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1 Journal of Rheumatic Diseases Vol. 22, No. 5, October, Review Article 류마티스질환환자에서생물학적제제사용시 B 형간염바이러스의재활성화 : 스크리닝및치료 이정일 연세대학교의과대학강남세브란스병원내과학교실소화기내과 Reactivation of Hepatitis B Virus in Patients with Rheumatologic Disease Treated with Biologic Disease Modifying Anti-rheumatic Drugs: Screening and Treatment Jung Il Lee Division of Gastroenterology, Deparmtment of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea Reactivation of hepatitis B virus (HBV) is not infrequently reported in patients with rheumatologic diseases treated with biologic disease modify anti-rheumatic drugs (DMARDs) such as a tumor necrosis factor-α inhibitor or a B cell depleting molecule. HBV reactivation is reported not only in patients with chronic hepatitis B but also in cases with resolved HBV where HBsAg is negative and anti-hbc positive. Studies suggest that with treatment using biologic DMARDs, the risk of HBV reactivation increases when HBsAg is positive independent of HBV DNA replication status, and in those with anti-hbc positive and serum HBV DNA positive. Therefore, testing for HBsAg as well as anti-hbc is important before initiating treatment with a biologic DMARD. In addition, evaluation of serum HBV DNA may be required when either HBsAg or anti-hbc turns out to be positive. Although series of reports suggest that prophylactic antiviral therapy in patients with higher risk of HBV reactivation would diminish morbidity and mortality from hepatic cause, solid guidelines pertaining to when to initiate and terminate HBV antiviral therapy and which agent should be used should be provided in the future. (J Rheum Dis 2015;22: ) Key Words. Hepatitis B virus, Anti-rheumatic drugs, Reactivation, Prophylactic antiviral therapy 서론 류마티스관절염은전신적인활막관절의염증반응을특징으로하는일종의자가면역질환으로, 다양한염증성사이토카인들이중요한역할을하는것으로알려져있다 [1]. 최근이러한사이토카인을표적으로하는생물학적제제가도입되어기존의항류마티스약물 (disease modify anti-rheumatic drug, DMARD) 과병용되어쓰이면서류마티스관절염의새로운치료전략으로부각되고있다. 현재 까지류마티스관절염치료에쓰이는생물학적제제로는항 tumor necrosis factor (TNF)-α 제제 (etanercept, infliximab, adalimumab, golimumab, certolizumab), 항 interleukin (IL)-6 수용체제제 (tocilizumab), B 세포를표적으로하는제제 (rituximab), 그리고 T 세포를표적으로하는제제 (abatacept) 가있다 [2]. 이들생물학적 DMARD들은모두감염과연관된합병증발생의위험을가지고있는것으로생각되는데, 특히비활동기에있는감염질환, 예를들어비활동성만성 B형간염 (inactive chronic hepatitis Received:September 8, 2015, Accepted:October 14, 2015 Corresponding to:jung Il Lee, Division of Gastroenterology, Deparmtment of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Korea. mdflorence@yuhs.ac pissn: X, eissn: Copyright c 2015 by The Korean College of Rheumatology. All rights reserved. This is a Free Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited. 282

2 HBV and DMARD B) 혹은잠복 B형간염 (occult hepatitis B) 의재활성화에대한우려가있어주의를요한다. 본글에서는만성 B형간염이동반되어있거나혹은과거 B형간염바이러스 (hepatitis B virus, HBV) 에노출된후회복된사람들에서생물학적 DMARD 사용시 HBV에대한선별검사와치료에대해서논하고자한다. 본 만성 B형간염의역학및자연경과만성 B형간염은우리나라에서현재제2군법정전염병으로분류되어국가예방접종사업의대상이되는질환이다 [3]. 우리나라 HBV 감염률은 B형간염백신이상용화되기이전인 1980년대초에남자 8% 9%, 여자 5% 6% 로보고되었고 [4], 1983년국내에서처음으로백신이사용된이후 1991년신생아예방접종, 1995년국가예방접종사업, 2002년주산기감염예방사업이시작되면서점차감소하는경향을보이고는있으나 2012년도에발표된보건복지부조사에의하면 HBsAg 양성률은남자 3.4%, 여자 2.6% 로아직도전체인구의 3.0% 정도가감염되어있다 [5]. 아직국내의연구조사는없으나일반적으로류마티스질환환자에서의 HBV 감염률은일반인구에서와다르지않다고알려져있다. 만성 B형간염의자연경과는 HBV 감염후만성 B형간염면역관용기 (chronic hepatitis B, immune tolerant phase), 만성 B형간염활동기 (chronic hepatitis B, immune active phase), 만성 B형간염비활동기 (chronic hepatitis B, inactive phase), HBeAg 음성만성간염 (HBeAg negative chronic hepatitis B) 및 HBsAg 소실기 (HBsAg clearance phase) 등의 5개임상단계로나누어볼수있다 [6,7]. 대부분의면역관용기는수직감염과관련이있으며 HBeAg 양성, 높은 HBV DNA 수치를보이지만바이러스에대한면역반응이거의없고, alanine aminotransferase (ALT) 수치가정상이며간조직의염증이없거나경미한시기이다 [8-11]. HBV DNA 수치가높음에도불구하고조 론 직학적으로는간손상이미미한데, 이것은바이러스에대한면역관용때문으로생각된다 [12]. 따라서일반적으로는이시기에항바이러스치료는권장되지않는다. 면역관용기 HBV 보유자들은나이가들면서바이러스에대한면역반응이시작되어 HBeAg 양성, 혈청 HBV DNA 수치의저하, ALT의간헐적혹은지속적상승을나타내는임상단계인만성 B형간염활동기에들어간다 [13,14]. 이시기조직검사소견은중등도이상의염증소견을보이고다양한섬유화가존재한다 [15]. 이러한변화는 HBcAg 혹은 HBeAg에대한세포독성 T 림프구의활성이증가하여감염된간세포가파괴되어나타나는것으로 [16] 일부에서는지속적으로 HBV DNA 증식이억제되면서 HBeAg의 혈청전환이이루어지고만성 B형간염비활동기에들어가기도한다. HBeAg 혈청전환과 HBV DNA 억제가이루어지지않는경우에서는항바이러스치료를시작하여추가적인간손상이없도록해야한다. 만성 B형간염비활동기의대부분환자들은 HBeAg 음성, anti-hbe의전환, 지속적인정상 ALT 수치를보이고 HBV DNA 수치가측정치이하로검출되거나매우낮은단계로지속된다 [17-19]. 비활동기는대부분환자에서장기간지속되어양호한예후를보이지만약 20% 의환자에서는 HBeAg 음성간염혹은 HBeAg 양성활동기로재활성화및비활성화를반복하면서간경변증으로진행하게된다 [20,21]. HBeAg 음성만성 B형간염은자연관해율이낮고지속적으로간세포에염증을일으켜대부분환자에게서섬유화및간경변증으로진행하게되는데 [22-24], 이시기에항바이러스제제를이용한치료로병의진행을막을수있다. HBsAg이소실된환자에서는대부분혈청 HBV DNA가검출되지않으며, anti-hbc가 anti-hbs 검출과관계없이혈청에서검출된다. Hepatitis B virus 재활성화만성 B형간염의경과는바이러스와숙주면역능사이의상호작용에의해결정되므로면역억제치료혹은항암화학요법등에의해면역능이저해될경우재활성화 (reactivation) 의위험이증가한다 [25]. B형간염의재활성화는크게두가지로나눌수있는데, 만성 B형간염의악화 (exacerbation of chronic HBV infection) 와과거감염후회복된상태 (resolved hepatitis) 에서의재발 (relapse) 이있다 [26,27]. 만성 B형간염의악화는 HBsAg 양성이면서 HBV DNA가기저치에비해 100배이상증가하는경우이거나 HBV DNA가음성이었다가 100 IU/mL 이상증가하는경우로정의하고, 과거 B형간염의재활성화는 HBsAg 음성에서양성으로나타나거나 HBsAg 음성이면서 HBV DNA가음성에서양성으로나타나는경우로정의한다 [28]. 전형적인재활성화는면역억제치료나항암화학요법중 HBV DNA 검출에이어면역억제중단후 ALT 상승이나타난다. B형간염의재활성화를예측할수있는임상적인자로는바이러스인자로서치료전 HBV DNA 농도, HBeAg 양성여부, 간세포내 cccdna, precore/core promotor 변이, 숙수인자로서악성종양의종류, 남성, 젊은연령, 높은수치의 ALT, 그리고치료적인자로서면역억제제혹은항암화학요법제의종류및강도, 조혈모세포이식및장기이식등이있다 [1]. 항암치료와연관된 HBV 재활성화에대한보고가가장많지만이외에도스테로이드제제는면역억제뿐아니라직접적으로 HBV의증식을촉진하여재활성화위험을높이는것으로알려져있으며, 류마티스질환치료제중생물학적제제에의한재활성화도보고되어있다 [29-31]

3 Jung Il Lee 1) 항 tumor necrosis factor-α 항체항 TNF-α 항체 (infliximab, etanercept, adalimumab 등 ) 의경우 HBV 재활성화는 HBsAg 양성환자에서뿐만아니라 HBsAg 음성, anti-hbc 양성인잠복 B형간염 (occult hepatitis B) 에서도보고되어있다. HBsAg 양성인경우재활성화빈도는보고자에따라차이가있는데, 12.3% 에서 39% 까지보고되어있으며, anti-hbc만양성인경우는 1.7% 에서 5% 까지의발생률이보고되었다 [31-33]. 이때예방적항바이러스치료를한경우재활성화율을유의하게낮출수있었다 [32]. 한편면역억제조건하에서는 anti-hbc만양성인환자들이 anti-hbc와 anti-hbs 모두양성인환자들보다 B형간염재활성화위험도가높으며이런환자들에서항바이러스제의예방적치료는간염의재활성화를막는데효과적일수있다 [34]. 2) Rituximab CD20에작용하여 B 세포고갈을유발하는 rituximab 사용후 HBV 재활성화에대한보고는혈액암에서많은데, 특히림프종의치료에서 rituximab은재활성화의위험을한층높이는것으로알려져있다 [35,36]. Rituximab 치료를받은림프종환자들에대한후향적관찰연구에서 B형간염재활성화는 HBsAg 양성환자에서 27.8% (45/162) 였으며예방적항바이러스제치료를받은군에서더낮았고 (22.9%, 32/140 vs. 59.1%, 13/22; p<0.001), 예방적항바이러스치료에도불구하고 20% 이상재활성화되었다고보고하고있다. 항바이러스제는라미부딘이가장많이사용되었고, 엔테카비어사용군에서라미부딘사용군보다의미있게 B형간염재활성화율이낮았다 (6.3% vs. 39.3%, p<0.05). 또다른후향적연구에서 HBsAg 음성 /anti-hbc 양성인환자에서는 HBV 재활성화는 2.4% 로낮았으나역시보고가있었다 [37]. 한편 HBsAg 음성 /anti-hbc 양성이면서 rituximab-cyclophosphamide, doxorubicin, vincristine, and prednison 항암치료를받은림프종환자들에대한전향적관찰연구에서 B형간염재활성화와그에따른간염악화가흔히발생한다 (10.4 및 6.4 per 100 person-year). HBsAg 및 HBV DNA의모니터링과 B형간염재활성화시즉각적인항바이러스제치료로대부분대처가능하였으나, 간염이악화된경우가있었으며, 특히표면항원 (HBsAg) 이재출현하는경우가 B형간염관련간손상의가장중요한지표였다 (100% vs. 28%)[38]. Rituximab 치료는 HBsAg 음성 /anti-hbc immunoglobulin (Ig)G 양성이거나 HBsAg 양성인비호지킨스림프종환자에서 B형간염의재활성화의위험성을높이며 (relative risk [RR] 2.14, 95% confidence interval , p=0.0003) 특히 isolated anti-hbc 양성환자에서 rituximab을사용하는경우, 사용하지않는경우에비해재활성화의상대적위험도가높았다 (RR 5.52)[39]. Rituximab 치료시에예방적항바이러스제치료를하였던군과하지않았던군에서 B형간염의재활성화는의미있는차이가있었다 (13.3% vs. 60%)[40]. 류마티스질환에서의 rituximab 치료와 HBV 재활성화에대한보고는혈액암의경우에비해상대적으로많지않지만 HBsAg 양성환자에서는물론 HBsAg 음성, anti-hbc 양성인잠복감염에서도보고가있었다 [41-44]. 최근에시행된한전향적연구에서는 HBsAg 양성인만성 B형간염환자는 rituximab 치료와 HBV 항바이러스제제를같이사용하였고 (n=2) anti-hbc 양성인경우에서는 HBV DNA 검사확인후추적관찰하였을때 (n=12) HBV 재활성화가발생하지않았다고보고하였다 [45]. 3) Abatacept CD80/86에작용하여 T 세포를억제하는것으로알려진 abatacept의사용과관련해서도만성 B형간염의재활성화및잠복감염의재발에대한보고가있었다 [2,46,47]. 특히 8명의 HBsAg 양성환자를보고한연구에따르면 abatacept 치료시작당시혈청 HBV DNA가검출되지않았더라도 abatacept와함께 HBV에대한항바이러스제제를투여하지않은경우에는 HBV 재활성화를경험했다고보고를했으며, 항바이러스제제를같이쓴경우에는재활성화가없었다 [47]. 4) Tocilizumab 만성 B형간염이동반된류마티스질환환자에서의 IL-6 수용체항체인 tocilizumab 사용경험은매우제한적이다. 항바이러스제제제인 entecavir로 HBV가완전하게조절된환자에서 tocilizumab의사용은 HBV 재활성화가동반되지않았다는증례보고가있었으며 [48], HBsAg는음성이지만 HBV에노출되었던경력이있었던환자 57명환자중 3명에서 HBV DNA가검출되었으나항바이러스제제사용없이바이러스가조절되었다는보고가있었다 [33]. 다른한보고에서는 18명의 HBsAg 음성이지만 anti-hbc 양성인잠복감염류마티스질환환자에서항바이러스제제사용없이 tocilizumab을사용하였을때 2명의환자에서 HBV 재발이발생하였다고하여적지않은 HBV 재활성화율을보고하기도하였다 [33]. 류마티스질환환자에서의 hepatitis B virus 진료가이드라인 HBV는일단재활성화가발생할경우간부전및사망의위험까지도있으므로예방이무엇보다중요하고, 이를위해면역억제혹은항암화학요법전 HBsAg 및 anti-hbc IgG의선별조사가필요하다. 과거 HBV 감염의증거가없는경우 (HBsAg 음성, anti-hbc IgG 음성 ) 는 HBV 백신접종을고려할수있다. HBsAg 양성인경우 HBV DNA 수치에관계없이예방적항바이러스제를투여하는것이추천된다 [49]. 라미부딘은 284 J Rheum Dis Vol. 22, No. 5, October, 2015

4 HBV and DMARD 홍콩과대만등지에서림프종환자를대상으로시행된무작위대조연구를포함하여가장널리연구된약제로서재활성화, 간부전, 사망등을유의하게줄일수있음이잘알려져있다 [50-53]. 류마티스질환을생물학적제제로치료한환자에서예방적항바러스제투여효과에대한연구는부족하다. HBsAg 양성인 18명의환자에서항 TNF-α 항체투여전에예방적으로라미부딘을투여한 10명의환자에서는 HBV 재활성화가일어나지않았으나예방적치료를받지않은 8명의환자중 5명 (62.5%) 에서 HBV 재활성화가있었다는보고가있다 [54]. HBsAg 양성인경우예방적항바이러스제는 HBV DNA가상승하기를기다려투여하는것이아니라면역억제혹은항암치료의시작과함께투여를시작하는것이특정상황에서는더효과적임이보고가되었고 [52,55], 치료종료후에도일정기간지속할것이권고된다. 예방적항바이러스제는이론적으로는면역체계가충분히회복될시점까지투여를지속하는것이바람직하겠으나, 현재까지종료시점을명확히제시할근거는불충분하다. 특히류마티스질환의치료의경우치료종료시점이확실하지않다는어려움이있는데, 항암치료에서의경우종료후약 3개월뒤예방적라미부딘투여를중단한경우바이러스재증식의위험이높고특히치료전 HBV DNA가높은경우 ( 2,000 IU/mL) 그위험이증대됨이보고된바있었다 [56]. 그러므로바이러스상태가활동성일때는예방적항바이러스제투여기간을만성 B 형간염의치료종료지침에따르는것이약제중단이후바이러스재증식을막는방법일수있다. 현재대한간학회에서권장하고있는치료종료시점은 HBeAg 양성만성 B형간염의경우 HBeAg 혈청전환이이루어진후적어도 12개월이상치료를지속하는것을권장하고있으며, HBeAg 음성만성 B형간염의경우 HBsAg 소실을치료종료시점으로보고있다. 예방적항바이러스치료시치료약제의경우라미부딘을이용한치료에대한보고가가장많지만현재까지의치료결과를고려할때이후에승인된약제들인아데포비어, 테노포비어, 엔터카비어, 텔비부딘, 클레부딘등도예방적으로도사용이가능하리라생각된다. 특히엔테카비어는라미부딘에비해더좋은 B형간염재활성화억제효과가있는것으로보고되고있다. 즉라미부딘은예방적치료시에도내성이보고되고있어투여기간이길것으로예상되는경우내성률을감안하여치료약제를선택할필요가있다 [53]. 최근림프종환자를대상으로한후향적연구에서엔터카비어치료군이라미부딘치료군에비해 HBV 재활성화로인한간염과항암치료중단 (chemotherapy disruption) 등의빈도가유의하게낮았으나 [57], 현재까지어떤약제가재활성화예방에더우월한지혹은비용효과면에서어떠한약제를우선적으로권고할지등에관한근거는부족하다. 아울러대부분의예방적치료에관한연구는림프종환자를대상으로시행되었으므로류마티스질환 치료제사용중적절한예방적항바이러스치료약제에및치료기간등에관한전향적연구가필요하다. 다만비용적문제를배제하면효능 (potency), 일차치료실패율, 내성률등을감안할때엔테카비어나테노포비어등이상대적으로안전한선택일것으로예측된다. 인터페론알파를 B형간염재활성화의예방치료로는추천하지않는것은골수억제및간염악화등의우려가있기때문이다. 한편 HBsAg 음성이면서 anti-hbc IgG 양성인경우는 anti-hbs 여부에관계없이재활성화의우려가있으나면역억제제 / 항암제의종류에따라그위험도가명확히밝혀지지않아일률적으로권고안을제시하기에는근거가부족하다. 단 HBsAg 음성이면서 HBc IgG 양성인경우중혈청 HBV DNA가양성이라면예방적치료를하고, HBV DNA가음성이라면 HBV DNA를주기적으로 ( 예컨대 1 2개월간격 ) 추적하면서예방적항바이러스치료시작여부를결정할수있을것이다. 결 론 생물학적 DMARD 사용시 HBV의재활성화를막기위해서다음이권고된다. 먼저 HBV 감염여부가확인되지않은경우생물학적 DMARD 시작전 HBsAg 및 anti-hbc IgG를검사하고둘중하나이상양성인경우 HBV DNA 검사를한다. 만약 HBsAg 음성이고 anti-hbc IgG 음성으로 HBV 감염의증거가없는경우 HBV 백신접종을고려한다. 검사결과 HBsAg 양성이거나혹은 HBV DNA 양성인경우생물학적 DMARD 시작전에 HBV에대한항바이러스제치료를시행한다. 이때항바이러스제는혈청 HBV DNA 수준, 면역억제요법의강도및기간, 경제적측면등을종합적으로고려하여선택하되, 초기혈청 HBV DNA가높거나장기간의치료가예상될경우내성장벽이높은약제의사용을우선적으로고려한다. HBsAg 음성및 HBV DNA 음성이고 anti-hbc IgG가양성인경우잠복감염의위험이있으므로생물학적 DMARD 치료중에 HBV DNA를정기적으로모니터링하며, HBV 재활성화가발생할경우항바이러스치료를시행한다. CONFLICT OF INTEREST No potential conflict of interest relevant to this article was reported. REFERENCES 1. Jang JW. Hepatitis B virus reactivation in patients with hepatocellular carcinoma undergoing anti-cancer therapy. World J Gastroenterol 2014;20: Nard FD, Todoerti M, Grosso V, Monti S, Breda S, Rossi S, 285

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KOL Slidekit (Sep 2005)

KOL Slidekit (Sep 2005) 만성 B 형간염의치료 - 증례토의 2013.5.20 성균관의대내과학교실삼성서울병원소화기내과곽금연 치료대상 2004 2007 2011 HBeAg 양성 / 음성 HBV DNA 10 5 copies/ml ALT 2 ULN HBeAg 양성 HBV DNA 20,000 IU/mL AST/ALT 2 ULN 간생검이상 HBeAg 양성 HBV DNA 20,000 IU/mL