Clinical Symposium 3 B 형간염치료의실제 The monitoring and end point of treatment for chronic hepatitis B Ji Hoon Kim Korea University Guro Hospital, Seoul, Korea To prevent the development of liver cirrhosis, liver failure and hepatocellular carcinoma is the ultimate goal for treatment of hepatitis B. Unfortunately, such clinical outcomes evolve over years and decades, therefore, these clinical outcomes are not appropriate to follow up as a clinical relevant end points for therapy. To monitor properly and stop treatment adequately, physicians need clinically useful surrogate biomarker and end points that correctly reflect therapeutic efficacy and precisely predict clinical outcomes such as the development of liver cirrhosis, liver failure and hepatocellular carcinoma. The biochemical, histological, virological and serological biomarkers and end points have been proposed and used in practice and clinical trials. The currently used surrogate biomarkers and end points have acceptable validity and also unacceptable pitfalls. This review discuss the validity and pitfalls of the currently used surrogate biomarkers and end points. 서론 B형간염은전세계적으로 3억명이상의감염자가있을것으로추정되는전세계적으로주요한질환중하나이며국내에서도 1980년초까지유병률이 7% 를상회할정도로만연한질환이었으나 1 1991 년부터신생아예방접종이이루어지고 1995년부터는전국민예방접종이이루어지면서 2005년국민영양조사에서는유병률이 3.7% 로보고될정도로감소하였고 2 특히 2006년조사에서는 4-6세아동에서 0.2% 정도까지보고하고있어 3 만성 B형간염의유병률감소가뚜렷하다. 하지만현재까지국내의만성간질환환자의 70% 가 B형간염에의한간질환으로 4 가장많은부분을차지하고있으며만성 B 형간염환자가간염의급성악화, 간경변으로의진행, 비대상성변화및간암이발생하므로 B형간염환자에대한적절한모니터링과치료등의관리가중요하다. 만성 B형간염의역사를보면, 1965년 Blumberg에의해 Australia 항원이발견되고 5 1973년에 WHO가이항원을 Hepatitis B antigen으로공식화하였으나 1990년대초반에서야 B형간염에대한인터페론치료가시작되었다. 특히, 1990년대후반부터경구용항바이러스치료제들이임상에나오기시작하면서만성 B형간염치료에있어많은발전이이루어지고있다. 하지만이들치료제모두가 B형간염바이러스를완전히제거하는것을목표로하고있지못하고크고작은부작용이나내성발현등의문제를가지고있어이들치료제를사용하는동안환자를어떻게모니터해야하는가? 치료는언제까지하는것이적절한가? 에대한의문이있는것이사실이다. 따라서본고에서는치료중인만성 B형간염환자의모니터링과치료의종결시점에대해고찰해보고자한다. - 116 -
김지훈 The monitoring and end point of treatment for chronic hepatitis B 만성 B 형간염치료중모니터링 만성 B형간염환자의치료효과를판정하기위해서는만성 B형간염의치료목적을이해해야한다. 만성 B형간염의치료의목적은체내 B형간염바이러스의완전한제거및만성 B형간염이야기하는장기적생존에직접적영향을미치는간경변의진행, 간부전의발생, 간암의발생을막는것이다. 하지만, 현재까지의만성 B형간염의치료제로국내에서사용되는주사형인터페론제제와 6가지의경구용항바이러스제제는간세포내의 covalently closed circular (ccc) DNA를포함하는모든 B형간염바이러스의완전한제거를목표로하는제제가아니라는한계점이있으며또한간경변, 간부전, 간암의발생은수십년의추적기간을두고서야그발생또는예방의효과를평가할수있으므로치료중모니터링의목표로삼기에는적절하지않다. 따라서, 이러한만성 B형간염의치료목적을대변할 (surrogate) 수있는임상적으로유용한마커를확인하여이를추적함으로써대안을찾아야한다. 만성 B형간염에의해간경변, 간암으로의진행에영향을주는주요한기전은간염바이러스에대한인체면역반응에의해야기되는만성적간내염증반응및섬유화이다. 따라서, 간내염증및섬유화반응을대변하는임상적마커가유용한모니터링의수단이될수있다. 간내염증, 섬유화정도를평가하는가장좋은지표는현재로선조직검사이다. 하지만, 조직검사는매우침습적인방법으로이로인한주요한합병증의발생이 2.5% 까지보고되고있으며 6 특히간경변환자에서는더욱위험할수있어반복추적에는상당한문제점이존재한다. 6 또한조직검사는간전체의극히일부에서의변화만을반영하게되어조직체취에따른오류를가지게된다. 가장큰문제점은실제치료에의한간조직검사소견의호전이장기적인예후의호전과직접적인관련이있다는것을증거할만한전향적연구가없으므로간조직검사는현재로선유용한치료반응추적마커로이용하기어렵다. 혈청의 alanine aminotransferase (ALT) 는간세포에가장풍부하게존재하고간내염증반응에의해간세포가파괴되면서배출되면혈청내수치의상승을유도하므로간의염증정도를간접적으로평가하는쉽고, 간편하면서반복시행이가능한추적방법이다. 따라서, 치료중 ALT의감소및정상화를확인함으로써간내의염증정도의호전을간접적으로평가하고있다. 하지만, ALT 는몇가지한계점을가진다. 먼저, HBeAg 양성만성간염환자의 40%, HBeAg 음성만성간염환자의 13% 에서는 ALT가정상임에도이미상당한간내섬유화를동반하고있을수있으며, 7 항바이러스치료로 ALT가정상화되는정도가 70% 정도이고이들중조직학적염증의호전을보이는환자도 56% 정도만보고되고있다는것이다. 8 또한, 현재의 ALT 정상수치가너무고평가되어있어남자에서는 30, 여자에서는 19 IU/L 정도로낮추어야한다는보고도있으며 9 이를기준으로정상상한치의 1.5배이내에있는만성 B형간염환자의 20-27% 도상당한조직의염증및섬유화가있다고보고하고있으므로 10 ALT가유용한마커이나 ALT 만으로치료반응을추적하는것은문제가있다하겠다. 간내염증반응을매개하는인자는 B형간염바이러스이므로혈청내분비되는 HBV DNA를측정하는것이유용할것이다. 실제로 26개의전향적항바이러스치료제연구의메타분석에서 HBV DNA 가 1 log 10 copies/ml 감소하면 2점의조직학적호전을유도할수있다고보고하였다. 11 또한, 혈청 HBV DNA 수치가증가하면비례적으로간경변, 간암의발생이유의하게증가한다는보고는 12,13 HBV DNA의감소가주요한장기적치료의예후인자임을보여주고있고항바이러스치료를함으로써간경변의임상적악화뿐만아니라간암의발생도유의하게줄일수있다고알려있으므로 14 혈청 HBV - 117 -
2013 년대한간학회추계학술대회 DNA는유용한치료반응모니터의도구라하겠다. 혈청 HBV DNA 검사의가장큰문제점은여러가지검사법이아직도시행되고있으므로넓은참고치와낮은검출한계를가진검사를통해같은방식으로반복적인검사가이루어지는것이정확한치료효과판정에매우중요하다고하겠다. 혈청학적마커로서는 HBeAg과 anti-hbe 가유용할수있다. HBeAg 양성만성 B형간염환자는음성환자에비해높은 HBV DNA 수치를가지며, HBeAg 양성환자에서항바이러스치료로 HBV DNA의억제가충분히일어난환자에서주로 HBeAg 혈청전환이일어나며 HBV DNA가검출되는환자에서는거의혈청전환이일어나지않으며, 15 HBeAg HBeAg 양성환자가음성환자에비해장기적예후에있어서도간암의발생이뚜렷이높다. 16 따라서, HBeAg 양성만성 B형간염환자에서 HBeAg/anti-HBe 측정은유용한치료반응확인의지표가될수있다또한, HBeAg 혈청전환이일어난환자의장기적추적에서도 HBeAg의양성재전환 (reversion) 이일어난환자에서혈청전환이일어난후계속안정경과를보인환자뿐아니라 HBeAg 음성만성간염을보이는환자보다도장기적으로유의하게간경변이많이발생한다는보고는 HBeAg 음성만성 B형간염환자에서도 HBeAg/anti-HBe 측정이유용할수있다는것을시사한다. 17 최근혈청 HBsAg 의정량적측정을하는자동시스템이보급되면서 HBsAg의반복적측정이용이해지고 HBsAg의임상적유용성에대한연구가많이보고되고있다. HBsAg은간내 HBV DNA 및 cccdna의수치와비례하고 18,19 혈청내 HBV DNA 수치와도비례한다. 20 Table1. The parameters of antiviral treatment efficacy and its follow interval which are recommended in clinical guidelines. IFN therapy Nucleoside analogue Parameter Interval Parameter Interval AASLD 2009 LFT 1 month LFT 3 months HBV DNA 3 months HBV DNA 3-6 months HBeAg/anti-HBe * 3 months HBeAg/anti-HBe * 6 months HBsAg 6-12 months HBsAg 6-12 months KASL 2011 LFT 1-3 months LFT 1-3 months HBV DNA 1-3 months HBV DNA 1-3 months HBeAg/anti-HBe 1-3 months HBeAg/anti-HBe 1-3 months EASL 2012 LFT (ALT) 1 month LFT (ALT) 3-6 months HBV DNA 3 months HBV DNA 3-6 months $ HBeAg/anti-HBe * 6 and 12 months HBeAg/anti-HBe * 6 months HBsAg 12 months HBsAg # 12 months Anti-HBs Should be checked AASLD, American Association of Study of Liver Disease; KASL, Korean Association of Study of Liver; EASL, European Association of Study of Liver. * HBeAg positive patients at baseline. Patients with HBeAg neative and undetectable HBV DNA. Patients with HBsAg seroclrearance. # Patients with HBeAg seroconversion. $ HBV DNA should be checked at initial 3 months and the frequency might be decreased once patients compliance and treatment efficacy are confirmed in entecavir or tenofovir therapy. - 118 -
김지훈 The monitoring and end point of treatment for chronic hepatitis B Table 2. The parameters of antiviral treatment side effect and its follow interval which are recommended in clinical guidelines IFN therapy Nucleoside analogue Parameter Interval Parameter Interval AASLD 2009 CBC 1 month Creatinine * 3 months TSH 3 months KASL 2011 Need monitoring Need monitoring EASL 2012 CBC 1 month Creatinine 3 months for 1st year and then 6 months TSH 3 months Phosphate * NA AASLD, American Association of Study of Liver Disease; KASL, Korean Association of Study of Liver; EASL, European Association of Study of Liver; NA, not available * In case of Adefovir or Tenofovir. The frequency should be increase if patients have high risk renal impairment (decompensation, CCR < 60 ml/min, poorly controlled DM or HTN etc.). HBsAg은 B형간염환자의자연경과에따른변화에도연관성을보여 HBeAg 양성에서높고 HBeAg 음성만성간염에서는감소하며비증식성의상태에서가장낮아자연경과상의만성 B형간염의경과를반영한다. 20 또한, 항바이러스치료를하는경우 HBsAg 수치는감소하며 HBsAg 감소정도와 HBV DNA의감소정도는비례하고 HBsAg 감소는 HBeAg 혈청소실을예측할수있다. 21 하지만, 항바이러스치료에의해 HBsAg의감소는매우미미하여인터페론 1년치료에 1 log 10 IU/L 정도이며 22 경구용항바이러스치료 1년에는 0.4 log 10 IU/L 정도여서 21 그추적이어느정도효용성이있을지는의문이있는실정이다. 그렇다면어떤마커를얼마의간격으로추적하는것이가장합당할까? 이러한의문에서시작한가이드가될만한연구는거의없다. 따라서현재까지나와있는국내와미국, 유럽의가이드라인을참고하여결정하는것이가장합리적일것으로보이며이를 Table 1에정리하였다. 23-25 또한, 치료중부작용에대한모니터링에대해서도 Table 2에정리하였다. 만성 B 형간염치료종료시점 만성 B형간염의치료중모니터링에서와마찬가지로이론적으로만성 B형간염의치료종료시점또한치료목표라할수있는 B형간염바이러스의체내에서완전제거와간경변, 간부전, 간암의발생을막을수있는지점을종료시점으로하여야한다. 하지만, 치료에의한이들의효과는수십년의경과를보아야확인할수있으므로이들의효과를대신할수있는대체종료시점을 (surrogate end point) 를이용할수밖에없다. 대체종료시점으로서합당한생체지표 (biomarker) 가되기위해서는당연히장기적으로임상적잇점과위험도를충분히예측, 대변할수있어야하고생체지표의측정이쉬워야하며이들의치료효과에서나타나는변화가임상적종료시점에비해당연히더잛고자주확인될수있어야하며생체지표에서일어나는변화의효과가그에따른임상적경과에미치는효과를충분히설명할수있어야한다. 26,27 하지만, 최근의전문가들의검토에서도현재사용되고있는만성 - 119 -
2013 년대한간학회추계학술대회 B형간염치료의대체종료시점이실제임상적경과를대체한다고할수있는타당성에의문을제기하고있다. 28 이는실제만성 B형간염의치료중대체종료시점이임상적종료시점을반영한다고할만한잘조절된전향적연구가거의없는것에기인한다고하겠다. 하지만, 대체종료시점이임상적경과를반영할수있다는증거는간경변, 간부전, 간암등의장기적임상적경과와여러대체종료시점의연관성에대한자연사연구로부터상당히유추될수있으며항바이러스치료를하며장기추적관찰한일련의연구도대체종료시점을달성한환자에서임상적경과가좋다는자료를보여주고있다. 따라서현재의대부분의전문가집단이제시하는대체종료시점은 ALT의정상화로대변되는생화학적반응, HBeAg 소실또는혈청전환과같은혈청학적반응, HBV DNA가검출한계이하로확인되는바이러스반응마지막으로섬유화의악화없이 2점이상의염증소견의호전으로대부분정의되는조직학적반응이있다. 29,30 생화학적대체종료시점인혈청 ALT의정상화는쉽고간편하게그리고반복적인측정이용이한좋은생체지표이다, 하지만, 이를통해치료를종료하기에는문제가많다. 실제 1년의페길레이트인터페론을사용한후치료를종결하는경우 40-68% 의환자에서종료 6개월이내에 ALT가다시정상상한치이상으로상승하고 31-33 항바이러스제 1년치료후에는 51-68% 의환자에서치료종료 6-12개월내에 ALT가다시상승한다. 34,35 게다가, 경구용항바이러스치료종료후 ALT의심하게상승하는경우가 1-29% 에이르고일부는간부전도나타난다고알려져있어 36-39 ALT 정상화를대체종료시점으로하여항바이러스치료를종료하는것은적절하다고하기어렵다. 게다가, 만성 B형간염에서 ALT 가정상상한치의 0.5 배인하인환자에비해 0.5에서 1배이거나정상상한치를벗어나는환자모두간의장기적합병증의발생은유의하게증가하며 40 현재의 ALT 정상수치가너무높다는연구가있으며 9,41 국내의간이식기증자의조직학적으로확인된간내염증이없는정상 ALT 수치가남자 35, 여자 26 IU/L이라는보고도있어 42 현재의 ALT 정상기준을반영하는 ALT의정상화가진정장기적인치료반응을대변할수있는지가의문시된다. 혈청학적반응으로서 HBeAg 혈청전환은 HBeAg 양성만성 B형간염환자에서주요한대체종료시점으로많은임상연구에서효과를판정하는주요한인자로이용되어왔다. HBeAg 양성만성 B형간염환자에대한자연경과의연구들에서 HBeAg 양성환자는음성환자에비해장기추적에서 6.27 배 ( 비교위험도 60.2 : 9.6) 간암의발생위험이높고, 43 HBeAg 혈청전환이일어난환자의 88% 와 79% 에서 ALT가정상을유지하고조직학적인호전을보이고 44 HBeAg의혈청전환이유지된환자는 25년추적연구에서 95% 의생존을보여 45 HBeAg의혈청전환이의미있는대체종료시점으로서의의의를보여주고있다. 또한, 인터페론치료후혈청전환이일어난환자는혈청전환을이루지못한환자에비해유의한생존율과간연관합병증의발생이감소한다는사실이보고되어있어대체종료시점으로서의가치를가지게하는증거가되고있다. 하지만, HBeAg 혈청전환은페길레이트인터페론 1년치료에약 24-30% 정도에서일어나고대체로치료종료후에도지속적으로유지되지만, 46 경구용항바이러스제 1년사용후에는 16-22% 에서만혈청전환이일어나고, 47 최근의내성발현이거의없는약제를 5년까지장기적으로사용하더라도 40% 정도에서만일어나고 48,49 약제를종료하는경우반응이유지되는경우는 60% 에미치지않는다. 47 게다가, 혈청전환이일어난환자의 8년장기추적연구에서 24% 가 HBeAg 음성만성간염으로진행하고 4.2% 에서는 HBeAg의양성재전환이일어난다는보고도있어 17 제한점이있는것도사실이다. 하지만, 최근의라미부딘치료로 HBeAg의혈청전환을 - 120 -
김지훈 The monitoring and end point of treatment for chronic hepatitis B 이룬후적어도 1년이상공고 (consolidation) 치료를유지한환자에서는 5년추적에서 8% 에서만재발이일어난다는보고는, 혈청전환후 1년이상치료를유지하는것이유용한대체치료종료시점일수있음을시사한다. 50 근래에는혈청학적지표로 HBsAg 의소실이주요한대체종료시점으로대두되고있다. HBsAg은오랫동안 B형간염바이러스감염의확인검사로주로이용되어왔다. 만성 B형간염에서 HBsAg 혈청소실된환자를평균 63개월간추적한연구에서 HBsAg 소실시점에간경변의증거가없는환자는추적중간경변이나간암이발생하지않았지만 HBsAg이계속양성이었던환자는 3.4% 에서간경변이발생했고 51 0.7% 에서간암이발생하였으며, 96명의 HBsAg 소실을보인환자의 116개월추적연구에서도 24명이 HBsAg 소실당시이미간경변의증거가있었음에도 0.47%/year의간암발생률을보여 HBsAg 소실환자에서간암의발생은매우낮음을보여주고있다. 특히 45-50세이전에 HBsAg 혈청소실이일어난환자는간암이거의발생하지않는다는보고도있어 HBsAg 혈청소실은의미있는대체종료시점으로서가치가있다고할수있다. 52, 53 다만, HBsAg 소실은매우드물어서페길레이트인터페론 1년사용후 5-7% 정도이고 24 장기추적에서도 8-15% 이며 46,54 경구용항바이러스치료에는더적어서 1년치료에 0-3.2% 이며 24 테노포비어 5년치료에서 10% 정도만보고되고있다. 48 특히나치료에따른 HBsAg 소실은 B형간염의유전자형에따라달리나타나대체로유전형 A에서많이나타나나 46 국내에많은유전형 C에서는드물며인터페론치료후 HBV DNA가충분히감소한환자에서는 3년추적에 9.4% 에서 HBsAg 소실이나타나지만 HBV DNA가검출되는환자에서는 2% 로적어 54 HBsAg 소실은 HBV DNA의충분한억제가선행되어나타난다는것은 HBsAg 소실의치료종료시점으로써의제한점이라하겠다. 넓은영역의검출범위를갖는 HBV DNA 측정이가능해진후 HBV DNA 수치의정도가간경변으로의진행이나간암의발생과정비례한다는자연사연구가이루어졌는데이들연구에서 HBV DNA 가 2,000 IU/L 이하인경우그이상인경우에비해유의하게간경변, 간암의발생이적었으며 12,13 간경변이없는 HBeAg 양성환자 70명의 25년추적에서 HBeAg 혈청전환이일어나고 HBV DNA가검출한계이하인환자는 HBV DNA가검출되었던환자보다생존율이뚜렷이높아각각 95% 와 50% 였다. 45 그리고, 대상성간경변이있는환자의 6년추적에서도 HBeAg이음성이며바이러스가검출한계이하인환자가검출되는환자에비해비대상성진행이나생존율모두에있어나았다. 55 이는적어도 HBV DNA가 2,000 IU 이하로감소시키는것은만성 B형간염환자의임상적경과에결정적영향을미친다는간접적인증거가된다. 치료를하는경우에있어서도, 항바이러스치료를통한 HBV DNA의감소정도가조직학적소견의호전정도와비례한다는보고가있고 11 전향적으로라미부딘치료를한진행된섬유화를가진환자를위약과비교한연구에서라미부딘치료는간암의발생뿐아니라임상적악화에있어서도유의한감소효과가있음을증명하였고특히라미부딘치료중바이러스돌파현상이나타나 HBV DNA가증가되는환자는이러한효과가뚜렷이감소하였다. 14 추가하여후향적인 656명의연구에서도항바이러스치료로지속적바이러스반응을유지하는군에서돌파현상을보이는군보다뚜렷한 B형간염의임상적악화가나타난다는것은 56 HBV DNA를검출한계이하로감소유지하는것이유용한대체종료시점임을시사한다. 하지만, 치료를종료한이후의 HBV DNA가재발률은상당히높다는것이주요한제한점이라하겠다. 페길레이트인터페론치료종료 3-5년추적에서 81-85% 의환자가 HBV DNA가상승하는재발을나타내었고경구용항바이러스치료에서는, - 121 -
2013 년대한간학회추계학술대회 Table 3. The end points of antiviral treatment which are recommended in clinical guidelines HBeAg (+) CHB HBeAg (-) CHB AASLD 2009 KASL 2011 EASL 2012 At least 6 months after HBeAg seroconversion with undetectable HBV DNA in PCR At least 12 months after HBeAg loss with undetectable HBV DNA in PCR HBsAg seroclearance (Ideal) At least 12 months after HBeAg seroconversion (Satisfactory) HBsAg seroclearance in severe fibrosis In corrhosis, indefinte Rx recommended HBsAg seroclearance HBsAg seroclearance HBsAg seroclearance In cirrhosis, indefinte Rx recommended AASLD, American Association of Study of Liver Disease; KASL, Korean Association of Study of Liver; EASL, European Association of Study of Liver. 최근의내성이적은약제는장기간사용으로 HBV DNA 불검출율이 90% 를넘게보고되고있어종료후에도이러한반응이유지될지좀더연구되어야하겠으나경구용항바이러스제들의 1년치료후추적에서 12개월내에 92% 이상의환자에서 HBV DNA의재발이나타난다고알려져있다. 24 따라서, HBV DNA는치료중효과를판정하는주요한마커라할것이나대체치료종료시점으로써의가치를가지려면치료종료후에도반응이유지될수있는약제가먼저선행되어야할것이다. 간의조직학적호전은가장직접적인만성 B형간염의질환의진행을평가하는방법이다. 만성 B 형간염의치료에서조직학적호전은 38-74% 까지다양하게나타나고 24 간경변으로분류되는환자 Ishak 분류 6에서도장기적인치료후에간섬유화의호전으로 4 이하의간경변이나교량섬유화 (bridging fibrosis) 가없는정도로호전될수있음이보고되어왔고 57,58 최근의테노포비어 5년추적검사에서는 Ishak 분류 6인환자의 66% 가 Ishak 분류 4 이하로호전되고간경변이없는환자에서간경변으로의진행은없었다고보고하고있어 48 치료로간경변으로진행을막고간경변의호전도이룰수있는가능성이있음을확인시켜주고있으므로간조직검사의호전은하나의대체치료종료시점으로서의의를갖는다하겠다. 하지만, 조직학적호전은침습적검사를적어도 2회이상반복해야하는문제점과조직검사가가지는검사의적정상, 판독상의오류등의문제로인해임상적으로유용한검사라할수없으며간조직의어느정도호전이실제임상적경과를반영하는지치료에의해이런호전도임상적경과를호전시킬수있는지에대한조절연구가없고이루어지기어렵다는제한점을가진다. 현재의전문가집단이추천하는대체종료시점이지역마다다양한것은이러한여러타당성제한점이존재하기때문이다. 하지만현재로서유용할것으로추천되는데체종료시점을이해하고이를운용하는것이가장현실적인대안일것이다. 이에현재전세계적인가이드라인에서제시하는치료종료시점을 Table 3에정리하였다. 23-25 - 122 -
김지훈 The monitoring and end point of treatment for chronic hepatitis B 결론 만성 B형간염의치료의최종적인목적은체내의 B형간염바이러스를완전히제거하고간경변, 간부전, 간암의발생을막는것이지만실제이러한결과를얻기위해서는수십년의추적관찰이필요하다. 따라서, 환자의치료중적절한모니터와치료종결시점의결정뿐아니라여러가지연구에서나오는결과들을서로비교할수있는임상적으로유용한대체마커가꼭필요하다. 이를통해환자의치료중효과를정확히모니터하고치료를종결하는시점을확인할수있으며장기적인예후도판별할수있기때문이다. 현재모든전문가집단이제시하고있는네가지대체마커, ALT 정상화, HBV DNA 불검출, HBeAg 혈청전환, 조직학적호전은모두유용성과한계점을가진다. 따라서이들모두의유기적인해석을위한모니터를통해치료종료시점을정하여야할것으로보인다. 현재전세계적인가이드라인에서제시하는치료종결시점은 HBsAg 소실까지항바이러스제를쓰는것이다. 하지만이는매우드물게일어나는결과이며유전형 C가많은국내에서는더욱이쉽지않은목표이다. 그래서 HBeAg 양성만성 B형간염에서는 HBV DNA가음전되고 HBeAg 혈청전환이나타나는경우 6-12개월이상약제를유지한후치료를종결할수있다는보조적치료종결시점을제시하고있다. 이에반해 HBeAg 음성환자에서는 HBsAg 소실만을목표로제시하고있는실정이다. 하지만 HBeAg 혈청전환후에약제를 2년이상유지한연구에서도 2년누적 HBV DNA 양전율과 HBeAg 재양전율이 31% 와 16% 에이르고 59 HBsAg 소실은드물게얻을수있는결과임을고려할때장기적환자의임상적경과를정확히반영할수있는치료중모니터링과종료시점의대체마커개발을위한영구가지속적으로이루어져야할것으로보인다. 참고문헌 1. Sim JG SJ, Suh SJ. Prevalence and its changes of hepatitis B viral markers from 1988 to 1993 in Korean children. J Korean Pediatr Soc 1995;38:1535-1539. 2. Ministry of Helalth & Welfare KCfDCaP. The Third Korea National Health and Nutrition Examination Survey (KNHANES III), 2005: Health Examination. Ministry of Helalth & Welfare. 2006;68. 3. Prevention KCfDCa. 2006 Disease Control White Paper. Korea Centers for Disease Control and Prevention 2007;144. 4. Chae HB, Kim JH, Kim JK, Yim HJ. Current status of liver diseases in Korea: hepatitis B. Korean J Hepatol 2009;15 Suppl 6:S13-24. 5. Blumberg BS, Alter HJ, Visnich S. A "New" Antigen in Leukemia Sera. JAMA 1965;191:541-546. 6. Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD, American Association for the Study of Liver D. Liver biopsy. Hepatology 2009;49:1017-1044. 7. Kumar M, Sarin SK, Hissar S, Pande C, Sakhuja P, Sharma BC, et al. Virologic and histologic features of chronic hepatitis B virus-infected asymptomatic patients with persistently normal ALT. Gastroenterology 2008;134:1376-1384. 8. Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, et al. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med 1998;339:61-68. 9. Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, Del Vecchio E, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 2002;137:1-10. 10. Tsang PS, Trinh H, Garcia RT, Phan JT, Ha NB, Nguyen H, et al. Significant prevalence of histologic - 123 -
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