Clinical Symposium 3 B 형간염치료의실제 Management of hepatitis B virus in the liver transplantation and immunocompromised setting Su Jong Yu Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea Hepatitis B virus (HBV) infection is at risk for reactivation when the immune response is suppressed. Immune suppression including transplantation or anticancer chemotherapy enhances the hepatitis B viral load, whereas reduction in immune suppression may also be harmful because of immune restoration. In the absence of effective prophylaxis, the recurrence of hepatitis B after transplantation was as high as 75% leading to early graft loss and a reduction in long-term survival. Moreover, the clinical outcome of HBV reactivation during and after anticancer chemotherapy may lead to hepatic failure and even death. The negative impact of immune suppression is related to two non-exclusive factors: (i) high HBV viral load may result in a rare severe liver disease called fibrosing cholestatic hepatitis by the direct toxicity of high levels of HBV proteins; (ii) The pathophysiology of HBV reactivation is mainly immune-mediated via HBV-specific T lymphocytotoxicity. This double-edged sword explains why prophylactic therapy should be considered for all HBV-infected patients. This review addresses current knowledge on the clinical aspects and management of HBV in the liver transplantation and immunocompromised setting. Key words: Hepatitis B virus; Reactivation; Prophylaxis; Transplantation; Immunocompromised 서론 만성 B형간염의치료는항바이러스제제의사용과더불어지속적인발전을거듭하고있으나여전히전세계적으로유병률과사망률이높은감염성질환이고매년 50만명이상의환자가 B형간염과관련된만성간질환의합병증으로사망하고있어서간이식의적응증이된다. 1 그러나 1990년도초반까지 B형간염과관련된만성간질환은간이식의상대적금기증에해당되었는데, 그이유는 B형간염환자에서간이식후예방적치료를하지않은경우 75% 에이르는높은비율로이식후간염이재발하고이러한이식간의재발간염은, 진행속도가빠른담즙경화성간염 (fibrosing cholestatic hepatitis) 으로서 1년생존율이 33-65% 로낮고, 대개이식후 2-3년안에이식간을잃게되기때문이다. 2 그러나수동면역제제인 hepatitis B immune globulin (HBIG) 과라미부딘과같은항바이러스제제를이식전후예방적으로사용하기시작하면서이식후 B형간염의재발을 5년에 5% 미만으로줄일수있게되었고이로써 B형간염환자에서의간이식성적은 B형간염이외의간질환환자군과같거나오히려우수하게되었다. 2 경구항바이러스제제의이식전후사용은간이식의성적을향상시킬뿐아니라고 - 136 -
유수종 Management of hepatitis B virus in the liver transplantation and immunocompromised setting 비용의 HBIG 사용을줄일수있고 HBIG 치료에실패한환자에서도적용이가능하다. 3 이식후 B형간염의재발에관여하는요소로는이식전바이러스부하가적거나빨리제거될수있는경우에는이식후 B형간염의재발률이낮다고알려져있다. 즉, 이식전 HBeAg과 HBV DNA가음성인경우와 D형간염의중복감염, 급성간부전, 이식전내성돌연변이종이없는경우에는재발률이낮은반면, 반대의경우에는이식후재발률이높다. 만성 B형간염의합병증으로간이식시행후 HBV에재감염되는기전은 (i) 수혜자의혈중에존재하는 HBV에의한급속한재감염및 (ii) 간이외의부위에서 replication하는 HBV에의한재감염이제시되고있다. 4,5 이중후자에대해서는다소이견이있으나이식후주된 HBV strain은이식전환자의혈청에서검출된바이러스 strain이아니고말초혈액단핵구에존재하는 strain과일치함을보여주는연구결과가있다. 6 따라서이식전 B형간염바이러스의증식을최대한억제하고이식후 B형간염바이러스의재감염을예방하는치료가간이식의성적을향상시키기위해매우중요하다. 이식환자의 B 형간염치료 1. B형간염재발예방을위한이식전치료이식전항바이러스제제의투여는바이러스의증식을최대한억제하여이식후재발을예방하는데에목적이있다. 이식전에항바이러스제제를투여하여 HBeAg 혹은 HBV DNA 혈청음성전환을유도하여이식성적을향상시킬수있고, 간이식전항바이러스제치료는만성 B형간염치료가이드라인을따른다. 7,8 간이식의대상이되는비대상성간경변증환자에서라미부딘치료는간기능을호전시키고간이식의필요성을줄일수있는것으로보고되었으나, 4년치료시 60-65% 이상에서라미부딘내성바이러스가발생할수있고다른항바이러스제제의효능을떨어뜨리는부정적인영향으로인하여더이상일차치료약제로권유되지않는다. 9 아데포비어는비대상성간경변증환자의초치료제로서단독연구된바없는데비교적높은내성발생률 (5년에 30%) 과상대적으로낮은바이러스억제력으로인하여일차치료약제로권유되지않는다. 텔비부딘은라미부딘에비하여 HBV DNA 음전율 (<300 copies/ml) 이높으며 (47 vs. 36%), 바이러스돌파도적고 (29 vs. 39%), 104주치료동안생존률도높다 (83 vs. 75%). 7 그러나라미부딘에서와마찬가지로비대상성간경변증환자에서텔비부딘투여시에내성바이러스의발생은간부전으로진행할위험성이있다. 7 비대상성간경변증환자 191 명을대상으로무작위로엔테카비어 (1 mg/ 일 ) 또는아데포비어 (10 mg/ 일 ) 를 96주간투여한결과, 24 주및 48주째혈청 HBV DNA 불검출율 (<300 copies/ml) 은엔테카비어가아데포비어보다우수하였으며 (24주; 49% vs. 16%, 48주 ; 57% vs. 20%), 48주째 HBeAg 혈청전환율은양군간에차이가없었다 (6% vs. 10%). 10 55명의비대상성간경변증환자의초치료에서엔테카비어를사용하여 12개월치료한결과, 약절반 (49%) 에서 Child-Pugh 점수가 2점이상호전되었으며무이식 (transplantation-free) 1년생존율은 87.1% 였다. 11 진행된간경변증환자에서테노포비어를사용한연구결과는매우제한되어있으나 48주간 2상으로진행된이중맹검무작위임상연구에서테노포비어의항바이러스효과는비대상성간경변증이아닌환자군과동일하였다. 12 비대상성간경변증환자는신속하고적극적인치료가 - 137 -
2013 년대한간학회추계학술대회 요구되므로 HBV DNA가 PCR 검사상양성인경우항바이러스효과가우수하며내성발현율이적은엔테카비어또는테노포비어같은경구용항바이러스제치료를권장한다. 항바이러스제를 13 투여받은일부환자에서는 3-6개월정도시간이경과하면서간이식이필요하지않은정도로임상적인호전을보이는경우가있는데, 항바이러스제투여에도불구하고간부전으로진행되는경우에는간이식이필요하며, 이식전후항바이러스제치료가이식후간염의재발위험을줄여준다. 14 2. 이식후 B형간염재발의예방적치료 1) Hepatitis B immune globulin (HBIG) 단독치료 HBIG의작용기전은명확하지않으나, 간이외의부위에서증식하는 HBV로부터 naïve hepatocyte 를보호하는것으로생각되며면역복합체를형성하여순환하는 virion을중화시킨다는가설도제시되고있다. 15 이식후초기에 HBIG 용량이불충분경우나후기에 HBIG에대한내성돌연변이종이발생하는경우 B형간염이재발한다. 재발고위험군환자에서초기 HBIG 고용량요법으로 8 효과적인치료가가능한데무간기및이식후 7일간매일 HBIG 10,000-20,000 IU을정주하고, 이후매달 HBIG 10,000 IU을정주하는고용량요법을사용하여, anti-hbs 역가를 500 IU/L 이상유지한다. 2 HBIG 고용량요법으로간이식후약 16-35% 의 B형간염의재발률을보고하였다. 저위험군에서는 anti-hbs 역가를 100-150 IU/L 이상유지하는방법을사용할수있다. 2 그러나 HBIG의장기간사용으로 HBV 표면단백에대한내성에의한 B형간염이재발할수있으며, 이외에도 HBIG 정주에따르는불편과고비용및혈청을이용한 HBIG 제작시의감염가능성등때문에최근에는 HBIG과항바이러스제제를병합하여 HBIG의사용량을줄이거나 HBIG을전혀포함하지않는요법이시도되고있다. 2) 뉴클레오사 ( 타 ) 이드유사체단독치료 (Complete HBIG free strategy) 일부연구에서선별적인라미부딘단독요법을시행하고 17개월간추적하여 5.2% 의내성발생률과 87% 의환자생존율을보고한바있으나일반적으로치료 2년째 B형간염재발율이 35-50% 에이르고 16 HBV DNA 양성인경우재발율이 60% 까지되기때문에현재권장하고있지않다. 17 최근개발된뉴클레오사 ( 타 ) 이드유사체인엔테카비어나테노포비어의경우바이러스억제력이강력하고약제내성이적은항바이러스제로서간이식전만성 B형간염에서의치료성적으로미루어볼때, 간이식후이약제들의단독사용시 B형간염재발이효과적으로억제되는지규명하는잘계획된대규모의연구가필요하다. 실제로 Fung 등이 80명의 HBsAg 양성환자를대상으로 HBIG 없이엔테카비어단독으로예방적치료를시행하고 26개월간추적하였을때간이식당시 B형간염바이러스의완전반응률은 26% 였으나 1, 2년째 HBsAg 소실률이각각 86%, 91% 였고, HBV DNA 소실률이 98.8% 에달한다고보고하였다. 18 3) HBIG 과뉴클레오사 ( 타 ) 이드유사체병합치료 (1) 고용량 HBIG 라미부딘과고용량 HBIG 병합요법으로 B 형간염의 1-2 년재발률을 10% 미만으로줄일수있게되 - 138 -
유수종 Management of hepatitis B virus in the liver transplantation and immunocompromised setting 었으며, 비용-효과적인측면에서도고용량 HBIG 단독요법에비해우수하였다. 19-22 6개의독립적인연구결과를종합하여메타분석을시행한결과라미부딘과 HBIG 병합요법은 HBIG 단독요법에비해 B형간염의재발률및이와연관된사망률을각각 12 배낮추는것으로확인되었다. (2) 저용량 HBIG HBIG은고비용, 감염위험성, 납중독등의문제가있어 anti-hbs 역가에따라저용량의 HBIG을적용였을때고용량 HBIG과효과가유사함이보고되었다. Angus 등은라미부딘과함께첫주에저용량의 HBIG을 400 또는 800 IU로매일근주한뒤이후매달근주하였는데 18.4개월동안추적관찰하였을때 32명중 31명이 HBsAg 음성으로유지되었고모든환자가 HBV DNA 음성으로유지되었다. 23 2개의 meta-analysis에서라미부딘과저용량 HBIG 병합요법은라미부딘단독또는 HBIG 단독요법에비하여모두 B형간염재발의위험도가낮았다. 24,25 이상의결과에근거하여라미부딘과 HBIG 병합요법이간이식후 B형간염재발의예방을위한표준치료로권고되고있으나 HBIG의적정용량, 투여경로, 목표 anti-hbs 역가등에대한추가연구가필요하며, 저용량의 HBIG이라고하더라도주기적인추적검사, 비경구투여의불편및비용등은여전히해결이필요한문제이다. 최근에바이러스억제력이강력하고약제내성이적은엔테카비어또는테노포비어를 HBIG 와병합치료하여좋은성적을보여준초기연구결과가있어향후이러한약제들의역할이더욱기대된다. 26 (3) HBIG withdrawal 1 라미부딘단독유지상술한 HBIG의문제점으로인하여몇몇연구에서 HBIG을중단하고라미부딘만단독으로유지하는요법을평가하였으나라미부딘내성바이러스발생이여전히우려된다. 한전향적연구에서 29 명의환자를간이식후 1개월째까지는 HBIG과라미부딘병합치료한뒤병합치료군과라미부딘단독유지군으로무작위배정을하고 18개월간추적하였을때양군에서 B형간염의재발은관찰되지않았다. 27 그러나이후추적관찰에서는 15% 의환자에서 B형간염재발이관찰되었는데위험도는양군사이에유의한차이가없었다. 28 2 라미부딘과아데포비어병합전향적연구에서간이식후최소 12개월이경과한시점에저용량 HBIG을아데포비어로전환하였을때 16명의환자는라미부딘 / 아데포비어병합치료를받았고 18명의환자는라미부딘과저용량 HBIG 병합요법을유지하여 21개월을추적관찰하였는데양군모두에서 B형간염이재발한환자는없었다. 29 유사한다른연구에서는 47명의환자에서간이식후라미부딘과 HBIG을병합투여한뒤 12 개월경과시점에 28명의환자에서는 HBI을중단하면서아데포비어 (n=23) 또는테노포비어 (n=5) 로치환하여라미부딘과병합치료하였고, 나머지 19명의환자에서는테노포비어단독 (n=10) 또는엔테카비어단독 (n=9) 요법으로전환하였는데모든군에서 24개월추적기간동안 HBV DNA가음성으로유지되었다. 30 또다른연구에서는라미부딘내성바이러스에감염된 16명의 B형간염환자에서간이식후라미부딘과아데포비어의병합치료를시행하였는데 8명은 HBIG을중단하면서라미부딘에아데포비어를병합하여치료하였고나머지는 HBIG을사용하지않고처음부터라미부딘 / 아데포비 - 139 -
2013 년대한간학회추계학술대회 어병합치료를시행하였을때 21개월의추적관찰시양군에서 HBV DNA는검출되지않았다. 31 3 테노포비어 / 엠트리시타빈 21명의환자에서간이식후 HBIG을 6개월이상투여하고중단한뒤테노포비어 / 엠트리시타빈으로교체하였을때 31개월추적관찰시 21명전원에서 HBV DNA는검출되지않았고 20명에서는 HBsAg이음성으로유지되었다. 21명중 3명에서신기능장애가발생하였는데 2명은 tacrolimus가원인이었고 1명은테노포비어가원인이었다. 32 비록소규모연구이나바이러스억제력이강력하고약제내성이적은약제가 HBIG을대체할수있다는가능성을시사한다. 3. 간이식후재발한 B형간염의치료간이식전 / 후예방적치료에도불구하고 B형간염이재발한경우라미부딘치료는비교적효과적이지만, 장기간사용하였을때 3 년에 50% 이상의내성률이보고되었으며, 이러한라미부딘내성은간이식의성적을저하시키는것으로알려져있다. 33-35 최근간이식후재발한 B형간염치료에있어테노포비어와엔테카비어의효과에대한소규모연구가보고되었으나, 36 잘계획된대규모연구결과가필요하다. 간이식후라미부딘내성을보이는 241명의재발성 B형간염환자를라미부딘과아데포비어의병합요법으로치료하였을때 96주후 65% 의 HBV DNA 음성화율및 2% 의라미부딘내성률을보였다. 37 비록소규모의단기간연구결과들이지만최근간이식후라미부딘내성변이종의치료에있어테노포비어가좋은성적을보고한바있어향후추가적인연구결과가주목된다. 35 하지만엔테카비어의경우이미라미부딘내성환자에서구제요법으로단독치료하였을때높은엔테카비어내성발생률을보고된바있어, 38 간이식환자에서도라미부딘내성을보이는경우에는추천되지않는다. 따라서간이식후 B형간염이재발하는경우바이러스억제력이강력하고약제내성이적은항바이러스제를사용하며, 만약약제내성이있는경우에는만성 B형간염치료가이드라인을따른다. 7 간이식환자에서 B형간염의예방및치료에대하여 Table 1에정리하였다. Table 1. Recommendations for the management of hepatitis B virus infection before and after liver transplantation Indication Treatment strategy Decompensated cirrhosis Possible referral for LT If detectable serum HBV-DNA NA (e.g., entecavir or tenofovir) * Prophylaxis after LT Low or undetectable viremia at LT NA ± HBIG High viremia at LT NA + HBIG Post-LT HBV recurrence NA (e.g., entecavir or tenofovir) * * According to the treatment guideline. 7 LT, liver transplantation; NA, Nucleos(t)ide analogs; HBIG, hepatitis B immunoglobulin; HBV, hepatitis B virus. - 140 -
유수종 Management of hepatitis B virus in the liver transplantation and immunocompromised setting 4. HBV에대한숙주면역반응복원 1) 예방접종간이식후 B형간염예방접종을시행하였을때 82.4% 에서혈청전환이일어나고 14개월추적관찰시 HBsAg이나 HBV DNA의재발이관찰되지않음을보고한연구가있으나 39 다른연구에서는반응률이 17.6% 에불과하였고, 40 또다른연구에서는이보다더낮은 7.7% 였다. 41 그러나특정환자군에서는높은반응률을보이는경우가있어이에대한연구가필요하다. 2) Adoptive immunity transfer 홍콩에서수행된연구에서간이식을받은 50명중 21명 (42%) 에서간이식후 HBsAg이소실되고 anti-hbs가자연적으로나타나는것이처음으로보고되었다. 42 21명중 19명은 anti-hbs가양성인공여자로부터간을공여받았으며공여받은간을통한 adoptive immunity의전달에의한현상으로해석된다. 동일한연구자들이후속연구를통하여공여된간을조사하였을때공여자에서기인한 HBV 특이 T 림프구와 B 림프구가각각 59%, 28% 에서관찰됨을보고하였다. 43 일부환자에서 anti-hbs 역가가 1,000 IU/mL를넘었지만이후 7개월에걸쳐감소하는것이관찰되어 B형간염에대한평생면역이형성되었다고말하기어렵다. 따라서향후면역력의강도와지속시간을향상시키는방안에대한연구가필요하다. 면역억제환자의 B 형간염바이러스치료 1. 서론 B형간염의효과적인예방백신및수직감염예방법의개발이후전세계적으로 B형간염바이러스보유율은점차감소하고있는상황이다. 그러나아직까지 HBsAg 양성률은서구에비하여유의하게높으며 HBsAg은음성이더라도 anti-hbc IgG 가양성인경우나, 혈중 HBV DNA 농도가 1,000 IU/mL 미만이고혈청간효소수치가정상범위에있는 B형간염건강보유자의경우에도면역억제제나항암화학요법제를사용하는경우 HBV 증식및면역체계의활성이모두영향을받을수있고이에따라간염이악화될수있다. 44-46 HBV 재활성화는보통혈중 HBV DNA 농도가기저치의 10배이상또는 10 8 IU/mL 이상으로상승하면서혈청간효소수치가정상상한치의 3배이상또는 100 IU/L 이상으로상승하는것으로정의된다. 47,48 HBV 재활성화로진단하기이전에, 항암제의사용과관련된간손상, 간전이, 또는다른바이러스에의한간염등을감별하여야한다. HBV 재활성화의빈도는약 20-50% 로알려져있는데대부분초기에무증상인경우가많으나, 일부는황달과비대상성간부전의증상을동반하는임상적악화를보이며간부전에의하여사망에이르기도한다. 47,49-51 특징적으로, HBV DNA 는면역이억제되는시기에나타나기시작하고면역억제제의사용을중단한뒤 ALT의상승을동반한다. 만약 HBV 재활성화가악성종양으로항암화학요법을시행받는환자에서발생하게되면항암치료의중단또는조기종료에의하여항암치료의성적에부정적인영향을미칠수있다. 52-54 - 141 -
2013 년대한간학회추계학술대회 2. HBV 재활성화의위험인자 HBV 재활성화의위험인자로는치료전의혈중 HBV DNA 농도, 악성종양의종류, 면역억제제또는항암화학요법의종류와강도등이보고되고있다. 예를들면 HBV 재활성화는다른고형암 (14-21%) 에비하여비호지킨림프종환자에서 24-67% 의빈도로빈번하게관찰되는데림프종의치료에사용되는항암요법의강도가강하며림프종환자에서 HBsAg 양성빈도가더욱높게나타나기때문이다. 50,55-57 유방암환자에서도 41-56% 의빈도로높게관찰되며고농도항암제의사용및 anthracycline 제제의사용과관련이있다. 58,59 부신피질호르몬제는면역을억제하여 HBV 재활성화의위험도를증가시키는동시에 HBV 복제를직접자극하는것으로알려져있다. Rituximab은부신피질호르몬제와함께림프종의치료에흔히사용되는약제로서 HBV 재활성화의위험을더욱증가시킨다. 60,61 재활성화의위험도는혈액종양환자가조혈모세포이식전고강도항암요법을받는경우상승하게된다. 62,63 이외에도 HBV genotype 또는 HBV genome의특정돌연변이등이재활성화와관련되어있다고알려져있다. 64-66 3. HBV 재활성화의치료 HBV 재활성화는예방이중요한데항암화학요법시행전 HBsAg과 anti-hbc IgG 에대한선별검사를시행하여양쪽모두음성인경우예방접종을시행하고, HBsAg 양성환자에서는혈중 HBV DNA 농도에관계없이항바이러스제제의예방적투여를시행한다. 66 라미부딘의예방적투여는 HBV 재활성화및이로인한간부전과사망을유의하게줄이는것으로보고되었다. 56,63,67,68 따라서 HBV DNA 가상승할때까지기다리기보다는항바이러스제제를예방적으로투여하고항암제치료종료후최소 6개월에서 12개월까지상당기간동안유지하는것이추천된다. 68-70 예방적항바이러스제제의정확한투여기간에대해서는다소이견이있으나라미부딘을 3개월미만으로투여한경우항암치료전혈중 HBV DNA 농도가 2,000 IU/mL를초과했던경우특히 HBV 재활성화의위험이높았다. 반면 HBV DNA 농도와관계없이 6개월이후에도재활성화에대한주의가필요하다. 라미부딘의예방적투여에의해서도내성바이러스가발생할수있는것으로보고되어, 바이러스억제력이강력하고약제내성이적은항바이러스제의장기간예방적투여에대한연구가필요한실정이다. 56 아시아에서수행된후향적다기관연구에서는 HBsAg 양성인림프종환자를대상으로 rituximab이포함된항암요법을시행하기전엔테카비어와라미부딘을예방적으로투여하였을때 HBV 재활성화의비율이엔테카비어군에서유의하게낮음을보고하였다 (6.3% vs. 39.3%; P<0.05). 71 인터페론은골수의억제및간염의악화가능성이있어금기에해당한다. HBsAg이음성이지만 anti-hbc IgG 양성인환자 (HBV 잠복 / 과거감염 ) 에서도 HBV 재활성화가가능하지만, 기저암종및항암요법제제의종류에따라재활성화의위험도가달라지기때문에이러한환자들에게통일된권고안을제시하기는어려운상황이다. 그러나 rituximab이포함된항암요법을받는림프종환자와같은고위험군에서혈중 HBV DNA가검출되는경우에는예방적항바이러스제제의투여가필요하며조혈모세포이식을시행한백혈병환자에서는기저 HBV DNA가검출되지않더라도매 1-2개월마다 HBV DNA를검사하여예방적항바이러스제제의투여를결정하는것이좋다. - 142 -
유수종 Management of hepatitis B virus in the liver transplantation and immunocompromised setting 항바이러스제제를얼마동안유지할것인지에대해서유럽간학회권고안에서는 12개월을유지하도록권고하고있으나근거논문이라미부딘을대상으로한것이어서엔테카비어나테노포비어를대상으로하는연구결과가필요하다. 51,56,70 또한미국간학회의권고안에서는사용기간이 12개월미만으로예상될경우라미부딘이나텔비부딘도사용할수있으며그이상의기간동안사용해야될경우엔테카비어나테노포비어를권고하고있다. 72 그러나이러한권고안들을지지하는근거자료가부족한실정이다. 미국간학회, 유럽간학회, 그리고아시아태평양간학회권고안의차이점을 Table 2 에정리하였다. 70,73 4. B 형간염재활성화의최근연구성과및전망 Pei 등은 29명의림프종환자를대상으로시행한후향적연구에서 HBsAg가음성이고기저 anti-hbs 역가가 100 miu/ml 미만인경우 rituximab 치료후에 anti-hbs 항체역가가더욱감소하고 HBV 재활 Table 2. Comparison of prophylactic strategies for reactivation of hepatitis B in recent major guidelines AASLD (2009) EASL (2012) APASL (2012) Screening tests HBsAg, anti-hbc HBsAg, anti-hbc HBsAg; anti-hbc in rituximab- or anti-tnf-α-treated patients Duration of therapy Antiviral agent Occult/past infection 6 months after completion of chemotherapy/immune-suppression, if baseline HBV DNA <2,000 IU/mL; continue treatment until treatment endpoints as immunocompetent patients if HBV DNA >2,000 IU/mL Lamivudine or telbivudine if duration of treatmetn 12 months and baseline HBV DNA is undetectable; tenofovir or entecavir if longer treatment duration Monitor HBV DNA; treat if HBV DNA becomes detectable 12 months after cessation of chemotherapy At least 24 weeks after the end of chemotherapy Lamivudine if low HBV DNA Lamivudine; entecavir or (<2,000 IU/mL) and a finite and tenofovir can be used short duration of immunosuppression is planned; entecavir or tenofovir if high HBV DNA and/or lengthy and repeated cycles of immunosuppression Test for HBV DNA; if HBV Monitor HBV DNA; treat DNA-positive, treat similarly to when needed HBsAg-posive patients; if HBV DNA-negative, follow every 1-3 months with ALT and HBV DNA and treat upon reactivation before ALT elevation; preemptive therapy can be given if monitoring is not guaranteed or in case of stem cell transplantation AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of the Liver; APASL, Asian Pacific Association for the Study of the Liver; TNF, tumor necrosis factor; HBV, hepatitis B virus; ALT, alanine aminotransferase. - 143 -
2013 년대한간학회추계학술대회 성화의위험도가증가함을보고하였다. 74 캐나다에서시행된항암치료전 HBV 선별검사에대한비용-효과분석에서는이전의분석결과와달리, rituximab이포함된항암치료를받는모든림프종환자에서치료전 HBV 감염여부에대한선별검사를시행하였을때 HBV 재활성화가 10분의 1로감소됨을보여비용-효과적이라고분석하였다. 75 B형간염재활성화의예방에대한연구는대부분라미부딘을대상으로하고있어라미부딘의높은내성률을고려할때최근에개발된강한바이러스억제효과와낮은내성률을보이는약제들에대한연구가필요하다. 몇몇후향적연구에서엔테카비어나텔비부딘이라미부딘에비하여우월한효과를보인다고보고하였다. 76,77 이와관련하여림프종또는고형암 ( 유방, 대장, 위, 폐암 ) 환자에서엔테카비어와라미부딘의효능을비교하는전향적다기관무작위배정임상이진행중이어서결과가주목된다 (NCT01580202). 결론 만성 B형간염환자는간이식후 B형간염이재발할수있고이식간에빠르게섬유화가진행하는등의부작용으로인하여간이식의성적이저하된다. 따라서 B형간염의재발을예방하기위하여라미부딘과 HBIG을단독혹은병합하여치료하게된다. 그러나라미부딘은내성바이러스의발생률이높아강한바이러스억제능력과낮은바이러스내성률을보이는항바이러스제제들로대체하는연구가진행중이다. 한편 HBIG의경우고비용, 감염의위험및투여방법의불편등으로인하여 HBIG 의용량을줄이거나사용기간을단축하고다른항바이러스제제로전환하는등의다양한요법이연구되고있다. 만성 B형간염환자가항암화학요법을받는경우항암치료중이나종료후에 HBV 재활성화의위험성이높아진다. 이러한환자들에게예방적항바이러스제제의투여가권고되나대부분내성발생률이높은라미부딘을대상으로이루어진연구에근거하고있으며최근에개발되어임상에적용중인강한바이러스억제능력과낮은바이러스내성률을보이는약제들에대한연구는부족한실정이다. 향우어떤약제를얼마의기간동안사용하는것이더나은결과를보일것인지에대한연구가필요하다. 참고문헌 1. Maddrey WC. Hepatitis B: an important public health issue. J Med Virol 2000;61:362-366. 2. Suh KS. [Prophylaxis against hepatitis B recurrence following liver transplantation]. Korean J Hepatol 2005; 11:21-24. 3. Papatheodoridis GV, Sevastianos V, Burroughs AK. Prevention of and treatment for hepatitis B virus infection after liver transplantation in the nucleoside analogues era. Am J Transplant 2003;3:250-258. 4. Todo S, Demetris AJ, Van Thiel D, Teperman L, Fung JJ, Starzl TE. Orthotopic liver transplantation for patients with hepatitis B virus-related liver disease. Hepatology 1991;13:619-626. 5. O'Grady JG, Smith HM, Davies SE, Daniels HM, Donaldson PT, Tan KC, et al. Hepatitis B virus reinfection - 144 -
유수종 Management of hepatitis B virus in the liver transplantation and immunocompromised setting after orthotopic liver transplantation. Serological and clinical implications. J Hepatol 1992;14:104-111. 6. Brind A, Jiang J, Samuel D, Gigou M, Feray C, Brechot C, et al. Evidence for selection of hepatitis B mutants after liver transplantation through peripheral blood mononuclear cell infection. J Hepatol 1997;26:228-235. 7. KASL Clinical Practice Guidelines: Management of chronic hepatitis B. Clin Mol Hepatol 2012;18:109-162. 8. Lok AS. Prevention of recurrent hepatitis B post-liver transplantation. Liver Transpl 2002;8:S67-73. 9. Papatheodoridis GV, Manolakopoulos S, Dusheiko G, Archimandritis AJ. Therapeutic strategies in the management of patients with chronic hepatitis B virus infection. Lancet Infect Dis 2008;8:167-178. 10. Liaw YF, Raptopoulou-Gigi M, Cheinquer H, Sarin SK, Tanwandee T, Leung N, et al. Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients with hepatic decompensation: a randomized, openlabel study. Hepatology 2011;54:91-100. 11. Shim JH, Lee HC, Kim KM, Lim YS, Chung YH, Lee YS, et al. Efficacy of entecavir in treatment-naive patients with hepatitis B virus-related decompensated cirrhosis. J Hepatol 2010;52:176-182. 12. Liaw YF, Sheen IS, Lee CM, Akarca US, Papatheodoridis GV, Suet-Hing Wong F, et al. Tenofovir disoproxil fumarate (TDF), emtricitabine/tdf, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology 2011;53:62-72. 13. Papatheodoridis GV, Cholongitas E, Archimandritis AJ, Burroughs AK. Current management of hepatitis B virus infection before and after liver transplantation. Liver Int 2009;29:1294-1305. 14. Fontana RJ, Hann HW, Perrillo RP, Vierling JM, Wright T, Rakela J, et al. Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy. Gastroenterology 2002;123: 719-727. 15. Shouval D, Samuel D. Hepatitis B immune globulin to prevent hepatitis B virus graft reinfection following liver transplantation: a concise review. Hepatology 2000;32:1189-1195. 16. Lo CM, Fan ST, Liu CL, Lai CL, Wong J. Prophylaxis and treatment of recurrent hepatitis B after liver transplantation. Transplantation 2003;75:S41-44. 17. Villamil FG. Prophylaxis with anti-hbs immune globulins and nucleoside analogues after liver transplantation for HBV infection. J Hepatol 2003;39:466-474. 18. Fung J, Cheung C, Chan SC, Yuen MF, Chok KS, Sharr W, et al. Entecavir monotherapy is effective in suppressing hepatitis B virus after liver transplantation. Gastroenterology 2011;141:1212-1219. 19. Han SH, Ofman J, Holt C, King K, Kunder G, Chen P, et al. An efficacy and cost-effectiveness analysis of combination hepatitis B immune globulin and lamivudine to prevent recurrent hepatitis B after orthotopic liver transplantation compared with hepatitis B immune globulin monotherapy. Liver Transpl 2000;6:741-748. 20. Markowitz JS, Martin P, Conrad AJ, Markmann JF, Seu P, Yersiz H, et al. Prophylaxis against hepatitis B recurrence following liver transplantation using combination lamivudine and hepatitis B immune globulin. Hepatology 1998;28:585-589. 21. Marzano A, Salizzoni M, Debernardi-Venon W, Smedile A, Franchello A, Ciancio A, et al. Prevention of hepatitis B virus recurrence after liver transplantation in cirrhotic patients treated with lamivudine and passive immunoprophylaxis. J Hepatol 2001;34:903-910. 22. Steinmuller T, Seehofer D, Rayes N, Muller AR, Settmacher U, Jonas S, et al. Increasing applicability of liver transplantation for patients with hepatitis B-related liver disease. Hepatology 2002;35:1528-1535. 23. Angus PW, McCaughan GW, Gane EJ, Crawford DH, Harley H. Combination low-dose hepatitis B immune globulin and lamivudine therapy provides effective prophylaxis against posttransplantation hepatitis B. Liver Transpl 2000;6:429-433. 24. Loomba R, Rowley AK, Wesley R, Smith KG, Liang TJ, Pucino F, et al. Hepatitis B immunoglobulin and Lamivudine improve hepatitis B-related outcomes after liver transplantation: meta-analysis. Clin Gastroenterol Hepatol 2008;6:696-700. 25. Rao W, Wu X, Xiu D. Lamivudine or lamivudine combined with hepatitis B immunoglobulin in prophylaxis of hepatitis B recurrence after liver transplantation: a meta-analysis. Transpl Int 2009;22:387-394. 26. Jimenez-Perez M, Saez-Gomez AB, Mongil Poce L, Lozano-Rey JM, de la Cruz-Lombardo J, Rodrigo-Lopez JM. Efficacy and safety of entecavir and/or tenofovir for prophylaxis and treatment of hepatitis B recurrence post-liver transplant. Transplant Proc 2010;42:3167-3168. 27. Buti M, Mas A, Prieto M, Casafont F, Gonzalez A, Miras M, et al. A randomized study comparing lamivudine monotherapy after a short course of hepatitis B immune globulin (HBIg) and lamivudine with long-term lamivudine plus HBIg in the prevention of hepatitis B virus recurrence after liver transplantation. J Hepatol - 145 -
2013 년대한간학회추계학술대회 2003;38:811-817. 28. Buti M, Mas A, Prieto M, Casafont F, Gonzalez A, Miras M, et al. Adherence to Lamivudine after an early withdrawal of hepatitis B immune globulin plays an important role in the long-term prevention of hepatitis B virus recurrence. Transplantation 2007;84:650-654. 29. Angus PW, Patterson SJ, Strasser SI, McCaughan GW, Gane E. A randomized study of adefovir dipivoxil in place of HBIG in combination with lamivudine as post-liver transplantation hepatitis B prophylaxis. Hepatology 2008;48:1460-1466. 30. Cholongitas E, Vasiliadis T, Antoniadis N, Goulis I, Papanikolaou V, Akriviadis E. Hepatitis B prophylaxis post liver transplantation with newer nucleos(t)ide analogues after hepatitis B immunoglobulin discontinuation. Transpl Infect Dis 2012;14:479-487. 31. Lo CM, Liu CL, Lau GK, Chan SC, Ng IO, Fan ST. Liver transplantation for chronic hepatitis B with lamivudine-resistant YMDD mutant using add-on adefovir dipivoxil plus lamivudine. Liver Transpl 2005;11: 807-813. 32. Stravitz RT, Shiffman ML, Kimmel M, Puri P, Luketic VA, Sterling RK, et al. Substitution of tenofovir/ emtricitabine for Hepatitis B immune globulin prevents recurrence of Hepatitis B after liver transplantation. Liver Int 2012;32:1138-1145. 33. Ben-Ari Z, Mor E, Shapira Z, Tur-Kaspa R. Long-term experience with lamivudine therapy for hepatitis B virus infection after liver transplantation. Liver Transpl 2001;7:113-117. 34. Ben-Ari Z, Pappo O, Zemel R, Mor E, Tur-Kaspa R. Association of lamivudine resistance in recurrent hepatitis B after liver transplantation with advanced hepatic fibrosis. Transplantation 1999;68:232-236. 35. Neff GW, O'Brien C B, Nery J, Shire N, Montalbano M, Ruiz P, et al. Outcomes in liver transplant recipients with hepatitis B virus: resistance and recurrence patterns from a large transplant center over the last decade. Liver Transpl 2004;10:1372-1378. 36. Karlas T, Hartmann J, Weimann A, Maier M, Bartels M, Jonas S, et al. Prevention of lamivudine-resistant hepatitis B recurrence after liver transplantation with entecavir plus tenofovir combination therapy and perioperative hepatitis B immunoglobulin only. Transpl Infect Dis 2011;13:299-302. 37. Schiff E, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, et al. Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results. Liver Transpl 2007;13:349-360. 38. Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy. Hepatology 2009;49:1503-1514. 39. Sanchez-Fueyo A, Rimola A, Grande L, Costa J, Mas A, Navasa M, et al. Hepatitis B immunoglobulin discontinuation followed by hepatitis B virus vaccination: A new strategy in the prophylaxis of hepatitis B virus recurrence after liver transplantation. Hepatology 2000;31:496-501. 40. Angelico M, Di Paolo D, Trinito MO, Petrolati A, Araco A, Zazza S, et al. Failure of a reinforced triple course of hepatitis B vaccination in patients transplanted for HBV-related cirrhosis. Hepatology 2002;35: 176-181. 41. Lo CM, Liu CL, Chan SC, Lau GK, Fan ST. Failure of hepatitis B vaccination in patients receiving lamivudine prophylaxis after liver transplantation for chronic hepatitis B. J Hepatol 2005;43:283-287. 42. Lo CM, Fung JT, Lau GK, Liu CL, Cheung ST, Lai CL, et al. Development of antibody to hepatitis B surface antigen after liver transplantation for chronic hepatitis B. Hepatology 2003;37:36-43. 43. Luo Y, Lo CM, Cheung CK, Lau GK, Fan ST, Wong J. Identification of hepatitis B virus-specific lymphocytes in human liver grafts from HBV-immune donors. Liver Transpl 2007;13:71-79. 44. Dienstag JL. Hepatitis B virus infection. N Engl J Med 2008;359:1486-1500. 45. Gupta S, Govindarajan S, Fong TL, Redeker AG. Spontaneous reactivation in chronic hepatitis B: patterns and natural history. J Clin Gastroenterol 1990;12:562-568. 46. Lok AS, McMahon BJ. Chronic hepatitis B: update of recommendations. Hepatology 2004;39:857-861. 47. Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. Hepatology 2006;43:209-220. 48. Yeo W, Zee B, Zhong S, Chan PK, Wong WL, Ho WM, et al. Comprehensive analysis of risk factors associating with Hepatitis B virus (HBV) reactivation in cancer patients undergoing cytotoxic chemotherapy. Br J Cancer 2004;90:1306-1311. - 146 -
유수종 Management of hepatitis B virus in the liver transplantation and immunocompromised setting 49. Lok AS, Liang RH, Chiu EK, Wong KL, Chan TK, Todd D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study. Gastroenterology 1991;100:182-188. 50. Yeo W, Chan PK, Zhong S, Ho WM, Steinberg JL, Tam JS, et al. Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors. J Med Virol 2000;62:299-307. 51. Loomba R, Rowley A, Wesley R, Liang TJ, Hoofnagle JH, Pucino F, et al. Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med 2008;148:519-528. 52. Kwak LW, Halpern J, Olshen RA, Horning SJ. Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: results of a tree-structured survival analysis. J Clin Oncol 1990;8:963-977. 53. Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med 1995;332: 901-906. 54. Yeo W, Chan PK, Hui P, Ho WM, Lam KC, Kwan WH, et al. Hepatitis B virus reactivation in breast cancer patients receiving cytotoxic chemotherapy: a prospective study. J Med Virol 2003;70:553-561. 55. Takai S, Tsurumi H, Ando K, Kasahara S, Sawada M, Yamada T, et al. Prevalence of hepatitis B and C virus infection in haematological malignancies and liver injury following chemotherapy. Eur J Haematol 2005;74:158-165. 56. Hsu C, Hsiung CA, Su IJ, Hwang WS, Wang MC, Lin SF, et al. A revisit of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in non-hodgkin's lymphoma: a randomized trial. Hepatology 2008;47:844-853. 57. Engels EA, Cho ER, Jee SH. Hepatitis B virus infection and risk of non-hodgkin lymphoma in South Korea: a cohort study. Lancet Oncol;11:827-834. 58. Dai MS, Wu PF, Shyu RY, Lu JJ, Chao TY. Hepatitis B virus reactivation in breast cancer patients undergoing cytotoxic chemotherapy and the role of preemptive lamivudine administration. Liver Int 2004;24:540-546. 59. Kim MK, Ahn JH, Kim SB, Im YS, Lee SI, Ahn SH, et al. Hepatitis B reactivation during adjuvant anthracycline-based chemotherapy in patients with breast cancer: a single institution's experience. Korean J Intern Med 2007;22:237-243. 60. Cheng AL, Hsiung CA, Su IJ, Chen PJ, Chang MC, Tsao CJ, et al. Steroid-free chemotherapy decreases risk of hepatitis B virus (HBV) reactivation in HBV-carriers with lymphoma. Hepatology 2003;37:1320-1328. 61. Yeo W, Chan TC, Leung NW, Lam WY, Mo FK, Chu MT, et al. Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J Clin Oncol 2009;27:605-611. 62. Lau GK, Leung YH, Fong DY, Au WY, Kwong YL, Lie A, et al. High hepatitis B virus (HBV) DNA viral load as the most important risk factor for HBV reactivation in patients positive for HBV surface antigen undergoing autologous hematopoietic cell transplantation. Blood 2002;99:2324-2330. 63. Lau GK, He ML, Fong DY, Bartholomeusz A, Au WY, Lie AK, et al. Preemptive use of lamivudine reduces hepatitis B exacerbation after allogeneic hematopoietic cell transplantation. Hepatology 2002;36:702-709. 64. Hui CK, Cheung WW, Zhang HY, Au WY, Yueng YH, Leung AY, et al. Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy. Gastroenterology 2006;131:59-68. 65. El-Sayed MH, Mohamed MM, Karim A, Maina AM, Oliveri F, Brunetto MR, et al. Severe liver disease is caused by HBV rather than HCV in children with hematological malignancies. Hematol J 2003;4:321-327. 66. Yeo W, Chan PK, Ho WM, Zee B, Lam KC, Lei KI, et al. Lamivudine for the prevention of hepatitis B virus reactivation in hepatitis B s-antigen seropositive cancer patients undergoing cytotoxic chemotherapy. J Clin Oncol 2004;22:927-934. 67. Rossi G, Pelizzari A, Motta M, Puoti M. Primary prophylaxis with lamivudine of hepatitis B virus reactivation in chronic HbsAg carriers with lymphoid malignancies treated with chemotherapy. Br J Haematol 2001;115: 58-62. 68. Lau GK, Yiu HH, Fong DY, Cheng HC, Au WY, Lai LS, et al. Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology 2003;125:1742-1749. 69. Saab S, Dong MH, Joseph TA, Tong MJ. Hepatitis B prophylaxis in patients undergoing chemotherapy for lymphoma: a decision analysis model. Hepatology 2007;46:1049-1056. 70. European Association For The Study Of The L. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012;57:167-185. - 147 -
2013 년대한간학회추계학술대회 71. Kim SJ, Hsu C, Song YQ, Tay K, Hong XN, Cao J, et al. Hepatitis B virus reactivation in B-cell lymphoma patients treated with rituximab: Analysis from the Asia Lymphoma Study Group. Eur J Cancer 2013;49: 3486-3496. 72. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009;50:661-662. 73. Liaw Y-F, Kao J-H, Piratvisuth T, Chan HLY, Chien R-N, Liu C-J, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatology International 2012;6:531-561. 74. Pei SN, Ma MC, Wang MC, Kuo CY, Rau KM, Su CY, et al. Analysis of hepatitis B surface antibody titers in B cell lymphoma patients after rituximab therapy. Ann Hematol 2012;91:1007-1012. 75. Zurawska U, Hicks LK, Woo G, Bell CM, Krahn M, Chan KK, et al. Hepatitis B virus screening before chemotherapy for lymphoma: a cost-effectiveness analysis. J Clin Oncol 2012;30:3167-3173. 76. Li HR, Huang JJ, Guo HQ, Zhang X, Xie Y, Zhu HL, et al. Comparison of entecavir and lamivudine in preventing hepatitis B reactivation in lymphoma patients during chemotherapy. J Viral Hepat 2010. 77. Yoo J-J, Kim HY, Lee J-H, Yu SJ, Kim YJ, Yoon J-H, et al. Comparison of Lamivudine, Telbivudine, and Entecavir as Antiviral Prophylaxis for Patients with Hepatitis B Undergoing Cytotoxic Chemotherapy. In: HEPATOLOGY. Vol 56: WILEY-BLACKWELL 111 RIVER ST, HOBOKEN 07030-5774, NJ USA, 2012: 631A-631A. - 148 -