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1 대한내과학회지 : 제 78 권제 5 호 2010 종설 (Review) B 형간염바이러스약제내성의기전과치료 제주대학교의학전문대학원내과학교실 송병철 The mechanism and treatment of anti-viral resistant hepatitis B virus Byung-Cheol Song, M.D. Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Korea Even though substantial advances have been made in the treatment of chronic hepatitis B in the past decade with the use of oral nucleos(t)ide analogues (NAs), emergence of anti-viral resistance is the most important factor in treatment failure for chronic hepatitis B. Therefore, prevention and management of antiviral resistant HBV is major challenge in the era of oral NAs therapy. Recently, several guidelines for the management of antiviral resistant HBV have been published. Herein, I will discuss how to prevent and manage antiviral resistance. (Korean J Med 78: , 2010) Key Words: Chronic hepatitis B; Antiviral resistance; Nucleos(t)ide analogues; Combination therapy 서론만성 B형간염의치료목표는장기적으로혹은영구적으로바이러스의증식을억제하고혈청아미노전이효소를정 상으로유지시켜, 간경변증으로의진행을예방하고간세포암의발생을억제하며이를통하여사망률을감소시키고삶의질을향상시키는데있다 1). 지난수년간 B형간염의자연사에대한이해및치료에의미있는진전들이있었으며 2-4), Table 1. Response rate to approved antiviral therapy in patients with chronic hepatitis B at 1 year Peginterferon Lamivudine Emtricitabine Telbivudine Adefovir Entecavir Tenofovir In HBeAg-positive patients Undetectable HBV DNA by PCR based assays 25% 39% 39% 60% 21% 67% 76% HBeAg loss 30% 22% 14% 26% 24% 22% 21% * Normalization of ALT 39% 66% 65% 77% 48% 68% 68% Histologic improvement 38% 59% 62% 65% 53% 72% 74% In HBeAg-negative patients Undetectable HBV DNA by PCR based assays 63% 72% 79% 88% 51% 90% 93% Normalization of ALT 38% 74% 65% 74% 72% 78% 76% Histologic improvement 48% 63% 59% 66% 64% 70% 72% Adapted from references 17, 45, 47, HBeAg seroconversion

2 - Byung-Cheol Song. The mechanism and treatment of anti-viral resistant hepatitis B virus- 현재전세계적으로광범위하게사용되는항바이러스제제의효능은표 1에요약하였다. 현재사용되는경구용항바이러스제제들은 HBV DNA의증식을효과적으로억제하고부작용이없어간질환의진행을예방하여 1차치료제로광범위하게사용되고있으나치료중단시대부분재발하고 5,6) 간기능이악화될수있으므로궁극적으로장기간혹은평생사용해야한다. 그러나경구용항바이러스제제의장기사용은내성의위험도가증가하며 7-10), 이는특히 HBV가불완전하게억제될때흔하게발생한다 11). 실제임상에서치료실패의가장중요한원인은약제의내성과환자의순응도가감소하는것이며 12), 약제내성시그예후가매우나쁘며결국간질환의진행을유발한다 8-10). 따라서경구용항바이러스사용시대에내성의발생은의사와환자모두에게해결해야할중요한과제로남아있다. 따라서본종설에서는만성 B형간염의치료에대한적절한이해, 내성의기전및이를극복할수있는방법들에대해기술하고자한다. 항바이러스치료및내성과관련된용어항바이러스내성과관련된용어는표 2에정리하였다 12-14). 1차치료실패혹은무반응 (primary treatment failure or non-response) 은항바이러스제제를최소 24주이상사용한경우에도혈청 HBV DNA치가기저치의 100배이상감소하지않은경우이며 1차치료실패후지속적으로동일한약제를사용할경우궁극적으로내성이발생한다 12,15). 1차치료실패는타경구용항바이러스제제에비해특히아데포비어에서흔한데, 이는아데포비어활성화형태로전환하는숙주의효소의다형성에기인하거나혹은인산화과정의차이로발생할것으로추정되고있다 16). 또한현재시판되고있는아데포비어 10 mg이치료에필요한최적의용량이아닌것도중요한이유중의하나이다 17). 바이러스돌파현상 (virologic breakthrough) 혹은 2차치료실패 (secondary treatment failure) 는항바이러스제제에순응도가좋은환자가항바이러스치료로 HBV DNA가음전되거나기저치로된후최소 1개월이상간격으로 2번이상검사에서 10배이상상승하는경우로정의한다 1,12). 바이러스돌파현상이생기는가장중요한이유는항바이러스약제에대한내성이나임상연구에포함된환자들에서바이러스돌파현상의 30% 정도가약제에대한순응도가나쁜경우이므로투약에순응도를확인한후약제내성검사를시행해야한다 12). 이러한바이러스돌파현상은임상적으로항바이러 Table 2. Nomenclature for antiviral resistance 12-14) Term Definition Primary treatment failure (non-response) Inability of nucleos(t)ide analogue treatment to reduce serum HBV DNA by 2 log10 IU/mL after the first 6 months of treatment Secondary treatment failure (virologic breakthrough) Increase in serum HBV DNA by 1 log10 above nadir on 2 occasions 1 month apart, while on treatment, after achieving initial response in a medication compliant patient Viral rebound Increase in serum HBV DNA to 20,000 IU/mL or above pretreatment level after achieving virologic response, during continued treatment Biochemical breakthrough Elevation in serum alanine aminotransferase (ALT) while on treatment, after achieving normalization in a medication compliant patient Genetic barrier Threshold probability that the virus will mutate and escapes from the selective action of the drug, thereby making the virus resistant to specific drug. Number of amino acid substitution needed for development of primary antiviral drug resistance. Genotypic resistance Detection of viral populations bearing amino acid substitutions in the reverse transcriptase region of the HBV genome that have been shown to confer resistance to antiviral drugs in phenotypic assay, during antiviral therapy. These mutations are usually detected in patients with virologic breakthrough but they can also be present in patients with persistent viremia and no virologic breakthrough. Phenotypic resistance Decreased susceptibility of an HBV polymerase to an antiviral treatment in vitro Cross resistance Decreased susceptibility to more than one antiviral drug conferred by the same amino acid substitution or combination of amino acid substitutions

3 - 대한내과학회지 : 제 78 권제 5 호통권제 597 호 Table 3. Summary of the most frequent anti-viral resistant HBV mutants Domain A Domain B Domain C Domain D Domain E Lamivudine rtl80i/v rtl180m rtv173l rta181t/v * rtm204i/v/s * Telbivudine rtm204i * Clevudine rtl180m rtm204i/v * Adefovir rtv84m rta181t/v * rtn236t * Tenofovir rta194t * Entecavir * Primary resistant mutations. rtk169t rts/t184g rts202g/i/c * rtm250v * % patients Year 1 Year 2 Year 3 Year 4 Year LMV LdT ADV ETV TDF Figure 1. Cumulative rated of genotypic antiviral resistance in patients with chronic hepatitis B. Data from references 5,6,33,47,49, 67,69,72-75). Abbreviations: LMV, lamivudine; LdT, telbivududine; ADV, adefovir; TDF, tenofovir; ETV, entecavir. 스내성이발생하는첫번째임상적인지표이다 12). 현재사용되는항바이러스제제의돌연변이바이러스형태는표 3에요약하였고, 각각의약제에대한내성의빈도는그림 1에요약하였다. 약제내성돌연변이바이러스의경구용항바이러스제제에대한겹저항성 (resistant fold) 은표 4 에요약하였다. 바이러스돌파현상당시혈청 HBV DNA치는대개낮은데, 그이유는대부분의항바이러스내성바이러스의증식능 (replication fitness) 은야생종에비해감소한다 ( 그림 2). 그러나동일약제를지속적으로사용시순차적으로보상성돌연변이가추가되면서바이러스의증식능이야생종수준까지증가하여궁극적으로는혈청 HBV DNA치가치료전수준혹은그이상으로증가하기도한다 18-21). 생화학적돌파현상 (biochemical breakthrough) 은항바이러 Table 4. Summary of in vitro drug susceptibility for most frequent HBV mutants 32,62,63,70). HBV mutants Fold resistance * Mutants Lamivudine Telbivudine Emtricitabine Clevudine Entecavir Adefovir Tenofovir Wild M204I >1,000 >322 >2,000 >1, ~ L180M+M204I >1,000 > >1, L180M+M204V >700 >322 >2,000 >1, I169T+M250V+M240V >300 >300 NA NA >1, NA T184G+S202I+M240V >1,000 > 100 NA NA >1, NA A181A/T 6~10 >15 15 >117 1~12 2~8 1.5~3.2 N236T 1~ ~ ~1 3~10 4 A181T/V+N236T 35 >19 47~ ~21 5~18 1.2~6.8 * Fold resistance=(mutant IC 50)/(wild type IC 50)

4 - 송병철. B 형간염바이러스약제내성의기전과치료 - Replication fitness (% of wild type) W ild 10 rtm2 04V 14 rtm 204I 40 rtm204v + rtl180m 55 rtm20 4I + rtl180m 90 M2 04V + L180M + rtv173l Figure 2. Replication fitness of wild and drug-resistant hepatitis B virus 18,19). 스제제치료중정상화되었던혈청아미노전이효소치가치료를지속하는중에다시상승하는경우로, 바이러스돌파현상후혈청아미노전이효소치는수주혹은수년간정상으로유지되기도하나대부분생화학적돌파현상이발생하며급성악화를흔하게동반한다 22-24). 유전자형내성 (genotypic resistance) 은표현형내성 (phenotypic resistance) 검사에서항바이러스제제에내성을보이는돌연변이바이러스가환자혈청에발견되는것으로, 이러한바이러스는주로바이러스돌파현상을보이는환자에서발견되나지속적으로바이러스반응이없는경우에도발견된다. 표현형내성은특정한변이가 in vitro 실험에서항바이러스제제에감수성이감소하여약제에대한저항성이증가하는경우로정의한다. 저항성의증가정도를겹저항성으로표시하는데이를고도내성 (>100-fold increase), 중등도내성및경도내성 (<10-fold increase) 으로분류한다 25). 그러나이러한분류가임상적인관찰과일치하지않으며아데포비어내성변이인경우겹저항성은야생종의 2~10배정도이며라미부딘에의한내성변이종인경우 100배이상의저항성을보임에도불구하고, 아데포비어내성변이의발현역시임상적으로바이러스돌파현상과함께간염의급성악화, 간부전등을발생시키기도한다 26). 내성의기전 B형간염바이러스는 3,200개염기로구성된 DNA 바이러스이나역전사중합효소를통한 RNA 중간체 (RNA intermediate) 를이용하여증식을한다. B형간염바이러스는매우높은증식력을보이는데, 하루에약 10 비리온 11) 이생성된다 27). 그러나 B형간염의증식에이용되는역전사중합효소는교정쇄 (proof reading) 기능이없어서돌연변이가흔히발생하고변이의확률은다른 DNA 바이러스의약 10배에해당한다 28). 하루에엄청난바이러스생성과높은돌연변이발생확률로바이러스증식이많은환자에서는하루에 개의점돌연변이가발생한다 28). 따라서이론적으로는매일 B형간염바이러스전체염기에돌연변이가일어날수있으나 B 형간염바이러스는 4개의 ORF가서로중복되기때문에실제로증식이가능한 B형간염바이러스의발생에는어느정도제한이가해지고돌연변이가발생하여도증식적합능이있는개체만선택된다. 한개체의바이러스집단에서우세한집단의안정성은여러가지선택압력 (selection pressure) 에의해유지되는데, 이중에서중요한것은숙주의면역체계이고, 또다른한가지는바이러스의증식능이다 28). 또한항바이러스제제에의한선택압력에서증식능에이점을가진돌연변이바이러스가선택이되고이들이궁극적으로가장우세한바이러스집단이형성된다 29). 항바이러스내성의발생에몇가지요소들이관여하는데, 그중에서도가장중요한요소들은항바이러스제제의역가 (potency), 바이러스의증식능, 그리고항바이러스제제의유전적장벽과환자의약제에대한순응도이다 1,29). 항바이러스치료중돌연변이의발생확률은항바이러스제제의역가와매우밀접한관계가있는데 30), 항바이러스역가가낮은약제는바이러스에대한선택압력으로작용하지못하여약제에대한내성확률이낮고, 반면에중등도의항바이러스효과를보이는약제인라미부딘인경우, 약제내성바이러스선택압력이매우커져서내성의발생확률이가장높다. 역가가매우높은경우바이러스증식이완전히억제되면내성발생은발생하지않는데이는바이러스의돌연변이발생은증식에의존하기때문이다 28,30). 바이러스의증식능은특정한환경에서바이러스가증식할수있는능력을말하며, 일반적으로돌연변이바이러스는증식능이야생종에비해감소되어있으나점차보상성돌연변이가발생한다. 예로라미부딘내성바이러스인경우 rtm204i/v 변이는야생종에비행현저히증식능이현저히감소되어있으나점차적으로 rt80, rt180, rt173 부위에보상성변이가추가되면서증식능이거의야생종수준의증식능까지회복된다 ( 그림 2) 18-20,31). 항바이러스제제의유전자장벽 (genetic barrier) 은해당약제에대한내성을나타내기위해필요한바이러스의아미노

5 - The Korean Journal of Medicine: Vol. 78, No. 5, 산치환의수이다. 한두부위의변이만으로바이러스가내성을획득하는라미부딘, 텔비부딘등의유전자장벽은상대적으로 (low genetic barrier) 낮아내성의빈도가높은반면 1), 엔테카비어의유전자장벽은매우높아 (high genetic barrier) 초치료환자에서내성의빈도는매우낮다 32,33). 또한이미존재하던돌연변이는유전자장벽을낮추고항바이러스내성을증가시킬수있는데, 예로라미부딘내성바이러스 (rtm204i/v) 가존재하는경우엔테카비어를사용하는경우유전자장벽이낮아지는효과로인하여내성이증가한다. 항바이러스내성의예방항바이러스제제의내성을미리예방하는것은내성바이러스치료못지않게중요한부분이다. 따라서내성을방지하기위해신중하고적절한약제의선택과불필요한약제의사용의금지및지속적인약제내성의감시등이매우중요하다. 많은만성 B형간염환자들은현재의항바이러스치료가도움이되지않는경우가많다. 특히, 면역관용기의환자들은혈청아미노전이효소치가정상이고, 바이러스증식이매우높은것이특징이다 34). 대부분의연구에서치료전 HBV DNA치가높을수록항바이러스제제에대한내성빈도는증가한다고보고되고있으므로 35-38) 면역관용기의환자들에서경구용핵산유사체를사용하는경우약제의내성위험이매우높다. 따라서대부분의가이드라인들은혈청아미노전이효소치가상승한경우혹은간경변등간질환이진행된경우항바이러스치료를권장하고있다 1,13,39-41). 약제내성바이러스의발생은증식력에의존하므로, 일단항바이러스치료를시작하면가능하면빨리바이러스증식을최대한억제해야한다 42). 이는초치료로가장강력한항바이러스제제를선택해야함을의미한다. 그러므로대부분의가이드라인들은현재까지사용가능한약제중경구용 약제중가장강력한약제인엔테카비어혹은테노포비어및내성이발생하지않은인터페론을초치료로권장하고있다 1,13,40,41,43). 내성을줄이기위해후천성면역결핍증환자의치료경험에서처럼서로기전이다른약제의병합요법이가장이상적이고치료효과의상승작용을통해내성의발생을줄인다고하나 44), 불행하게도현재까지 B형간염의초치료로시행된병합요법의결과는부정적이었다 45). 경구용항바이러스제제치료시혈중바이러스의변화는두가지시기로구분된다. 첫번째급격한바이러스감소시기는바이러스가혈중에서소실되는정도를반영하고, 이어서서서히바이러스가감소하는두번째감소시기는일반적으로감염된간세포에서바이러스가소실되는것을반영한다 46). 그러므로초기에바이러스의감소정도가항바이러스제제에관계없이한개체에서항바이러스제제의역가를반영한다. Yuen 등 15) 이 159명의중국인 HBeAg 양성만성간염을대상으로라미부딘을평균 29.6개월치료한환자에서치료 24 주 HBV PCR 이음성인경우 8.3% 에서내성이발생하였으나 HBV PCR 이양성인경우에는 59.9% 의환자에서내성이발생하였다. 또한 1,367명 (HBeAg 양성환자 921명, HBeAg 음성 446명 ) 의만성 B형간염환자를대상으로시행한텔비부딘과라미부딘의치료효과의 3상연구에서도치료 24주후 HBV DNA치에따라 1년후임상결과가상이하였다 ( 표 5) 47). 라미부딘내성만성 B형간염환자에서엔테카비어치료를하는경우에도 24주 HBV DNA 반응이장기적으로항바이러스치료효과에영향을미치는주요한인자였다 48). 그러나아데포비어처럼약제의작용이비교적늦게나타나는경우에는초치료시 48주에 HBV DNA치가내성을예측하는중요한인자로보고되었는데 49), 아데포비어치료중 48주에 HBV DNA치가 1,000 copies/ml 이하인경우에는 192주치료 Table 5. Effect of early viral suppression (24 week) on 1 year treatment outcomes in HBeAg-positive chronic hepatitis B patients treated with lamivudine or telbivudine Percentage response at 1 year Serum HBV DNA at 24 week (copies/ml) HBV DNA PCR-negative Normalization of ALT HBeAg seroconversion Resistance Not detected (< 300 copies/ml) 90% 90% 41% 2% < 3 log 89% 89% 26% 6% 3 log-4 log 80% 80% 13% 12% > 4 log 54% 54% 4% 15% Adapted from Lai et al 47)

6 - Byung-Cheol Song. The mechanism of anti-viral resistance and treatment - 중 6% 에서내성이발생하였으며, 1,000 copies/ml 이상인환자에서는 49% 에서내성이발생하였다 49). 본연구자등도라미부딘내성만성 B형간염환자에서아데포비어단독요법시치료 1년이내에 HBV PCR 이음성인경우 (<60 IU/mL) 에양성인경우보다 4년째바이러스돌파현상이낮았다 (6.2% vs. 54.5%) 50). 현재까지연구결과들을바탕으로 24주에바이러스반응 (HBV DNA<60 IU/mL 혹은 <300 copies/ml) 을보이는경우사용중인항바이러스제제를지속사용하고 51), 24주에바이러스반응이없는경우에는항바이러스역가가중등도인라미부딘혹은텔비부딘으로치료를하는경우에는강력한약제 ( 엔테카비어혹은테노포비어 ) 로전환하거나교차내성이없는약제를추가할것을권하고있다 40,41). 엔테카비어혹은테노포비어처럼항바이러스제제의역가가크고유전자장벽이높은약제를사용하는경우에는정기적으로 HBV DNA 치를추적관찰하면서 48주까지사용하기를권장하고있다. 반면에아데포비어처럼항바이러스효과가늦게나타나는경우 48주까지사용후변경혹은병합요법을권장하고있다 40,41). 최근에박등이라미부딘치료를 24주이상시행하였으나 HBV DNA치가지속적으로양성인 (HBV DNA>60 IU/mL) 환자에서엔테카비어 1 mg으로전환한경우와라미부딘을지속적으로유지한경우엔테카비어전환군에서 48주 HBV DNA치가음전율이 85%, 내성율 0% 인반면에라미부딘유지군에서는 48주 HBV DNA 음전율 12%, 내성율 64.7% 가발생하였다 52). 또한본연구자등은라미부딘을 24주이상사용하였으나 HBV DNA치가양성인 (HBV DNA>60 IU/mL) 환자에서엔테카비어 0.5 mg으로전환하는경우와라미부딘을유지하는경우 48주에바이러스반응 (71% vs. 15%) 및내성율이 (8.7% vs. 62.5%) 차이가있음을확인하였다 53). 따라서항바이러스치료중 24주에바이러스반응을보이지않는경우강력한항바이러스제제로전환하는기존의방침을지지하고있다. 항바이러스내성의치료경구용항바이러스제제치료중내성바이러스는바이러스돌파현상과동시에또는돌파현상이전에서발생한다. 그러나임상적으로바이러스내성의첫임상적지표는바이러스돌파현상이다. 내성바이러스출현시혈청 HBV DNA 치는낮을수있으나시간이지남에따라혈청 HBV DNA치 는점차대부분의환자에서생화학적돌파현상이발생하여혈청아미노전이효소치의상승이동반된다 1). 이러한일련의임상경과중어느시점에서항바이러스치료를변경할지임상의사는결정해야한다. 내성바이러스의치료와관련하여최근에중요한몇가지개념이 ( 언제치료할것인가? 어떻게치료할것인가?) 정립이되었다. Lampertico 등 37) 은라미부딘내성 HBeAg 음성만성간염환자 (n=74) 을대상으로라미부딘과아데포비어를병합치료하는경우, 치료전혈청 DNA치가낮은경우 (HBV DNA 3~6 log 10 copies/ml 이면서정상아미노전이효소치 ) 에혈청 HBV DNA치가높은경우보다 (HBV DNA>6 log 10 copies/ml) 치료 2년째바이러스반응 ( 정의 : HBV DNA<2,000 copies/ml) 이우월함을보고하였다 (100% vs. 78%) 37). HBeAg 양성라미부딘내성만성 B형간염환자를 (n=207) 대상으로한신등 54) 의국내연구에서도아데포비어라미부딘치료시바이러스반응 (HBV DNA<50 copies/ml) 은치료전 HBV DNA와음의상관관계를보고하였다. 따라서경구용항바이러스제제내성만성 B형간염환자에서바이러스돌파현상이생기면즉시항바이러스치료방침을변경해야한다. 두번째로중요한개념은경구용항바이러스제제에대한내성환자에서병합요법혹은타약제로전환하는방법이다. 두개의무작위연구가보고되었는데 36,55), Peter 등 55) 이시행한라미부딘내성환자를대상으로한연구에서라미부딘 / 아데포비어병합요법과아데포비어로전환하는요법에서 1년후 HBV DNA 억제정도에는차이가없었다. 또한치료 1년째양군모두에서내성은보고되지않았다. 따라서지난수년간라미부딘내성만성 B형간염환자에서아데포비어전환요법이광범위하게사용되었다. 그러나국내및외국의연구에서라미부딘내성환자에서아데포비어로전환하는경우 1년시점에서내성율이 18% 까지보고되었고 56), Chen 등 57) 은 2년내성발생빈도를 38.3% 까지보고하였다. 최근몇개의연구에서아데포비어- 라미부딘병합요법이전환요법보다바이러스반응율이높고내성발생율이낮다고보고되었다 36,58). 588명의라미부딘내성만성 B형간염환자를대상으로시행된후향적분석에서병합요법군과아데포비어로전환한군에서바이러스반응율은각각 78% 와 71% 로비슷하였으나, 바이러스돌파현상은 6% 와 30%, 내성발생율은 0% 와 16% 로병합군에서의미있게낮았다 58). 이어보고된 HBeAg 음성환자를대상으로시행한연구에서도 15~18 개월치료후바이러스반응은양군에서비슷하였으나내성발생율은아데포비어로전환한군에서 21% 발생하였고, 병합군

7 - 대한내과학회지 : 제 78 권제 5 호통권제 597 호 ,41, 43, 71 Table 6. Treatment guidelines for the chronic hepatitis B patients with antiviral resistant hepatitis B virus Resistance to KASL 2007 AASLD 2007 Panel of U.S hepatologist 2008 EASL 2009 Lamivudine (LMV) Telvivudine (LdT) Add or switch to ADV Stop LMV, switch to ETV * Treat as LMV Add ADV or TDF Stop LMV, switch to Truvada Stop LMV, switch to ETV * Add ADV or TDFa Switch to Truvada Add ADV or TDF Add ADV or TDF Stop LdT, switch to Truvada Switch to Truvada Stop LdT, switch to ETV Clevudine Treat as LMV Not mentioned Not mentioned Not mentioned Entecavir (ETV) Adefovir (ADV) Tenofovir (TDF) Switch to or add ADV Switch to or add ADV Switch to or add TDF Add LMV Switch to or add ETV Add LMV Stop ADV, switch to Truvada Switch to or add ETV Switch to or add ADV or TDF Switch to Truvada Add LMV or LdT Switch to or add ETV (if no prior LMV-resistance) Switch to Truvada Add TDF (add ADV if TDF not yet available). Add TDF (add ADV if TDF not yet available). Add TDF It is recommended to switch to TDF,if available and add a second drug without cross resistance. If an N236T is present, add LMV, ETV or LdT or switch to Truvada. If an A181T/V is present, add ETV or switch to Truvada. Not mentioned Not mentioned TDF resistance has not been described. It is recommended that genotyping and phenotyping be done to determine the cross-resistance profile. ETV, LdT, LMV or emtricitabine could be added Truvada is a combination pill with emtricitabine 200 mg and tenofovir 300 mg. * Preexisting lamivudine-resistant mutation predispose to entecavir resistance. TDF might be preferred over ADV as the add-on agent. 에서 0% 발생하였다 36). 병합요법을장기간시행한연구결과에서도 4년째바이러스반응율은 82%, 내성발생율은 4% 였고, 바이러스돌파현상은 0% 의환자에서관찰되었다 59). 이러한결과들을종합하면라미부딘내성혹은타경구용항바이러스제제에내성발생시순차적인전환요법보다는병합요법을시행해야함을의미한다. 최근에임상의사들은라미부딘내성만성 B형간염환자에서순차적으로아데포비어혹은엔테카비어전환요법후이들에대한내성이발생하는환자를흔히접하고있다. 그러나현재까지이러한환자들을대상으로어떠한치료를하는것이좋은지에대한연구는미미한실정이다. 다만이전의라미부딘내성환자의교훈에서단독요법으로전환요법보다는병합요법을하는것이타당할것이라고추정하고있다. 최근에양등 60) 은라미부딘내성후아데포비어를순차적으로사용중내성이발생한환자를대상으로아데포비어- 라미부딘병합요법 (n=13) 과엔테카비어 1 mg으로전환한 경우 (n=27) 를비교하였을때, 엔테카비어로전환한경우에추적관찰 18개월째 55% 에서바이러스돌파현상이관찰되었으나아데포비어- 라미부딘병합군에서는바이러스돌파현상이없었다고보고하였다. 이러한연구는항바이러스제제에관계없이내성이발생하였을경우병합요법을시행해야함을지지하고있다. 구조적인유사성으로인해한군에속하는핵산유사체에대한내성이존재할때같은군내의약제에대한교차내성은놀라운일이아니다. 일반적으로뉴크레오사이드유사체 ( 라미부딘, 텔비부딘, 엔테카비어 ) 는뉴클레오타이드유사체에 ( 아데포비어, 테노포비어 ) 내성인바이러스에감수성이유지되고뉴클레오타이드유사체에내성인바이러스에뉴클레오사이드유사체에대한감수성이유지된다 ( 표 4) 25,61-63). 따라서특정한군에속한약제에내성이발생하였을경우에는동일한군내의약제를사용하면안되며다른계통의항바이러스제제를사용해야하며, 경우에따라서특정한항바이

8 - 송병철. B 형간염바이러스약제내성의기전과치료 - 러스제제의효과에대한임상연구결과가없는경우에는위에언급한일반적인원칙을감안하여 in vitro에서약제감수성의결과를바탕으로병합요법을시행하는것이바람직할것이다. 최근에임상에적용된테노포비어는라미부딘내성환자에서매우효과적으로바이러스증식을억제하였는데, 35명이테노포비어치료를받은경우 48주바이러스반응이 100% 였으며, 반면에아데포비어치료를받은경우 44% 에서바이러스반응이보고되었다. 130주추적중내성바이러스는발견되지않았다 64). 따라서테노포비어를바탕으로한병합요법이아데포비어를바탕으로한병합요법보다더효과적일것이라고생각되며최근에많은가이드라인들은아데포비어대신테노포비어를바탕으로하는병합요법을선호하고있다 ( 표 6). 결 현재광범위하게사용되는경구용항바이러스제제는대부분의환자에서부작용이없이안전하게사용할수있고 HBV DNA의증식을효과적으로억제하나, 장기적으로사용시내성은피할수없다. 그러므로경구용항바이러스제제의내성의기전을이해하고이들을적절하게사용하는것이매우중요하다고생각된다. 내성의발생을최소화하기위해불필요한항바이러스제제의사용을최대한자제하고일단항바이러스치료를시작하면가능한빠른시간내에완전한바이러스의증식을억제해야한다. 또한지속적인바이러스모니터링을통하여조기에바이러스내성이발생을확인하여바이러스돌파현상즉시병합요법을시행해야한다. 그럼에도불구하고장기적인경구용항바이러스제제는내성이발생하므로후천성면역결핍증환자의치료의예처럼작용기전이서로다르거나작용부위가다른항바이러스제제개발을통하여병합치료의새로운방법을고안하여내성을예방하고궁극적으로는 B형간염바이러스를퇴치할수있기를바란다. 중심단어 : 만성 B형간염 ; 항바이러스내성 ; 경구용핵산유사체 ; 병합요법 론 REFERENCES 1) Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 45: , ) Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, Huang GT, Iloeje UH. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 295:65-73, ) Iloeje UH, Yang HI, Jen CL, Su J, Wang LY, You SL, Chen CJ. Risk and predictors of mortality associated with chronic hepatitis B infection. Clin Gastroenterol Hepatol 5: , ) 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 130: , ) Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, Crowther L, Condreay LD, Woessner M, Rubin M, Brown NA. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 341: , ) LaiCL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, Wu PC, Dent JC, Barber J, Stephenson SL, Gray DF. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med 339:61-68, ) Dienstag JL, Cianciara J, Karayalcin S, Kowdley KV, Willems B, Plisek S, Woessner M, Gardner S, Schiff E. Durability of serologic response after lamivudine treatment of chronic hepatitis B. Hepatology 37: , ) Lok AS, Lai CL, Leung N, Yao GB, Cui ZY, Schiff ER, Dienstag JL, Heathcote EJ, Little NR, Griffiths DA, Gardner SD, Castiglia M. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology 125: , ) Andreone P, Gramenzi A, Cursaro C, Biselli M, Camma C, TrevisaniF, Bernardi M. High risk of hepatocellular carcinoma in anti-hbe positive liver cirrhosis patients developing lamivudine resistance. J Viral Hepat 11: , ) Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee T, Tao QM, Shue K, Keene ON, Dixon JS, Gray DF, Sabbat J. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 351: , ) Yuen MF, Fong DY, Wong DK, Yuen JC, Fung J, Lai CL. Hepatitis B virus DNA levels at week 4 of lamivudine treatment predict the 5-year ideal response. Hepatology 46: , ) Lok AS, Zoulim F, Locarnini S, Bartholomeusz A, Ghany MG, Pawlotsky JM, Liaw YF, Mizokami M, Kuiken C. Antiviral drug-resistant HBV: standardization of nomenclature and assays andrecommendations for management. Hepatology 46: , ) Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok AS. Management of hepatitis B: summary of a clinical research workshop. Hepatology 45: , ) Pawlotsky JM, Dusheiko G, Hatzakis A,Lau D, Lau G, Liang TJ, Locarnini S, Martin P, Richman DD, Zoulim F. Virologic monitoring of hepatitis B virus therapy in clinical trials and practice:

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