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1 2013 대한간학회 C 형간염진료가이드라인 The Korean Association for the Study of the Liver 2013 대한간학회 C 형간염진료가이드라인 대한간학회 대한간학회

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3 2013 대한간학회 C 형간염진료가이드라인

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5 목차 1 서론 5 역학 10 예방 13 자연경과 16 진단및중증도평가 24 치료목적 25 치료대상 28 치료반응의정의 31 치료반응예측인자 33 만성 C형간염의치료 34 유전자형 1, 4형만성 C형간염의치료 40 유전자형 2, 3형만성 C형간염의치료 44 유전자형 6형만성 C형간염의치료 45 급성 C형간염의치료 47 치료부작용모니터링과대처 53 특수상황에서의치료 66 참고문헌 104 별첨 별첨 별첨 3

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7 서론 개정취지 2004년대한간학회 C형간염치료가이드라인이처음제정되었다. 이후역학과예후, 치료반응의정의와치료반응에따른치료전략및치료결과등에대한많은연구결과가발표되었다. 더욱이최근새로운항바이러스치료제, direct acting antivirals (DAA) 가개발되어임상적용되면서 C형간염의치료는빠르게발전하고있다. 이에대한간학회는지난가이드라인제정이후최근까지축적된국내외연구결과와전문가의견을종합하여근거중심에기반하여가이드라인을개정하였다. 대상집단및독자층이가이드라인의대상집단은 C형간염으로새로진단되거나기존에진단되어치료받고있는환자들이다. 만성 C형간염및간경변증환자뿐아니라급성 C형간염환자군을포함하였고특수상황으로분류할수있는정맥주사약물남용자, 만성콩팥병환자, HIV나 B형간염바이러스와 C형간염이중복감염된환자군및소아 C형간염환자군도대상으로포함하였다. 이가이드라인의독자층은 C형간염환자의진단과치료를담당하고있는진료의및의료관련자이며, 수련과정중의전공의및전임의, 이들을지도하는교육자에게도유용한임상정보와방향을제공하고자하였다. 개정위원, 개정경과및기금에관한정보대한간학회이사회의발의와승인에따라구성된 C형간염진료가이드라인개정위원회는동학회소속의간장학을전공하는소화기내과전문의 9인으로구성되어개정작업을진행하였다. 각위원은각자담당한분야의근거자료수집, 분석과함께원고작성을담당하였고개정경과는별첨 2에, 각위원의이해관계상충정보는별첨 3에기술하였다. 이가이드라인개정과정에소요된모든경비는대한간학회가지원하였다

8 대한간학회 근거수집을위한문헌고찰개정위원회는최신연구및근거에입각한가이드라인제정을위하여최근까지발표된국내외 C형간염관련문헌을 Pubmed, MEDLINE, KoreaMed 등을통해수집하고체계적으로분석하였다. 검색어는 hepatitis C virus, hepatitis C, liver cirrhosis, liver cancer 및해당세부주제의특정한검색어를포함하였다. 근거수준과권고등급의분류 근거의수준 (level of evidence) 은수정된 GRADE 체계 (Grading of Recommenda- tions, Assessment, Development and Evaluation) 에의해분류하였다 (Table 1). 1 연구 의설계에따라무작위대조군연구는높은근거수준에서, 관찰연구는낮은근거수준 에서분류를시작한후연구의질에영향을주는요소를고려하여해당연구의근거수 준을올리거나내려조정하는방법을이용하였다. 후속연구를통해해당결과또는결 Table 1. Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Quality of Evidence High (A) Moderate (B) Low (C) Strength of Recommendation Strong (1) Weak (2) Criteria Further research is very unlikely to change our confidence in the estimate of effect. Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Any change of estimate is uncertain. Criteria Factors influencing the strength of the recommendation included the quality of the evidence, presumed patient-important outcomes, and cost. Variability in preference and values, or more uncertainty. Recommendation is made with less certainty, higher cost or resource consumption. NOTE: Of the quality levels of evidence, we excluded very low quality (D) in our guideline for convenience, which was originally included in the GRADE system

9 론이바뀔가능성에따라분류하였으며, 바뀔가능성이가장낮은, 즉가장높은근거수준은 (A), 바뀔가능성이있는중간수준은 (B), 바뀔가능성이높은, 즉가장낮은근거수준은 (C) 로각각정의하였다. 권고등급 (Strength of recommendation) 역시 GRADE 체계에따라제시하였다. 각연구의근거수준자체뿐아니라연구결과의임상적파급효과및비용이나편이성과같은사회경제적측면등을종합적으로고려하여강한권고등급 (1) 과약한권고등급 (2) 으로분류하였다. 강한권고란특정사안에대해권고를따를경우바람직한효과가나타날가능성이그렇지않을가능성보다높고근거의질이높으며다른중재와비교하여효과, 비용적측면, 선호도및순응도등이우수하기때문에대부분의환자에서시행할것을권하는등급이다. 약한권고란그근거의질이다소약하지만바람직한효과가있어다수의환자에서시행되어도좋을것으로판단되는등급이다. C 형간염진료가이드라인 세부주제목록개정위원회는 C형간염진료가이드라인제정과관련하여다음과같은세부주제를선별하여각항목에대한근거와권고안을제시하고자하였다. 1. 국내 C형간염의역학과자연경과는어떠하며예방수칙은무엇인가? 2. 급성및만성 C형간염의진단과간질환중증도평가는어떻게하는가? 3. 만성 C형간염치료의목표는무엇이며치료대상은누구인가? 4. 치료반응의정의와예측인자는무엇인가? 5. 유전자형 1, 4형만성 C형간염환자를어떻게치료할것인가? 6. 유전자형 2, 3, 6형의만성 C형간염환자를어떻게치료할것인가? 7. 급성 C형간염환자를어떻게치료할것인가? 8. 항바이러스치료부작용모니터링과대처는어떻게하는가? 9. 특수상황에서의치료 ( 간경변증, 간이식및간외장기이식환자, 면역억제제또는항암화학요법치료환자, 정맥주사약물남용자, 만성콩팥병환자, HIV 또는 HBV 중복감염자, 혈우병및소아환자군 ) 는어떻게하는가? 가이드라인의내외부검토및승인 각위원이작성한원고는개정위원회의회의를통해검토, 합의및승인되었다. 원 고는원고내용의충실성과함께 AGREE II (Appraisal of Guidelines for Research and - 3 -

10 대한간학회 Evaluation II) 의기준에따라가이드라인의질을평가하였다. 원고작성시감염내과전문의 1인, 신장내과전문의 1인및소아청소년과전문의 1인의자문을받았다. 대한간학회소속의간장학분야전문가총 14명으로구성된자문위원회및전문가와일반인이참가하는공청회를통해제시된의견을따라수정보완하였다. 이러한과정을통해완성된가이드라인은대한간학회이사회의최종승인을받았다. 가이드라인공표및향후개정계획 2013 대한간학회 C형간염진료가이드라인은 2013년 11월 21일대한간학회추계학술대회에서발표되었다. 이가이드라인의한글판은대한간학회웹사이트 ( 를이용하여제공되며, 영문판은대한간학회공식학술지 Clinical and Molecular Hepatology 에게재된다. 향후 C형간염과관련된새로운검사방법이나치료법등에관한연구결과가축적되어우리나라국민의건강증진에필요하다고판단되면대한간학회는이가이드라인을개정할계획이다. 또한, 2013년현재 DAA가우리나라에서시판허가가나지않은상태이므로향후 DAA 사용이용이해지면이가이드라인의부분적개정이진행될예정이다

11 역학 C 형간염진료가이드라인 C형간염바이러스 (Hepatitis C virus, HCV) 는우리나라에서급, 만성간염, 간경변증및간세포암종의주요원인중하나이다 년현재 C형간염은우리나라법정감염병분류에서지정감염병에속하며표본감시대상이다. 아직효과적인백신이개발되어있지않으므로우리나라의역학을이해하고전염경로를차단하기위한예방대책이국민보건에중요하다. HCV 유병률 2005년세계적인 HCV 항체유병률은 2.8% 로, 약 1억8천5백만명이 HCV 항체양성으로추산된다. 3,4 HCV 유병률은지역에따라다양한데유병률이 3.5% 이상으로높은지역은몽골을포함하는중앙아시아와중국, 파키스탄, 태국등지의동남아시아, 이집트를위시한북아프리카등이다. HCV 유병률이 1.5% 미만인지역은우리나라와일본을포함하는아시아, 미국을포함하는북미국가, 그리고남미지역이다 성인검진자의유병률 HCV가발견된직후인 1990년초반에국내성인검진자들을대상으로주로 1세대효소면역검사법 (enzyme immunoassay, EIA) 으로측정한 HCV 유병률은 1.7% 로보고되었다 년부터 2000년까지건강검진자들을대상으로서울, 울산, 전남, 대구에서보고된 HCV 유병률결과들을모아당시우리나라인구의연령을보정하여산출하면국내 40세이상성인의 HCV 유병률은 1.29% (95% confidence interval ) 로약 193,000 명의 HCV 항체양성자가있을것으로추산되었다 년국내 29개검진센터에서 20세이상성인검진자 291,314명을대상으로 3 세대 EIA법을이용한연구에서연령, 성별, 지역을보정한국내 HCV 항체양성률은 0.78% 였다. 11 HCV 항체양성률은남자 (0.75%) 보다여자 (0.83%) 에서더높았으며연령에따라증가하는경향을보여 60세이상에서가장높은유병률을보였다 (20-29세 0.34%, 30-39세 0.41%, 40-49세 0.60%, 50-59세 0.80%, 60-69세 1.53%, 70세이상 - 5 -

12 대한간학회 Figure 1. Map of South Korea showing age and sex-adjusted anti-hcv seroprevalence in each area %). 또한, 지역에따라 HCV 항체양성률이차이를보여서울과경기도를포함한 대부분의지역에서는 % 였으나, 부산과전남지역의경우에는각각 1.53%, 2.07% 로높았으며제주도의경우에는 0.23% 로낮게나타났다 ( 그림 1). 한편, 2012 년 도부터국민건강영양조사검진항목에 HCV 항체검사가포함되어우리나라인구에서 HCV 유병률결과가곧발표될것으로기대된다

13 2. 헌혈자, 임신부및소아의유병률 1997년국내 2,040,151명의헌혈자들에서 3세대 EIA법을이용한 HCV 항체양성률은 0.34% 였다 년간국내헌혈자 11,064,532명에서 3세대 EIA법을이용한 HCV 항체양성률은 0.16%, HCV RNA 양성률은 10만명의헌혈자중 8.4명 (0.0084%) 이었는데, 헌혈자 81% 가 10대와 20대의젊은연령이었다. 13 우리나라에서는 2005년 2월부터헌혈혈액선별검사에 HCV에대한핵산검사법 (nucleic acid test) 을시행하면서수혈을통한 HCV 감염위험도가 2000/2001년의경우 1/81,431 건에서 2009/2010년의경우 1/2,984,415건으로감소하였다. 14 산모에서 HCV 감염률은 % 이며, 천명이상의산모를대상으로한국내보고에서는 HCV 항체양성률이 % 였고, 18,19 HCV 항체양성인산모의 57-60% 에서 HCV RNA 양성이었다. 18,19 국내소아와청소년들에서 HCV 유병률에관한연구는매우부족하며, 1996년서울에거주하는 2,080명의 6-11세어린이들을대상으로 3세대 EIA법을이용한 HCV 항체양성률이 0.82% 로보고되었다. 20 그러나이후소아와청소년을대상으로진행된연구가없어서최근국내소아나청소년들에서 HCV 유병률을파악하기는어렵다. C 형간염진료가이드라인 3. 고위험군의유병률정맥주사약물남용자, 혈액투석환자, HIV감염자, 혈우병환자, 한센병환자들은 HCV 감염의고위험군으로알려져있지만, 이들고위험군에서 HCV유병률은대부분 2000년이전에보고되었고최근연구결과는많지않다. 국내정맥주사약물남용자에서 HCV 항체양성률은 % 로보고되었다 년 185명의정맥주사약물남용자들에서 HCV 항체유병률은 79.2% 로보고되었고 21 최근발표된연구에서는 2007년부터 2010년사이국내 318명의정맥주사약물남용자들에서 HCV 항체유병률은 48.4% 이었으며, HCV 항체양성자들중 98.1% 에서 HCV RNA가양성이었다. 24 한편, 정맥주사약물남용이아닌코카인흡입관을공유하는경우에도 HCV 유병률이정맥주사약물남용자와비슷한것으로보고되었다 년과 1998년혈액투석을받는 200명이상의만성콩팥병환자들을대상으로한국내연구들에서 HCV 항체유병률은 % 였고 26,27 HCV 항체양성은혈액투석기간과유의한상관관계를보였다. HIV 감염자들에서는 HCV 중복감염률이높으며, 서구 HIV 감염자의약 25% 가, 국내 HIV 감염자의 % 가 HCV에중복감염되어있다

14 대한간학회 2002년 104명의혈우병환자들에서 3세대 EIA법으로검사한 HCV 항체유병률은 42.3% 였고, HCV 감염위험은환자의나이및혈우병의중증도와연관이있었다. 31 한국혈우재단이발표한 2012년연차보고서에따르면혈우병환자들에서 HCV 항체유병률은 430/2,148(20.0%), HCV RNA 양성률은 118/2,148(5.5%) 였다. 32 한센병환자들은피부병변을가지고있고장기간제한된구역에서공동생활을하기때문에 HCV 감염의고위험군으로생각할수있다. 1997년 96명의한센병환자들에서 2세대 EIA법으로검사한 HCV 항체유병률은 67.7% 였고 HCV 항체양성인환자들의 82% 가면역탁본법 (immunoblot) 에서양성이었다. 33 HCV 발생률급성 HCV 감염의경우불과 20-30% 에서증상을동반한간염으로발현하므로 HCV 감염발생률을평가하기가어려워이에관한연구는많지않다. 서구선진국들의경우지난십년동안급성 HCV 발생률은점차감소추세를보이고있는데 34 미국의경우 1982년-1989년사이십만명당 7.4명에서 1994년-2006년사이에는십만명당 0.7명으로감소하였으며, 35 이탈리아의경우 1996년십만명당 2.02명에서 2006년십만명당 0.55명으로감소하였다. 36 한편, 국내에서 1994년부터 1996년까지 2회이상의헌혈자들을대상으로 HCV 항체양성자발생률을조사한결과연간헌혈자십만명당 13.8명으로추산되었다 년까지 2년동안 2회이상헌혈한사람들을대상으로산출한 HCV 감염발생률은연간십만명당 2001년 6.80명, 2003년 3.19 명, 2005년 2.69명, 2007년 1.83명, 2009년 0.80명으로추산되었다. 14 질병관리본부의국내 C형간염표본감시분석자료에따르면 C형간염보고건수가 2002년 1,927건에서 2008년 6,407건으로증가하였고 2012년에는 4,280건으로감소세를보였다. 향후국내인구집단에서 HCV 감염의발생률을평가하기위한연구가필요하다. HCV 유전자형분포 HCV 유전자형은세계적으로볼때 1, 2, 3형이광범위하게흔하며 4, 5, 6형은일부지역에국한되어있다. 38,39 유전자형 1a형은북유럽과북미에가장흔하며 1b형은극동아시아, 유럽에흔하다. 유전자형 2형은일반적으로 1형보다적게발견된다. 3형은동남아시아에흔하며 4형은중동지역, 이집트, 중앙아프리카, 5형은남아프리카, 6형은홍콩, 마카오, 베트남에서주로발견된다. 우리나라에서흔한 HCV 유전자형은 1b형 - 8 -

15 (45-59%) 과 2a형 (26-51%) 이고기타 1a형, 2b형, 3형, 4형, 6형등이보고되었다. 40,41 만성 C형간염의자연경과또는간이식후경과에서 HCV 유전자형의역할, 즉유전자형 1형이다른유전자형보다간질환의진행속도가빠른가에대해서는논란이있다. 최근의한메타분석에서 HCV 유전자형 1b형에감염된환자군에서 1b형을제외한환자군에비해간세포암종발생위험이상대위험도 1.78배 (95% CI, ) 로높다고보고하였다. 42 HCV 유전자형은항바이러스치료성적을결정하는가장중요한인자로 1, 4형이 2, 3, 6형보다항바이러스치료성적이낮다. 43 C 형간염진료가이드라인 - 9 -

16 대한간학회 예방 HCV 전염경로 HCV 전염은비경구적으로이루어지며주요전염경로는 HCV에오염된혈액또는혈액제제의수혈이나장기이식, 정맥주사약물남용, 불안전한주사나의료시술, 오염된주사기나바늘에찔리는경우, HCV 감염자와의성접촉, HCV에감염된산모로부터신생아로의수직감염등이다. 1991년이전까지는수혈에의한감염이주요전염경로였으나, 헌혈자에대한선별검사가도입되면서수혈에의한 HCV 전염위험은극히낮아졌다 최근 HCV 유병률이낮은미국과유럽등주요선진국의경우정맥주사약물남용이 HCV 감염의가장중요한전염경로인데 47 서구의정맥주사약물남용자에서 HCV 유병률은 50%-90% 까지높게보고되었다. 48 한편중등도내지높은 HCV 유병률을보이는개발도상국들의경우오염된주사기의재사용이나여러차례사용하는약병이나주사용백등의불안전한주사행위나, 소독이적절히시행되지않은외과수술, 내시경검사, 치과치료등과같은비위생적의료시술이 HCV 전염의주된요인으로보고되었다 또한, 소독이적절히되지않은피어싱 (piercing), 침술, 문신등도여러메타분석에서 HCV 전염의위험요인으로밝혀졌다 오염된주사바늘에찔리는경우와같이일회성소량의경피적노출을통한 HCV 감염위험은외국의보고에서는 1.8% (0-7%) 이고 국내보고에서는 0.92% 이다. 59 성접촉을통한 HCV의전염에관해서는일부논란이있으나, 이성간단일상대방과의성접촉을통한전염위험은매우낮은것으로알려져있다. 그러나, 성상대방이다수인경우, 항문성교나상처를동반한성행위, HIV나다른성매개질환을동반한경우, 남성간의성행위등에서는 HCV 전염위험이증가한다. 60,61 HCV 감염산모로부터신생아로의수직감염률은 1-6.2% 로보고되었는데, 62,63 HCV RNA 양성여부에관계없이 HCV 항체가양성인산모의경우수직감염률은 1.7%, HCV RNA 가양성인산모의경우 4.3%( %) 였다. 63,64 수직감염의위험은남아보다여아, HIV 양성산모, 산모의혈중 HCV RNA 농도가높은경우에더증가하였다. 65 제왕절개수술이 HCV 수직감염을예방하지못하였으며, 65,66 모유수유를통한 HCV 전염가능성은매우낮아유두에상처가있거나출혈하는경우가아니라면모유수유를제한

17 할필요는없다. 67 형제간이나 HCV 감염자의가족내접촉을통한수평감염이일어난다는이전의보고들은대부분근거수준이낮다 년부터 2011년사이국내 5개대학병원에서전향적으로진행된 1,173명의 HCV 환자군과 534명의대조군의비교연구에서는 69 정맥주사약물남용, 주사바늘찔림, 1995년이전수혈, 문신, 나이가국내 HCV 감염의독립적인위험요인으로보고하였다. 69 C 형간염진료가이드라인 예방수칙현재까지효과적인 HCV 백신이개발되지않은실정이므로 HCV 감염의위험요인과관련된표준위생지침을지키도록교육하고관리하는것이주된 HCV 감염예방전략이다. HCV에감염된사람이혈액, 장기, 조직, 정액등을공여하지않도록한다. HCV에감염된사람은피부를뚫는어떠한도구도타인과공유해서는안된다. 즉, HCV에감염된사람은칫솔, 구강위생용품, 면도기, 손톱깎이및피부에상처를줄수있는도구를개별사용하고출혈이있는상처는다른사람에게혈액노출이되지않도록해야한다. 우리나라에서흔히시행되는민간요법으로손가락을 따는 바늘도공유하지않도록한다. 정맥주사약물남용자는이를중단하도록권유하며, 주사기, 주사바늘, 주사용액, 솜이나알코올스펀지등을재사용하지말아야하고사용한주사바늘을함부로버리는경우다른사람이우연히바늘에찔려감염될수있음에유의하여야한다. 성상대가한명인경우성행위로인한 HCV 전파의위험은매우낮으므로 HCV 감염자임을인지하게되었다고해서콘돔을반드시사용해야할필요는없으나당사자가원하는경우또는성행위상대방이다수인경우에는 HCV 감염을예방하기위해콘돔을사용할것을권유한다. 임산부를대상으로 C형간염에대한일률적인선별검사를시행하는것은추천되지않지만, 산전진찰동안 HCV 감염의위험인자가발견되면 C형간염에대한검사를시행하고, HCV에감염되었다고해서임신이나모유수유를제한하거나제왕절개와같은특정한출산방법을선택하도록권유하지는않는다. 보건의료시설에서는 HCV 전염을차단하기위한일반적인주의가필요하다. 의료행위및문신, 피어싱, 침술을포함한침습적시술을시행할경우일회용또는적절히소독된재료를사용하고도구들에대한적절한세척과소독관리가필요하다

18 대한간학회 권고사항 1. HCV에감염된사람이혈액, 장기, 조직, 정액등을공여하지않도록한다. (A1) HCV 에감염된사람은칫솔, 구강위생용품, 면도기, 손톱깎이및피부에상처를줄수있는도구를개별사용하고출혈이있는상처는다른사람에게혈액노출이되지않게관리하도록교육한다. (C1) 2. 정맥주사약물남용자에게는이를중단하도록권한다. (A1) 이들에게 HCV 감염경로에대해교육하고 HCV 감염여부를정기적으로검사하도록한다. (B1) 3. 의료행위및문신, 피어싱, 침술을포함한침습적시술을시행할경우일회용또는적절히소독된재료를사용하고도구들에대한적절한세척과소독이필요하다. (B1) 4. HCV에감염된사람이한명의상대방과지속적인성관계를가지고있는경우에는 HCV가성행위를통해전염될가능성이낮으므로 C형간염이있다는이유만으로성행위방식을바꾸는것은추천하지않는다. (B1) 그러나, 성행위상대방이다수인경우에는 HCV 감염을예방하기위해콘돔을사용할것을권한다. (B1) 5. 임산부의산전진찰동안 HCV 감염의위험인자가발견되거나 C형간염이의심되면 HCV 항체검사를시행하여야한다. (B1) HCV에감염되었다고해서임신이나모유수유를제한하거나제왕절개와같은특정한출산방법을선택하도록권유하지는않는다. (B2)

19 자연경과 C 형간염진료가이드라인 급성 HCV 감염 HCV 감염후 1-3주후혈중에서 HCV RNA가검출되기시작하여급격한상승을보인다. 70,71 감염후 4--12주사이간세포손상에따른혈청 ALT 증가가나타난다. 대부분 (70-80%) 무증상이나일부환자들에서 2-12주사이에인플루엔자유사증상, 피로, 구역, 구토, 우상복부통증, 식욕감소, 근육통, 가려움증등의비특이적증상이나타난다. 급성 C형간염환자들중약 20% 에서황달을동반하며혈청빌리루빈은대개 3-8 mg/ dl 이하이고, 급성간부전은 1% 미만으로드물게발생한다. 급성 HCV 감염후 54-86% 의환자들은만성간염으로이행하지만 20-50% 에서는 3-4개월이내에바이러스가자연적으로제거되면서회복된다 감염경로에따라자연회복률에차이를보여수혈을통한급성 C형간염은 12% 에서자연회복을보인반면수혈을통하지않은경우 29-52% 에서자연회복을보였다 HCV 감염의자연회복과관련된요인으로황달과같은증상을동반한간염, 여자, 낮은바이러스농도, 유전자형 3형등이알려져있다 국내연구에따르면 18명의급성 C형간염환자들 (1명을제외하고 17명이증상을동반함 ) 을 6개월이상추적관찰하였을때 12명 (66.7%) 에서자연회복을보였으며 6명이만성화되었다. 78 국내 7개기관에서 47명의급성 C형간염환자들을대상으로진행된연구에서환자들의평균나이는 45.8세였고대부분증상은경미하였다. 이들중 21명 (44.7%) 의환자들은자연적으로회복되었다. 항바이러스치료를받은 16명중치료반응평가가가능하였던 12명은모두지속바이러스반응 (sustained virological response, SVR) 을보였으나, 항바이러스치료를시행하지않은 10명은만성 HCV 감염으로진행하였다. 79 최근연구에서 interleukin 28B (IL28B) 단일염기다형성 (single nucleotide polymorphism, SNP) 이급성 HCV 감염후바이러스제거와강력한연관성이있음이밝혀졌다 IL28B 유전자는염색체 19번에위치하며 interferon-lamda-3를발현한다. 한연구에서는 IL28B SNP rs 부위의유전자형 CC형의경우 53% 에서 HCV의자연회복이일어난반면 CT나 TT형의경우에는 28% 에서자연회복을보였다

20 대한간학회 (OR=0.33, p<10-12 ). 83 그러나, 국내급성 HCV 감염자들에서 IL28B SNP 에대한연구 는없으며향후연구가필요한실정이다. 만성 HCV 감염 HCV에감염된환자들의약 50-80% 가만성감염상태로이행하며일단만성화되면 HCV의자연회복은드물고지속적인간손상을유발하여간경변증과간세포암종을초래할수있다. 대부분 (60-80%) 증상이없으나일부복부불편감, 피로, 오심, 근육통, 관절통, 체중감소를나타내기도한다. 만성 HCV 감염자들의 60-70% 는지속적으로또는간헐적으로혈청 ALT의상승을동반하는만성간염소견을나타낸다. 만성 C형간염환자들중 15-56% 는 20-25년의기간을거치면서간경변증으로진행하게된다. 71,84-86 간경변증환자의경우연간 1-4.9% 에서간세포암종이발생하고, 연간 3-6% 에서비대상간경변증으로진행하며, 71,88-90 전체적인사망률은연간 2-4% 이다. 71,88-90 국내 1,137명의만성 HCV 감염자들을평균 55.2개월동안추적관찰하였을때간세포암종, 자발세균복막염, 정맥류출혈, 간성뇌증, 간질환관련사망등의질병의진행을보인경우가 14.2% 로 1년에 % 였다. 91 3년, 5년, 10년누적질병의진행률은 6.3%, 12.9%, 26.1% 였다. 전체 1,137명중 490명 (43.0%) 이항바이러스치료를받았으며 60.4% 에서 SVR을보였다. 항바이러스치료를받지않은경우가치료를받은경우보다 10년누적질병의진행률이유의하게높았으며 (37.4% vs. 10.7%, p<0.05), 항바이러스치료후 5년누적질병의진행률은 SVR을보이지않은경우에서 SVR을보인경우보다높았다 (13.0% vs. 3.7%, p<0.05). 만성 C형간염의진행에영향을주는요인들로는감염기간, 감염될당시나이 (40세이상 ), 남자, 알코올섭취, 다른바이러스중복감염 (HBV, HIV), 인슐린저항성, 비만, 면역억제자, 장기이식수혜자, ALT 상승, 유전적인요인등이알려져있다. 71 만성 C형간염자에서과다한알코올섭취는간경변증의발생및진행과강한연관성이있으며간세포암종발생위험을증가시킨다. 86,92-95 간내지방축적, 인슐린저항성과비만은만성 C형간염환자에서간섬유화의진행및간세포암종의발생위험을증가시킨다 만성 HCV 감염자에서 HIV나 HBV에중복감염된경우 HCV 단독감염에비해간질환의진행이빠르고간세포암종의발생위험이증가한다 또한, HCV에의한만성간질환자에서 A형간염바이러스 (HAV) 에중복감염될경우간부전의위험이높아진다. 103 만성 C형간염의진단시병리소견에서간섬유화정도는간경변증으로진행을예측하는가장중요한지표이다 ( 진단편참조 ). 86,100 간섬유화정도가 1단계인경우 15년

21 에걸쳐간경변증으로진행할가능성이 10-30% 이고, 3 단계이면 15 년내에대부분간 경변증으로진행할것으로예측된다. 따라서간섬유화 2 단계이상인환자는적극적인 치료를고려해야한다. C 형간염진료가이드라인 권고사항 1. 만성 C형간염환자들은간경변증과간세포암종발생에대한지속적인관리가필요하다. (A1) 2. 알코올, 비만, 인슐린저항성은질병의진행과연관이있으므로, 만성 HCV 감염자들에게단주또는절주를권하고, (B1) 운동과식이조절을통해적정체중을유지하도록한다. (B1) 3. HBV와 HAV에대한항체가없는만성 HCV 감염자들은 HBV와 HAV에대한예방접종을시행한다. (C1)

22 대한간학회 진단및중증도평가 HCV 감염여부확인을위해생화학적검사, 혈청검사및 HCV RNA 검사가필요하며, 질병의감염경로파악과감염의차단을위해면밀한병력청취를하고신체검사를시행한다. 항바이러스치료를위해 HCV 유전자형검사가필수적이며, 치료여부를결정하고간질환중증도를평가하기위해영상검사와간생검또는비침습적간섬유화평가검사를시행할수있다. 진단을위한검사결과해석을표 2에정리하였다 진단 1. 혈청검사 1) HCV 항체검사혈청이나혈장에서 HCV 항체 (anti-hcv) 를검출하는것은 HCV 감염의고위험군에대한선별검사, 그리고급성및만성 C형간염의진단을위한일차검사이다. 104 면역기능이정상인환자에서 HCV의 core, NS3, NS4, NS5 재조합항원을사용하여 HCV 항체를검출하는 3세대효소면역분석법 (enzyme immunoassay, EIA) 의진단민감도와진단특이도는각각 % 와 % 이다 HCV 항체검사의 signal to cutoff (S/CO) ratio가 3.8 이상이면면역탁본법 (recombinant immunoblot assay, RIBA) 을이용한검사결과도 95% 에서양성을보인다 하지만 S/CO ratio가높아도모두진양성은아니며장비에따라기준이되는 S/CO ratio가다를수있다. 111 최근에는 EIA 보다항원-항체반응을더민감하게검출하는증강화학발광면역분석법 (enhanced chemiluminescent immunoassay, CLIA) 이나전기화학발광면역분석법 (electrochemiluminescence immunoassay, ECLIA) 의사용이늘고있다. 한편특별한장비없이타액이나천자침채혈 (fingerstick blood) 을이용하여 20분이내신속하게 HCV 항체유무를진단할수있는현장검사 (point-of-care test) 도있다. 112 HCV에감염후 HCV 항체가양성으로검출되는평균시간은 8-9주이며 97% 이상

23 의감염자에서 6개월내에 HCV 항체가양전된다. 113,114 HCV 항체는중화항체가아니므로만성 C형간염환자는물론 HCV 감염후회복되어도 HCV 항체가대부분지속적으로검출된다. 따라서 HCV 항체양성여부로현재감염과자연회복된과거감염을구분하지못한다. HCV 항체검사는혈액투석, HIV 중복감염자, 장기이식수혜자나면역억제상태에있는환자, 저감마글로불린혈증또는무감마글로불린혈증과같이면역기능이심하게저하된환자, HCV와관련된본태성혼합한랭글로불린혈증 (HCVassociated essential mixed cryoglobulinemia) 환자, 그리고급성 C형간염의초기에는검사의민감도가감소하여위음성률이높으므로 3,105,115 이런환자들에서는 C형간염의진단을위해서 HCV RNA 검사가필요하다. 반면자가면역질환을가진경우에는위양성률이높다. 116 C 형간염진료가이드라인 2) 면역탁본법 (recombinant immunoblot assay, RIBA) RIBA는 4개의 HCV 항원이코팅된니트로셀룰로스띠 (nitrocellulose strip) 를이용하여혈청내 HCV 특이항체를검출한다. 114 EIA나 CLIA를이용한 HCV 항체검사가양성인경우 HCV 항체검사의위양성여부를확인하기위해특이도가높은 RIBA를시행할수있으나민감도가낮다. 110,117 최근에는만성 C형간염이의심되는환자에서 HCV 항체가양성이면확진을위하여바로 HCV RNA 검사를시행하므로 RIBA의진단적역할은사라져가고있다. 2. 바이러스검사 1) HCV RNA 검사 HCV RNA 검사는정성검사와정량검사로분류된다. 정성검사의검출한계는 50 IU/mL로과거의정량검사보다민감하여진단을위해서는정성적방법을사용하고치료의추적관찰을위해서는정량적방법을사용하였다. 104,110,118 그러나실시간중합효소연쇄반응법 (real-time PCR) 과 transcription-mediated amplification (TMA) 이도입된이후 HCV RNA 정량하한값이 IU/mL 로매우예민하고정량상한값도 7-8 log IU/mL에이를정도로측정범위가넓으며유전자형에무관하게 98-99% 의진단특이도를보이므로 104, 최근에는진단및치료반응평가에정량 HCV RNA 검사가널리사용된다. 125,126 WHO는 1997년부터혈청 HCV RNA의측정단위를 HCV copies 수보다는국제표

24 대한간학회 준인 IU를사용하도록권고하였다. 127,128 그러나 IU/mL 단위를사용하더라도동일한검체를서로다른시약으로검사하면검사결과간에약간의차이가발생하므로 129 치료전과치료기간, 치료후에가급적동일한시약을이용하여검사하는것이좋다. 114,125 HCV에감염된후 2주가경과하면혈액에서 HCV RNA가검출되기시작하고 74 이후빠르게증가하여정점지속 (plateau) 을이루지만, ALT가최고로상승된시점이후에 HCV RNA는 ALT와거의같이감소하기시작한다. 130 만성간염으로진행되면혈중 HCV RNA는항정상태 (steady state) 를유지한다. 130,131 혈중 HCV RNA의양은간의염증이나섬유화정도와유의한상관관계가없고항바이러스치료를하지않은상태에서는시간이경과하여도거의변화가없다. 132,133 2) HCV 유전자형 (genotype) 검사 HCV 유전자형검사는역학연구에도유용하지만항바이러스치료반응을예측하는가장중요한인자로최적의치료기간과약물용량을결정하기위해항바이러스치료전에반드시시행해야한다 형부터 6형까지 6개의 HCV 유전자형이있으며유전자아형 (subtype) 은소문자로 1a, 1b 등으로표시한다. HCV 유전자형간에는염기서열이 31-33% 이상서로차이가나고, 유전자아형간에는 20-25% 차이가난다. 135 동일환자에서 HCV 유전자형은재감염이되지않는한변하지않는다. 직접염기서열분석 (direct sequence analysis), 역교잡법 (reverse hybridization) 과제한절편질량다형성분석 (restriction fragment mass polymorphism, RFMP) 등을이용하여유전자형과아형을구분한다. 136 대부분의유전자형검사는염기서열이잘보존되어있는 5 -untranslated region (5 -UTR) 과 HCV core 부위를분석한다 UTR 부위를분석하는검사법을이용하면유전자형을잘못판정할가능성이 3% 미만이지만유전자아형을잘못동정할가능성은 10-25% 로특히 1a와 1b 유전자아형을구분하지못하는경우가많다 인터페론제제와리바비린을투여하는병합요법에서는유전자아형에따라치료의선택이달라지지않으나바이러스에직접작용하는 direct acting antiviral agents (DAA) 의투여시에는유전자아형의확인이필요할수있다. 140 혈청 HCV RNA 농도가매우낮거나 PCR 증폭과정중문제가발생한경우, HCV 내핵산의심한다양성이있으면유전자형을확인할수없는경우도 5% 미만에서있다 ) HCV 약제내성검사 HBV 와는다르게 HCV 의경우약제내성검사가아직임상검사실에서시행되지않 고있다. 다양한종류의 DAA 가치료에이용되면서 C 형간염치료성적은향상되었으나

25 Table 2. Interpretation of HCV Assays 114 Anti-HCV HCV RNA Interpretation Further evaluation Positive Positive Acute hepatitis C Chronic hepatitis C Positive Negative Resolution of HCV infection Acute HCV infection during period of lowlevel viremia. False positive anti-hcv test False negative HCV RNA test Negative Positive Early acute HCV infection Chronic HCV infection in setting of immunosuppressed state False positive HCV RNA test Recheck anti HCV & HCV RNA, 3-6 months later Recheck anti HCV & HCV RNA, 3-6 months later C 형간염진료가이드라인 이와더불어 DAA 에내성을보이는아미노산변이도발견되어 142 향후이들약제를사 용하는경우약제내성검사가임상적으로필요할수있다. HCV 항체선별검사대상 일반적으로 C 형간염선별검사는 1992 년이전에수혈이나장기이식을받은경우, 정 맥주사약물남용자, 혈액투석환자, HIV 감염자, 혈우병환자, 한센병환자, HCV 감염 산모에서태어난아이, HCV 양성인혈액에오염된주사바늘에찔리거나점막이노출 Table 3. Recommended persons for HCV infection screening 114 1) Persons who are suspected of having acute or chronic HCV infection 2) Persons who have received blood/blood products transfusions or organ transplants prior to screening program 3) Persons who have ever injected illicit drugs 4) Persons who have ever been on hemodialysis 5) Persons with HIV infection 6) Persons with hemophilia 7) Persons who have current sexual contact with HCV-infected persons* 8) Children born to mothers infected with HCV 9) Health care providers after a needle stick injury or mucosal exposure to HCV positive blood * The prevalence of infection is low

26 대한간학회 된보건의료종사자등고위험군에서하도록권고된다 (Table 3). 114 그러나 2012년미국에서는비용대비효과를고려하여고위험군은물론 년사이에태어난성인모두도일생에한번선별검사를받도록선별검사대상의확장을권고하였다 일본의연구에서도 C형간염항체선별검사가고위험군은물론일반인구군모두에서비용대비효과적이었으나 146 유럽의연구에서는 C형간염유병률이높은인구군에서만비용대비효과적이었다. 147 이와같이국가별로역학적특성과보건의료체계가다르므로비용대비효과연구에따른우리나라실정에맞는선별검사전략이필요하다. 우발적노출시진단보건의료종사자가우발적으로 HCV 감염혈액에노출된후 HCV 감염률이외국에서는 1.8%, (0-7%), 57,58, 우리나라에서는 0.92% 로보고되었다. 59 HCV 감염혈액이나체액에노출된경우즉시 HCV 항체와혈청 ALT를검사하며, HCV 항체가음성이면조기진단을위해 4-6주에 HCV RNA 검사를시행한다. 초기검사에서모두음성이더라도노출후 4-6개월에 HCV 항체와혈청 ALT 추적검사를한다. 125,149 HCV 항체가양성으로판정되면확진검사가필요하다. 중증도평가 C형간염환자에서치료를결정하기위해간질환의중증도를평가해야하며그방법으로는간생검과기타비침습적검사가있다. 치료전간경변증유무에따라치료반응과예후에차이가있고간세포암종에대한감시검사전략도달라지므로간경변증유무를확인하는것이중요하다. 1. 간생검간생검을통해간손상의등급과병기를파악할수있다. 114,153 세계적으로가장많이쓰이는등급체계는 METAVIR, 154 Ishak 155 점수체계가있으며우리나라에서는대한병리학회소화기병리연구회에서제안한등급체계를 156 이용한다 (Table 4). 치료시작전간생검이필수적이지는않으나간생검을통하여치료시작시기를결정하거나치료반응및예후에대한정보를얻을수있다. 질병의자연경과, 치료의부작용과비용을고려하여조직소견에서 2단계 (Metavir stage 2 또는대한병리학회병기 periportal

27 Table 4. Comparison of Scoring Systems for Histological Stage 114 Stage Metavir 154 Ishak 155 for the Pathology of Korean Study Group Digestive Diseases No fibrosis No fibrosis No fibrosis (F0) 1 Periportal fibrotic expansion 2 Periportal septae 1(septum) 3 Porto-central septae Fibrous expansion of some portal areas with or without short fibrous septa Fibrous expansion of most portal areas with or without short fibrous septa Fibrous expansion of most portal areas with occasional portal to portal bridging 4 Cirrhosis Fibrous expansion of most portal areas with marked bridging (portal to portal and portal to central) 5 Marked bridging (portal to portal and portal to central) with occasional nodules (incomplete cirrhosis) 6 Cirrhosis Portal fibrosis (F1) Periportal fibrosis (F2) Septal fibrosis (F3) Cirrhosis (F4) C 형간염진료가이드라인 fibrosis, 이하 F2로표기 ) 미만의경도섬유화를보이면치료를미룰수있다. 74,157,158 이경우에는 4-5년후다시간생검을하여질병의진행여부를확인하고치료개시를결정한다. 159 유전자형 1형이면서지속적으로혈청 ALT가정상인환자군의약 5-30% 에서는심한섬유화가동반되어있으므로 이들에서치료여부를결정하는데간생검이유용하다. 86,164,165 간세포내지방침착과 153,166,167 과도한철분침착이 168 있으면치료반응이불량할것을시사하지만치료의금기증은아니다 간생검도시행하지않았고치료도받지않은경우에는지속적인모니터링을해야하며혈청 ALT의상승과간질환진행의증거가있으면간생검과치료개시를고려해야한다 비침습적섬유화검사간생검이간질환상태를파악하는표준검사로인정받고있으나, 172,173 침습적검사이므로합병증이발생할수있으며 174,175 표본추출오차가발생할수있고 176 조직판독에는숙련자가필요하고의료비용이많이소요된다. 따라서 AST, ALT, 프로트롬빈시간,

28 대한간학회 혈소판, 콜레스테롤등을이용하여산출하는 aspartate aminotransferase-platelet ratio index (APRI), AST/ALT 비 (AAR), Forns index 와 α-2 macroglobulin 과 haptoglobin 등의간섬유화의간접표지자를이용한 FibroTest, Hepascore, FibroMeter 가있고 hyaluronic acid 와 tissue inhibitor of matrix metalloproteinase-1 등의직접표지자를이 용한 FibroSpect II, Enhanced Liver Fibrosis test 와같은다양한혈액검사가간섬유화 의정도를알아보기위해개발되었다 APRI 는 (AST/upper limit of normal for AST) 100/platelet count ( 10 9 /L) 라는공 식을이용하여계산하는것으로만성 C 형간염환자에서 APRI 가 1.5 를초과하면 Ishak 점수 3 이상의의미있는섬유화를예측하는 area under the receiver operating characteristic curve (AUROC) 값은 0.80 이며 APRI 가 2 를초과하면간경변증ㄱ을예측할수 있는 AUROC 값은 0.89 로보고되었다. 189 AAR 의정상치는 0.8 정도이나간섬유화가 진행됨에따라증가하여만성 C 형간염에서 AAR 이 1 이상이면간경변증의양성예측률 은 % 로알려져있다. 182,190,191 순간탄성도측정을이용하여섬유화정도를파악할수있으나 년현재 FDA 의승인을받지못했으며비만한환자에서는측정이불가능한경우가많고급 성간염과같이섬유화는심하지않아도염증괴사가심한경우에순간탄성도가실 제보다높은경우가많아아직간생검을대체하지못한다. 196,197 만성 C 형간염의경 우 F2 이상의의미있는섬유화를판정하는 cutoff 값은 kpa 로연구마다차이 가있고 AUROC 가 으로보고되었으며, 198 cutoff 값 kpa 에서간 경변증진단의 AUROC 는 이었다 ( 양성예측도 77-78%, 음성예측도 95-97%). 177,184,192, 이외새로개발된비침습적섬유화검사로는 acoustic radiation force impulse (ARFI) imaging, real time elastography, magnetic resonance (MR) elastography, diffusion-weighted MR image 와 MR spectroscopy 등이있으나아직유효성에대한검 증이필요하다 권고사항 1. 급성또는만성간염이의심되면 HCV 감염여부확인을위해 HCV 항체를검사한다. (A2) 2. HCV 항체양성자에서는혈중 HCV RNA 를검사하여 HCV 감염을확진한다. (A1) 3. HCV 항체는음성이어도급성 C 형간염이의심되거나면역억제상태에서원인미상의 간질환이있으면혈중 HCV RNA 를검사한다. (B1)

29 4. 항바이러스치료전에는 HCV RNA 정량검사와 HCV 유전자형검사를시행한다. (A1) 5. HCV 감염혈액이나체액에노출된경우즉시 HCV 항체와혈청 ALT를검사하며, HCV 항체가음성이면조기진단을위해 4-6주에 HCV RNA 검사를시행하고, 초기검사에서모두음성이더라도노출후 4-6개월에 HCV 항체와혈청 ALT 추적검사를한다. (B2) 6. 항바이러스치료전에간질환중증도를평가한다. (B1) 7. 항바이러스치료시작시기결정과예후판정을위해간생검을시행할수있고, (B2) 비침습적간섬유화검사를사용할수있다. (C2) C 형간염진료가이드라인

30 대한간학회 치료목적 만성 C형간염치료의목표는 HCV를박멸하여간경변증의합병증과간세포암종의발생을막고궁극적으로이로이한사망을예방하는것이다. 만성 C형간염은수십년에걸쳐서서히진행하여궁극적치료목표를단기간내에평가하기어려우므로실제항바이러스치료의구체적목표는치료종료후 24주에검출한계 50 IU/mL 이하의예민한검사법으로혈중 HCV RNA가검출되지않는상태인지속바이러스반응 (sustained virological response, SVR) 에도달하는것이다. SVR에도달하면 99% 이상의환자에서혈중 HCV가지속적으로검출되지않아, 206,207 SVR은실질적 HCV 박멸로간주된다. SVR에도달한환자의 90% 이상에서조직학적간섬유화가호전되거나최소한악화되지않으며, 208,209 간경변증의합병증발생률이 SVR이없는군에비하여유의하게감소하며 210 간세포암종의발생이감소하고 211,212 생존율이향상된다. 213,214 권고사항 1. 만성 C형간염치료의궁극적목표는 HCV를박멸하여 HCV 감염으로인한간경변증의합병증과간세포암종의발생및이로인한사망을예방하는것이다. (A1) 2. 만성 C형간염의단기치료목표는치료종료 24주에검출한계 50 IU/mL 이하의예민한검사법으로혈중 HCV RNA가검출되지않는상태인 SVR에도달하는것이다. (A1)

31 치료대상 C 형간염진료가이드라인 만성 C형간염환자에서치료의금기증이없으면누구나치료의대상이될수있다. 그러나, 병의자연경과를고려할때치료에따르는이득과위험을저울질하여이득이클경우치료의대상이된다. 일반적으로간섬유화단계 F2 이상이면적극적으로치료를권하는데, 간섬유화가진행한경우 (F3-4) 치료를가급적빨리시작하는것이좋다. 간섬유화가경미한경우에는환자의연령, 치료의지, 향후적용가능한새로운치료법등을고려하여치료시기를결정할수있다. 이러한원칙을개별환자에게적용하기위하여대상환자를선택할때에는치료의부작용및치료효과에대해충분히설명하여환자와정보를공유하고환자의치료의지를확인하고결정해야한다. 페그인터페론알파와리바비린병합요법시심각한부작용이예상되는치료의절대적금기는조절되지않는우울증이나정신질환 ; 조절되지않는자가면역질환 ; 간이외의고형장기이식 ; 치료되지않은갑상선질환 ; 임신중이거나피임의의지가없는경우 ; 조절되지않는고혈압, 심부전, 관상동맥질환, 조절되지않는당뇨, 만성폐색성폐질환등의심각한내과질환 ; 2세이하 ; HCV 치료제에과민성이있는경우등이다 (Table 5). 비대상성간경변증환자, 간이식환자, 정맥주사약물남용자, 만성콩팥질환, HIV 중 Table 5. Contraindications to the treatment with peginterferon-alpha and ribavirin 114 Uncontrolled psychiatric illness or depression Uncontrolled autoimmune disease Transplantation of solitary organ except liver Untreated thyroid illness Pregnancy or unwilling to comply with adequate contraception S evere concurrent medical illness such as poorly controlled hypertension, heart failure, significant coronary heart disease, poorly controlled diabetes mellitus, and chronic obstructive pulmonary disease Age 2 years Hypersensitivity to peginterferon-alpha or ribavirin

32 대한간학회 복감염, 18세미만, 간생검에서간섬유화가없거나경미한경우등에서는개별환자에따라이득과위험을고려하여치료를결정하여야한다 (Table 6). 향후더효과적이면서부작용이적은 DAA가임상에적용될것으로예상되므로치료금기나개별치료군의대상이달라질수있다. 6개월에걸쳐적어도 1개월간격으로 2-3회시행한 ALT 값이 40 IU/mL 이하인경우를지속정상 ALT군으로정의한다. 지속정상 ALT군은대체로 ALT 상승군에비하여조직학적으로경미한섬유화소견을보이지만, 215,216 지속정상 ALT 값을보이는환자의약 5-30% 는진행된섬유화소견을보이고간경변증이동반된경우도있다 국내연구에서도치료받지않은정상 ALT군에서간질환의진행이관찰되었으며, 정상 ALT군내에서도 ALT 값이 23 IU/mL 이상일때그미만인사람보다간질환진행위험도가더높았다. 220 따라서, 정상 ALT 값의재정립이필요하며, 정상 ALT 군일지라도조직학적으로진행된섬유화를보이면적극적으로치료해야한다. 정상 ALT군의 SVR 률은비정상 ALT군의 SVR률과비슷하다. 221, 세이상의고령자의경우, 진행된간질환을보이는경우가흔하여치료의필요성이높으나, 223 치료부작용이더흔하며 SVR률이낮은것으로알려져있다. 224,225 그러나, 고령자에서도 C형간염치료가간암발생을낮추고생존율을향상시킬수있다. 226,227 최근에는 60-65세이상의고령자에서특히유전자형 2형의경우 SVR률이 50 대와비슷하다는연구들이있다. 228,229 70세이상만성 C형간염환자의치료에대한자료는거의없어추가연구가필요하며, 치료여부결정은일반적인원칙을따른다. Table 6. Persons for whom therapy should be individualized 114 Acute hepatitis C No or mild fibrosis on liver biopsy Decompensated cirrhosis Liver transplant recipients Current users of illicit drugs or alcohol Chronic renal disease Coinfection with HIV Age less than 18 years

33 권고사항 1. 치료금기가없는모든 C형간염환자는치료의대상으로고려한다. (A2) 2. 치료여부는간질환의중증도, 치료성공확률, 심각한부작용발생가능성, 동반질환유무, 환자의치료의지등을종합적으로고려하여개별화해야한다. (B1) C 형간염진료가이드라인

34 대한간학회 치료반응의정의 페그인터페론알파와리바비린병합요법은상당한부작용과비용을동반한다. 한편, 치료중혈중 HCV RNA 소멸시기가빠를수록 SVR률이높아진다. 230 치료 4, 12, 24 주째혈청 HCV RNA를측정하여치료에대한개인별바이러스반응을평가하고그에따른 SVR 예측률에따라치료기간을줄이거나연장하는전략을 치료반응에따른요법 (response-guided therapy) 이라고한다. 급속바이러스반응 (rapid virological response, RVR) 은치료 4주째검출한계 50 IU/mL 이하의예민한검사법으로혈중 HCV RNA가검출되지않는상태로정의하며, 유전자형 1형만성 C형간염환자에서 RVR이있으면 SVR은 % 로, RVR이없으면 SVR은 % 로예측된다 유전자형 2,3형만성 C형간염환자에서 RVR 유무에따른 SVR 예측률은각각 % 와 % 이다. 232,234 조기바이러스반응 (early virological response, EVR) 은치료 12주째혈중 HCV RNA가치료전기저값에비해 2 log 이상감소하거나검출한계 50 IU/mL 이하의예민한검사법으로검출되지않는상태로정의하는데, 유전자형 1형만성 C형간염환자에서 EVR이없으면 SVR에도달할가능성이 3% 로매우낮다 따라서 EVR이없으면치료를중단함으로써치료에따르는부작용과비용을줄일수있다. EVR은치료 12주째검출한계 50 IU/mL 이하의예민한검사법으로혈중 HCV RNA가검출되지않는완전조기바이러스반응 (complete EVR, cevr) 과 HCV RNA가 2 log 이상감소하였으나검출되는부분조기바이러스반응 (partial EVR, pevr) 으로나뉘어정의된다. pevr에도달한유전자형 1형 HCV 감염환자중치료 24주째혈중 HCV RNA가검출되지않는경우를지연바이러스반응 (delayed virological response, DVR) 으로정의한다. 238,239 치료무반응 (null response) 은치료 12주째혈중 HCV RNA가 2 log 미만으로감소하는상태로정의되며, 부분무반응 (partial nonresponse) 은치료 12주째혈중 HCV RNA가 2 log 이상감소하나 12-24주사이에 HCV RNA가검출되는상태이다. 치료종료시점에검출한계 50 IU/mL 이하의예민한검사법으로혈중 HCV RNA 가검출되지않는상태를치료종료바이러스반응 (end-of-treatment response, ETR) 이라정의한다. 치료종료 24주째검출한계 50 IU/mL 이하의예민한검사법으로혈중 HCV RNA가검출되지않는상태를 SVR로정의한다. 치료종료 12주째평가한

35 Table 7. Definitions of virological responses during therapy 114,125 Virological response Definition Clinical implication Rapid virological response (RVR) Early virological response (EVR) Complete EVR (c-evr) Partial EVR (p-evr) Delayed virological response (DVR) End of treatment response (ETR) Sustained virological response (SVR) Null response (NR) Undetectable HCV RNA (< 50 IU/mL) at week 4 of therapy 2 log reduction of HCV RNA level from baseline at week 12 of therapy Undetectable HCV RNA at week 12 of therapy EVR but detectable HCV RNA at week 12 of therapy 2 log reduction of HCV RNA level from baseline but detectable HCV RNA at week 12 and undetectable HCV RNA at week 24 Undetectable HCV RNA at the end of 24 or 48 weeks of treatment Undetectable HCV RNA (<50 IU/mL) at 24 weeks after treatment < 2 log reduction of HCV RNA level from baseline at week 12 of therapy Partial nonresponse 2 log reduction of HCV RNA level from baseline but detectable HCV RNA at week 12 and 24 Breakthrough Relapse Reappearance of HCV RNA in serum during treatment after virological response Reappearance of HCV RNA after treatment is discontinued May allow shortening of course for genotypes 2&3 and possibly genotype 1 with low viral load Negative predictor of SVR Best predictor of a long-term response to treatment C 형간염진료가이드라인 SVR(SVR12) 이치료종료 24주에평가한 SVR과거의일치한다는보고가있고 240 최근신약임상시험에서는 SVR12으로치료효과를평가하기도한다. 치료중소실되었던혈중 HCV RNA가재출현하면바이러스돌파현상 (breakthrough), 치료종료후소실되었던혈중 HCV RNA가재출현하면재발 (relapse) 로정의한다 (Table 7)

36 대한간학회 권고사항 1. 치료중각개인의치료반응을평가하고치료기간을결정하기위하여 HCV 유전자형에따라치료 4주, 12주, 24주등에검출한계 50 IU/mL 이하의예민한검사법으로혈중 HCV RNA 검사를시행하여야한다. (B1) 2. 만성 C형간염에대한항바이러스치료의효과를평가하기위하여치료종료시점과종료후 24주째에혈중 HCV RNA를측정하여 SVR 도달여부를확인하여야한다. (A1)

37 치료반응예측인자 C 형간염진료가이드라인 각환자에서항바이러스치료를시작하기전 SVR률을예측하면치료여부와시작시기를결정하는데도움을줄수있다. 치료전 SVR을예측하는가장중요한인자는 HCV 유전자형, 235,241,242 조직학적섬유화정도, 243 그리고숙주의 IL28B 유전적다형성이다. 243,244 HCV 유전자형 1형환자의 SVR률은 40-60% 인데비해 2, 3형환자의 SVR 률은약 70-80% 이다. 235,245 조직학적으로섬유화단계 F0-F2군이 F3-F4군에비하여 SVR률이약 2.7배높다. 243 혈중 HCV RNA가 400, ,000 IU/mL 이하이면그이상인경우보다 SVR률이약 배높다. 231,243,246 40세이상의고령 235, 흑인, 247 체중 > 70 kg, 235,241 인슐린저항성 248,249 등의조건이있으면 SVR률이낮아진다. 최근의연구결과숙주의 IL28B 유전적다형성이강력한 SVR 예측인자로밝혀졌다. 243,244,250 IL28B 유전자의 SNP, 즉 rs 위치의 C 또는 T allele 여부에따라 SVR이달라진다. 유전자형 1형의 SVR률은백인에서각각 CC형 69%, CT형 33%, TT 형 27% 이고, 흑인에서각각 48%, 15%, 13% 였다. 243,250 유전자형 1형 HCV에감염된국내환자의경우 SVR률이 CC형에서는 73-88%, CT형에서는 0-40% 였다 인종마다유전적다형성의분포가달라 CC형이우리나라에서는약 88-89% 를차지하는데비해, 흑인에서 17% 로상대적으로드물며, 백인에서는 37% 이다. 243 따라서서구에서는치료전 SVR을예측하기위해 IL28B 유전자형검사를실시하는기관이많지만우리나라에서는약 90% 의인구가 CC형을보이므로어떤대상군에서이검사의유용성이높은지에대한연구가필요하다. IL28B 근처의 rs 유전적다형성도 SVR 에영향을미치며 TT형에서 TG 또는 GG형에서보다 SVR률이높다. 254 치료중 SVR을예측하는지표로는 RVR이가장강력하여, 231,232 RVR이있으면그렇지않은군에비해 SVR이 9배증가한다. 243 한편 EVR은 SVR의강력한음성예측인자로, EVR이없으면 SVR에도달할가능성이 3% 로매우낮다. 236 또한치료약제에대한순응도가 80% 이상일때 SVR이증가하므로, 255 순응도를점검하고유지하려는노력을통하여 SVR률을높일수있다

38 대한간학회 Table 8. Predictors of SVR Pretreatment Predictors Genotype IL28B genetic polymorphism Stage of fibrosis Baseline HCV RNA levels Age, Ethnicity, Insulin resistance, Obesity On-treatment Predictors RVR EVR Treatment adherence

39 만성 C 형간염의치료 C 형간염진료가이드라인 C형간염의치료는빠른속도로발전하고있다. 인터페론 6개월요법으로 SVR률이약 10% 이었던초기성적에비해페그인터페론알파와리바비린병합요법으로 SVR 률은약 54-56% 가되었고 boceprevir나 telaprevir 를추가한 3제요법으로 SVR률은약 75% 까지증가하였다. 235,241, 우리나라에서는아직 DAA가인가되지않아페그인터페론알파와리바비린병합요법이 2013년현재표준치료이며치료에따르는부작용을줄이고효과를유지하기위한치료반응에따른요법이사용되고있다. 곧우리나라에서도강력한항바이러스효과와상대적으로부작용이적은 DAA들을포함한약제들로치료하게될전망이다. DAA는바이러스생활사의특정부위에작용하는데그작용부위에따라 NS3/4A 단백분해효소억제제, NS5A 억제제, NS5B 중합효소억제제등이있고, 숙주에작용하는약제 (host-targeting antiviral agents) 에는 cyclophylline A 억제제, mir-122 억제제등다양한약물들이개발되고있으며기존의표준치료에추가하여 3제또는 4제요법으로치료하거나페그인터페론알파가포함되지않고경구약제들만의병합요법도가능할것으로예상된다. 260,261 아직충분한연구결과가보고되지않았으나일부연구들은 262,263 90% 에가까운 SVR률을보고하고있고치료기간도단축될것으로예상되나높은가격, 약제내성, 약물상호작용및새로운부작용등의문제점도고려하여야한다

40 대한간학회 유전자형 1, 4 형만성 C 형간염의치료 치료경험이없는유전자형 1, 4 형만성 C 형간염환자의치료 2013 년현재우리나라에서유전자형 1, 4 형만성 C 형간염의표준치료는페그인터 페론알파와리바비린병합요법으로 48 주치료한다. 235,241,242 페그인터페론알파에는 페그인터페론알파 -2a (pegasys, Hoffmann-La Roche, USA) 와페그인터페론알파 -2b (peg-intron, MSD, USA) 의두종류가현재시판되고있는데, 페그인터페론알파 -2a 는 40-kd 크기의 polyethylene glycol (PEG) 를, 페그인터페론알파 -2b 는 12-kd 크기의 PEG 를각각인터페론에결합시켜반감기를길게하여장시간혈중농도를유지함으 로써주 1 회피하주사로기존의주 3 회인터페론주사보다효과적인치료가가능하게 하였다. 264 페그인터페론알파 -2a 는환자의체중에관계없이 180 μg 을주 1 회피하주사 하며, 페그인터페론알파 -2b 는환자의체중에따라 1.5 μg/kg 를주 1 회피하주사한다. 리바비린은체중에따라용량을조절한다. 대부분의연구에서페그인터페론알파 -2a 투여시에는체중 75 kg 이하의환자에게는리바비린 1,000 mg/d, 75 kg 을초과할때 는 1,200 mg/d 으로투여하고, 페그인터페론알파 -2b 투여시는체중 65 kg 미만은 800 mg/d, kg 은 1,000 mg/d, kg 은 1,200 mg/d, 105 kg 을초과하면 1,400 mg/d 으로투여하였다. 유전자형 1 형만성 C 형간염환자들에서페그인터페론알파와리바비린병합요법으 로치료하였을때미국또는유럽에서 SVR 률은 40-50% 로보고되었으나, 265 우리나라 환자들에서 SVR률은 % 이었고 228,245, 개의국내연구를 pooled analysis 한결과 SVR 률은 62.7% 로보고되어서구에비해상대적으로좋은치료성적을보 였다. 269 이는치료에좋은반응을보이는 IL28B 유전자형의빈도가백인이나흑인에 비해우리나라사람에서유의하게높다는사실과관련이있다. 81,244,252,254,270,271 유전자형 4 형만성 C 형간염환자는유전자형 1 형과같이페그인터페론알파와리바 비린병합요법으로 48 주간치료하며이경우 SVR 률은 72% 로보고되었다. 272 국내에는 유전자형 4 형에대한치료성적보고가없다

41 치료반응에따른요법 (Response-guided therapy) 의적용유전자형 1형만성 C형간염환자중에서페그인터페론알파와리바비린병합치료 4 주째 RVR을보이면치료기간을 48주에서 24주로단축시킬수있는가에대한연구가시도되었다. 그결과치료전 HCV RNA 농도가낮고 RVR이있으면 24주치료와 48 주치료의 SVR률은각각 %, % 로다양하였는데대부분 24주치료의 SVR률이 48주에비해낮은경향을보였으나통계적으로유의하지않았다. 230,231, 그리고연구마다 HCV RNA 농도의낮고높음의기준이 400, ,000 IU/mL로일률적이지않았으며, 대상환자수도적었다. 최근 RVR을보이는환자들만을대상으로시행한무작위대조연구들을메타분석한 2개의연구결과 48주치료에비해 24주치료가 SVR률이낮고재발률이높지만, 치료전 HCV RNA 농도가 400,000 IU/mL 미만인경우에는두치료군사이에 SVR률의유의한차이가없었다. 277,278 따라서치료전 HCV RNA 농도가 400,000 IU/mL 미만이고 RVR을보이는유전자형 1형만성 C형간염환자들은진행된간섬유화또는간경변증, 비만이나인슐린저항성등의치료실패예측인자가없는경우치료기간을 24주로단축할것을고려한다. 230 한편, 유전자형 4형환자에서 RVR을보일경우치료전바이러스농도에관계없이 24주치료가 48주치료와비슷한 SVR률을보였다. 275,279 유전자형 1형환자에서페그인터페론알파와리바비린병합요법 12주에 EVR이없으면 SVR 가능성이 3% 이하이므로치료를중단해야한다. 또 pevr이면서치료 24 주째도 HCV RNA 양성으로검출되면치료를중단해야한다. 235,236,280 그러나 pevr이면서치료 24주검사에서 HCV RNA가음성이면일반적으로 48주치료하지만치료기간을 72주까지연장하면 SVR률이약 10-20% 정도추가로증가한다는보고가있으므로, 238,239,278,281 부작용이나순응도등환자의여러면을고려하여신중하게연장치료를결정한다. RVR은없으나 cevr이있는경우 SVR률은약 62-70% 로보고되었는데 230,237,239,275 이경우 72주로연장치료를하여도 SVR률증가는없었다. 238,278 C 형간염진료가이드라인 치료경험이있는유전자형 1, 4형만성 C형간염환자의치료이전치료에실패한환자들은재발과무반응으로구분한다. 초치료후재발한경우, 즉이전에인터페론알파단독, 인터페론알파와리바비린병합요법, 또는페그인터페론알파단독으로치료한경험이있는환자에서페그인터페론알파와리바비린병합요법으로재치료하면 SVR률이 31-47% 이었으므로재치료를고려할수있다 그러

42 대한간학회 나페그인터페론알파와리바비린으로초치료하였으나재발한경우동일한약제로재치료할경우 SVR률은 23% 에불과하므로이경우재치료는환자와상의하여신중하게결정하여야한다. 284 초치료가인터페론알파단독, 인터페론알파와리바비린병합요법, 또는페그인터페론알파단독으로치료하였으나무반응을보인경우페그인터페론알파와리바비린병합요법으로재치료하면 SVR률은 8-28% 로매우낮으므로재치료의결정은신중하게내려야한다 초치료로페그인터페론알파와리바비린병합요법을사용했으나무반응자의경우동일한약제로재치료를하였을때 SVR률은 4-8% 로재치료를권하지않으며 284,287 향후 DAA를사용할수있을때까지치료를연기한다. 재치료시에 cevr, pevr, EVR이없는경우각각 SVR률이 %, %, 0-1% 이므로 cevr은치료지속여부를결정하는데유용한지표로사용할수있다. 284,287,288 진행된간섬유화또는간경변증환자에서저용량페그인터페론알파유지요법은장기합병증발생을감소시키지못하여권장되지않는다. 285,289 유전자형 1 형만성 C 형간염환자에서 DAA 를포함한치료성적 1. Boceprevir 또는 telaprevir 포함 3제요법의치료성적 2011년부터 2013년현재까지미국과유럽에서유전자형 1형만성 C형간염의표준치료는페그인터페론알파, 리바비린, 그리고경구단백분해효소억제제 (protease inhibitor) 인 boceprevir나 telaprevir 를병합한 3제요법이다. 그러나 2013년현재국내에서는 boceprevir와 telaprevir 가아직승인되지않았다. Boceprevir를사용한 2개의 3상연구와 257,290 telaprevir를사용한 3개의 3상연ㄸ구 258,259,291 결과, 치료경험이없는환자, 과거페그인터페론알파와리바비린병합요법후재발했던환자, 페그인터페론알파와리바비린병합요법에무반응자에서 SVR률은각각 63-75%, 69-88%, 29-33% 로페그인터페론알파와리바비린병합요법보다초치료에서는약 25-30%, 재치료에서는약 25-60% 의추가적인치료성적의향상을보였다. 그러나 boceprevir나 telaprevir가포함된 3제요법으로치료할때기존의치료보다부작용이많았다 ,290,291 특히 boceprevir는이상미각 (dysgeusia), 빈혈, 호중구감소증등이흔히나타났고, telaprevir는피부발진, 빈혈, 항문직장증상 (anorectal

43 symptom: discomfort, pruritus) 등이흔히나타났다. 그리고하루 3회다량의약을복용해야하는불편감으로순응도가떨어질수있고이로인한약제내성발현위험성도유의해야한다. Boceprevir와 telaprevir는시토크롬 P-450 시스템 (cytochrome P450: CYP2C, CYP3A4, CYP1A) 에서대사되어많은약제와약물상호작용을하므로치료전반드시현재사용하고있는모든약물에대해상호작용여부를파악하여야한다. 그정보는여러웹사이트 ( 예 : 에서얻을수있다. 높은비용부담이동반되는치료이므로당장치료해야할환자와추후이러한문제점들이개선된약제가시판된후치료할환자들을구별하는것이중요한이슈가되고있다. C 형간염진료가이드라인 2. 그외새로운치료제의현황페그인터페론람다는페그인터페론알파와는다른수용체에작용하는데인터페론람다수용체는간세포에주로분포하고있다. 한임상연구에서페그인터페론람다가페그인터페론알파보다 RVR률이높았고, 혈액학적부작용및독감증상, 근육통등의부작용이유의하게낮게발생하였다. 292 새로운 DAA에는 NS3/4A 단백분해효소억제제 (asunaprevir, faldaprevir, ABT-450 등 ), NS5A 억제제 (daclatasvir 등 ), NS5B 중합효소억제제 (sofosbuvir, deleobuvir, ABT-333 등 ) 가있고, 숙주에작용하는약제에는 cyclophylline A 억제제, mir-122 억제제 (miravirsen) 등이임상시험중이다. 221, , 이들은복용이간편하고 ( 단, miravirsen은주사제 ), 부작용은적으며, 항바이러스효과도더강력하다. 치료경험이없는유전자형 1, 4, 5, 6형 (5, 6형은총 7명 ) 만성 C형간염환자 327명 (17% 의간경변증환자가포함됨 ) 을대상으로시행된 3상연구에서페그인터페론알파, 리바비린과함께 nucleotide analogue HCV NS5B 중합효소억제제인 sofosbuvir를포함한 3제요법으로 12주간치료한결과치료종료후 12주째반응률 (SVR12) 이 90% 임을보고하였다. 263 페그인터페론알파를제외하고이러한약제들만으로치료하는임상시험들도많이진행되고있는데약제들의조합에따라 SVR률의차이가크고, 유전자아형 (1a vs 1b) 에따라치료성적에차이가날수있다. 261,262,293,295,296 따라서향후이러한새로운약제들중어떤조합이가장효과적인지, 이들약제들의부작용이나약제내성발현에대한연구결과도주목된다

44 대한간학회 권고사항 1. 치료경험이없는유전자형 1형또는 4형만성 C형간염의항바이러스치료 ( 그림 2) 1) 페그인터페론알파와리바비린을병합하여 48주간투여한다. (A1) 페그인터페론알파-2a는체중에관계없이 180 μg을주 1회피하주사하고, 리바비린은 75 kg 이하이면 1,000 mg, 75 kg을초과하면 1,200 mg을매일경구투여한다. 페그인터페론알파-2b는 1.5 μg/kg로주 1회피하주사하고, 리바비린은체중이 65 kg 미만은 800 mg, kg은 1,000 mg, kg은 1,200 mg, 105 kg을초과하면 1,400 mg을경구투여한다. (A1) 2) 유전자형 1형은치료 4주째 RVR이있고치료전 HCV RNA 농도가 400,000 IU/mL 미만이며치료실패예측인자 ( 진행된간섬유화또는간경변증, 비만이나인슐린저항성등 ) 가없는경우 24주간의단축치료를고려한다. (B1) 3) 유전자형 4형은 RVR이있으면치료전바이러스농도에상관없이 24주간치료를고려할수있다. (B2) 4) 치료 12주째 EVR이없으면치료를중지한다. (A1) cevr이있으면 48주간치료한다. (A1) pevr인경우는치료 24주째 HCV RNA 검사를하여음전되지않으면치료를중지하고, (A1) 음전되면 72주로연장치료를고려할수있다. (B2) 2. 치료경험이있는유전자형 1형또는 4형만성 C형간염의항바이러스치료 1) 이전에인터페론알파단독, 인터페론알파와리바비린병합요법, 또는페그인터페론알파단독으로치료한경험이있는환자에서재발했거나치료무반응인경우페그인터페론알파와리바비린병합요법으로재치료를고려할수있다. (B2) 2) 이전에페그인터페론알파와리바비린병합요법으로치료하였으나치료에실패한경우에는동일한약제로재치료하는것은권장되지않는다. (A2) 3) 페그인터페론알파와리바비린병합요법으로치료실패한경우저용량페그인터페론알파유지요법은권장되지않는다. (A1) 3. 유전자형 1형환자의초치료및재치료에서페그인터페론알파및리바비린과함께 boceprevir 또는 telaprevir를포함하는 3제요법이권장된다. (A1) 추후더효과적인 DAA 치료에대한연구결과에따라우리나라환자들에서도이러한약제들을포함한치료법을적용하는것이바람직하다

45 C 형간염진료가이드라인 Figure 2. Treatment algorithm for patients with genotype 1 chronic HCV infection. This algorithm applies to genotype 4 at a B2 grade of evidence. The dotted lines indicated weaker strength of recommendation compared with the solid lines. *Negative factors for response include advanced liver fibrosis or cirrhosis, obesity, insulin resistance

46 대한간학회 유전자형 2, 3 형만성 C 형간염의치료 치료경험이없는유전자형 2, 3형만성 C형간염환자의치료유전자형 2, 3형만성 C형간염의표준치료는 24주간페그인터페론알파와리바비린병합요법이다. 235,241,242, 페그인터페론알파-2a는환자의체중에관계없이 180 μg을주 1회피하주사하며, 페그인터페론알파-2b는환자의체중에따라 1.5 μg/ kg를주 1회피하주사한다. 리바비린용량은사용하는페그인터페론알파종류에관계없이 800 mg의고정된용량을매일투여하며, 체중에따라리바비린의용량을다르게결정하는것이고정된용량을투여하는것보다더효과적이라는증거는부족하다. 241,242,297 우리나라유전자형 2형만성 C형간염환자들에서표준치료후 SVR률은 80% 이상이다. 245,300 유전자형 3형만성 C형간염은국내에드물어치료성적에대한보고가부족한데, 해외의경우 235,242,278,297 유전자형 3형에서의 SVR률이 2형에서보다약 10-20% 정도더낮게보고된다. 246,299, 치료반응에따른요법의적용유전자형 2, 3형만성 C형간염환자에서총치료기간을 24주대신 12 16주로단축하였을때 SVR률이동등할것인가에대한 8개의연구는 246, 치료기간이나페그인터페론알파및리바비린용량, RVR이있는환자의비율등이상이하여연구결과를직접비교하기어렵다. 각각 350명이상의유전자형 2형만성 C형간염환자들을대상으로 16주치료와 24주치료를비교한연구에서는 16주치료군의 SVR률 65% 에비해 24 주치료군의 SVR률이 82% 로유의하게높았다. 303 그러나이연구에서는치료기간을결정함에있어서 RVR 유무는고려하지않고치료기간을무작위로배정하여결과해석에주의를요한다. 한편이연구에서유전자형 3형환자의경우 16주치료군의 SVR 률이 61%, 24주치료군의 SVR률은 71% 로두군간에통계학적으로유의한차이는없었다. 또다른연구에서는 RVR이있는유전자형 2형만성 C형간염환자 200여명씩을대상으로 16주치료와 24주치료효과를비교하였는데, 16주치료군의 SVR률은 81%, 24주치료군에서는 92% 로 SVR률의차이는통계적으로유의하지않았지만, 재발률의

47 경우 16주치료군에서 17% 로 24주치료군의 5% 에비해유의하게높았다. 305 이연구에서는페그인터페론알파와함께 1,000-1,200 mg의높은용량의리바비린을사용하여단축치료를하였는데 24주치료와동등한 SVR률을얻었음에도불구하고높은재발율을보였다. 치료기간외에재발을예측할수인자로는진행된간섬유화, 치료전높은바이러스농도, 환자의체중, 성별및나이등이제시되었으나, 246,305,306 이러한인자들에따른재발률의차이가없다는결과도있어서 301,303 이에대한연구가더필요하다. 결론적으로유전자형 2, 3형만성 C형간염환자들에서 RVR이있는경우, 치료전혈중 HCV RNA 농도가낮고, 진행된간섬유화나간경변증이없고, 다른치료실패예측인자들이없으면 16주로치료를단축할수있으나재발률이높음을고려한신중한결정이필요하다. 진행된섬유화나간경변증이있는환자에서는 RVR이있고치료전 HCV RNA가낮더라도치료기간의단축은고려하지않는다. 한편유전자형 2, 3형환자에서 RVR이없거나, 치료전혈중 HCV RNA가높은경우, 진행된간섬유화나간경변증을동반한경우에치료기간을 48주로늘리는것에대한연구도있었다. 이중 1,311명의환자를대상으로한연구에서유전자형 2, 3형환자중, 치료전혈중 HCV RNA와간섬유화정도에근거한 SVR 예측률이낮은환자에서치료기간을 48주로늘려도 SVR률의유의한향상은없었다. 242 C 형간염진료가이드라인 치료경험이있는유전자형 2, 3형만성 C형간염환자의치료유전자형 2, 3형만성 C형간염환자중에서이전에리바비린과병합하거나또는병합하지않고인터페론알파를근간으로한치료를받았던환자나페그인터페론알파단독요법으로치료받았던환자중 SVR이없었던경우에페그인터페론알파와리바비린병합요법으로재치료할수있다 , 이전에인터페론을기반으로치료후재발한환자에서페그인터페론알파와리바비린병합용법으로재치료하면 SVR률이 % 로보고되어무반응환자에서재치료후 SVR률 % 에비해더높은경향을보였다. 282,284 2, 3형의재치료시적절한치료기간에대한연구는충분치않으나, 기존의연구에서는 24주혹은 48주동안임의로정하여재치료를시행하였고, ,308,310 치료기간에따른효과를비교한연구는없었다. 페그인터페론알파와리바비린병합요법으로 24주간치료하였으나재발한환자에서다시동일한약제로 48주간치료한한연구결과에서 (n=92) SVR률은 57% 였다. 284 그러나이러한재치료에대한근거가부족하여현재로서는페그인터페론알파와리바비린병합요법으로치료하였으나 SVR이없었던환자에서, 특히무반응자에서는페그인터페론의종류를바꾸는것

48 대한간학회 을포함한동일한약제로재치료하는것을권장하지않는다. 유전자형 2, 3 형만성 C 형간염환자에서새로운치료법 유전자형 2, 3 형은페그인터페론알파와리바비린의 24 주치료로도높은 SVR 을이 룰수있으나일부 SVR 획득에실패한환자나페그인터페론알파를근간으로하는치 료법을시행받을수없는환자에서는새로운치료법이요구되고있다. 치료경험이없는유전자형 2 형만성 C 형간염환자 70 명을대상으로시행한 3 상임 상시험에서페그인터페론알파없이 HCV NS5B 중합효소억제제의일종인 sofosbu- vir 와리바비린 2 제요법으로 12 주간치료한결과치료후 12 주째 HCV RNA 음전율 (SVR12) 은 97% 였다. 263 또한이전치료에실패한유전자형 2 형환자 32 명을대상으로 sofosbuvir 와리바비린 2 제요법으로 16 주간치료하였을때에는치료후 12 주째 HCV RNA 음전율 (SVR12) 이 94% 였다. 311 그러므로향후표준치료에부작용을보인환자 에서뿐아니라치료에실패한환자에서도인터페론이제외된 DAA 를포함한병합요 법의효과가기대된다. 권고사항 1. 치료경험이없는유전자형 2, 3형만성 C형간염의항바이러스치료 ( 그림 3) 1) 페그인터페론알파와리바비린을 24주간투여한다. (A1) 2) 페그인터페론알파-2a는 180 μg을, 페그인터페론알파-2b는 1.5 μg/kg을주 1회피하주사한다. (A1) 리바비린은체중에관계없이 800 mg을매일경구투여한다. (A2) 3) 치료 4주째 RVR이있고다른치료실패예측인자가없는경우에는치료기간을 16 주로단축하는것을고려할수있다. (B2) 단, 치료기간을단축하는경우에는 24 주치료에비해재발률이높음에주의한다. (A2) 2. 치료경험이있는유전자형 2, 3형만성 C형간염의항바이러스치료 1) 이전에인터페론알파단독, 인터페론알파와리바비린병합요법, 또는페그인터페론알파단독으로치료했으나재발, 또는치료무반응인경우페그인터페론알파와리바비린병합요법으로재치료할수있다. (B2) 2) 이전에페그인터페론알파와리바비린병합요법으로치료하였으나무반응이었던경우동일한약제로재치료하는것은권장하지않는다. (B2)

49 C 형간염진료가이드라인 Figure 3. Treatment algorithm for patients with genotype 2, 3 chronic HCV infection. The dotted lines indicate weaker strength of recommendation compared with the solid lines. *Negative factors for response may include advanced fibrosis, cirrhosis and others. **The shortened therapy may result in higher relapse rate

50 대한간학회 유전자형 6 형만성 C 형간염의치료 유전자형 6형환자는대부분동남아와중국의남부, 홍콩, 마카오등에국한되어있고우리나라만성 C형간염환자의약 1% 를차지하고있다. 312 현재까지발표된연구들에따르면 HCV 유전자형 6형은페그인터페론알파와리바비린병합요법을시행하였을때 SVR률이 % 로유전자형 3형과비슷하며, 유전자형 1형보다높다 페그인터페론알파와함께투여되는리바비린의최적용량에대하여고정용량과체중에따라조절된용량의효과를비교한연구는없다. 그러나유전자형 6형에대한연구중페그인터페론알파를근간으로했던모든연구에서리바비린을체중에따라조절된용량을사용하였다 두개의무작위대조군연구에서유전자형 6형의페그인터페론알파와리바비린병합요법시 24주치료군의 SVR은 48주치료군과통계학적차이를보이지않았다. 72,80,318, 항바이러스치료에실패한유전자형 6형환자의재치료에대한연구는없다. 권고사항 1. 치료경험이없는유전자형 6형만성 C형간염의항바이러스치료 1) 페그인터페론알파와리바비린을 24주간투여한다. (A1) 2) 페그인터페론알파-2a는체중에관계없이 180 μg을, 페그인터페론알파-2b는 1.5 μg/kg을주 1회피하주사한다. (A1) 리바비린은페그인터페론알파-2a와함께투여할경우에는환자의체중이 75 kg 이하이면리바비린 1,000 mg, 75 kg 이상이면 1,200 mg을매일경구투여하며, 페그인터페론알파-2b와함께투여할경우에는체중 65 kg 미만은 800 mg, kg은 1,000 mg, kg은 1,200 mg, 그리고 105 kg을초과하면 1,400 mg을경구투여한다. (B2)

51 급성 C 형간염의치료 C 형간염진료가이드라인 급성 C형간염의자연관해율은연구에따라차이가있어서약 20-50% 로다양하게보고되었다. 72,80, 그러므로급성 C형간염을진단즉시치료할수도있지만진단후 8-12주정도기다리면서자연관해의기회를가지는치료전략이있다. 72,324,325 진단즉시치료하는것과진단후 12주의관찰기간을가진후치료하는것을비교한무작위대조연구에따르면급성 C형간염의자연관해율과치료로획득된 SVR률을모두고려하였을때 12주때치료를시작하는것은진단즉시시작하는것에비해그결과가열등하지않았다. 326 다만급성 C형간염의진단이용이하지않다는문제가있는데, 특히만성 C형간염의급성악화와의감별이어려울경우만성 C형간염에준하여치료를할수있다. 급성 C형간염에서 HCV 항체는 ALT가최고로높고혈중 HCV RNA치는떨어지는시점에서출현하기시작하므로이는실제감염이있은후 8-12주이후가되며이때에도대부분의환자에서는특별한증상을동반하지않는다. 130 그러므로급성 C형간염이의심되고 HCV 항체가음성인경우에는 HCV RNA를측정하는것이진단과치료에도움이된다. 급성 C형간염은인터페론알파, 혹은페그인터페론알파단독으로 24주간치료하였을때 SVR률이 80-98% 로높다 페그인터페론알파-2b에리바비린을추가한경우에도 SVR률은페그인터페론알파-2b 단독치료에비해통계학적으로의미있는증가를보이지않았다. 326,329 현재까지의연구결과인터페론혹은페그인터페론알파단독요법으로도높은 SVR을이룰수있어리바비린병합의추가적이익은확실하지않다. 급성 C형간염의적절한치료기간에대한연구는아직부족하다. HCV 유전자형에관계없이치료기간을 8주, 12주및 24주간나눈한무작위대조연구 ( 각군에서 n=34) 에서 12주간치료한환자의 SVR률은 82.4% 인데비해 24주간치료한군의 SVR률은 91.2% 였으나이는통계학적으로는유의한차이를보이지않았다. 333 하지만급성 C형간염의치료성적이좋음을보고한여러연구에서의치료기간이 24주였기때문에추후 24주치료에반하는더확실한증거가제시될때까지치료기간은 24주를권장한다. 327,328,332,

52 대한간학회 권고사항 1. 급성 C형간염환자에서는항바이러스치료를고려한다. (A1) 2. 치료시작시점은자연관해의기회를갖도록급성간염진단후 8-12주연기할수있다. (B2) 3. 급성 C형간염의치료는페그인터페론알파단독치료를우선적으로고려하며, (B1) 치료기간은 24주로한다. (B2)

53 치료부작용모니터링과대처 C 형간염진료가이드라인 항바이러스치료부작용모니터링의필요성페그인터페론알파와리바비린병합요법시많은환자가부작용을경험한다. 치료의부작용때문에전체치료환자의약 10-20% 가치료를중단하고, 추가로약 20-30% 의환자들이치료약제용량을줄이게된다. 334,335 페그인터페론알파와리바비린을이용한만성 C형간염치료에서두약제를모두 80% 이상의용량을투여하고계획된치료기간의 80% 이상을치료받은경우의 SVR률 (63%) 은두약제중어느하나를 80% 미만으로치료받은경우의 SVR률 (52%) 보다유의하게높았다. 255 따라서, 치료부작용에대한적극적인모니터링과대처로약제중단이나감량의경우를줄여치료성적을향상시킬수있다. 항바이러스치료부작용과대처방법페그인터페론알파와리바비린병합요법시 20% 이상의환자에서흔하게발생하는부작용들은두통, 발열, 근육통, 근육경직, 관절통, 오심, 식욕부진, 체중감소, 설사, 탈모, 피부발진, 가려움증, 주사부위염증, 호흡곤란, 피로감, 불면증, 자극과민성, 우울증등이다. 235,241,242,336 그러나, 이러한부작용의빈도는주로임상연구에서선택된환자들에서보고되었던것으로실제일반적임상상황에서는개별환자에따라그빈도나양상이다를수있다. 336 페그인터페론알파주사후발생하는부작용은크게독감유사증상 (flu-like symptoms), 골수기능억제에의한부작용, 신경정신학적부작용및자가면역성부작용등으로나눌수있다. 발열, 피로, 근육통, 두통, 오한등의독감유사증상은약 37% 이상발생하는데, 235,241,242 적절한해열진통제투여로증상을완화시킬수있으며, 대부분치료 4주나 6주후에는이러한증상이약화된다. 336 백혈구감소증이나혈소판감소증은페그인터페론알파의골수기능억제에의한것으로치료약제감량의주요한원인이며, 간경변증환자에서치료를제한하는부작용이기도하다. 페그인터페론알파의용량은심한부작용이발생하면줄이거나중단해야하는데, 특히절대호중구수가

54 대한간학회 750/mm 3 미만으로감소하거나혈소판수가 50,000/mm 3 미만으로감소하면용량을 줄이는것을고려하고, 절대호중구수가 500/mm 3 미만으로감소하거나혈소판수가 25,000/mm 3 미만으로감소하면투여중단을고려한다. 이후절대호중구수와혈소판 수가적절히호전되면감량된용량으로다시투여를고려하는데, 예를들어절대호중 구수 1,000/mm 3 이상, 혈소판수 75,000/mm 3 이상으로회복되면 50% 의용량으로다 시투여하고, 절대호중구수와혈소판수를지속관찰한다. 백혈구감소증을극복하기 위해 granulocyte colony-stimulating factor (G-CSF) 를사용하는것이감염률을낮추 고 SVR 률을높인다는증거는부족하지만간경변증환자등일부환자에서 G-CSF 사 용을고려해볼수있다. 337 한편, 치료도중 ALT 가정상상한치의 10 배이상상승하는 급성간염악화상태가발생하거나패혈증과같은심한세균성감염등이발생하면치 료를중지한다. Thrombopoietin receptor agonist 는 HCV 에의한간경변증환자에서 혈소판수를치료전에상승시킬수있지만 338 아직이러한약물사용이 SVR 률을향상 시킨다는증거가부족하고한편약물에의한혈전증위험증가로문맥혈전증등을유발 할가능성에주의하여야한다. 339 불면증, 집중력저하, 기억장애, 자극과민성또는감정둔마 (apathy) 와같은신경정신 학적이상도페그인터페론알파에의해발생할수있는데특히, 심한우울증이발생하 게되면자살을기도할수있으므로주의해야한다. 340 치료전에우울증의과거력이있 는경우는치료의금기상태가아닌지확인하고치료중에우울증발생에대해특히주 의한다. 치료중우울증은약 28% 에서발생하는데, 341 이경우 serotonin uptake inhibitor 등과같은항우울제를사용할수있고이를통해치료중단을줄일수있다. 342 예방 적항우울제의복용은치료중에발생하는우울증의빈도를낮출수있으나 SVR 률을 높이지는못했다 페그인터페론알파의면역조절기능에의해유발되는부작용인갑상선질환은치료 받는환자의약 15-20% 에서발생한다. 336,344 인터페론제제에의한갑상선손상은크게 자가면역성과비자가면역성으로나뉘고, 자가면역성은그레이브스병, 하시모토갑상 선염, 갑상선자가항체생성등으로분류되고 345 비자가면역성은 HCV 자체에의해갑 상선손상이발생하는경우이다 하시모토갑상선염이가장흔하게발생하는데 대개갑상선기능항진증으로시작해서갑상선기능저하증이되고치료종료후에도정 상화되지않을수있다 인터페론제제투여중갑상선기능항진증이심할경우에 는치료중단을고려하고, 350 심하지않은경우에는치료를유지하며갑상선기능저하 증으로변하는지주기적으로관찰하여야한다. 처음부터갑상선기능저하증으로나타 나는경우에는갑상선호르몬제를투여하며치료를유지할수있다. 344 한편, 갑상선기

55 능이상은치료종료후에도발생할수있으므로 336 갑상선염발생여부를확인하기위해치료중에는 2-4개월마다, 그리고치료후에는 1년간 thyroid stimulating hormone (TSH) 과 free thyroxine 값을측정하는것이바람직하다. 한편, 페그인터페론알파에의해드물지만전신홍반루푸스, 제1형당뇨, 천식, 폐간질섬유화등다양한종류의자가면역질환이유발될수있다. 351 갑상선질환이나당뇨는항바이러스치료로악화될수있으므로치료전이에대한기저검사가필요하나, 이러한질환이치료의절대금기는아니며, 잘관리되고있는경우적극적인치료를고려할수있다. 336,344 그외페그인터페론알파와주로연관된부작용은시야장애, 망막출혈과부종, 청력장애, 이명, 오심, 구토, 피부가려움, 체중감소, 탈모등이있으며, 336 대부분치료종료후에증상이개선된다. 여러연구들에서치료중망막질환의발생빈도가약 % 로다양하게보고되고있으며, 심각한시야장애를일으키는경우부터증상이없는경우까지임상양상도다양하여망막에대한사전검사나추적검사의필요성에대해논란이있으나, 고령, 고혈압이나당뇨와같이망막질환의위험인자가있는경우 치료전에망막검사를하여기저상태를확인하는것이바람직하다. 356 페그인터페론알파치료중발생하는청력손실은약 1% 미만에서발생하는데, 치료를중단하여도완전히회복되지않을수있다. 359 리바비린의흔한부작용은용혈성빈혈인데, 이는리바비린의적혈구에대한직접적인용량의존성독성에의한것으로치료유지에장애를초래할수있다. 360 심장질환이나폐질환이있을경우리바비린에의해발생하는빈혈이허혈성심폐질환을악화시킬수있다. 360 혈색소 10 g/dl 미만의빈혈이발생하면리바비린감량을고려하며, 혈색소가 8.5 g/dl 미만으로감소하면리바비린투여중지를고려한다. 예를들어, 혈색소 10 g/dl 미만의빈혈이발생하면리바비린을한번에 200 mg씩감량하고, 혈색소가 8.5 g/ dl 미만으로감소하면리바비린투여를중지한다. 이후빈혈이호전되면감량된용량으로리바비린을다시투여할수있다. 빈혈이심할경우 recombinant erythropoietin 이사용될수있다. 즉, 혈색소 10 g/dl 미만의빈혈이발생할경우리바비린의감량이나중단을막기위해투여해볼수있지만, 이의사용으로 SVR률을높인다는증거는부족하다. 337,361 한편, 리바비린은임신중선천성기형을유발할우려가있으므로남녀를불문하고치료기간과치료후 6개월동안피임을철저하게해야한다. 362 그외리바비린투여와주로연관된부작용은피로, 소양증, 발진, 부비동염, 통풍등이있다. 치료전에치료과정과치료로인한부작용및이의대처법에대해환자에게충분한교육을하는것이환자가치료를지속하는데도움을준다. 치료를시작후 2-4주에여러부작용여부를확인하고, 이후에는약 4-12주간격으로경과관찰을하는것이필요하다. C 형간염진료가이드라인

56 대한간학회 권고사항 1. 치료부작용및독성을모니터링하기위해치료전우울증, 심장질환, 폐질환, 고혈압, 당뇨, 갑상선질환, 빈혈등에대한사전검사가필요하다. (B1) 2. 치료시작후 2-4주에, 그이후에는약 4-12주간격으로치료부작용에대한정기적인경과관찰이필요하다. (C1) 3. 절대호중구수가 750/mm 3 미만으로감소하거나혈소판수가 50,000/mm 3 미만으로감소하면페그인터페론알파의용량감량을고려하며, 절대호중구수가 500/mm 3 미만으로감소하거나혈소판수가 25,000/mm 3 미만으로감소하면페그인터페론알파의투여중단을고려한다. 이후적절히회복되면감량된용량으로다시시작할수있고, 절대호중구수와혈소판수를지속관찰한다. (C2) 4. 혈색소 10 g/dl 미만의빈혈이발생하면리바비린을감량하고, 혈색소가 8.5 g/dl 미만으로감소하면리바비린투여를중지한다. 이후빈혈이호전되면감량된용량으로리바비린을다시투여할수있고, 혈색소를지속관찰한다. (C2) 5. 갑상선염발생여부를확인하기위해서약 2-4개월마다 TSH와 free thyroxine 값을측정한다. (C1) 6. 치료중에우울증이발생하는경우적절한개입이필요하며증상이심한경우치료를중단한다. (C1) 치료후모니터링 SVR에도달한후에도 HCV에노출되면 HCV에재감염될수있다. 주로정맥주사약물남용자에서발생한다 따라서, SVR 후에도재감염또는재출현의가능성이있으므로추적관찰이필요한데, SVR을이룬후추적검사에서혈중 HCV RNA를측정하여지속적으로검출되지않으면완치가유지되는것으로간주할수있다. SVR에도달한경우라도치료전이미간경변증이나진행된간섬유화가있는경우간세포암종의발생위험이잔존하므로 214 간경변증의일반합병증관리및간세포암종감시전략에준하여모니터링해야한다. SVR에도달하지못한경우질환진행과간세포암종발생률이 SVR에도달한경우에비해유의하게높으므로 214,367 만성간염에준한꾸준한관리가필요하다

57 권고사항 1. SVR에도달한경우, 추적검사에서혈중 HCV RNA가지속적으로검출되지않으면 SVR이유지되는것으로본다. (C1) 2. SVR에도달한경우에도치료전에진행된간섬유화가있는경우, 만성간염에준한지속적인관리가필요하다. (B1) 3. SVR에도달하지못한경우, 만성간염에준한지속적인관리가필요하다. (B1) C 형간염진료가이드라인 Table 9. Adverse events of pegylated interferon-alpha (or interferon-alpha) and ribavirin Possible related drug Pegylated interferon-alpha Flu-like symptoms or interferon-alpha Bone marrow suppression Neuropsychiatric symptoms Autoimmune diseases Others Gastrointestinal Side effects Fatigue Headache Fever Chill Myalgia Arthralgia Neutropenia Thrombocytopenia Depression Irritability Insomnia Apathy Hashimoto thyroiditis Graves disease Systemic lupus erythematosus Type 1 diabetes mellitus Bronchial asthma Pulmonary fibrosis Interstitial pneumonitis Nausea

58 대한간학회 Possible related drug Ribavirin Dermatologic Ophthalmologic Respiratory Etc. Side effects Anorexia Dyspepsia Diarrhea Alopecia Rash Dry skin Skin itching Dry eye Dry mouth Stomatitis Psoriasis Reaction at injection site Vision impairment Retinal swelling Retinal hemorrhage Cough Hearing loss Tinnitus Memory impairment Weight loss Hemolytic anemia Fatigue Rash Skin itching Teratogenic effect

59 특수상황에서의치료 C 형간염진료가이드라인 특수상황의환자들을대상으로시행된임상연구들은상당히제한점이많으므로이 들에서 HCV 항바이러스치료를적용할때에는각환자의개별적상황을충분히고려 하여야한다. 간경변증 1. 대상성간경변증환자의치료대상성간경변증환자는비대상성간경변증으로의진행과간세포암종의발생등 HCV 감염으로인한장기합병증의가능성이높으므로절대적금기증이없는한적극적으로항바이러스치료를시행할것이권장된다. 간경변증및진행된간섬유화환자에서항바이러스치료에의해 SVR에도달하면간질환으로인한사망률과간세포암종발생빈도가낮아지기때문이다. 211,214,368,369 그러나간경변증및진행된간섬유화환자에서페그인터페론알파와리바비린병합치료시, SVR률은간섬유화가경미한환자에서보다유의하게낮다. 국내연구결과는 Child-Turcotte-Pugh (CTP) 분류 A 간경변증환자에서 SVR률을유전자형 1형에서 20.8%, 유전자형 2형에서 52.6% 로보고하고있다. 370 아울러간경변증환자들은다른환자들에비해고령인경우가많고항바이러스치료중부작용이흔히발생하므로투약중철저한감시와부작용에대한대비가필요하다. 간경변증환자들은문맥압항진증과비장과다증으로백혈구와혈소판수가낮으며, 투약중빈혈, 호중구감소증, 혈소판감소증과같은혈액학적부작용이더빈번하게발생하여이경우에는 recombinant erythropoietin 이나 G-CSF와같은성장인자의사용이부작용극복에도움이될수있다. 371 유전자형 1형의대상성간경변증환자에서초치료혹은재치료시 boceprevir, 혹은 telaprevir 를포함한삼제요법은페그인터페론알파와리바비린병합요법보다 SVR 이좋은경향을보였고, 또한 치료반응에따른요법 보다 48주치료가 SVR률이더높았다. 258,291,372 따라서추후 DAA의국내사용이가능해지면간경변증환자에서치료효과의향상을기대할수있을것으로여겨진다

60 대한간학회 간경변증환자들은항바이러스치료후 SVR 에도달하더라도간세포암종의발생가 능성이있으므로간경변증의합병증에대한추적과간세포암종발생에대한감시검사 를지속적으로받아야한다. 2. 비대상성간경변증환자의치료비대상성간경변증환자는대상성간경변증환자에비해치료성적이더욱불량하며부작용발생도빈번하다. 국내에서의소규모치료성적을살펴보면 ( 총 10명, 유전자형 1형 8명, 유전자형비1형 2명 ), 비대상성간경변증환자에서페그인터페론알파와리바비린병합요법시 SVR률은 20.0% 에불과하였다. 373 그러므로비대상성간경변증환자중에서 CTP 분류 B의환자들은경험이많은의사에의해부작용에대한적극적모니터링과함께조심스럽게치료를시도해볼수있는데, 혈중 HCV RNA 농도가낮거나 HCV 유전자형 2형이나 3형에서치료성적이좋을것으로예상된다. 치료는처음부터표준용량으로시작할수도있으나이경우절반이상의환자에서용량감소나투약중단이필요하므로 low accelerated dose regimen ( 페그인터페론알파-2a 90 μg/wk, 또는페그인터페론알파-2b 0.5 μg/kg/wk와리바비린 600 mg/d로시작하여표준용량혹은최대한견딜수있는용량에도달할때까지 2주마다증량 ) 에따르는것이신중한접근이다. 374 CTP 분류 C의환자들은사망을포함한위중한합병증의발생가능성이높아현재의페그인터페론알파와리바비린병합요법은금기이다. 374 그리고아직까지비대상성간경변증환자들에있어서 DAA의효과와안전성은입증되지않았다. 권고사항 1. CTP 분류 A에속하는대상성간경변증환자는비대상성간경변증으로의진행과간세포암종의발생등 HCV 감염으로인한장기합병증의가능성을줄이기위하여절대적금기증이없는한적극적으로항바이러스치료를고려한다. (A1) 2. 간경변증환자들은페그인터페론알파와리바비린병합요법중문맥압항진증및비장과다증과연관된혈액학적부작용이발생할확률이높아투약중철저한감시와이에대한대비가필요하다. (A2) 이때혈액학적부작용극복에성장인자의사용이도움을줄수있다. (C2) 3. 간경변증환자들은 SVR에도달한이후에도간경변증의합병증에대한추적과간세포암종발생에대한정기적감시검사를지속적으로받도록한다. (B1)

61 4. CTP 분류 B의환자들은경험이많은의사에의해조심스럽게치료를시도해볼수있으나부작용발생에주의하여야한다. (C2) 치료는페그인터페론알파와리바비린표준용량, 혹은저용량으로부터시작한다. (C2) 5. CTP 분류 C의환자들에서현재의페그인터페론알파와리바비린병합요법은사망을포함한위중한합병증발생가능성이높아권고하지않는다. (C1) C 형간염진료가이드라인 간이식및간외장기이식환자 1. 간이식후치료간이식당시 HCV 감염이있는환자들은감염이없는환자들에비해간이식후이식편소실률 (hazard ratio, 1.30; 95% CI, ) 과사망률 (hazard ratio, 1.23; 95% CI, ) 이유의하게높다. 375 간이식당시 HCV RNA가검출된환자의거의대부분에서이식후수시간이내에 HCV 재감염이일어난다. 376 HCV 관련간질환은간이식후악화속도가더욱빨라져대략 3분의 1의환자들이이식후 5년이내에간경변증으로진행한다. 375,377 하지만이식후 HCV를성공적으로퇴치하게되면이식편과환자의생존율을모두향상시킬수있다. 378 이식후 HCV에재감염된환자들은이식후 6개월이상경과하고조직학적으로만성 C형간염이증명된후에치료를시작할것이권장된다. 그이유는이식직후재감염된급성기의환자들은면역저하가심하고전신상태가아직회복되지않았을가능성이높으므로약제부작용에잘견디지못하고인터페론제제투여에의한이식거부반응발생위험성이높기때문이다. 이들에비해이식후 6개월이상경과한환자들은전신상태가호전되고부작용이나이식거부반응발생위험이줄어든다. 이식후에진행된간섬유화 (numerous septa without cirrhosis) 나문맥압항진증이발생하면간질환의급격한진행과이식편손실을예측할수있으므로조속히항바이러스치료를시작한다. 379,380 문맥압항진증이동반되지않은문맥역에국한된섬유화가있는경우라면항바이러스치료결정은치료성공가능성과합병증발생위험성을저울질하여결정한다. 이식후항바이러스치료로 SVR에도달할확률은 30-40% 정도이며, 유전자형 2형또는 3형이유전자형 1형에비해치료성적이우수하다. 378,381,382 그리고이식후환자에서페그인터페론알파와리바비린병합치료와페그인터페론알파단독요법의치료성적은유사한것으로보고되었는데 (SVR률, 각각 33% 와 38%) 이는리바비린에대한잦은부작용으로용량감소나중단이빈번하였기때문으로생각된다. 383 빈혈은치료중

62 대한간학회 단의가장흔한원인으로 recombinant erythropoietin의사용이추천된다. 381,382 이식거부반응은간혹인터페론알파사용과연관하여발생할수있다. 따라서항바이러스치료도중간기능이악화될때에는원인감별을위해간생검이필요하다. 간이식후재발한만성 C형간염환자들에있어서 boceprevir 혹은 telaprevir 삼제요법의치료중 24 주째 virological response는 50-60% 정도로보고되었다 간외장기이식후치료 HCV 감염이있는콩팥이식환자들은간섬유화의진행이빨라지고간관련사망률이증가하므로콩팥이식전에간경변증의존재여부를확인하여야한다. 385 간경변증의진단을위하여서는간혹간생검이필요한데, 말기신부전환자에서는혈소판기능장애로인한높은출혈경향때문에간생검시행에의한출혈성합병증의우려가있다. 하지만, 그간말기신부전환자에서경피적간생검후심각한부작용의발생은매우드물게보고되었으며, 정상신기능환자들에비해부작용의빈도가유의하게높지않았다. 386 출혈성합병증의우려가있는경우생검전 desmopressin (1-deamino-8-Darginine vasopressin, DDAVP) 0.3 mg/kg을투여하기도한다. 387 콩팥이식환자에서페그인터페론알파와리바비린치료를하게되면 30% 이상에서이식거부반응이일어나이식편손실과생존율감소로이어지므로생명을위협하는섬유화담즙정체성간염이발생한경우를제외하고는인터페론을포함한치료는절대금기이며, 콩팥이식대기자들은이식전에 HCV에대한치료를먼저받는것을고려한다. 388 심장이식환자에서 HCV 치료성적은한증례모음에서인터페론을이용한 2명의성공적인치료사례를보고하였으나 389 아직은자료가부족하여생명을위협하는섬유화담즙정체성간염을제외하고는치료를추천하지않는다. 그외에폐, 췌장이나소장, 각막이식환자에서의 HCV 치료에대한자료는전무하다. 권고사항 1. 간이식후 HCV에재감염된환자들은조직학적으로만성간염이확인된후에치료를시작할것이권장된다. (B2) 간이식후진행된간섬유화나문맥압항진증이발생하면간질환의급격한진행과이식편손실이예측되므로조속히항바이러스치료를시작한다. (B2) 항바이러스치료로는페그인터페론알파와리바비린병합요법, 또는페그인터페론알파단독요법을시행한다. (B2)

63 2. 인터페론알파투여와연관하여이식거부반응이발생할수있으므로항바이러스치료중간기능이악화될때에는원인감별을위하여간생검이필요하다. (C1) 3. 인터페론제제를포함한항바이러스치료는콩팥, 심장, 폐이식을받은환자에서는생명을위협하는섬유화담즙정체성간염이발생한경우를제외하고는절대금기이다. (C1) C 형간염진료가이드라인 면역억제제또는항암화학요법치료환자 HCV의재활성화의정의는아직공통적으로마련된기준이없으나대개는혈중 ALT와 HCV RNA를기준으로하며, 일부연구에서는 HCV RNA의재출현, 혹은상승과함께 ALT의 3배이상상승이있는경우로정의하였다. 390 면역억제제또는항암화학요법을받는환자에서 HCV의재활성화는 HBV에비하여그빈도가매우낮다고알려져있다 예를들어, 한연구에서는 B 세포비호치킨림프종환자 98명에서항암치료를하였을때 HBV 재활성화율은 38%(8명중 3명 ) 였던데에비해, HCV 재활성화율은0%(11 명중 0명 ) 였다. 395 하지만, 또다른 B 세포비호치킨림프종환자연구에서는, 만성 HCV 감염환자에서 ALT 상승빈도가 HCV 감염이없는환자에서보다유의하게높아 (26.3% 대 2.1%) HCV 재활성화가실제로일어나며임상적으로유의한합병증을일으킬수있음을시사하였다. 396 HCV 재활성화는혈액암환자에서더흔하게발생하는것으로보고되었으나 392,397 고형암이나조혈모세포이식환자에서도발생하며, 아직까지 HCV 재활성화를예측할수있는위험인자는알려지지않았다. HCV 재활성화와관련되어보고된사망례는매우적으나 402 일단 HCV의재활성화에의하여심한간염이발생하면그로인한사망률은 HBV의경우와유사하였다 면역억제제또는항암화학요법중에 HCV 재활성화를예방할수있는방법은아직까지밝혀지지않았고, 일단면역억제제또는항암화학요법도중에 HCV 재활성화가발생하면해당약제중단에따른불이익과 HCV 재활성화에따른위험성을개별적으로평가하여신중하게약제중단을고려하고보존적인치료를하도록한다. 추후새로운항바이러스제를이용하여면역억제제또는항암화학요법중 HCV 재활성화예방과치료를도모하기위한연구가필요하다

64 대한간학회 정맥주사약물남용자정맥주사약물남용은 HCV 전파의주된경로로서정맥주사약물남용자는약물사용력이없는사람에비하여유의하게높은 HCV 감염률을보인다. 114,406 국내정맥주사약물남용자에서 HCV 항체양성률은 % 로보고되었다. 22,24,407 한편, 정맥주사약물남용이아닌코카인흡입관을공유하는경우에도 HCV 감염률이정맥주사약물남용자처럼유의하게높다고알려져있다. 25 2,800명이상의정맥주사약물남용자자료를메타분석한결과를보면, 38.2% 의환자가정맥주사약물남용을계속하고있는상황에서페그인터페론알파와리바비린병합요법을하였을때 SVR률은유전자형 1형에서 44.9%, 유전자형 2, 3형에서 70.0% 였다. 408 정맥주사약물남용의과거력이있으나현재중단한만성 C형간염환자들에게는현재의표준치료를권고한다. 그러나현재정맥주사약물을사용중인환자들은치료의지, 피임및정기적인추적관찰에대한주의가부족하고, 치료중약물복용에대한순응도가떨어지며, 치료후정맥주사약물재사용에따른 HCV 재감염의위험이있으므로치료여부를결정할때환자의치료의지등을분명히평가해야한다. 그리고근거는약하지만일반적으로 6-12개월정도의약물중단기간이필요하다. 125 또한정맥주사약물남용중단을위한정신건강의학과, 사회사업과등다학제간협동치료를하면치료중단율이유의하게감소하였고, 408 이러한노력을통해 SVR에도달하면질병의진행억제를통한사회경제적인비용대비효과가있었다. 409 권고사항 1. 현재정맥주사약물을사용중인환자의경우정신과적인상담과약물남용, 사회적환경개선에관해다른전문가들과의협동치료가항바이러스치료의순응도를높일수있다. (B2) 만성콩팥병환자만성콩팥병환자에서 HCV의감염률은일반인에비하여높으나모든환자에게 HCV 항체검사를시행하지않으며, 혈뇨나단백뇨또는한랭글로불린혈증등 HCV 감염과관련된사구체신염의존재를의심할경우에선별적으로시행한다. 그러나유지

65 혈액투석을처음시행하려는환자나다른투석병원에서전원되는환자에서는 HCV 항체검사를반드시시행하여야한다. 혈액투석을받는환자들에서의 HCV 유병률은지역에따라 3% 에서 80% 까지다양하게보고되는데, 410 국내유병률은 5-15% 로보고된다. 26,27 또한기존의투석환자의경우에도설명되지않는 ALT 이상이확인되거나 HCV에노출이의심될때는 HCV 항체검사를시행하여야하고, 반복해서검사해도음성이면 HCV RNA 검사를해야한다. 378 HCV 항체검사가음성인환자의추적검사간격은환자가속한투석병원의 HCV 감염률을고려하여야하며통상 6-12개월간격으로시행할것을추천한다. HCV에감염된혈액투석환자는간경변증또는간세포암종으로의진행이빠르고, 혈액투석을받지않는환자에비하여유의하게높은사망률을보인다 콩팥이식을예정하고있는환자에서는 HCV 항체검사를반드시시행하여야한다. 이는 HCV 감염자는비감염자에비해콩팥이식을받은경우생존율이낮을뿐아니라이식후당뇨와막성콩팥염의발생도증가하지만콩팥이식후인터페론치료는이식콩팥에대한거부반응을유발할수있기때문이다 따라서, 만성콩팥병환자들은 HCV RNA 검사를통해감염이확인되면콩팥이식의필요성이임박하기전에인터페론을기반으로한항바이러스치료를고려하여야한다. 378 만성콩팥병환자에서 C형간염치료의적응증은일반환자와마찬가지로간질환의상태및치료의부작용등을고려하여결정한다. 그러나현재 HCV 항바이러스제로사용되는페그인터페론알파와리바비린은콩팥기능장애에따르는약제배설장애가발생하므로두약제모두콩팥기능의장애정도에따라용량조절이필요하다. 아울러리바비린은혈액투석을통하여제거되지않기때문에만성콩팥병환자들에서는심한용혈성빈혈을유발할수있어크레아티닌청소율이 50 ml/min 이하인경우에는리바비린사용시에주의를요한다. 421 경한콩팥질환 ( 사구체거름률 60 ml/min) 에서는콩팥질환이없는경우와동일하게투약하도록하며, 투석전단계의콩팥기능장애를가진경우 ( 사구체거름률 ml/min) 에는페그인터페론알파-2a 135 μg 또는페그인터페론알파-2b 1 μg/ kg과함께리바비린 mg/d을하루두번으로나누어서투여하되소량에서점차증량해가는방법이권고된다. 378 투석을받는환자에서는인터페론알파, 또는페그인터페론알파를투여할수있으며, 리바비린병용은일반적으로권장되지않는다. 투석중인환자에서페그인터페론알파-2a (135 μg/wk) 와저용량의리바비린 (200 mg/d) 병합요법을시도해본연구결과 SVR률이 7-97% 로다양하며치료중단율이높았다. 새로운 HCV 치료제인 boceprevir와 telaprevir는주로간에서대사가이루어지고, 그대사산물은주로대변으로배설되며극히일부만소변으로배설되므로만성콩팥병 C 형간염진료가이드라인

66 대한간학회 환자에서약제의용량조절은필요하지않다. 422 아직 HCV에감염된만성콩팥병환자에서이러한약제들의 SVR률은보고되지않았다. HCV 감염과연관된한랭글로불린혈증이나막성증식성사구체신염등이있는환자에서는 HCV 항바이러스치료를시행한다. 이환자중신증후군이나급격한콩팥기능의감소가있는경우및혈관염의심한전신적소견이있는환자에서는면역억제제투여나혈장교환등의치료를 HCV 항바이러스치료에선행하여시행할수있다 권고사항 1. 혈액투석이나콩팥이식등의콩팥대체치료를준비하는만성콩팥병환자에서는향후치료와관리를계획하기위하여 HCV 항체검사를시행한다. (B1) 2. HCV 항체양성인경우, 또는음성이지만원인불명의간질환을가진만성콩팥병환자에서는 HCV 감염을확인하기위하여혈중 HCV RNA를검사한다. (B1) 3. 혈액투석을요하지않는중한콩팥기능장애 ( 사구체거름률 ml/min) 가있는만성 C형간염환자에서는부작용을면밀하게관찰하면서감량된페그인터페론알파 (2a, 135 μg/wk, 또는 2b, 1 μg/kg/wk) 와리바비린 ( mg/d) 병합요법을할수있다. (C2) 4. 투석중인만성 C형간염환자에서는인터페론알파 (2a, 또는 2b 300만 unit, 주 3회 ), 또는감량된페그인터페론알파 (2a, 135 μg/wk, 또는 2b, 1 μg/kg/wk) 단독으로치료할수있다. (C2) 중복감염환자 1. HIV 중복감염환자서구 HIV 감염자에서는약 25%, 28 국내 HIV 감염자의 % 가 HCV에중복감염되어있는것으로보고되었다. 29,30,426 HIV와 HCV의중복감염빈도가비교적높기때문에모든 HIV 감염자에서는 HCV에대한검사를시행하여야하는데일차적으로는 HCV 항체검사를시행한다. 그러나, HIV 감염자의약 6% 에서는 HCV 항체가생성되지않을수있으므로 HCV 항체음성이지만원인불명의간질환을가진 HIV 감염자에서는 HCV RNA 검사를시행하여야한다. 427,428 HCV 감염자에서 HIV에대한위험인자를가진사람은 HIV 검사를시행한다

67 HIV와 HCV의중복감염자는단독감염자에비하여간질환의진행이유의하게빠르고, 간경변증발생률도약 2배높다. 따라서 1996년 highly active antiretroviral therapy (HAART) 의도입이후로 HCV에의한간질환은 HIV 감염자에서사망률과이환율에영향을미치는중요한원인으로대두되고있다 특히 CD4 양성림프구수가낮고면역기능의장애가심할수록간질환의진행속도가빨라지고, 432 항레트로바이러스치료로면역기능이회복되면간질환의진행을늦출수있다 일반적으로 HIV 중복감염자에서는 CD4 양성림프구수와상관없이항레트로바이러스치료를권유하는데, 이는항레트로바이러스치료의이득이약제독성의가능성보다크기때문이다. 하지만 HIV와 HCV 중복감염자에서는항레트로바이러스치료후간독성의발생위험이높고, 특히진행된간질환환자에서이러한위험성이더높으므로주의가필요하다. 436,437 HIV 중복감염자에서는 CD4 양성림프구수가낮으면 (< 200 cells/mm 3 ) 먼저항레트로바이러스치료를시작하고, CD4 양성림프구수가상승한후에 HCV 치료를하는것이바람직하다. 한편, CD4 양성림프구수가 > 500 cells/mm 3 인환자에서는 HCV 치료를먼저하고항레트로바이러스치료를연기하기도한다. 438 HIV 중복감염자에서 HCV 치료에사용되는페그인터페론알파는 HCV 단독감염자에서권해지는용량과동일하게, 리바비린은유전자형에관계없이체중에따라용량을조절하며 (75 kg 미만은 1,000 mg/d, 75 kg 이상은 1,200 mg/d), 439 치료기간은일반적으로 48주를권한다. 유전자형 2, 3형에서 RVR이있는경우 24주단축치료도효과적일수있으며, 유전자형 1, 4형에서 pevr이있었으나 RVR이없었던경우치료기간을 60-72주까지연장하는것이도움이될수있다. 114, HIV 중복감염자에서페그인터페론알파와리바비린의병합요법시에 SVR률은유전자형 1형에서 29%, 유전자형 2, 3형에서는 62% 로보고되었다. 444 이는 HCV 단독감염자에비하여낮은경향을보이는데, HCV 단독감염자에비하여 HIV 중복감염자에서일반적으로혈중 HCV RNA 농도가높음과관련이있다 HIV 중복감염자의치료시에는단독감염자와비교하여리바비린과연관된빈혈이중요한문제로대두되는데, 특히 zidovudine (AZT) 을복용하는환자에서빈혈이더흔하고심하게나타난다. 449 리바비린은 inosine-5-monophosphate dehydrogenase 를억제하여 didanosine (ddi) 독성을더악화시킬수있고, 리바비린과 ddi를같이복용하는환자들에서심한젖산증이보고되었다 따라서, HCV와중복감염된 HIV 환자는 AZT와 ddi를피하여다른항레트로바이러스제들을선택하는것이좋다. 이들환자군에서 boceprevir를포함한삼제치료시 SVR률은 60.7% 로표준병합요법의 26.5% 보다우수하였으며, telaprevir 를포함한삼제치료시에도 SVR률은 74% 로 C 형간염진료가이드라인

68 대한간학회 표준병합요법의 45% 보다우수하였다. 삼제치료의부작용은 HCV 단독감염자에서와 HIV 중복감염자에서유사한것으로보고되었으나, 추가연구가필요하다. 454 또한 boceprevir나 telaprevir 를사용할경우약물상호작용이다양하게발생할수있으므로약물사용에주의를요하며세심한모니터링이필요하다. 422 권고사항 1. 모든 HIV 감염자는 HCV 항체검사를시행하여야한다. (B1) 2. HCV 항체양성인경우, 또는음성이지만원인불명의간질환을가진 HIV 감염자에서는 HCV 감염을확인하기위하여혈중 HCV RNA를검사한다. (B1) 3. HIV 중복감염자에서만성 C형간염의치료는 HCV 단독감염자에서사용되는용량의페그인터페론알파와 HCV 유전자형에관계없이체중에따라조절된리바바린병합요법으로 48주간시행한다. (B1) 2. HBV 중복감염환자 HBV/HCV 중복감염자는전세계적으로약 1천 5백만명가량으로추산되는데, 455 국내에서는 HCV 항체양성자의 2.37% 에서 HBV 중복감염이있는것으로보고되었다 년이상의추적관찰을통한자료에서 HCV 단독감염자에서의간세포암종발생률은 28%, HBV/HCV 중복감염자에서의간세포암종발생률은 45% 로, 중복감염자에서간세포암종의발생률이유의하게높았다. 457 또한 HBV 감염자에서도 HCV 중복감염이있으면 HBV 단독감염에비해중증간염과전격간염의위험도가증가하고간경변증및간세포암종의발생률이높아진다 HBV 중복감염자에서는 HBV와 HCV의증식상태를각각평가하고, HCV 감염이간질환의주원인이라면 HCV 단독감염의경우와동일하게치료를권하며, 이경우 SVR은 HCV 단독감염자에서의성적과유사하다 HCV의치료중, 또는치료후 HCV RNA가제거된이후에 HBV의재활성화가일어날수있으며, 456 HBV의유의한증식이확인되면이에대한경구용항바이러스제를투약할수있다

69 권고사항 1. HBV/HCV 중복감염자에서는어떤바이러스가간질환의원인이되는지를확인한후단독감염과동일한기준에의하여치료를권고하며, C형간염의치료중또는후에 HBV의유의한증식이확인되면 HBV에대한경구용항바이러스제의투약을고려한다. (B1) C 형간염진료가이드라인 혈우병 / 지중해빈혈증 (Hemophilia/Thalassemia) 혈우병이나지중해빈혈증환자들에서 HCV 감염이동반되면 HCV 감염이없는경우에비하여사망률과이환율이유의하게높아진다 따라서이들에서도 HCV 치료를적극적으로고려하여야하며, 페그인터페론알파와리바비린의병합요법이권고된다. 혈우병을동반한 HCV 환자와동반하지않은 HCV 환자에서의치료성적은유사하였으며, 출혈과동반된부작용의차이도보이지않았다. 470 지중해빈혈증환자에서는리바비린에의해심한빈혈이발생할수있고수혈을요하는경우가 30-40% 에달하며혈색소치를 9-10 g/dl로유지하기위해 3-4주마다수혈이필요할수있는것으로보고되어치료중혈액학적부작용을확인하기위한주의깊은모니터링이필요하다. 그러나이환자들에서실제로치료중단이나다른주요부작용이더증가되지는않았다. 465 권고사항 1. 혈우병이나지중해빈혈증을동반한만성 C 형간염환자에서는페그인터페론알파와 리바비린의병합요법을권고한다. (B1) 소아 1996년 6-11세소아 2,080명을대상으로시행한국내연구에서 HCV 항체양성률은 0.82% 였다. 20 소아에서의 HCV 감염은수혈이나수직감염에의한경우가가장흔한원인으로, 471 수혈후발생하는 C형간염환자는 1991년선별검사도입이후국내소아연령에서는거의보고되지않았다. 산모에서 HCV 감염률은 % 이며,

70 대한간학회 국내 5천명과 2만명이상의산모를대상으로한연구에서 HCV 항체양성률은 % 로, HCV 항체양성인산모의 57-60% 에서 HCV RNA 양성이었다. 18,19 주산기동안 HCV 전파는 1-6.2% 로보고되었는데 65,67,472,473 제왕절개법으로분만을해도 HCV 전파의위험성이낮아진다는근거는약하다. 474 HCV 감염산모의모유에서 HCV가확인되기는하지만모유를통해서 HCV가전파된다는근거는없기때문에 HCV 감염산모에서의모유수유는금지되지않으며, 소아에서소아로의수평감염은드물어학교생활이나운동등의일상적인활동을제한할필요는없다. 474 산모에서생성된항체가신생아에게전달될수있으므로, 소아에서의항체검사는 18개월이넘어서하도록권고된다 조기진단을원하는경우에는출생후 1-2개월이지난후에 HCV RNA 검사를시행할수있으나출생시 HCV RNA 검사의민감도는 22% 로낮으므로민감도가 85% 가되는생후 6개월이후에검사하는것이바람직하다. 475,477 소아에서의 HCV 감염의자연경과는성인에비하여좀더높은빈도로자연적관해가이루어지고, 정상 ALT를보이는경향이높으며, 478 섬유화진행속도도느리고심한형태의간손상을보이는경우도드물다. 하지만, 소아환자들은성인에비해비교적규칙적인일과를보내고치료순응도가높은경향을보이므로성인이될때까지기다리지않고적극적으로치료를하자는의견도있다. 지속적으로혈청 AST 또는 ALT가높거나간생검에서진행된간섬유화로평가된경우치료를적극적으로고려하고, 혈청 AST 또는 ALT가정상이거나간생검에서섬유화가경하더라도소아에서는질병의진행을예측할수있는수단이충분하지못하므로치료를고려할수있다. 479 소아에서의치료에관한과거연구에서는리바비린의기형발생잠재력때문에인터페론알파단독치료에국한되어있었지만, 리바비린을추가하였을때인터페론알파단독치료와비교하여더높은 SVR률이보고되었고, 성인에서페그인터페론알파와리바비린병합요법이표준치료법이된후소아에서도대부분의연구에서페그인터페론알파와리바비린을사용하고있다. 북미와유럽에서는 3세이상의소아에서도페그인터페론알파의사용이허용되었다. 479 소아에서페그인터페론알파는 2b 는 60 μg/m 2 /wk의용량으로, 2a는 180 μg/1.73 m 2 /wk의용량으로사용되며, 리바비린은 15 mg/kg/d의용량으로하루 2회나누어복용하도록한다. 성인에서와마찬가지로유전자형 1, 4형에서는 48주동안, 유전자형 2, 3형에서 24주동안투약한다. 479 소아에서의페그인터페론알파와리바바린병합요법후 SVR은인터페론알파와리바비린병합요법의결과보다우수하여유전자형 1형에서 47-53%, 유전자형 2, 3형에서 % 로보고되었다 좋은 SVR을예측할수있는인자는유전자형 2, 3형과 HCV RNA농도 < 600,000 IU/mL이다. 480,483,484 Boceprevir나 telaprevir 는소아나 18세미만

71 의청소년들에게는그안정성과효과가아직입증되지않았다. 422 권고사항 1. HCV 감염이의심되는소아에서의진단및평가는성인에서와동일하게진행한다. (B1) 2. 신생아에서 HCV 감염을확인하기위한 HCV 항체검사는산모에서생성된항체가신생아에게로전달될수있으므로생후 18개월이상지난이후에시행할것을권고한다. 조기진단을원하는경우출생후 6개월이지난후에 HCV RNA 검사를시행할수있다. (B2) 3. HCV에감염된 3세이상소아에서치료대상여부평가는성인과동일한기준을따른다. (B1) 4. 소아에서의치료는페그인터페론알파-2b, 60 μg/m 2 /wk, 또는페그인터페론알파-2a, 180 μg/1.73 m 2 /wk와리바비린 15 mg/kg/d를유전자형 1, 4형에서는 48주간, 유전자형 2, 3형에서는 24주간투여한다. (B1) C 형간염진료가이드라인

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110 대한간학회 별첨 1 C 형간염진료가이드라인요약 예방 1. HCV에감염된사람이혈액, 장기, 조직, 정액등을공여하지않도록한다. (A1) HCV에감염된사람은칫솔, 구강위생용품, 면도기, 손톱깎이및피부에상처를줄수있는도구를개별사용하고출혈이있는상처는다른사람에게혈액노출이되지않게관리하도록교육한다. (C1) 2. 정맥주사약물남용자에게는이를중단하도록권한다. (A1) 이들에게 HCV 감염경로에대해교육하고 HCV 감염여부를정기적으로검사하도록한다. (B1) 3. 의료행위및문신, 피어싱, 침술을포함한침습적시술을시행할경우일회용또는적절히소독된재료를사용하고도구들에대한적절한세척과소독이필요하다. (B1) 4. HCV에감염된사람이한명의상대방과지속적인성관계를가지고있는경우에는 HCV가성행위를통해전염될가능성이낮으므로 C형간염이있다는이유만으로성행위방식을바꾸는것은추천하지않는다. (B1) 그러나, 성행위상대방이다수인경우에는 HCV 감염을예방하기위해콘돔을사용할것을권한다. (B1) 5. 임산부의산전진찰동안 HCV 감염의위험인자가발견되거나 C형간염이의심되면 HCV 항체검사를시행하여야한다. (B1) HCV에감염되었다고해서임신이나모유수유를제한하거나제왕절개와같은특정한출산방법을선택하도록권유하지는않는다. (B2) 자연경과 1. 만성 C형간염환자들은간경변증과간세포암종발생에대한지속적인관리가필요하다. (A1) 2. 알코올, 비만, 인슐린저항성은질병의진행과연관이있으므로, 만성 HCV 감염자들에게단주또는절주를권하고, (B1) 운동과식이조절을통해적정체중을유지하도록한다. (B1)

111 3. HBV 와 HAV 에대한항체가없는만성 HCV 감염자들은 HBV 와 HAV 에대한예 방접종을시행한다. (C1) 진단및중증도평가 C 형간염진료가이드라인 1. 급성또는만성간염이의심되면 HCV 감염여부확인을위해 HCV 항체를검사한다. (A2) 2. HCV 항체양성자에서는혈중 HCV RNA를검사하여 HCV 감염을확진한다. (A1) 3. HCV 항체는음성이어도급성 C형간염이의심되거나면역억제상태에서원인미상의간질환이있으면혈중 HCV RNA를검사한다. (B1) 4. 항바이러스치료전에는 HCV RNA 정량검사와 HCV 유전자형검사를시행한다. (A1) 5. HCV 감염혈액이나체액에노출된경우즉시 HCV 항체와혈청 ALT를검사하며, HCV 항체가음성이면조기진단을위해 4-6주에 HCV RNA 검사를시행하고, 초기검사에서모두음성이더라도노출후 4-6개월에 HCV 항체와혈청 ALT 추적검사를한다. (B2) 6. 항바이러스치료전에간질환중증도를평가한다. (B1) 7. 항바이러스치료시작시기결정과예후판정을위해간생검을시행할수있고, (B2) 비침습적간섬유화검사를사용할수있다. (C2) 치료목표 1. 만성 C형간염치료의궁극적목표는 HCV를박멸하여 HCV 감염으로인한간경변증의합병증과간세포암종의발생및이로인한사망을예방하는것이다. (A1) 2. 만성 C형간염의단기치료목표는치료종료 24주째검출한계 50 IU/mL 이하의예민한검사법으로혈중 HCV RNA가검출되지않는상태인 SVR에도달하는것이다. (A1) 치료대상 1. 치료금기가없는모든만성 C 형간염환자는치료의대상으로고려한다. (A2)

112 대한간학회 2. 치료여부는간질환의중증도, 치료성공확률, 심각한부작용발생가능성, 동반 질환유무, 환자의치료의지등을종합적으로고려하여개별화해야한다. (B1) 치료반응의정의 1. 치료중각개인의치료반응을평가하고치료기간을결정하기위하여 HCV 유전자형에따라치료 4주, 12주, 24주등에검출한계 50 IU/mL 이하의예민한검사법으로혈중 HCV RNA 검사를시행하여야한다. (B1) 2. 만성 C형간염에대한항바이러스치료의효과를평가하기위하여치료종료시점과종료후 24주째에혈중 HCV RNA를측정하여 SVR 도달여부를확인하여야한다. (A1) 유전자형 1형또는 4형만성 C형간염의치료 1. 치료경험이없는유전자형 1 형또는 4형만성 C형간염의항바이러스치료 1) 페그인터페론알파와리바비린을병합하여 48주간투여한다. (A1) 페그인터페론알파-2a는체중에관계없이 180 μg을주 1회피하주사하고, 리바비린은 75 kg 이하이면 1,000 mg, 75 kg을초과하면 1,200 mg을매일경구투여한다. 페그인터페론알파-2b는 1.5 μg/kg로주 1회피하주사하고, 리바비린은체중이 65 kg 미만은 800 mg, kg은 1,000 mg, kg은 1,200 mg, 105 kg을초과하면 1,400 mg을투여한다. (A1) 2) 유전자형 1형은치료 4주째 RVR이있고치료전 HCV RNA 농도가 400,000 IU/mL 미만이며치료실패예측인자 ( 진행된간섬유화또는간경변증, 비만이나인슐린저항성등 ) 가없는경우 24주간의단축치료를고려한다. (B1) 3) 유전자형 4형은 RVR이있으면치료전바이러스농도에상관없이 24주간치료를고려할수있다. (B2) 4) 치료 12주째 EVR이없으면치료를중지한다. (A1) cevr이있으면 48주간치료한다. (A1) pevr인경우는치료 24주째 HCV RNA 검사를하여음전되지않으면치료를중지하고, (A1) 음전되면 72주로연장치료를고려할수있다. (B2) 2. 치료경험이있는유전자형 1형또는 4형만성 C형간염의항바이러스치료 1) 이전에인터페론알파단독, 인터페론알파와리바비린병합요법, 또는페그인

113 터페론알파단독으로치료한경험이있는환자에서재발했거나치료무반응인경우페그인터페론알파와리바비린병합요법으로재치료를고려할수있다. (B2) 2) 이전에페그인터페론알파와리바비린병합요법으로치료하였으나치료에실패한경우에는동일한약제로재치료하는것은권장되지않는다. (A2) 3) 페그인터페론알파와리바비린병합요법으로치료실패한경우저용량페그인터페론알파유지요법은권장되지않는다. (A1) 3. 유전자형 1형환자의초치료및재치료에서페그인터페론알파및리바비린과함께 boceprevir 또는 telaprevir를포함하는 3제요법이권장된다. (A1) 추후더효과적인 DAA 치료에대한연구결과에따라우리나라환자들에서도이러한약제들을포함한치료법을적용하는것이바람직하다. C 형간염진료가이드라인 유전자형 2, 3형만성 C형간염의치료 1. 치료경험이없는유전자형 2, 3형만성 C형간염의항바이러스치료 1) 페그인터페론알파와리바비린을 24주간투여한다. (A1) 2) 페그인터페론알파-2a는 180 μg을, 페그인터페론알파-2b는 1.5 μg/kg을주 1 회피하주사한다. (A1) 리바비린은체중에관계없이 800 mg을매일경구투여한다. (A2) 3) 치료 4주째 RVR이있고다른치료실패예측인자가없는경우에는치료기간을 16주로단축하는것을고려할수있다. (B2) 단, 치료기간을단축하는경우에는 24주치료에비해재발률이높음에주의한다. (A2) 2. 치료경험이있는유전자형 2, 3 형만성 C형간염의항바이러스치료 1) 이전에인터페론알파단독, 인터페론알파와리바비린병합요법, 또는페그인터페론알파단독으로치료했으나재발또는치료무반응인경우페그인터페론알파와리바비린병합요법으로재치료할수있다. (B2) 2) 이전에페그인터페론알파와리바비린병합요법으로치료하였으나무반응이었던경우동일한약제로재치료하는것은권장하지않는다. (B2) 유전자형 6 형만성 C 형간염의항바이러스치료 1. 치료경험이없는유전자형 6 형만성 C 형간염의항바이러스치료

114 대한간학회 1) 페그인터페론알파와리바비린을 24주간투여한다. (A1) 2) 페그인터페론알파-2a는체중에관계없이 180 μg을, 페그인터페론알파-2b는 1.5 μg/kg을주 1회피하주사한다. (A1) 리바비린은페그인터페론알파-2a와함께투여할경우에는환자의체중이 75 kg 이하이면리바비린 1,000 mg, 75 kg 이상이면 1,200 mg을매일경구투여하며, 페그인터페론알파-2b와함께투여할경우에는체중 65 kg 미만은 800 mg, kg은 1,000 mg, kg은 1,200 mg, 그리고 105 kg을초과하면 1,400 mg을경구투여한다. (B2) 급성 C형간염의치료 1. 급성 C형간염환자에서는항바이러스치료를고려한다. (A1) 2. 치료시작시점은자연관해의기회를갖도록급성간염진단후 8-12주연기할수있다. (B2) 3. 급성 C형간염의치료는페그인터페론알파단독치료를우선적으로고려하며, (B1) 치료기간은 24주로한다. (B2) 치료부작용모니터링과대처 1. 치료부작용및독성을모니터링하기위해치료전우울증, 심장질환, 폐질환, 고혈압, 당뇨, 갑상선질환, 빈혈등에대한사전검사가필요하다. (B1) 2. 치료시작후 2-4주에, 그이후에는약 4-12주간격으로치료부작용에대한정기적인경과관찰이필요하다. (C1) 3. 절대호중구수가 750/mm 3 미만으로감소하거나혈소판수가 50,000/mm 3 미만으로감소하면페그인터페론알파의용량감량을고려하며, 절대호중구수가 500/mm 3 미만으로감소하거나혈소판수가 25,000/mm 3 미만으로감소하면페그인터페론알파의투여중단을고려한다. 이후적절히회복되면감량된용량으로다시시작할수있고, 절대호중구수와혈소판수를지속관찰한다. (C2) 4. 혈색소 10 g/dl 미만의빈혈이발생하면리바비린을감량하고, 혈색소가 8.5 g/ dl 미만으로감소하면리바비린투여를중지한다. 이후빈혈이호전되면감량된용량으로리바비린을다시투여할수있고, 혈색소를지속관찰한다. (C2) 5. 갑상선염발생여부를확인하기위해서약 2-4개월마다 TSH와 free thyroxine 값을측정한다. (C1)

115 6. 치료중에우울증이발생하는경우적절한개입이필요하며증상이심한경우치 료를중단한다. (C1) 치료후모니터링 C 형간염진료가이드라인 1. SVR에도달한경우, 추적검사에서혈중 HCV RNA가지속적으로검출되지않으면 SVR이유지되는것으로본다. (C1) 2. SVR에도달한경우에도치료전에진행된간섬유화가있는경우, 만성간염에준한지속적인관리가필요하다. (B1) 3. SVR에도달하지못한경우, 만성간염에준한지속적인관리가필요하다. (B1) 특수상황에서의치료 간경변증 1. CTP 분류 A에속하는대상성간경변증환자는비대상성간경변증으로의진행과간세포암종의발생등 HCV 감염으로인한장기합병증의가능성을줄이기위하여절대적금기증이없는한적극적으로항바이러스치료를고려한다. (A1) 2. 간경변증환자들은페그인터페론알파와리바비린병합요법중문맥압항진증및비장과다증과연관된혈액학적부작용이발생할확률이높아투약중철저한감시와이에대한대비가필요하다. (A2) 이때혈액학적부작용극복에성장인자의사용이도움을줄수있다. (C2) 3. 간경변증환자들은 SVR에도달한이후에도간경변증의합병증에대한추적과간세포암종발생에대한정기적감시검사를지속적으로받아야한다. (B1) 4. CTP 분류 B의환자들은경험이많은의사에의해조심스럽게치료를시도해볼수있으나부작용발생에주의하여야한다. (C2) 치료는페그인터페론알파와리바비린표준용량, 혹은저용량으로부터시작한다. (C2) 5. CTP 분류 C의환자들에서현재의페그인터페론알파와리바비린병합요법은사망을포함한위중한합병증발생가능성이높아권고하지않는다. (C1) 간이식및간외장기이식환자 1. 간이식후 HCV 에재감염된환자들은조직학적으로만성간염이확인된후에치

116 대한간학회 료를시작할것이권장된다. (B2) 간이식후진행된간섬유화나문맥압항진증이발생하면간질환의급격한진행과이식편손실이예측되므로조속히항바이러스치료를시작한다. (B2) 항바이러스치료로는페그인터페론알파와리바비린병합요법, 또는페그인터페론알파단독요법을시행한다. (B2) 2. 인터페론알파투여와연관하여이식거부반응이발생할수있으므로항바이러스치료중간기능이악화될때에는원인감별을위하여간생검이필요하다. (C1) 3. 인터페론제제를포함한항바이러스치료는콩팥, 심장, 폐이식을받은환자에서는생명을위협하는섬유화담즙정체성간염이발생한경우를제외하고는절대금기이다. (C1) 정맥주사약물남용자 1. 현재정맥주사약물을사용중인환자의경우정신과적인상담과약물남용, 사회적환경개선에관해다른전문가들과의협동치료가항바이러스치료의순응도를높일수있다. (B2) 만성콩팥병환자 1. 혈액투석이나콩팥이식등의콩팥대체치료를준비하는만성콩팥병환자에서는향후치료와관리를계획하기위하여 HCV 항체검사를시행한다. (B1) 2. HCV 항체양성인경우, 또는음성이지만원인불명의간질환을가진만성콩팥병환자에서는 HCV 감염을확인하기위하여혈중 HCV RNA를검사한다. (B1) 3. 혈액투석을요하지않는중한콩팥기능장애 ( 사구체거름률 ml/min) 가있는만성 C형간염환자에서는부작용을면밀하게관찰하면서감량된페그인터페론알파 (2a, 135 μg/wk, 또는 2b, 1 μg/kg/wk) 와리바비린 ( mg/d) 병합요법을할수있다. (C2) 4. 투석중인만성 C형간염환자에서는인터페론알파 (2a, 또는 2b 300만 unit, 주 3 회 ), 또는감량된페그인터페론알파 (2a, 135 μg/wk, 또는 2b, 1 μg/kg/wk) 단독으로치료할수있다. (C2) HIV 중복감염환자 1. 모든 HIV 감염자는 HCV 항체검사를시행하여야한다. (B1)

117 2. HCV 항체양성인경우, 또는음성이지만원인불명의간질환을가진 HIV 감염자에서는 HCV 감염을확인하기위하여혈중 HCV RNA를검사한다. (B1) 3. HIV 중복감염자에서만성 C형간염의치료는 HCV 단독감염자에서사용되는용량의페그인터페론알파와 HCV 유전자형에관계없이체중에따라조절된리바바린병합요법으로 48주간시행한다. (B1) C 형간염진료가이드라인 HBV 중복감염환자 1. HBV/HCV 중복감염자에서는어떤바이러스가간질환의원인이되는지를확인한후단독감염과동일한기준에의하여치료를권고하며, C형간염의치료중또는후에 HBV의유의한증식이확인되면 HBV에대한경구용항바이러스제의투약을고려한다. (B1) 혈우병 / 지중해빈혈증 1. 혈우병이나지중해빈혈증을동반한만성 C 형간염환자에서는페그인터페론알 파와리바비린의병합요법을권고한다. (B1) 소아 1. HCV 감염이의심되는소아에서의진단및평가는성인에서와동일하게진행한다. (B1) 2. 신생아에서 HCV 감염을확인하기위한 HCV 항체검사는산모에서생성된항체가신생아에게로전달될수있으므로생후 18개월이상지난이후에시행할것을권고한다. 조기진단을원하는경우출생후 6개월이지난후에 HCV RNA 검사를시행할수있다. (B2) 3. HCV에감염된 3세이상소아에서치료대상여부평가는성인과동일한기준을따른다. (B1) 4. 소아에서의치료는페그인터페론알파-2b, 60 μg/m 2 /wk, 또는페그인터페론알파-2a, 180 μg/1.73 m 2 /wk와리바비린 15 mg/kg/d를유전자형 1, 4형에서는 48 주간, 유전자형 2, 3형에서는 24주간투여한다. (B1)

118 대한간학회 별첨 대한간학회 C 형간염진료가이드라인개정경과 2013년 2월 12일 2013 대한간학회 C형간염진료가이드라인개정위원구성개정위원장 : 정숙향 ( 서울의대 ) 개정위원 : 김인희 ( 전북의대 ), 역학, 예방과자연경과김영석 ( 순천향의대 ), 진단및중증도평가김경아 ( 인제의대 ), 치료목표와대상, 치료반응의정의와예측인자이연재 ( 인제의대 ), 유전자형 1, 4형만성 C형간염의치료 ( 초치료및치료경험군 ) 이정일 ( 연세의대 ), 유전자형 2, 3, 6형만성 C형간염의치료 ( 초치료및치료경험군 ), 급성 C형간염의치료김창욱 ( 가톨릭의대 ), 치료부작용모니터링과대처곽금연 ( 성균관의대 ), 간경변증, 간이식및간외장기이식환자, 면역억제제또는항암화학요법치료환자정우진 ( 계명의대 ), 정맥주사약물남용자, 만성콩팥병환자, HIV, HBV 중복감염자, 혈우병, 지중해빈혈증환자, 소아 2013년 3월 16일 1차개정위원회 ( 대한간학회사무실 ) 2013년 5월 17일 2차개정위원회 ( 대한간학회사무실 ) 2013년 6월 22일 3차개정위원회 ( 대한간학회사무실 ) 2013년 8월 10일 4차개정위원회 ( 대한간학회사무실 ) 자문 : 김신우 ( 경북의대감염내과 ), 채동완 ( 서울의대신장내과 ), 최병호 ( 경북의대소아청소년과 ) 2013 년 9 월 1 일 5 차개정위원회 ( 대한간학회사무실 ) 2013 년 10 월 4 일 6 차개정위원회 ( 그랜드하얏트호텔 2 층남산홀 ) 2013 년 10 월 4 일대한간학회자문위원회개최 ( 그랜드하얏트호텔 2 층남산홀 )

119 자문위원 : 김동준 ( 한림의대 ), 김병익 ( 성균관의대 ), 김주현 ( 가천의대 ), 김홍수 ( 순천향의대 ) 백승운 ( 성균관의대 ), 이명석 ( 한림의대 ), 이영상 ( 울산의대 ), 이준성 ( 인제의대 ), 조몽 ( 부산의대 ), 최문석 ( 성균관의대 ), 최성규 ( 전남의대 ), 탁원영 ( 경북의대 ), 한광협 ( 연세의대 ), 황성규 ( 포천중문의대 ) C 형간염진료가이드라인 2013년 10월 22일대한간학회공청회개최 ( 서울삼성병원암센터지하 1층세미나실 1번 ) 2013년 11월 12일대한간학회이사회승인 2013년 11월 21일대한간학회추계학술대회에서발표 2014년월일가이드라인영문판 Clinical and Molecular Hepatology 게재

120 대한간학회 별첨 개정위원회위원들의최근 2 년의이해관계상충정보 정숙향 : 한국 MSD, 한국 BMS, 한국베링거잉겔하임, 한국 Gilead 의후원연구곽금연 : 한국 BMS 자문위원, 한국 Roche 후원강의김경아 : 한국 BMS 자문위원, 한국 MSD 후원강의김영석 : 한국 BMS, 한국 Gilead, 한국 Roche, 한국 MSD, 한국베링거잉겔하임, 파마넷코리아, 태평양제약, 한국오츠카, Celcion Co, Gambro, Kormipharm, 바이엘헬스케어후원연구, 한국로슈, 한국 BMS, 동아제약, 유한양행, 한국 Gilead, GSK, 한국오츠카후원강의김인희 : 한국 MSD, 한국 Gilead, 한국 Roche, 동아제약후원연구, 한국 BMS, 한국 Gilead, 유한양행후원강의김창욱 : BMS, 파미셀, 파마킹후원연구, 한국 BMS, 한국 Gilead, 한국 GSK, 한국 Roche, 한국 MSD, 한국오츠카, 동아제약, 유한양행후원강의이연재 : 한국 BMS, 한국 Roche, 한국 GSK 후원강의및임상연구, 한국베링거잉겔하임, 한국 MSD, 한국 Norvatis, Taiho 후원연구이정일 : 한국 MSD, 한국 BMS, 한국 Gilead, 한국 Bayer, 한국 Roche, KOWA Pharmaceutical Company, Eisai Pharmaceutical Company 후원연구 ; 한국 BMS, 한국 Gilead 후원강의 ; Gilead 자문위원정우진 : 한국 MSD, 한국 BMS, 바이엘코리아, 한국 Roche, 한독약품, 대웅제약의후원연구

121 C 형간염진료가이드라인 대한간학회 C 형간염진료가이드라인 발행인편집인인쇄일발행일 김창민정숙향 2013년 11월 17일 2013년 11월 20일 발행처대한간학회주소서울시마포구마포대로 53, A1201호 ( 마포트라팰리스 ) 전화 (02) 팩스 (02) 이메일 [email protected] 홈페이지 인쇄처 도서출판진기획서울특별시중구수표로 6 길 26 ( 동성빌딩 ) 전화 :(02) ( 代 ) 팩스 :(02) [email protected] 홈페이지