PG1 PG Course 2016 Management of Viral Chronic Liver Disease, Liver Cirrhosis, and Hepatocellular Carcinoma B 형간염의치료 충남대학교의학전문대학원소화기내과 주종석, 이병석 Jong Seok Joo, Byung Seok Lee Department of Gastroenterology and Hepatology, Chungnam National University School of Medicine, Daejeon, Korea The successful treatment of chronic hepatitis B infection was achieved in earnest in the early 1990s with the increasingly widespread use of interferons. Currently, pegylated interferon (PEG-IFN) and six oral antiviral agents are used in clinical situations. Although the ideal therapeutic target of antiviral agents is to remove the hepatitis B virus completely, current therapeutic agents are unable to remove the cccdna in hepatocytes, and are limited in terms of the development of resistance during long-term administration. Thus, a variety of drugs are under investigation in order to overcome this challenge. In this article, the natural course of hepatitis B infection is reviewed, together with indications for treatment, issues surrounding hepatitis B treatment and the management of hepatitis B management (past and present).various drugs under investigation are discussed. Key words: Hepatitis B virus, Treatment, Antiviral agents 서론 전세계적으로약 2억 4천만명이 B형간염바이러스에감염된것으로추산되며매년 78만명의환자들이간경변증, 간암을포함한합병증으로사망한다. 1 1990년대초반에인터페론이사용되면서부터본격적인만성 B형간염의치료가이루어졌고, 현재는페그인터페론과 6가지경구항바이러스제가임상에서사용되고있다. 만성 B형간염의이상적인치료는간염바이러스의완전한제거이지만현재의치료약제들은간세포내의 cccdna를제거할수없으며, 장기투여에내성발생가능성및안전성등이있어서이를극복하기위한약제들이연구중에있다. 본고에서는 B형간염의자연경과와치료의대상, 과거및현재의 B형간염의치료와현재연구중인다양한약제에대하여간단히살펴보고자한다. B 형간염의자연경과 (2015 대한간학회만성 B 형간염진료가이드라인에서발췌 ) 2015 년세계보건기구 (WHO) 는 B 형간염의자연경과에서간염바이러스보유자라는개념은삭제하였다. 2015 12
Byung Seok Lee 년에개정된대한간학회만성 B형간염진료가이드라인에서는자연경과를면역관용기 (immune tolerant phase), 면역활동기 (immune active phase), 면역비활동기 (immune control phase), 면역탈출기 (immune escape phase), HBsAg 소실기 (HBsAg clearance phase) 의 5단계로분류하였다. 2 각각의임상단계는다양한기간을나타내며, 반드시연속적으로나타나지는않으며, 항바이러스제치료의기준이나적응증에직접적으로연관된것은아니다. 3 1. 면역관용기 (immune tolerant phase) 면역관용기는주산기나유아기에감염된 HBsAg 양성인소아나청소년에해당된다. 전형적으로 HBeAg이양성이고 HBV DNA치가높으며, ALT치가정상이다. 조직검사에서염증이없거나경미하며, 섬유화로진행하지않거나진행속도가느리고, HBeAg 의자연소실은드물다. 4-7 2. 면역활동기 (immune active phase) 대부분의면역관용기감염자들은나이가들면서간염바이러스에대한면역반응이시작되어혈청 HBV DNA치가저하되고, HBeAg 양성, ALT치의지속적혹은간헐적상승을보이는면역활동기로이행된다. 8,9 간생검에서중등도이상의염증소견및다양한단계의섬유화가나타난다. 10 3. 면역비활동기 (immune control phase) 면역활동기에서 HBeAg의혈청전환이이루어진환자들의대부분은면역비활동기의단계로된다. 이시기에는 HBeAg이음성, HBe 항체로의혈청전환, ALT치가지속적으로정상이며, HBV DNA치가음전화또는 2,000 IU/mL 미만으로유지된다. 11-13 전형적인조직간생검소견은경한염증과섬유화이지만이전의심한염증과섬유화가있었던환자에서중등도이상의염증과섬유화가남아있을수도있다. 11,12 4. 면역탈출기 (immune escape phase) Anti HBe로의혈청전환이이루어진환자들중약 20% 정도에서는 HBeAg 음성, HBeAb 양성이지만 HBV DNA 치가 2,000 IU/mL 이상이고, ALT 치의상승과활동성의괴사성염증소견을보이는면역탈출기의임상단계로된다. 14 HBV DNA precore (PC) 혹은 basal core promotoer (BCP) 유전자부위에변이는 HBeAg 생성에실패하여음성을나타내게된다. 15-17 5. HBsAg 소실기 (HBsAg clearance phase) 매년 1-2% 의면역비활동기환자들에서 HBsAg이소실된다. HBV DNA가검출되지않으며, anti-hbs 의검출여부와관계없이 anti-hbc 가검출된다. HBsAg 의소실의의미는간경변증의진행위험성이낮아지지만이와별도로간세포암종의발생위험은지속적인것으로알려져있어서이에대한정기추적검사가꼭필요하다. 18-25 13
Postgraduate Course 2016 B 형간염치료약제 1. 인터페론알파 / 페그인터페론알파면역조절작용및바이러스억제효과가있다. 기존의인터페론에 PEG (polyethylene glycol) 분자를결합한페그인터페론은반감기가길게하여투여횟수를주 1회로줄임에도불구, 치료효과가우수하다. 26,27 페그인터페론알파는경구약제와비교하였을때치료기간이정해져있으며약제내성이없는장점이있지만많은부작용과반응률이낮다는단점이있다. 2. 라미부딘최초의경구항바이러스제로현재는일차약제로권고되고있지는않지만간경변증환자를대상으로시행한연구에서간세포암과간경변증합병증의위험도를유의하게낮춰주는이점이있었다. 28 하지만치료기간이길어질수록내성발생이높아 1년에 14-32%, 5년치료에 60% 이상의내성발현이있다. 28,29 3. 텔비부딘다른뉴클레오시드유사체와비교하여바이러스치료효과는약간우수하였으나내성발현율은 10-25% 로비교적높은편이었다. 30 임신안전성 B등급으로산모에서항바이러스치료가필요한경우에효과적이며안전한약제이다. 26 4. 클레부딘 뉴클레오시드계열로강력한바이러스억제효과와약제중단후바이러스억제효과의유지라는장점이있다. 31,32 그러나교차내성으로라미부딘치료경험환자에서내성발현율이높다. 33 5. 아데포비어뉴클레오티드유사체로 1년에 12%, 5년복용에 48% 의 HBeAg 혈청전환과우수한조직학적개선을나타났다. 34 또한혈청전환후높은유지율을나타내었다. 35 하지만높은내성발생과장기간사용시에신기능저하의문제가있어서주의해야한다. 6. 엔테카비어라미부딘, 아데포비어에비해바이러스억제효과가매우우수하고, 36,37 기본적인라미부딘내성변이 (M204V/I) 와추가변이가발생했을경우에만엔테카비어에대한감수성이현저히저하된다. 38 높은유전적장벽으로 6년간누적내성발생은 1.2% 로매우낮았다. 39 6년간엔테카비어를처방한장기간의연구결과에서 96% 에이르는환자들에서조직학적개선을나타내어 88% 의환자에서섬유화가개선되었다. 40 엔테카비어치료는간경변증환자에서합병증발생과간세포암의발생위험을의미있게낮추었다. 41 현재는엔테카비어의우수한항바이러스효과와낮은내성발생으로인하여초치료환자에서테노포비어와함께우선적으로권고된다. 14
Byung Seok Lee 7. 테노포비어 2012년에국내에출시된뉴클레오티드유사체로서다른어느항바이러스제보다강력한바이러스억제효능을나타낸다. 8년간장기투여한연구에서치료기간동안테노포비어의내성변이는나타나지않았으며 HBeAg 양성유무와관계없이항바이러스효과가우수하였다. 42 또한간경변증이있는만성 B형간염환자에서테노포비어를 5년간처방한경우 87% 의환자에서임상적, 조직학적으로간경변증이호전되었으며, 43 간세포암발생예측연구에서적어도 5년이상처방한경우간세포암의발생률을감소시킬수있을것으로예측되었다. 44 비록발생빈도는낮지만장기간사용시신기능의저하, 골밀도감소, 골다공증의악화에대한우려가있어서정기검사가이루어져야한다. B 형간염의치료대상 (2015 대한간학회만성 B 형간염진료가이드라인에서발췌 ) 2 1. HBeAg 양성만성 B형간염 1) 혈청 HBV DNA 20,000 IU/mL 인경우, AST 혹은 ALT가정상상한치의 2배이상이거나간생검에서중등도이상의염증괴사소견혹은문맥주변부섬유화이상의단계를보이면치료를권장한다. (A1) 자연적 HBeAg 혈청전환가능성이있으므로 3-6개월경과관찰후치료여부를고려할수있다. (B2) 그러나, 황달, 프로트롬빈시간의연장, 간성혼수, 복수등간부전이발생하거나우려되는경우에는즉각적인치료를고려한다. (B1) 2) 혈청 HBV DNA 20,000 IU/mL 이고 AST 혹은 ALT가정상상한치의 1-2배사이인경우, 추적관찰하거나간생검을시행하여중등도이상의염증괴사소견혹은문맥주변부섬유화이상의단계를보이면치료를권장한다. (A1) 3) 초치료약제로는테노포비어, 엔테카비어, 페그인터페론알파중하나의사용을권장한다. (A1) 2. HBeAg 음성만성 B형간염 1) 혈청 HBV DNA 2,000 IU/mL 인경우, AST 혹은 ALT가정상상한치의 2배이상이거나간생검에서중등도이상의염증괴사소견혹은문맥주변부섬유화이상의단계를보이면치료를권장한다. (A1) 2) 혈청 HBV DNA 2,000 IU/mL 이고 AST 혹은 ALT가정상상한치의 2배미만인경우, 추적관찰하거나간생검을시행하여중등도이상의염증괴사소견혹은문맥주변부섬유화이상의단계를보이면치료를권장한다. (A1) 3) 초치료약제로는테노포비어, 엔테카비어, 페그인터페론알파중하나의사용을권장한다. (A1) 3. 대상성간경변증 1) 혈청 HBV DNA 2,000 IU/mL 인경우, AST/ALT와관계없이치료를권장한다. (A1) 2) 혈청 HBV DNA <2,000 IU/mL 이라도 PCR 검사양성인경우, AST/ALT와관계없이치료를고려할수있다. (C1) 3) 경구용항바이러스제치료를권장하며, 테노포비어, 엔테카비어중하나의사용을우선적으로권장한다. (A1) 4) 간기능이좋은경우에는간기능악화와약물부작용등에주의하며신중하게페그인터페론알파사용을고려할수있다. (B2) 15
Postgraduate Course 2016 4. 비대상성간경변증 1) 혈청 HBV DNA가 PCR검사양성인경우, AST/ALT에관계없이신속히경구용항바이러스제치료를한다. (B1) 2) 경구용항바이러스제치료를권장하며, 테노포비어, 엔테카비어중하나의사용을우선적으로권장한다. (A1) 3) 페그인터페론알파치료는간부전위험성때문에금기이다. (A1) 4) 간이식을고려한다. (B1) 내성발생시치료전략 (2015 대한간학회만성 B 형간염진료가이드라인에서발췌 ) 2 1. 항바이러스내성치료의일반적인원칙 1) 경구용항바이러스치료중에바이러스돌파가발생하면환자의약물순응도확인및약제내성검사를시행해야한다. (A1) 2) 내성치료는바이러스돌파가관찰되고유전자형내성이확인되면가급적빨리시작한다. (A1) 2. 라미부딘, 클레부딘, 텔비부딘내성 1) 테노포비어단독치료또는테노포비어와뉴클레오시드유사체의병합치료를권장한다. (A1) 2) 테노포비어를사용할수없는경우에는아데포비어와뉴클레오시드유사체의병합치료를고려한다. (B1) 3) 대상성간기능을가진환자에서는라미부딘을중단하고페그인터페론알파투여를고려할수있다. (B2) 3. 아데포비어내성 1) 테노포비어단독치료또는테노포비어와엔테카비의병합치료를고려한다. (B1) 2) 테노포비어와뉴클레오시드유사체 ( 엔테카비어이외 ) 의병합치료를고려할수있다. (B2) 3) 테노포비어를사용할수없는경우에는아데포비어와엔테카비어의병합치료를고려할수있다. (B2) 4. 엔테카비어와다약제내성 1) 테노포비어단독치료또는테노포비어와엔테카비어의병합치료를고려한다. (B1) 2) 테노포비어를사용할수없는경우에는아데포비어와엔테카비어의병합치료를고려할수있다. (B2) B 형간염치료의다른쟁점들 1. 내성발생시단독치료와병합치료의선택대한간학회가이드라인에서는경구용항바이러스제치료중에내성발생시테노포비어단독치료또는병합치료를고려하도록제시하고있다. 2 하지만테노포비어단독치료와병합치료중어느치료가적절한지에대해서는아직임상적근거가부족하다. 다약제내성이발생한만성 B형간염환자들을대상으로테노포비어와 16
Byung Seok Lee 엔테카비어의병합치료를시행한전향적다기관연구에서 48주치료기간동안바이러스억제효과가우수하게나타났다. 45 한편아데포비어와엔테카비어에대한내성이발생한만성 B형간염환자들을대상으로테노포비어단독치료와테노포비어와엔테카비어의병합치료를무작위배정하여시행한각각의다기관연구들에서 48주치료후 HBV DNA의감소정도, HBV DNA의불검출률 (<15 IU/mL) 을비교했을때두치료군사이에유의한차이는나타나지않았다. 46,47 2. 항바이러스제치료의종료시점대한간학회가이드라인에서는 HBeAg 양성만성 B형간염환자에서 HBeAg의소실및혈청전환이이루어진이후적어도 12개월이상의치료를지속한뒤에경구용항바이러스제치료중단을고려해볼수있으며, HBeAg 음성만성 B형간염환자에서 HBsAg이소실될때까지경구용항바이러스제를사용하도록권장하고있다. 또한간경변증환자에서는장기간의치료를권장하고있다. 2 최근발표된경구용항바이러스제치료종료에대한체계적문헌고찰에따르면항바이러스제치료종료후 HBV DNA가검출한계이하로확인되는바이러스반응을지속적으로유지하는비율은 6개월, 12개월, 24개월, 36개월후 68%, 51%, 39%, 38% 이며치료전 HBeAg 양성인환자에서음성인환자에비해높게나타났고, 대부분 2년이내에재발하였다. HBeAg 음성인환자에서치료종료후바이러스반응유지가능성과관련된중요인자는치료중바이러스반응의유지기간으로기간이 24개월이상인경우치료종료후바이러스반응을지속적으로유지할가능성이현저하게증가한다고보고하였다. 반면치료전 HBeAg 양성인환자에서는치료중바이러스반응의유지기간과치료종료후바이러스반응유지가능성은유의한관련성이나타나지않았다. HBeAg 의혈청전환유지비율은치료종료 6개월, 12개월, 24개월후에 95%, 92%, 88% 로비교적높았으며치료중바이러스반응의유지기간이나공고치료의기간과유의한관련성은없었다. 48 B 형간염의새로운치료제 1. 새로운경구항바이러스제 1) Tenofovir alafenamide (TAF, GS 7340) Tenofovir alafenamide (TAF) 는 tenofovir의 prodrug으로 HIV 감염환자를대상으로한연구에서테노포비어보다적은혈중농도로보다강력한항바이러스효과를나타냈다. 49 최근간경변증이없는초치료만성 B형간염환자를대상으로 28일간 TAF 8 mg에서 120 mg까지무작위로배정한연구에서 TAF 용량에관계없이테노포비어와유사한항바이러스반응을보였으며골밀도감소와신독성과같은부작용은보고되지않았다. 50 2) Besifovir (LB80380) 베시포비어는테노포비어, 아데포비어와구조적으로유사한 acyclic nucleotide phosphonate이며간세포내에서빠르게활성화되어 HBV 역전사효소를억제한다. 51 아시아환자들을대상으로한 96주간베시포비어 90 mg, 150 mg과엔테카비어 0.5 mg을비교한연구에서 HBV DNA 치의음전화 (80.7%, 78.6%, 80%) 와 ALT 치의감소, 혈청전환환자의비율에있어서모두유사하였으며, 내성이나신독성은나타나지않았다. 하지만베시포비어를처방한환자에서혈청 L-carnitine이감소하였으나 carnitine을복용한후에정상화되었으며신기능의이상은없었다. 52 17
Postgraduate Course 2016 2. cccdna 억제핵내에서안정된형태의 HBV 유전자로 cccdna 는지속적인 HBV 복제의주형으로작용하는데, 현재사용중인항바이러스제의한계가이러한 cccdna 를제거하지못하여치료를중단하면대부분재발된다는것이다. 53 따라서 cccdna 를표적으로하는약제들이개발되어연구중에있다. 이에는 cccdna 의형성억제와절단, 제거, 기능억제등이있다. Zinc finger nuclease는 cccdna를절단하여 cccdna가소멸되도록유도하며, 54 disubstituted sulfonamide는정확한억제기전은밝혀지지않았으나 cccdna 의전구물질인 relaxed circular DNA 의 deproteination 을방해하여 cccdna 형성을억제하는것으로생각하고있다. 55 그외에 transcription activator-like effector nucleass (TALENs), RNA-guided clustered regulatory interspaced short palindromic repeats (CRISPR), CRISPR-associated (Cas) protein endonuclease 등이연구중에있다. 3. Nucleocapsid 형성억제 Necleocapsid 형성을억제함으로써바이러스복제과정을차단할수있는데전임상연구에서 HAP (Bay 41-4109, GLS4) 와 phenylpropenamide 유도체 (AT-61, AT-130) 는역전사에불충분한바이러스입자를생성하여 capsid를불안정화시켜서조립을방해한다고알려져있다. 56-59 4. 유전자발현의억제 Antisense oligonucleotide, small interfering RNA (sirna) 는 cccdna가 pregenomic RNA로전환되는전사과정을억제하여 HBV 발현을효과적으로억제하는것으로밝혀졌다. 60,61 최근기존의 sirna 보다효과가뛰어난 ARC-520 은동물실험에서 HBV DNA, HBsAg, 및 HBeAg의현저한감소효과를나타냈다. 62,63 5. HBV 의침입차단 B형간염바이러스의간세포내침입자체를차단하는원리로, 2012년에 HBV가간세포내로침입하는데관여하는기능적인수용체가 NTCP (natrium taurocholate cotransport polypeptide) 임이밝혀진이후활발한연구가진행중이다. 64 Myrcludex-B, Cyclosporin 등이 NTCP를표적으로연구중이다. 이는간세포내 cccdna의증폭을억제하고간내감염의확산을막아준다. 6. 면역조절과치료백신 1) TLR-7 agonist (gs-9620) TLR는다양한병원체에대한내인성면역과획득성면역반응에관계하는데, HBV는 TLR 관련내인성면역반응을억제한다. 65 TLR 기능을강화시키는것은 HBV에대한내인성면역을조절하여치료하는원리이다. GS-9620은동물실험에서의미있는바이러스농도와, 표면항원등의감소효과를보여주었으며비교적안전한것으로보고되었다. 66,67 2) GS-4774 (tamogen) HBV X, HBV S, core 항원을포함한치료백신으로개발되어생체내 CD4 및 CD8 T-cell 반응을유도한다. 68 추가임상연구가진행중이다. 18
Byung Seok Lee 3) TG1050 (Novel adenovirus-based therapeutic vaccine) 장기간지속되는 B형간염특이기억세포 (CD8+T cell) 을유도하여면역치료에이용하고자하였으나기대만큼의효과는충분하지않다. 69 결론 인터페론알파가국내에소개된이후다수의경구용항바이러스제가도입되면서만성 B형간염의치료는한단계더발전하게되었다. 현재항바이러스효과가우수하고내성이적은경구용항바이러스제들이개발되어사용중이나간세포내의 cccdna를제거할수없으며장기간복용의경우내성발생가능성및안전성등의문제가있다. 이러한단점을극복하기위해새로운치료제들이연구되고있어서향후만성 B형간염치료의미래가밝다고생각한다. References 1. World Health Organization. Hepatitis B:World Health Organization fact sheet 204 (revised July 2014). Available at http://www.who.int/mediacentre/factsheets/fs204/en. [Accessed 4 April 2016]. 2. The Korean Association for the Study of the Liver. KASL clinical practice guidelines: management of chronic hepatitis B. Clin Mol Hepatol 2016;22:18-75. 3. World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection 2015. 4. Tran TT. Immune tolerant hepatitis B: a clinical dilemma. Gastroenterol Hepatol (N Y) 2011;7:511-516. 5. Lok AS, Lai CL. A longitudinal follow-up of asymptomatic hepatitis B surface antigen-positive Chinese children. Hepatology 1988;8:1130-1133. 6. Chang MH, Hsu HY, Hsu HC, Ni YH, Chen JS, Chen DS. The significance of spontaneous hepatitis B e antigen seroconversion in childhood: with special emphasis on the clearance of hepatitis B e antigen before 3 years of age. Hepatology 1995;22:1387-1392. 7. Hui CK, Leung N, Yuen ST, Zhang HY, Leung KW, Lu L, et al. Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase. Hepatology 2007;46:395-401. 8. Lee PI, Chang MH, Lee CY, Hsu HY, Chen JS, Chen PJ, et al. Changes of serum hepatitis B virus DNA and aminotransferase levels during the course of chronic hepatitis B virus infection in children. Hepatology 1990;12:657-660. 9. Lok AS, Lai CL. Acute exacerbations in Chinese patients with chronic hepatitis B virus (HBV) infection. Incidence, predisposing factors and etiology. J Hepatol 1990;10:29-34. 10. McMahon BJ, Holck P, Bulkow L, Snowball M. Serologic and clinical outcomes of 1536 Alaska Natives chronically infected with hepatitis B virus. Ann Intern Med 2001;135:759-768. 11. Martinot-Peignoux M, Boyer N, Colombat M, Akremi R, Pham BN, Ollivier S, et al. Serum hepatitis B virus DNA levels and liver histology in inactive HBsAg carriers. J Hepatol 2002;36:543-546. 12. Zacharakis GH, Koskinas J, Kotsiou S, Papoutselis M, Tzara F, Vafeiadis N, et al. Natural history of chronic HBV infection: a cohort study with up to 12 years follow-up in North Greece (part of the Interreg I-II/EC-project). J Med Virol 2005;77:173-179. 13. de Franchis R, Meucci G, Vecchi M, Tatarella M, Colombo M, Del Ninno E, et al. The natural history of asymptomatic hepatitis B surface antigen carriers. Ann Intern Med 1993;118:191-194. 14. Hsu YS, Chien RN, Yeh CT, Sheen IS, Chiou HY, Chu CM, et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology 2002;35:1522-1527. 15. Funk ML, Rosenberg DM, Lok AS. World-wide epidemiology of HBeAg-negative chronic hepatitis B and associated precore and core 19
Postgraduate Course 2016 promoter variants. J Viral Hepat 2002;9:52-61. 16. Lok AS, Akarca U, Greene S. Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal. Proc Natl Acad Sci U S A 1994;91:4077-4081. 17. Okamoto H, Tsuda F, Akahane Y, Sugai Y, Yoshiba M, Moriyama K, et al. Hepatitis B virus with mutations in the core promoter for an e antigen-negative phenotype in carriers with antibody to e antigen. J Virol 1994;68:8102-8110. 18. Chen YC, Sheen IS, Chu CM, Liaw YF. Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection. Gastroenterology 2002;123:1084-1089. 19. Chu CM, Liaw YF. HBsAg seroclearance in asymptomatic carriers of high endemic areas: appreciably high rates during a long-term follow-up. Hepatology 2007;45:1187-1192. 20. Ahn SH, Park YN, Park JY, Chang HY, Lee JM, Shin JE, et al. Long-term clinical and histological outcomes in patients with spontaneous hepatitis B surface antigen seroclearance. J Hepatol 2005;42:188-194. 21. Simonetti J, Bulkow L, McMahon BJ, Homan C, Snowball M, Negus S, et al. Clearance of hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort chronically infected with hepatitis B virus. Hepatology 2010;51:1531-1537. 22. Huo TI, Wu JC, Lee PC, Chau GY, Lui WY, Tsay SH, et al. Sero-clearance of hepatitis B surface antigen in chronic carriers does not necessarily imply a good prognosis. Hepatology 1998;28:231-236. 23. Yuen MF, Wong DK, Fung J, Ip P, But D, Hung I, et al. HBsAg Seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology 2008;135:1192-1199. 24. Fattovich G, Pantalena M, Zagni I, Realdi G, Schalm SW, Christensen E. Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients. Am J Gastroenterol 2002;97:2886-2895. 25. Niederau C, Heintges T, Lange S, Goldmann G, Niederau CM, Mohr L, et al. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med 1996;334:1422-1427. 26. Cooksley WG, Piratvisuth T, Lee SD, Mahachai V, Chao YC, Tanwandee T, et al. Peginterferon alpha-2a (40 kda): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat 2003;10:298-305. 27. Chan HL, Leung NW, Hui AY, Wong VW, Liew CT, Chim AM, et al. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone. Ann Intern Med 2005;142:240-250. 28. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351:1521-1531. 29. Allen MI, Deslauriers M, Andrews CW, Tipples GA, Walters KA, Tyrrell DL, et al. Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group. Hepatology 1998;27:1670-1677. 30. Liaw YF, Gane E, Leung N, Zeuzem S, Wang Y, Lai CL, et al. 2-Year GLOBE trial results: telbivudine Is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology 2009;136:486-495. 31. Yoo BC, Kim JH, Chung YH, Lee KS, Paik SW, Ryu SH, et al. Twenty-four-week clevudine therapy showed potent and sustained antiviral activity in HBeAg-positive chronic hepatitis B. Hepatology 2007;45:1172-1178. 32. Yoo BC, Kim JH, Kim TH, Koh KC, Um SH, Kim YS, et al. Clevudine is highly efficacious in hepatitis B e antigen-negative chronic hepatitis B with durable off-therapy viral suppression. Hepatology 2007;46:1041-1048. 33. Lee HJ, Eun JR, Lee CH, Hwang JS, Suh JI, Kim BS, et al. [Long-term clevudine therapy in nucleos(t)ide-naive and lamivudine-experienced patients with hepatitis B virus-related chronic liver diseases]. Korean J Hepatol 2009;15:179-192. 34. Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003;348:808-816. 35. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 2003;348:800-807. 36. Gish RG, Lok AS, Chang TT, de Man RA, Gadano A, Sollano J, et al. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology 2007;133:1437-1444. 37. Chang TT, Lai CL, Kew Yoon S, Lee SS, Coelho HS, Carrilho FJ, et al. Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology 2010;51:422-430. 38. Yang H, Qi X, Sabogal A, Miller M, Xiong S, Delaney WEt. Cross-resistance testing of next-generation nucleoside and nucleotide ana- 20
Byung Seok Lee logues against lamivudine-resistant HBV. Antivir Ther 2005;10:625-633. 39. Tenney D, Pokornowski K, Rose R, Baldick C, Eggers B, Fang J, et al. 20 entecavir maintains a high genetic barrier to HBV resistance through 6 years in naive patients. Journal of Hepatology 2009;50:S10. 40. Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 2010;52:886-893. 41. Hosaka T, Suzuki F, Kobayashi M, Seko Y, Kawamura Y, Sezaki H, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology 2013;58:98-107. 42. Buti M, Tsai N, Petersen J, Flisiak R, Gurel S, Krastev Z, et al. Seven-year efficacy and safety of treatment with tenofovir disoproxil fumarate for chronic hepatitis B virus infection. Dig Dis Sci 2015;60:1457-1464. 43. Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. The Lancet 2013;381:468-475. 44. Sherman M, Kim RW, Dziura J. Risk scores for hepatocellular carcinoma in chronic hepatitis B. Hepatology 2015;61:1784-1786. 45. Park JY, Kim CW, Bae SH, Jung KS, Kim HY, Yoon SK, et al. Entecavir Plus Tenofovir Combination Therapy in Patients with Multi-drug Resistant Chronic Hepatitis B: Results of A Multicenter, Prospective Study. Liver Int 2016 Feb 7. [Epub ahead of print] 46. Lim YS, Yoo BC, Byun KS, Kwon SY, Kim YJ, An J, et al. Tenofovir monotherapy versus tenofovir and entecavir combination therapy in adefovir-resistant chronic hepatitis B patients with multiple drug failure: results of a randomised trial. Gut 2015 Mar 23. [Epub ahead of print] 47. Lim YS, Byun KS, Yoo BC, Kwon SY, Kim YJ, An J, et al. Tenofovir monotherapy versus tenofovir and entecavir combination therapy in patients with entecavir-resistant chronic hepatitis B with multiple drug failure: results of a randomised trial. Gut 2016;65:852-860. 48. Papatheodoridis G, Vlachogiannakos I, Cholongitas E, Wursthorn K, Thomadakis C, Touloumi G, et al. Discontinuation of oral antivirals in chronic hepatitis b: A systematic review. Hepatology 2016 Mar 4. [Epub ahead of print] 49. Markowitz M, Zolopa A, Squires K, Ruane P, Coakley D, Kearney B, et al. Phase I/II study of the pharmacokinetics, safety and antiretroviral activity of tenofovir alafenamide, a new prodrug of the HIV reverse transcriptase inhibitor tenofovir, in HIV-infected adults. J Antimicrob Chemother 2014;69:1362-1369. 50. Agarwal K, Fung SK, Nguyen TT, Cheng W, Sicard E, Ryder SD, et al. Twenty-eight day safety, antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection. J Hepatol 2015;62:533-540. 51. Yuen MF, Kim J, Kim CR, Ngai V, Yuen JC, Min C, et al. A randomized placebo-controlled, dose-finding study of oral LB80380 in HBeAg-positive patients with chronic hepatitis B. Antivir Ther 2006;11:977-983. 52. Yuen MF, Ahn SH, Lee KS, Um SH, Cho M, Yoon SK, et al. Two year treatment outcome of chronic hepatitis B infection treated with besifovir vs. entecarvir: Results from a multicenttr study. Journal of Hepatology 2015;62:526-532. 53. Yang HC, Kao JH. Persistence of hepatitis B virus covalently closed circular DNA in hepatocytes: molecular mechanisms and clinical significance. Emerg Microbes Infect 2014;3:e64. 54. Weber ND, Stone D, Sedlak RH, De Silva Feelixge HS, Roychoudhury P, Schiffer JT, et al. AAV-mediated delivery of zinc finger nucleases targeting hepatitis B virus inhibits active replication. PLoS One 2014;9:e97579. 55. Cai D, Mills C, Yu W, Yan R, Aldrich CE, Saputelli JR, et al. Identification of disubstituted sulfonamide compounds as specific inhibitors of hepatitis B virus covalently closed circular DNA formation. Antimicrob Agents Chemother 2012;56:4277-4288. 56. Stray SJ, Bourne CR, Punna S, Lewis WG, Finn MG, Zlotnick A. A heteroaryldihydropyrimidine activates and can misdirect hepatitis B virus capsid assembly. Proc Natl Acad Sci U S A 2005;102:8138-8143. 57. Wu GY, Zheng XJ, Yin CC, Jiang D, Zhu L, Liu Y, et al. Inhibition of hepatitis B virus replication by Bay 41-4109 and its association with nucleocapsid disassembly. J Chemother 2008;20:458-467. 58. Feld JJ, Colledge D, Sozzi V, Edwards R, Littlejohn M, Locarnini SA. The phenylpropenamide derivative AT-130 blocks HBV replication at the level of viral RNA packaging. Antiviral Res 2007;76:168-177. 59. Wang XY, Wei ZM, Wu GY, Wang JH, Zhang YJ, Li J, et al. In vitro inhibition of HBV replication by a novel compound, GLS4, and its efficacy against adefovir-dipivoxil-resistant HBV mutations. Antivir Ther 2012;17:793-803. 60. Li GQ, Gu HX, Li D, Xu WZ. Inhibition of Hepatitis B virus cccdna replication by sirna. Biochem Biophys Res Commun 2007;355:404-408. 21
Postgraduate Course 2016 61. Huang W, Li X, Yi M, Zhu S, Chen W. Targeted delivery of sirna against hepatitis B virus by pres1 peptide molecular ligand. Hepatol Res 2014;44:897-906. 62. Wooddell CI, Rozema DB, Hossbach M, John M, Hamilton HL, Chu Q, et al. Hepatocyte-targeted RNAi therapeutics for the treatment of chronic hepatitis B virus infection. Mol Ther 2013;21:973-985. 63. Lanford R, Wooddell CI, Chavez D, Oropeza C, Chu Q, Hamilton HL, et al. ARC-520 RNAi therapeutic reduces HBV DNA, S and e antigen in a chimpanzee. Hepatology 2013;58:707A. 64. Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife 2012;1:e00049. 65. Wu J, Meng Z, Jiang M, Pei R, Trippler M, Broering R, et al. Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells. Hepatology 2009;49:1132-1140. 66. Lanford RE, Guerra B, Chavez D, Giavedoni L, Hodara VL, Brasky KM, et al. GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology 2013;144:1508-1517. 67. Lopatin U, Wolfgang G, Tumas D, Frey CR, Ohmstede C, Hesselgesser J, et al. Safety, pharmacokinetics and pharmacodynamics of GS-9620, an oral Toll-like receptor 7 agonist. Antivir Ther 2013;18:409-418. 68. Gaggar A, Coeshott C, Apelian D, Rodell T, Armstrong BR, Shen G, et al. Safety, tolerability and immunogenicity of GS-4774, a hepatitis B virus-specific therapeutic vaccine, in healthy subjects: a randomized study. Vaccine 2014;32:4925-4931. 69. Martin P, Dubois C, Jacquier E, et al. TG1050, an immunotherapeutic to treat chronic hepatitis B, induced robust T cells and exerts an antiviral effect in HBV-persistent mice. Gut 2015;64:1961-1971. 22