상으로테노포비어단독치료와테노포비어와엔테카비어병합치료를비교한두편에불과하다. 45,52 가. 아데포비어 : 엔테카비어내성환자들에서아데포비어를이용한대규모전향적임상시험결과는아직없고소규모후향적코호트연구결과가수편만있을뿐이다. 이코호트연구들은아데포비어와엔테카비어혹은아데포비어와라미부딘으로병합치료한결과를보고하였는데, 년혹은 2년치료후바이러스반응률은 24%-51% 로낮았으며치료중바이러스돌파현상은약 10% 까지나타났다. 나. 테노포비어 : 최근국내에서시행된전향적다기관연구를 52 보면엔테카비어내성을가진 90 명의환자들을테노포비어단독치료또는테노포비어와엔테카비어병합치료로무작위배정하여 48주간치료하였는데, 각각 71% 및 73% 에서 HBV DNA 불검출률 (HBV DNA <15 IU/mL) 을달성하여두치료군간에유의한차이가없었고, 추가적인약제내성은나타나지않았다. 아데포비어를포함한다약제에내성을가진환자들을대상으로하는다기관임상시험도국내에서별도로수행되었는데, 이연구에서도엔테카비어내성돌연변이를가진환자가약 42% 포함되었다. 45 이연구결과에서도엔테카비어내성의존재는테노포비어단독치료혹은테노포비어와엔테카비어병합치료의효능에영향을미치지않았다. 유럽에서다약제내성환자들을대상으로수행된다기관코호트연구에서는테노포비어와엔테카비어병합치료의효과를관찰하였는데, 엔테카비어내성을가진환자들이 4명포함되었다. 44 이연구에서도거의대부분의환자들이치료 12개월이내에바이러스반응을달성하였다. 7

10 [ 권고사항 ] 1 테노포비어단독또는테노포비어와엔테카비어병합치료를고려한다 (B1). 2 테노포비어를사용할수없는경우에는아데포비어와엔테카비어병합치료를고려할수있다 (B2). 6. 테노포비어내성 테노포비어는현재까지 6년간의임상추적결과가발표되었는데테노포비어내성발생예는없었다. 53 이연구대상환자들중바이러스돌파현상을보인일부예에서내성바이러스유전자검사를시행하였는데여러위치 (rtl101l/f, rta307a/t, rtv173l+rtl180m+rtm204v, rta181t) 의변이는발견되었지만테노포비어약제감수성과는무관하였고, 이들은대부분약제복용순응도가좋지않은경우였다. rta194t 변이는테노포비어에대한약제감수성을감소시킨다고알려져있으며 rtl180m, rtm204v와동반되었을때테노포비어에대한 IC50이 10배이상증가한다. 54 그러나다른 in vitro 연구들에서는 rta194t 변이가테노포비어에대한약제감수성과관련이없다는보고와 55 부분적인감수성의감소를보인다는상반되는보고가 56 있어추가적인연구와임상자료의축적이필요하다. 7. 다약제내성 다약제내성은국제적으로정의가명확히내려져있지않지만, 일반적으로다른계열의두가지이상의약제에대한내성변이를동시에나타내는것을말한다. 47,57 HBV에대한경구항바이러스제를크게뉴클레오시드유사체 [1) L-nucleoside(Lamivudine, Telbivudine, Clevudine), 2) Cyclopentane(Entecavir)] 와뉴클레오티드유사체 (Adefovir, Tenofovir) 로나눈다면뉴클레오시드유사체중하나이상과뉴클레오티드유사체중하나이상에대한내성돌연변이를가지는경우로정의할수있다. 그러나뉴클레오시드유사체인엔테카비어내성돌연변이 (rtt184a/c/f/g/i/l/s, rts202g, and rtm250l/v) 는 L-nucleoside 약제에대한돌연변이 (rtl180m+rtm204v/i) 를항상수반하므로예외적으로다약제내성으로분류할수있다. 다약제내성치료에대한연구들은대부분대상환자수가적고내성양상이균일하지않으며치료약제들의조합도다양하여아직까지정립된치료는없으나테노포비어단독치료, 테노포비어와엔테카비어의병합치료, 또는아데포비어와엔테카비어의병합치료등의경구용항바이러스제를투약하는것이가장많이선택되는방법이다. 다약제내성에서의페그인터페론또는인터페론의치료에대한보고는없으나경구용항바이러스제내성변이부위에대하여인터페론감수성 8

11 이저하된다는보고는없으므로, 간기능이잘보존된환자에서는시도해볼수있다. 105명의환자를대상으로테노포비어단독치료와테노포비어와엠트리시타빈병합치료를이중맹검법전향적으로비교한연구를 42 살펴보면 168주에각각 82%, 84% 환자에서 HBV DNA가검출한계치미만 (HBV DNA <400 copies/ml) 으로감소하였다. 이들연구에서는 13명의환자가아테포비어와라미부딘동시내성을보이고있었으며약제내성의종류와바이러스반응은무관하였다. 테노포비어를포함하는다른항바이러스제와의병합치료와테노포비어단독치료를비교한연구들에서도양군간에바이러스반응의차이는보이지않는다고보고하였다 테노포비어단독치료는 1년투약에 HBV DNA 불검출률이 60~92%, 2년에는 96.6% 로다양하게보고되었는데 또다른연구에서는 4년투약후 HBV DNA 불검출률이 63% 에불과하여 62 연구들마다차이를보였다. 단약제내성과다약제내성시테노포비어의효과가동일하다는보고도 61 있지만 rtl180m, rta194t, rtm204v 부위에다발성변이가발생한경우테노포비어에대한 IC50이 10배이상증가하고 54 다약제내성환자에게테노포비어단독으로사용했을때바이러스가다시증가하여엔테카비어를추가하였다는보고도있어 63 다약제내성환자에서의테노포비어단독치료에대한장기간대규모연구가필요할것으로보인다. 순차적단일약제투약에도불완전반응을보이거나다약제내성을보인 57명의환자에서테노포비어와엔테카비어의병합치료를시행한후향적코호트연구에서는 44 다양한비율의라미부딘 (38명), 아데포비어 (18명), 엔테카비어 (4명) 내성환자가포함되었다. 이연구에서의다약제내성은 rta181t/v 변이를보이거나혹은아데포비어내성 (rtn236t) 과라미부딘내성 (rtm204v/i), 라미부딘과엔테카비어내성을같이보이는경우로정의되었는데중앙값 6개월투약후 51명의환자 (89.4%) 에서 HBV DNA가검출한계미만 (HBV DNA <80 IU/mL) 으로감소하였으며 HBV DNA는치료전에비하여 3 log10 IU/mL 감소하였다. 최근국내에서보고된연구들에서는다약제내성환자에서테노포비어와엔테카비어병합치료에서바이러스불검출률은 6개월 28.6~64.6%, 1년 47.1~87.5% 로다양한결과를보였다. 60, 명의다약제내성 ( 라미부딘과아데포비어내성을동시에보이는예들 ) 환자에서엔테카비어와아데포비어병합치료 (n=12), 라미부딘과아데포비어병합치료 (n=20), 엔테카비어단독치료 (n=16) 를비교한연구에서는 69 치료 96주의 HBV DNA 불검출률은각각 40%, 20%, 20% 로각군간의차이를보이지않았다고보고하였으나바이러스반응이매우낮았다. 이중라미부딘과아데포비어에대한내성환자들을대상으로아데포비어와엔테카비어를병합치료한연구에서는추가바이러스돌파현상이 8.3% 에서발생하였다 명의환자를대상으로 2년간엔테카비어와아데포비어의병합치료를유지했던 45명의환자와, 라미부딘과아데포비어의병합치료에서 52주째엔테카비어와아데포비어의병합치료로전환한 44명의환자를대상으로한연구에서는각각다약제내성환자가 17.8%, 26.7% 포함되었는데치료 104주째 HBV DNA 불검출률 (HBV DNA <60 IU/mL) 이각각 42.2%, 34.1% 로각군간의의미있는차이는없었으며역시낮은바이러스반응을 9

12 보였다. 70 엔테카비어는유전적내성장벽이높은약제로엔테카비어초치료환자에서의약제내성은 6년에약 1.2% 로알려져있으며, 일차적으로 rtm204v/i 변이가발생한후 rtt184a/c/f/g/i/l/s, rts202g, rtm250l/v 변이가발생하면엔테카비어내성을보이게된다. 따라서 rtm204v/i에내성을보이는라미부딘, 텔비부딘, 클레부딘등과엔테카비어를병합치료하는방법은적절치않으며테노포비어단독치료, 테노포비어와엔테카비어병합치료, 또는아데포비어와엔테카비어병합치료등을고려할수있다. [ 권고사항 ] 1. 테노포비어단독또는테노포비어와엔테카비어병합치료를고려한다 (B1). 2. 테노포비어를사용할수없는경우에는아데포비어와엔테카비어병합치료를고려할수있다 (B2). References 1. van Bommel F, Wunsche T, Mauss S, Reinke P, Bergk A, Schurmann D, et al. Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. Hepatology 2004;40: Baran B, Soyer OM, Ormeci AC, Gokturk S, Evirgen S, Bozbey HU, et al. Efficacy of tenofovir in patients with Lamivudine failure is not different from that in nucleoside/nucleotide analogue-naive patients with chronic hepatitis B. Antimicrob Agents Chemother 2013;57: Seto WK, Liu K, Wong DK, Fung J, Huang FY, Hung IF, 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: Fung S, Kwan P, Fabri M, Horban A, Pelemis M, Hann HW, et al. Randomized comparison of tenofovir disoproxil fumarate vs emtricitabine and tenofovir disoproxil fumarate in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology 2014;146: Peters MG, Hann Hw H, Martin P, Heathcote EJ, Buggisch P, Rubin R, et al. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology 2004;126: Rapti I, Dimou E, Mitsoula P, Hadziyannis SJ. Adding-on versus switching-to adefovir therapy in lamivudine-resistant HBeAg-negative chronic hepatitis B. Hepatology 10

13 2007;45: Suzuki F, Hosaka T, Suzuki Y, Akuta N, Sezaki H, Hara T, et al. Long-term efficacy and emergence of multidrug resistance in patients with lamivudine-refractory chronic hepatitis B treated by combination therapy with adefovir plus lamivudine. J Gastroenterol 2014;49: Huang ZB, Zhao SS, Huang Y, Dai XH, Zhou RR, Yi PP, et al. Comparison of the efficacy of Lamivudine plus adefovir versus entecavir in the treatment of Lamivudine-resistant chronic hepatitis B: a systematic review and meta-analysis. Clin Ther 2013;35: Ha M, Zhang G, Diao S, Lin M, Wu J, Sun L, et al. Rescue therapy for lamivudine-resistant chronic hepatitis B: adefovir monotherapy, adefovir plus lamivudine or entecavir combination therapy. Intern Med 2012;51: Seto WK, Liu K, Fung J, Wong DK, Yuen JC, Hung IF, et al. Outcome of lamivudine-resistant chronic hepatitis B after up to 5 years of combination therapy with adefovir. Antivir Ther 2012;17: Ahn SH, Kweon YO, Paik SW, Sohn JH, Lee KS, Kim DJ, et al. Telbivudine in combination with adefovir versus adefovir monotherapy in HBeAg-positive, lamivudine-resistant chronic hepatitis B. Hepatol Int 2011: [Epub ahead of print]. 12. Lin MT, Chou YP, Hu TH, Yu HC, Hsu YC, Tsai MC, et al. Telbivudine and adefovir combination therapy for patients with chronic lamivudine-resistant hepatitis B virus infections. Arch Virol 2014;159: Park H, Park JY, Kim SU, Kim do Y, Han KH, Chon CY, et al. Efficacy of switching to telbivudine plus adefovir in suboptimal responders to lamivudine plus adefovir. World J Gastroenterol 2013;19: Chang TT, Gish RG, Hadziyannis SJ, Cianciara J, Rizzetto M, Schiff ER, et al. A dose-ranging study of the efficacy and tolerability of entecavir in Lamivudine-refractory chronic hepatitis B patients. Gastroenterology 2005;129: Sherman M, Yurdaydin C, Sollano J, Silva M, Liaw YF, Cianciara J, et al. Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology 2006;130: Sheng YJ, Liu JY, Tong SW, Hu HD, Zhang DZ, Hu P, et al. Lamivudine plus adefovir combination therapy versus entecavir monotherapy for lamivudine-resistant chronic hepatitis B: a systematic review and meta-analysis. Virol J 2011;8: Yim HJ, Seo YS, Yoon EL, Kim CW, Lee CD, Park SH, et al. Adding adefovir vs. switching to entecavir for lamivudine-resistant chronic hepatitis B (ACE study): a 2-year follow-up randomized controlled trial. Liver Int 2013;33: Lee SJ, Yim HJ, Hwang SG, Seo YS, Kim JH, Yoon EL, et al. Treatment of lamivudineresistant chronic hepatitis B infection: a multicenter retrospective study. Scand J Gastroenterol 2013;48: Seo SY, Kim IH, Sohn JY, Lee S, Kim SH, Kim SW, et al. Long-term efficacy of entecavir plus 11

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18 response during up to two years of entecavir-adefovir combination therapy in multipledrug-refractory chronic hepatitis B virus patients. Antimicrob Agents Chemother 2013;57: