台灣偏遠地區居民及原住民B型肝炎之研究

୯ҥᆵ᡼εᏢᙴᏢଣᖏ׉ᙴᏢࣴز܌

ᅺγፕЎ

Graduate Institute of Clinical Medicine College of Medicine

National Taiwan University Master Thesis

Ѡ᡼ୃᇻӦ୔ۚ҇ϷচՐ҇ B ࠠطݹϐࣴز Investigation of Hepatitis B in

Residents of Rural Areas and Aborigines in Taiwan

ℚ᐀๭

Hsiao-Ching Nien

ࡰᏤ௲௤Ǻ೚ߎο ௲௤ (Professor Jin-Chuan Sheu) ଯ჏ֻ ௲௤ (Professor Jia-Horng Kao)

ύ๮҇୯ ΐΜΐԃΒД

ठ ठᖴ

୯ᏢεৣЦ୯ᆢӧځ๱բȨΓ໔ຒ၉ȩύගϷǺȨђϞϐԋε٣཰εᏢୢޣǴ Ѹ࿶ΟᅿϐნࣚǺȬࢄڹՋ॥঒ጨᐋǴᐱ΢ଯኴǴఈᅰϺఱၡȭǴԜಃ΋ნΨǹ ȬՊ஥ᅌቨಖό৷ǴࣁҲ੃ளΓኍீȭǴԜಃΒნΨǹȬ౲္൨дίԭࡋǴ២ฅ ӣ२ǴٗΓ҅ӧᐩОᗣ࣑ೀǶȭǴԜಃΟნΨǶȩ೭ࢤ၉ుుӦឍॊךۺࣴز܌

ޑҒधЈ௃Ƕ

؂ډъڹ౲ΓࣣȨᅵȩךᐱᒬǴགྷ๱ࣴزፕЎޑᅿᅿǴόېᐱ೿όՉΑǴՠ

؈੆ځύ܌஥๏ךޑ኷፪ࠅࢂคሽޑǴӢࣁ୤Ԗӧ೭εတҔΚࡘԵޑਔڅǴᡣך

᝺ளךϝӸӧǶԋߏᕴࢂภधޑǴӢࣴزኍீԶߺዧӧ܌ᜤխǴՠֹԋ΋ҽፕЎ ਔᅈЈޑԋ൩གǴԐςᔆံΑੲ॰ޑЈǶ

ԖӵԜుڅࣴزᏢಞޑΓғᡏ཮Ǵ२ाགᖴ೚ߎο௲௤Ƕாᕴӧךෞ౽όۓ

൳ࡋགྷܫకᏢೌࣴزޑ౟ᓍਔǴགᖴா܎ΑᏢғ΋עǴ๏ϒךᙦ൤ޑΓғЇᏤᆶ ႴᓰǴ٠ගٮךቶεޑࣴزၗྍǴᡣךԖ߿਻ᝩុ߻຾Ƕඵޣӵாǵդ኷ӵாǴ යఈךૈόॄாޑਭ୻ԋࣁίٚଭǶ

ჴᡍ࠻΋ޔࢂך৮ឨޑӦБǴՠࣴز࡛ૈό຾ჴᡍ࠻ǻӧԜ੝ाགᖴଯ჏ֻ

௲௤ǴᡣךԖᜤளޑჴᡍ࠻ࣴز࿶ᡍǴ٠፾ਔ๏ϒך҅ዴޑࣴزБӛᆶࡰᏤǶଽ Զாออޑ΋ѡ၉Ǵᗨฅό஥ԖํᗺೢጜǴՠᕴᡣЈ຀ޑךϣЈᄏཎ࿤ϩǴࠀᓰ Ծρჹࣴزᔈ၀ӆ׳уӦ׫ΕǴགᖴԖாӵԜྕࢋගឫޑচ୏Κωૈ٬ךӧࣴز ၡ΢وޑ׳ᛙ଼Ƕ

ԜѦǴќ΋ި௢୏ךᝩុࣴزޑΚໆǴ၈Јགᖴഋ଼Ѷୋ௲௤ޑಒЈࡰᏤǴ όፕࣴز܈πբ΢๏ϒךӭԛޑ CPR ࡚௱୍ܺᆶᜢЈǴᡣࡘᆣ֚ႥЪ଎ைޑλۂ

ૈפډԖ΋చܴߝޑၰၡǴ೭ҽৱ௃ሎ૶ܭЈǶ

ᆙ஭ޑα၂ၸำύǴԖ۩ᡣ໚ܴᖏ׉ᙴᏢࣴز܌܌ߏֆᆬঙ௲௤ǵଯᙴطᖌ

ᏤǴᆒ៘ޑࡌ᝼ளаᡣҁࣴز׳ԖుࡋᆶሽॶǶӆޣǴ׳གᐟፏՏα၂௲௤ॺᆶ ഋ୻ণ௲௤ޑႴᓰᆶޭۓǴᡣך׳ԖߞЈᝩុոΚ۳Ꮲೌϐၡᗌ຾Ƕ

ࣴزၡ΢ૈᏱԖӵԜᙦ൤ޑޗ཮ၗྍǴനाགᖴ଄იݤΓطੰٛݯᏢೌ୷ߎ

཮ᆶֺྷኴ௲௤ǵ໳߷඾௲௤ǵླྀ୻ሎ௲௤ᆶ׵࠹ਜ௲௤฻዗וᔅշǴวචϦ੻

շΓޑ٬ڮ༅໣ޗ཮ޑངЈǴӧྣ៝ୃᇻӦ୔طधΓϐᎩǴΨ೷൩ΑᜤளޑᏢೌ

ว౜Ƕځύ੝ձགᖴ໳஀ᛏᕴᅱᆶځ܌஥ሦޑ୷ߎ཮܌ԖӕϘॺᆶᚳεޑကπܻ

϶ॺǴᗋԖوӧϦፁᆶᙴᕍྣៈന߻ጕЪ୏঩ΚຬமޑፁғᙴᕍൂՏߏ۔ॺᆶځ ӕϘॺȐѠεᙴଣ໦݅ϩଣଣߏ໳Шണǵࡀܿᑜᑜߏఆ௴ᗶϷፁғֽߏந௴݇฻ǵ Ѡܿᑜ߻ፁғֽߏֈൈࢩǵೱԢᑜፁғֽߏቅቚᔈǵਲ༜ᑜ߻ፁғֽߏ݅ഓᆺǵ ࠄ׫ᑜፁғֽߏᄃᓪϘǵ঵ٚ୷࿎௲ᙴଣ׵ඵ຦ᙴৣǵەើᑜፁғֽߏቅە༹ǵ ᛥܿറངᙴଣ೚റЎᙴৣϷЦරݒ៝ୢǵ჏ကᑜ߻ᑜߏഋܴЎϷፁғֽߏᗛܴܱ

฻ᆶځ܌ឦი໗πբӕϘॺǹѠܿ܌ԖໂᙼǵࡀܿᑜΟӦߐໂǵًࠤໂǵࡡࡾໂǵ أϏໂǵྰηໂǵ੥ౚໂϷଯᐋໂፁғ܌ǵೱԢᑜ܌Ԗໂᙼǵࠄ׫ᑜߞကໂϷϘ ངໂǵەើᑜࠄᐞໂϷεӕໂǵѠчᑜਜ਼ٰໂǵਲ༜ᑜൺᑫໂǵभਪᑜੀӼᑜϷ ε෫ໂǵ޸ጪᑜذ݅ໂϷ࿤ᄪໂϷڑྛໂǵ჏ကᑜߓٚξໂፁғ܌ǵዋ෫ᑜ෫Ջ ໂϷଭϦໂϷқ؅ໂ฻ፁғ܌ߏ۔ᆶπբӕϘॺȑޑ዗ЈࡰᏤᆶڐշǴεৎ௭క ଷВόᜏٌമӦᙌξຫᔂǵݽξੋНǴ΋ӕոΚ਍ፁ୯Γޑ଼நǴωૈӅӕֹԋ ೭ኬᖑᜤޑࣴزǶ

ฅԶჴᡍૈளа໩ճ຾ՉǴӧԜ࿤ϩགᖴڬችนറγόჇځྠޑ௲ᏤǴቅߪ Γୋ௲௤ᆶࣴزշ౛ഋߜϐޑ዗ЈڐշǴЦѶኾշ౛௲௤ӧ୷ӢᡏБय़ޑᔅԆǴ ჴᡍ࠻ӕϘॺ೚຦ሌǵ᝵ࡌЎǵ໳߲ᄪǵZachary Yu-Ching LinǵЦ๋࣑฻ӧჴᡍ ᏹբၸำޑࡰᏤᆶڐշǶჹܭೀ౛ࣴز่݀ӵԜᚳεޑၗ਑৤Ǵ׳ाుుགᖴӳ

϶ઔྷᗩǵቅऍ৒ᆶഋሤݒ๏ϒך಍ी΢ವεޑᔅԆǶԶനࡕख़ाޑЎዺዎႬǴ

੝ाགᖴӳ϶ම✎࣑ǵ݅ۏ᫉ǵᎄપەϷቅҏীޑܘΘ࣬շǶ

ᇟقᏢ΢ᏢೌӦՏ஖ଯޑѠεᇟقᏢࣴز܌໳࠹ጄ௲௤ǴჹாΨठ΢ךന၈ ኑޑᖴཀǴӧόමᒉय़ϐΠǴԖ۩࿶җѠεᐕўسണрਠ϶േ޲ើϟಏǴளаӛ

໳௲௤ፎ௲ࠄ৞ᇟ௼ޑᐕўసྍǴӭᖴா዗Јޑ௲Ꮴωૈᡣךޑ౳ࣚ׳ࣁቨቶǶ ೭΋ၡوٰǴ܍ᆾӵРҭৣޑѠεᙴଣৎ৥ᙴᏢ೽ঋчੇ۞ߎξᙴଣଣߏ׵

ᓪប௲௤ࠆངǴନΑࡑΓೀШޑ௲ᏤϐѦǴΨᡣך׳ᆒ຾ޗ୔୷ቫᙴᏢᆶࢬՉੰ

Ꮲޑޕ᛽ǴωளаԖૈΚֹԋҁፕЎޑࣴزǶԜѦǴ࿤ϩགᐟѠεᙴଣৎ৥ᙴᏢ

೽ഋቼᎩ௲௤ǵߋੀྍ௲௤ǵ໳୯ਕ௲௤ǵఉᝩ៾௲௤ǵ׵ӹ޹ᙴৣǵഋ඲ዝᙴ

ৣᆶำᥰሺᙴৣ฻Γਭ୻ᆶᜢངǴ๏ΑךΓғύಃΒঁȨৎȩǹΨགᖴѠεࢬՉ

ੰᏢࣴز܌Ϊܴཧ௲௤ǵѠεϦӅፁғᏢس΍דॣୋ௲௤฻ࡰᏤǴ׳ᡣךૈख़ྕ

ϦӅፁғᏢଣޑᚶܤǹᗋԖᓨᓨᜢЈ٠ႴᓰךޑଯᙴҜጥࣽᎄ၃ےᙴৣǵଯᙴૅ

๚ϣࣽЦܿᑽᙴৣᆶч΋ζύഋტऍԴৣǴӢࣁԖாॺޑࡰЇǴωૈᡣךӧፐ཰

ᆶπբ΢ǴᕇளΓғύᜤૈё຦ޑᐕግᆶԋߏǶ

ৎ৥ჹךԶقǴޑዴࢂ΋ঁӜ಄ځჴޑȨౡᇋޑॄᏼȩǴΓғၡ΢གᖴԴϦ റϘǵѦϦᆶ۳ғޑѦஇǵݿݿǵ༰༰ǵϦϦǵஇஇǵλߓ࠰ϷځӄৎǵٿঁЈ طλᝊنȐണඍᆶڻᑽȑǵ׌׌ǵߝሾǵᒃብߓ࠰ᆶጰ໢ߓդǵଈሺǵඁើǵԢ

௵ǵЛЛǵ₄✎ǵ⍌๮ǵ፣ࡹǵۏཁǵᅈ౺ৣР฻ᒃܻӳ϶ჹךޑྣ៝ǵᜢངǵ х৒ᆶЍ࡭ǴؒԖգॺ൩คݤԋ൩ϞВޑךǴᙣஒך܌Ԗޑᄪᝬᆶգॺ΋ӕϩ٦Ǽ

ૈԖԜᄪ۩ֹԋҁࣴزǴሡठᖴޣჴӧϼӭϼӭǼനࡕǴ੝ाགᖴࡹ۬ᐒᄬǵ

಍΋ຬ୘Ϸӄ୯ངЈΓγᆶҾ཰იᡏޑਈշǴѝӢԖգॺޑངЈǴᡣךॺ׳ගܹ

брޑ୏Κᆶ٬ڮགǴᝩុѐྣ៝܌ԖѠ᡼ޑȨطधΓȩǶӆޣǴ׳གᖴࣴزύ

ٰԾܭѠ᡼Ӛঁفပޑ؂΋Տ୯Γޑଅ᝘ǴӢࣁԖգॺޑбрǴωளаᡣᙴᏢࣴ

ز׳у຾؁ᆶว৖Ƕ

ᙣஒҁЎԋ݀᝘ϒ

~଄ ଄იݤΓطੰٛݯᏢೌ୷ߎ཮~

ύ

ύЎᄔा

΋ǵʳ ࣴزङඳϷҞޑ

BࠠطݹࢂѠ᡼ЇଆطᕎޑനЬाচӢǴฅԶਥᏵ಍ीǴѠ᡼চՐ҇ϐᄌ܄ط

ੰϷطฯϯԝΫ౗ᗨฅᇻଯܭߚচՐ҇௼ဂǴՠطᕎԝΫ౗ࠅౣեܭߚচՐ҇Ƕ ԜѦǴୃᇻӦ୔ϐطᕎӸࢲ౗Ψၨ΋૓೿཮Ӧ୔ࣁեǶѠ᡼ B ࠠطݹੰࢥ୷Ӣࠠ

Ьाࣁ B ࠠϷ C ࠠǴځύ୷Ӣࠠ B ౰Չ౗ଯၲ 80%Ǵ΋ՠᒿ๱طݹǵطฯϯϷط ᕎޑ຾৖Ǵ୷Ӣࠠ B ࠠϐ౰Չ౗Ψ೴ᅌΠफ़ǹќѦǴB ࠠطݹϐੰࢥໆୃଯᆶ e לচ໚܄ޣǴځ҂ٰᑡ஻طᕎ॥ᓀΨၨଯǶҁࣴزаѠ᡼ୃᇻӦ୔ۚ҇ϷচՐ҇

ࣁჹຝǴ௖૸΋૓ޗ୔௼ဂϐ B ࠠطݹ஻ޣǴځቹៜ҂ٰᑡ஻طᕎϐӢηᆶੰࢥ

୷ӢࠠϩթǴࢂցӸӧӦ୔܄ᆶόӕ௼ဂ໔ϐৡ౦Ƕ

Βǵʳ ࣴزБݤ

ଞჹѠ᡼ୃᇻӦ୔ԋԃ B ࠠطݹ஻ޣǴ຾Չ୷ҁၗ਑ԏ໣ǵୢڔǵܜՈᔠࢗ

ȐхࡴǺASTǵALTǵAFPǵe לচϷלᡏǵੰࢥໆǵ୷ӢࠠȑϷဎ೽ຬॣݢᔠࢗǶ аջਔᆫӝ䁙᜘ϸᔈݤȐReal-Time polymerase chain reactionȑמೌӃ຾Չ B ࠠط ݹੰࢥໆȐHBV DNA levelȑᔠෳǴаணԄᆫӝ䁙᜘ϸᔈݤ(nested polymerase chain reaction) کӭख़ᆫӝሇન᜘ᙹϸᔈȐmultiplex-polymerase chain reactionȑמೌᔠۓ

ੰࢥ୷ӢࠠǴӆٰϩ݋ੰࢥӄߏ୷Ӣᡏۓׇаዴۓ୷Ӣࠠϐ҅ዴ܄Ƕനࡕаόӕ ޑ಍ीБݤϩ݋܌ԏ໣ϐၗ਑่݀Ƕ

Οǵʳ ࣴز่݀

ࣴزύܕ༅ 3,488 ՏȐ1,527 ՏচՐ҇ᆶ 1,961 ՏߚচՐ҇ȑٰԾѠ᡼ӚӦୃ

ᇻޗ୔ޑ B ࠠطݹ஻ޣǴচՐ҇࣬ၨܭߚচՐ҇௼ဂϐΠǴٿޣѳ֡ԃសऊ 50 ྃ Ъѳ֡ ALT ࣁ 39 U/LǴ಍ी΢٠คܴᡉৡ౦ǹԶ಍ी΢ᡉ๱ว౜ޣࣁǺځ e לচ

໚܄౗ၨեȐ5.3% vs. 10.2%Ǵp-value<0.0001ȑǵHBV DNA>2, 000 IU/ml К౗Ψၨ

եȐ27.4% vs. 36.7%Ǵp-value<0.0001ȑǵԖ࿶த໯ଚಞᄍޣК౗߾ၨଯȐ40.0% vs.

19.3%Ǵp-value<0.0001ȑǶڗځύԖ୷Ӣࠠϩ݋่݀ϐ 1,178 ΓǴว౜ҺՖԃសቫ ϐচՐ҇୷Ӣࠠ B/C ౰Չ౗ࣣୃଯȐ92.7% vs. 72.7%Ǵp-value<0.05ȑЪаၽ௼ᇟ سᆶ௨᡼ᇟسࣁനଯȐ97%ȑǶԶᚆ৞Ӧ୔Ȑዋ෫ᑜᆶೱԢᑜȑߚচՐ҇ޑ B ࠠط ݹ஻ޣа୷Ӣࠠ C ࣁЬȐ60%ȑǴҁ৞Ӧ୔а୷Ӣࠠ B ࣁЬȐ89%ȑǶԜѦǴࣴز ύว౜ 13 ՏӧѠ᡼࣬྽شـޑ୷Ӣࠠ DǴЬा໣ύܭࡀܿᑜǴа྽Ӧ௨᡼௼ۚӭǴ ځੰࢥໆၨଯȐHBV DNA >2,000 IU/mlȑǴЪୢڔၗ਑ᡉҢᗨԖ೽ϩੰ஻ම࿶ௗڙ ᒡՈǵ໒Θǵڈߙ܈ऀᡏࢰǴՠคΓමӅҔଞᓐǶ

Ѥǵʳ ่ፕ

ҁࣴزว౜ቹៜᑡ஻طᕎ॥ᓀޑӢηǴӵǺB ࠠطݹੰࢥϐੰࢥໆǵe לচ໚

܄౗Ϸ୷Ӣࠠ C ౰Չ౗฻Ǵឦܭࠄ৞ᇟ௼ޑচՐ҇೿ၨߚচՐ҇௼ဂࣁեǶҗԜ ёޕ B ࠠطݹ٠ߚЬा೷ԋচՐ҇ᄌ܄طੰԝΫ౗ၨଯޑচӢǴёૈࢂଚᆒ܄ط ݹ܈ځдচӢ܌ᏤठǶќѦǴࢌ٤Ӧ୔ဂᆫѠ᡼ၨࣁشـϐ B ࠠطݹੰࢥ୷Ӣࠠ

DǴځགࢉ೼৩ᆶ໺ኞБԄǴ҂ٰ೿ॶள຾΋؁ࣴزᆶፓࢗǶ

ᜢ

ᜢᗖຒ: Ѡ᡼ୃᇻӦ୔ǵচՐ҇ǵB ࠠطݹǵ୷Ӣࠠǵੰࢥໆǵe לচ໚܄౗ǵࠄ

৞ᇟ௼

म

मЎᄔा

Background:

Hepatitis B virus (HBV) infection is the major cause of hepatocellular carcinoma

(HCC) in Taiwan. The standardized mortality rates of chronic liver diseases and liver

cirrhosis are higher in Taiwanese aborigines than non-aborigines. However, the

standardized mortality rate of HCC is slightly lower in Taiwanese aborigines. High

HBV DNA, positive HBeAg and genotype C have been shown be the risks for the

HBV-related HCC. Therefore, in this study we further investigated the distributions of

HCC related risk factors in HBV patients and HBV genotype among different regional

areas and ethnic groups.

Materials and methods:

A total of 3,488 patients (1,527 aborigines and 1,961 non-aborigines) with HBV

infection were recruited from various regions in Taiwan. Basic background information

and blood samples were collected and abdominal ultrasound examinations were done.

The blood samples were checked for AST, ALT, AFP, HBeAg, anti-HBe, HBV DNA

by Real-Time PCR (polymerase chain reaction, PCR) and genotype by nested PCR

(nested polymerase chain reaction) and multiplex-PCR (multiplex-polymerase chain

reaction). The accuracy of HBV genotypes was validated with full length sequence.

Results:

There were no differences in the mean age (50 years old) and mean ALT levels (39

U/L) between aborigines and non-aborigines. However, lower HBeAg-positive rate

(5.3% vs. 10.2%, p<0.0001), lower rate of HBV DNA > 2,000 IU/ml (27.4% vs. 36.7%,

p<0.0001), higher rate of drinking habitȐ40.0% vs. 19.3%, p<0.0001ȑwere noted in

aborigines than non-aborigines. Among 1,178 patients with complete data of genotype

and HBeAg, the prevalence of genotype B in aborigine group was higher (92.7%) than

that in non-aborigine group (72.7%) in any age group (p<0.05), especially in Tsou

(97%). The dominant genotype was C in non-aborigines in Penghu County and

Lienchiang County (60%) and was genotype B in the countries of Taiwan island (89%).

Besides, our research found 13 patients with genotype D, a very rare genotype in

Taiwan. Patients with genotype D were clustered in the local Paiwan tribe of Pingtung

County. These subjects had higher HBV DNA (greater than 2,000 IU/ml) without the

experience of sharing needles with others and some of them had received blood

Conclusion:

We found Taiwanese aborigines who belong to Austronesian language populations

have lower HBV DNA viral load, lower HBeAg-positive rate and higher prevalence of

HBV genotype B when compared with non-aborigines. Therefore, HBV infection is not

the major cause of the death of chronic liver diseases in Taiwanese aborigines. A cluster

of patients with HBV genotype D was found in the local area of southern Taiwan.

Key Words: Taiwanese rural areas, aborigine, hepatitis B virus (HBV), genotype, HBV

DNA, HBeAg-positive rate, Austronesian language populations

Ҟ

Ҟ ᒵ

α၂ہ঩཮ቩۓਜ .

ᇞᖴ

ύЎᄔा

मЎᄔा

Ҟᒵ

კҞᒵ

߄ҞᒵϷߕҹ

ᆣፕ

ಃ΋കǺङඳϷ၁ಒޑЎ᝘ӣ៝ ...1

ಃ΋࿯ǺѠ᡼ B ࠠطݹӧߚচՐ҇ᆶচՐ҇ޑفՅ...1

ಃΒ࿯ǺB ࠠطݹੰࢥϟಏ...2

ಃΟ࿯ǺB ࠠطݹੰࢥϐ୷Ӣࠠϩթᆶځ࣬ᜢੰݩ...3

ಃѤ࿯ǺѠ᡼Ӧ୔ϐ௼ဂᙁϟ...5

ಃΒകǵటࣴزޑୢᚒϷځख़ा܄ ...7

ಃ΋࿯ǺୃᇻӦ୔ϷচՐ҇ B ࠠطݹ஻ޣཷݩ ...7

ಃΒ࿯ǺB ࠠطݹੰࢥϐ୷Ӣࠠܭόӕ௼ဂϐϩթ...8

ಃΟകǵࣴزޑଷᇥᆶ੝ۓҞޑ ...9

ࣴزБݤᆶ׷਑

!

ಃ΋കǺڙ၂ޣᒧ᏷኱ྗ...10

ಃΒകǺࣴز೛ीᆶࢬำ...11

ಃ΋࿯Ǻࣴزࢲ୏೛ी...11

ಃΒ࿯Ǻࣴزࢲ୏ࢬำ...11

ಃΟകǺ಍ीБݤ...14

ࣴز่݀

ಃ΋കǺ୷ҁၗ਑ϷܜՈၗ਑่݀ϩ݋...16

ಃΒകǺ୷Ӣࠠ B Ϸ C ϐ่݀ϩ݋...18

ಃΟകǺߚচՐ҇ᆶচՐ҇௼ဂ໔୷Ӣࠠ B Ϸ C ϐ่݀ϩ݋ ...19

ಃѤകǺ୷Ӣࠠ D ϐ่݀ϩ݋୷ҁၗ਑ϷܜՈၗ਑่݀ϩ݋...20

૸ፕ

҂ٰ৖ఈ

मЎፕЎᙁॊ

Introduction...27

Methods...36

Results...42

Discussions...50

Future Prospects ...56

ୖԵЎ᝘

ߕᒵ

კ კҞᒵ

კ 1. Bࠠطݹੰࢥ่ᄬ ………..……….…64

კ 2. BࠠطݹੰࢥϐDNA่ᄬ ………..………....65

კ 3. BࠠطݹੰࢥϐЬा୷ӢࠠШࣚϩթკ ………...66

კ 4. ࠄ৞ᇟ௼ϐШࣚϩթ ………67

კ 5. ୢڔϣ৒ ………68

კ 6. ࣴزࢲ୏ࢬำ ………69

კ 7. BࠠطݹੰࢥϤᅿ୷Ӣࠠϐႝݚკ……….70

კ 8. όӕԃសቫߚচՐ҇ᆶচՐ҇ϐ୷ӢࠠB౰Չ౗………71

߄

߄ҞᒵϷߕҹ

߄ 1. ղۓBࠠطݹੰࢥ୷Ӣࠠ܌ҔϐNested PCRϷmultiplex-PCRϐЇη…...….72

߄ 2. Bࠠطݹੰࢥӄߏ୷ӢᡏۓׇϐЇη…...………...73

߄ 3. Bࠠطݹڙ၂ޣϐ୷ҁၗ਑ϷܜՈၗ਑ ……….………..74

߄ 4. ୷ӢࠠB܈CϐBࠠطݹڙ၂ޣ୷ҁၗ਑ϷܜՈၗ਑ ………75

߄ 5. ߚচՐ҇ᆶচՐ҇όӕ୷ӢࠠᆶeלচރᄊϐКၨ ………..76

߄ 6. ѤεচՐ҇ᇟسόӕ୷ӢࠠᆶeלচރᄊϐКၨ ………..77

߄ 7. ୷ӢࠠDޣϐ୷ҁၗ਑ϷܜՈၗ਑ ……….78

ߕҹ 1. ڙ၂ޣӕཀਜ………..79

ᆣ ᆣፕ

ಃ΋കǺङඳϷ၁ಒޑЎ᝘ӣ៝

ಃ΋࿯ǺѠ᡼

ࠠطݹӧߚচՐ҇ᆶচՐ҇ޑفՅ

ӄౚ՗ीऊԖ 4 ሹՏᄌ܄ B ࠠطݹ஥চޣǴᒿ๱طݹǵطฯϯǵطᕎΟ೽Ԕ ޑ຾৖Ǵ೭٤ᄌ܄ B ࠠطݹ஻ޣಖځ΋ғεऊԖ 15-40ʘޑΓ཮ᑡ஻طฯϯǵط૰

ᆃ܈ࢂطᕎǴࣗԿ؂ԃ׳ऊԖ 50 ࿤Γԝܭطᕎ[1-4]ǶӧѠ᡼؂ԃ୯ΓऊԖ 5000 Γԝܭᄌ܄طੰϷطฯϯǴऊԖ 7700 ΓԝܭطᕎǴԋࣁ୯ΓᕎੱԝӢޑಃΒՏǴ ӧت܄ύ׳ଯۚᕎੱԝӢಃ΋ՏǴځύ೷ԋ୯ΓطᕎޑЬाচӢࣁᄌ܄ B ࠠطݹ གࢉǴځԛࣁ C ࠠطݹགࢉϷځдطੰ฻[5-7]Ƕ

ࣴزፓࢗࡰрѠ᡼ऊԖ 15-20%ޑԋԃΓࣁ B ࠠطݹ஥চޣ[6, 8]ΔԶԾ 1984 ԃଆࡹ۬໒ۈ௢Չӄय़ཥғٽ B ࠠطݹࣝभࡼѺǴԜ΋ፁғࡹ฼εεफ़եߙϿԃ Bࠠطݹޑ஥চ౗Կऊ 1%ǴЪٽูᑡ஻طᕎޑК౗Ψε൯෧Ͽ[9-10]Ƕ

ᒿ๱ਔ໔ᆶੰำޑ຾৖ǴB ࠠطݹ஥চޣВࡕᡂԋᄌ܄طੰᆶطᕎޑ࠶ુϐε ό৒۹ຎǴӢ B ࠠطݹ౰Չ౗ӧ 30ɴ49 ྃϐ໔ၲډଯঢ়Ȑऊ 21%ȑ[8]Ǵ೭٤طੰ

ޑଯӒᓀ௼ဂ҅ࢂيࣁৎ৥࿶ᔮЍࢊޑߙ֧ԃǴ΋ѿғੰ᏾ঁৎ৥೿ၟ๱ڙಕǶ Ѡ᡼аӦୱ܄ٰ࣮ǴB ࠠطݹޑ౰Չ౗ӧѠ᡼Ӛᑜѱ໔Ԗܴᡉޑৡ౦[8]Ǵᄌ

܄طੰϷطฯϯ኱ྗϯԝΫ౗Бय़Ǵ߻൳ӜޑᑜѱࣁѠܿᑜǵ޸ጪᑜǵࡀܿᑜǵ ࠄ׫ᑜϷ໦݅ᑜȐ؂Μ࿤ΓαԝΫ౗ϩձࣁ 39.8ǵ33.5ǵ30.9ǵ28.5ǵ26.2ȑǹԶ طᕎ኱ྗϯԝΫ౗Бय़Ǵ߻൳Ӝޑᑜѱࣁዋ෫ᑜǵ໦݅ᑜǵ჏ကᑜǵ჏ကѱϷѠ ࠄᑜȐ؂Μ࿤ΓαԝΫ౗ϩձࣁ 47.6ǵ44.6ǵ39.6ǵ39.4ǵ35.6ȑǹѠ᡼Ӧ୔طᕎ ޑӸࢲ౗ΨԖӦୱ܄ޑৡձǴч೽Ӧ୔ޑӸࢲ౗ଯܭύࠄ೽Ǵ೿ѱӦ୔ଯܭໂ׸

Ӧ୔[7, 11]ǶёـѠ᡼ୃᇻӦ୔ޑطੰԝΫ౗ၨଯЪطᕎӸࢲ౗ၨեǶ

а௼ဂٰ࣮ǴচՐ҇ B ࠠطݹ౰Չ౗ΨӸӧᡉ๱ޑৡ౦ǴЪଯܭѠ᡼ځд௼

Ϋ౗ᇻКѠ᡼ӄΓαϐ኱ྗϯԝΫ౗ଯȐ؂Μ࿤ΓαԝΫ౗ࣁ 77.0 vs. 21.4ȑǴЀ аѲၭ௼ǵξӦໂǵت܄চՐ҇ၨଯǴࣁځΜεԝӢޑಃΒՏǴӧԃइ 25-44 ྃ໔ ޣ׳ଯۚಃ΋ՏǴЪѳ֡ԝΫԃស 49.7 ྃᇻեܭߚচՐ҇ǹՠচՐ҇ϐطᕎ኱ྗ

ϯԝΫ౗ࠅౣեܭѠ᡼ӄΓαϐ኱ྗϯԝΫ౗Ȑ؂Μ࿤ΓαԝΫ౗ࣁ 27.4 vs.

28.1ȑǴۚᕎੱԝӢϐಃΒՏǴаѲၭ௼Ȑ௨᡼ᇟسȑǵѳӦໂϷξӦໂǵت܄চ Ր҇ၨଯ[14]ǶКၨόӕচՐ҇௼ဂ໔ᆶόӕӦ୔ϐচՐ҇໔Ǵፓࢗว౜ت܄চՐ

҇ǵξӦໂচՐ҇ǵѲၭ௼܈ੀ໡௼Ǵځᑡ஻ᄌ܄طੰǵطฯϯϷطᕎԝΫ౗ޑ ᐒ౗ၨଯǴࢂឦܭطੰଯӒᓀဂǶ

߈ԃٰ೚ӭᏢޣࣴزว౜ǴBࠠطݹੰࢥeלচ໚܄ᆶցǵBطੰࢥໆଯեǵՈ ύALTॶࢂց౦தǵBࠠطݹੰࢥ୷ӢࠠǵBࠠطݹੰࢥӧځϣޑ୷ᘵਡЈߦ຾η (basal core promoter, BCP)ೀ܈߻ਡЈ୔(precore region)ೀวғँᡂᆶցǵԃសε λǵتζ܄ձ฻ӢનǴ೿཮ቹៜBط஻ޣ҂ٰᑡ஻طᕎޑ॥ᓀ[15-26]ǹځύBࠠط ݹ஻ޣᑡ஻طᕎޑ॥ᓀǴаت܄ǵԃសၨεǵalanine aminotransferase (ALT)౦தǵ HBeAg໚܄ǵԖطฯϯǵੰࢥໆၨଯǵ୷ӢࠠCǵprecore1896ೀคँᡂϷBCP (1762/1764)ೀԖँᡂޣၨଯǴځύёׯᡂޑኰફࣁBࠠطݹੰࢥໆǴё࿶җᛰނݯ ᕍफ़եՈύޑੰࢥໆǴа෧ϿطᕎޑวғǶයࡑ҂ٰૈճҔ೭٤Ⴃෳࡰ኱ڐշط ᕎޑԐයว౜ǴၲډطᕎႣٛޑቫԛ[26]Ƕ

ಃΒ࿯Ǻ

ࠠطݹੰࢥϟಏ

Bࠠطݹੰࢥ߄य़לচԐӧ1965ԃҗDr.Ѳউդ਱ȐBlumbergȑܭ΋Տᐞࢪচ Ր҇ޑՈమύว౜ǶBࠠطݹੰࢥᗧឦܭطੰࢥࣽȐHepadnaviridaeȑǴᡉ༾᜔Π

ੰࢥελऊ42ڼԯϐ༝׎ᚈቫᗭಈǴനѦቫࣁੰࢥޑѦ঺ጢȐenvelopeȑǴځ΢Ԗ ߄य़ೈқȐsurface proteinȑǴϣቫࣁਡᓋೈқȐnucleocapsidȑǴҗਡЈೈқȐcore proteinȑಔԋǴന္ቫࢂҗਡᓋೈқ܌х֖ੰࢥȨ೽ϩᚈި᚞ᕉ่ᄬȩȐpartially

double-strandedǴ relaxed circular ȑ ϐ ѐ ਼ ਡ ᗐ ਡ ለ Ȑ DNA ȑ Ϸ ੰ ࢥ ᆫ ӝ 䁙 ȐpolymeraseȑȐკ 1ȑǶԶೈқѦጢ཮ౢғHBsAgޑלচ੝܄Ǵਡᓋೈқ߾཮ౢ

ғHBcAgޑ੝܄ǴHBeAgࣁਡЈೈқᇙ೷ޑၸำύ཮ౢғޑ΋ᅿϩݜࠠೈқ፦Ǵ ӧੰࢥεໆፄᇙਔ཮೏ញܫԿՈనύǴёаբࣁੰࢥፄᇙޑՈమᏢ኱૶[27-29]Ƕ

ੰ ࢥ ޑ ੝ ਸ DNA ่ ᄬ х ࡴ ΋ చ ֹ ᏾ ޑ ॄ ި DNA а Ϸ ΋ చ ό ֹ ᏾ ޑ ҅ ި DNAǴځ୷ӢಔȐgenomeȑऊԖ3,200ঁᡵ୷ჹȐbase pairȑǴ֖Ԗ4ঁ໒ܫ᎙᠐ਣ

ࢎȐopen reading frameǴORFȑǴϩձᙯ᝿ੰࢥޑόӕೈқ፦ǴSᙯ᝿ԋ߄य़לচǵ Cᙯ᝿ԋਡЈלচکeלচȐHBeAgȑǵPᙯ᝿ԋᆫӝሇનǵXᙯ᝿ԋXೈқȐX proteinǴHBxȑ[27, 30-31]Ƕੰࢥፄᇙޑၸำύന৒ܰౢғᡂ౦ޑӦБӧǺ߻ਡЈ

୔Ȑprecore 1896ȑǵ୷ᘵਡЈߦ຾η(basal core promoter, BCP T1762/A1764)ೀϷ

߻߄य़୷ӢSȐPre-Sȑೀวғ୷ӢલഐǴԶ೭΋٤୷Ӣ؂ঁՏ࿼ޑᡂ౦ೲࡋεऊ؂

ԃࣁ1.4~3.2x10^-5/siteǴBࠠطݹੰࢥ࿶ၸӵԜߏයޑᄽϯǴ׎ԋΑ౜ӧ೚ӭόӕᜪ

ࠠޑ୷Ӣࠠǵ୷Ӣ٥ࠠǵ୷Ӣᗺँᡂ܈લഐǵ୷Ӣख़ಔ฻BࠠطݹੰࢥᏢ΢ޑᡂϯǴ Զࣴزว౜೭٤ᡂϯᆶ҂ٰBࠠطݹ஻ޣᑡ஻طฯϯᆶطᕎޑ॥ᓀԖཱུεޑ࣬ᜢ

܄[28, 32] Ȑკ 2ȑǶ

ಃΟ࿯Ǻ

ࠠطݹੰࢥϐ୷Ӣࠠ

ΓᅿόӕǴόՠӸӧ୷ӢϷ܄ރ߄౜ޑৡ౦ǴӦ౛΢ޑϩթΨόӕǶBࠠطݹ

ੰࢥΨԖᜪ՟௃ݩǴᄽϯԿϞѬॺԖӚᅿόӕޑ୷ӢࠠǴϩթӧӄౚόӕ୔ୱǴ ჹط᠌ޑఠ໾ΚΨଯեԖձǶ

Ҟ߻ςޕޑBࠠطݹੰࢥ୷ӢࠠЬाԖAǵBǵCǵDǵEǵFǵGǵHǵIǵJ฻10 ᅿǴ٩ྣว౜ޑ໩ׇڮӜǶӄౚӚӦୱ܌౰Չޑੰࢥ୷ӢࠠԖ܌όӕǴѠ᡼Ϸܿ

٥а୷ӢࠠBᆶCۚӭǴεഌߏԢача୷ӢࠠCࣁЬǴߏԢаࠄа୷ӢࠠBࣁЬǶ

ࢪϐ୷ӢࠠၨӭϡǴAǵBǵCǵD೭4ࠠ೿ԖǶኧໆၨϿޑ୷ӢࠠEЬाϩթӧՋߚǵ FၟHӧύࠄऍࢪǵGӧऍ୯ᆶኻࢪǹ IǵJٿᅿ୷Ӣࠠ߾Ьाϩթܭܿࠄ٥ϷВҁǶ ߈ԃٰǴऍ୯ᆶᐞࢪӢࣁ٥ࢪ౽҇ቚуǴ୷ӢࠠBᆶCޑКٯΨᒿϐቚуǶќѦǴ ӕ΋ঁ୷Ӣࠠӧόӕ୔ୱ཮ౣԖόӕǴٯӵߚࢪᆶኻࢪޑ୷ӢࠠA൩Ԗৡ౦Ǵջࣁ όӕϐ୷Ӣ٥ࠠ[17, 33-37]Ȑკ 3ȑǶ

ࣴز௢ፕBطੰࢥ୷ӢࠠޑϩթǴёૈᆶόӕ໺ࢉ೼৩ԖᜢǶӧࠟޔ໺ࢉȐջ

҆ᒃᚶѫғౢਔ໺๏ᓻٽȑࣁЬޑӦ୔ǴӵѠ᡼Ǵа୷ӢࠠBکCКၨӭǴՠӧН ѳ໺ࢉȐӵǺ܄Չࣁᆶᓉેᛰ᠅ݙ৔฻೼৩ȑޑӦ୔Ǵ߾а୷ӢࠠAᆶDࣁӭǴࢂ

όࢂӢࣁόӕ໺ࢉ೼৩཮Ծ୏ᒧ᏷р੝ۓޑ୷ӢࠠǴҞ߻ᗋόమཱ[20, 35, 38]Ƕ Ѡ᡼ޑ B ࠠطݹੰࢥ୷ӢࠠЬाࢂ B ᆶ C നதـǴགࢉ୷Ӣࠠ B ੰࢥޑੰ஻Ǵ ѳ֡ӧ 30 ྃਔ e לচ཮Ծ୏మନǴ୷Ӣࠠ C ߾ࢂ 40 ྃǴჹѠ᡼Ԑԃޑζ܄ B ࠠ طݹ஥চޣǴe לচԾ୏మନޑਔ໔ఁܭځғػԃសǴϩ৆ਔӭъϝࢂ e לচ໚܄Ǵ ω཮৒ܰ΋ж໺΋жǴӢԜԐԃѠ᡼ޑ B ࠠطݹ஥চޣӭࢂࠟޔགࢉ܈ 2 ྃ߻ޑ གࢉ[39-40]ǶќѦǴࣴزΨว౜Ծ 1945 ԃಃΒԛШࣚεᏯࡕǴҗεഌᎂ౽ٰѠۓ

ۚޑΓǴऩࣁ B ࠠطݹ஻ޣǴځ୷Ӣࠠ C ޑК౗཮ၨଯ[16, 19, 41]Ƕ

ӧѠ᡼ਈՈ҇౲ύ಍ीว౜ǴB ࠠطݹੰ஻ځ୷Ӣࠠ B/୷Ӣࠠ C Кٯऊ 80%/20%ǹคੱރޑ஥চޣύКٯऊ 70%/30%ǹᄌ܄ B ࠠطݹ஻ޣКٯऊ 60%/40%ǹ΋ѿр౜طฯϯǴКٯफ़եԿ 35%/65%ǹطᕎੰ஻ύКٯऊ 55%/45%[35, 38]Ƕёـᄌ܄ B ࠠطݹ஻ޣੰำၨᝄख़ޣǴ୷Ӣࠠ C ޑК౗཮ගଯǶ୷Ӣࠠ C ᗨ ฅӧ B ط஻ޣύК౗ၨϿǴՠ஻ޣޑੰ௃৒ܰൾϯǴᑡ஻طฯϯᆶطᕎޑ॥ᓀΨ КၨଯǹќѦǴځௗڙυᘋનݯᕍޑԋфᐒ౗ၨৡǹB طݯᕍᛰނȐLamivudineȑ ଶҔࡕൺว౗Ψၨଯ[16, 27, 41-43]Ƕ

ಃѤ࿯ǺѠ᡼ϐ௼ဂᙁϟ

Ѡ᡼ߏΦаٰ࿶ၸӭԛޑόӕ௼ဂޑᎂழᆶЎϯޑҬࢬǴ೷൩Α౜Ϟ௼ဂӭ ϡᑼӝޑޗ཮Ǵᄓ໒ࡹݯޑӢનᆶ၉ᚒǴதᇥѠ᡼Ѥε௼ဂࡰޑࢂѠ᡼መࠄΓȐ៪

٭ΓǴHō-Lóh-Langȑǵ࠼ৎΓȐHakkaȑǵѦ࣪ΓϷচՐ҇Ѥε௼ဂ[44]Ƕ

៪٭Γឦܭᅇ௼ǴΞᆀᅽ٭ΓǵݞࢶΓǵመࠄΓ܈Ѡ᡼Γ฻Ǵջࣁ౜ӧ೯ᆀ ޑȨѠ᡼Ѥε௼ဂȩ္Γኧ՞നӭޑ΋ঁ௼ဂȐऊ76%ȑǴࣁҞ߻Ѡ᡼ޑЬा௼ဂ [45]Ƕ ଓྉϐ߻ޑᐕўǴځࣁ߈Ѥԭԃٰҗύ୯ܿࠄݮੇޑᅽࡌ࣪౽ٰۚѠϐ౽

҇ޑࡕжǴЬाϩԋᄼԀΓکࢨԀΓٿεЍǴ΋ᇥаᅇϯޑԭຫ҇௼ࣁЬǴќ΋

ᇥ߾а೴ԃࠄᎂޑᅇΓࣁЬ[46]Ƕ

࠼ৎΓȐऊ՞20%ȑεऊԾநᅚΒΜΒԃ(Ջϡ1683ԃ)ࡕǴεץҗεഌٰѠۓ

ۚǴεӭᆫ໣ӧѠ᡼᎞ξޑЫഊӦ୔ǴӵǺਲԮभ΋஥Ƕځଆྍܭֺර໒ۈǴύ চᅇ҇εᖐࠄᎂǴ࿶ᡧࠄǵመՋډၲఘԀǴനಖ׎ԋ࣬ჹԋዕޑǵڀԖࡐமᛙۓ

܄ޑ௼ဂǶԜࡕǴ࠼ৎΓΞаఘԀǵᡧԀǵҋԀǵඁԀࣁ୷ӦǴεໆѦᎂډѠ᡼ǵ εഌӚ࣪ΏԿШࣚӚӦ[45, 47]Ƕ

Ѧ࣪ΓȐऊ՞10%ȑӧѠ᡼೯தࢂࡰ1945ԃѠ᡼ӀൺࡕǴٰѠۓۚޑεഌӚ࣪

ѱΓγǴᆶځ࣬ჹޑᆀڥࢂՐӧѠ᡼ҁ࣪ޑҁ࣪ΓǴᒿ๱ਔжޑᡂᎂѦ࣪Γޑᆀ ڥ೴ᅌ఩ᅃ[44-45, 48]Ƕ

ᆵ᡼চՐ҇Ȑऊ՞2%ȑǴ٩Ҟ߻ύ๮҇୯ՉࡹଣচՐ҇௼ہ঩཮܌܍ᇡޑѠ

᡼চՐ҇௼ᕴӅԖ14ঁ௼ဂǴхࡴǺੀ໡௼ǵᖻহ௼ǵѲၭ௼ǵၽ௼ǵᎹഩ௼ǵ ௨᡼௼ǵڒࠄ௼ǵߓऍ௼ǵ໡ऍ௼ǵ߉௼ǵᏚᅦើ௼ǵϼᎹሙ௼ǵኜڻ๲໡௼Ϸ

༞ቺլ௼Ƕऩ٩ྣځ੝ਸᇟس୔ϩǴёϩࣁ4εᇟسǴхࡴǺੀ໡ᇟسȐੀ໡௼ǵ ϼᎹሙ௼ǵ༞ቺլ௼ȑǹ௨᡼ᇟسȐߓऍ௼ǵ௨᡼௼ǵڒࠄ௼ǵѲၭ௼ǵᖻহ௼ǵ ߉௼ǵᏚᅦើ௼ǵኜڻ๲໡௼ȑǹၽ௼ᇟسȐၽ௼ǵᎹഩ௼ȑǹЃϏᇟسȐ໡ऍ

ۚՐӦ୔ϩࣁ೿཮୔ǵѳӦ୔ᆶξӦ୔Ǵځύа೿཮୔চՐ҇э40.3%ၨӭǹ ൩௼ձჄϩǴаߓऍ௼ऊ37.4%നӭȐӭۚՐܭ޸ጪᑜǵѠܿᑜϷѠчᑜȑǴځԛ ࣁੀ໡௼Ȑ18.3%ǴӭۚՐܭਲ༜ᑜǵཥԮᑜϷࠄ׫ᑜȑᆶ௨᡼௼Ȑ17.6%Ǵӭۚ

ՐܭࡀܿᑜǵѠܿᑜϷਲ༜ᑜȑǴ౜ϞۚՐӦӭՏܭ޸ጪᑜ(ऊ՞18.5%)ǵѠܿᑜ(ऊ

՞16.3%)Ϸࡀܿᑜ(ऊ՞11.5%)[14]Ƕ

ӧΓᜪᏢϩᜪ΢ǴѠ᡼চՐ҇ឦܭȨࠄ৞ᇟ௼ȩȐAustronesian languageȑǴ

ࢂࡰᅇΓ౽ۚѠ᡼߻നԐܢၲѠ᡼ۓۚޑ௼ဂǶ٩ᏵᇟقᏢǵԵђᏢϷЎϯΓᜪ Ꮲޑࣴز௢ᘐǴѠ᡼চՐ҇ӧѠ᡼ޑࢲ୏ςԖኧίԃϐΦǶࠄ৞ᇟ௼ࢂШࣚ΢ϩ թനቶޑ҇௼ǹϩթӦ୔Ջଆߚࢪܿࠄޑଭၲуථу৞Ǵຫၸӑࡋࢩޔܢϼѳࢩ ޑൺࢲ࿯৞ǹчଆѠ᡼ǴࠄډફՋើ[49-51]Ȑკ 4ȑǶԖᏢޣࡰрεऊϖǵϤί ԃ߻ࠄ৞҇௼ջҗεഌܿࠄݮੇ΋஥Ǵ෠ੇᎂழۓٰۚѠ᡼Ǵࣁځচۈޑۚ੮Ӧ ϐ΋Ǵϐࡕӆ۳๷ࡓᇯǵӑѭǵஏլᛥѭՋ٥ǵহ࠶Ӯǵൺࢲ࿯৞ǵફՋើ฻ݢ

ٚѭՋ٥Ӧ୔ᘉණ[51]Ƕ

୯ϣᏢޣॺӧआՈౚלচ߄౜ࠠޑϩ݋ࣴزᡉҢǴѠ᡼চՐ҇௼ဂکѠ᡼ޑ መࠄ܈࠼ৎ௼ဂ܈ύ୯εഌ௼ဂ໔Ǵࢌ٤आՈౚלচ߄౜ࠠᓎ౗ǴԖܴᡉޑৡ౦Ƕ ЀаѠ᡼ܿ೽ޑߓऍ௼ǵڒࠄ௼Ϸ௨᡼௼Ǵݔ౦ࡋၨεǶځύMiIIIՈࠠȐឦܭMNSs Ոࠠس಍ǴࣁีԖՈࠠȑӧߓऍ௼95%, ໡ऍ௼34%Ǵڒࠄ௼21%ǴࢂШࣚ΢ᓎ౗

നଯޑΟঁ௼ဂǴՠӦ౛୔࣬߈ޑᎹഩ௼ᆶ௨᡼௼ޑКٯϸԶࢂ0%Ǵё௢ፕѠ᡼

চՐ҇ࢂόӕޑԃжٰډѠ᡼ǴԶЪϕό೯ஆ[52-53]Ƕ

ᆕӝ΢ॊޑࣴز่݀ǴѠ᡼ୃᇻӦ୔ۚ҇ϷচՐ҇ϐ B ࠠطݹ஻ޣǴዴࣁᑡ

஻طᕎϐଯӒᓀဂǴЪࣁӸࢲ౗ၨեϐ௼ဂǴόӕ௼ဂ໔ёૈӸӧৡ౦܄Ǵॶள

຾΋؁ޑࣴزᆶ௖૸Ƕ

ಃΒകǵటࣴزޑୢᚒϷځख़ा܄

ಃ΋࿯ǺୃᇻӦ୔ۚ҇ϷচՐ҇ᑡ஻

ࠠطݹཷݩ

࿶җࣴزङඳёޕǴB ࠠطݹޑ౰Չ౗ӧѠ᡼ӸӧܴᡉޑӦୱ܄ᆶচՐ҇௼ဂ

܄ޑৡ౦ǴӵǺξӦໂচՐ҇Ϸੀ໡௼ၨଯǹᄌ܄طݹǵطฯϯᆶطᕎ኱ྗϯԝ Ϋ౗ǴӧୃᇻӦ୔ୃଯǴӵǺѠܿᑜǵ޸ጪᑜǵࡀܿᑜǵࠄ׫ᑜǵ໦݅ᑜǵዋ෫ ᑜǵ჏ကᑜǵ჏ကѱϷѠࠄᑜ฻ᑜѱǹচՐ҇௼ဂᄌ܄طੰԝΫ౗ၨଯǴӵǺѲ

ၭ௼Ȑ௨᡼ᇟسȑǵξӦໂϷت܄চՐ҇ǹطᕎޑӸࢲ౗ΨӸӧӦୱ܄ޑৡ౦Ǵ ӵǺч೽Ӧ୔ޑӸࢲ౗ଯܭύࠄ೽Ǵ೿ѱӦ୔ଯܭໂ׸Ӧ୔[8, 11-14]Ƕ

Bࠠطݹ஻ޣ಍ीว౜Ǵаت܄ǵԃសၨεǵALT ౦தǵHBeAg ໚܄ǵԖط ฯϯǵੰࢥໆၨଯǵ୷Ӣࠠ Cǵprecore 1896 ೀคँᡂϷ BCP (1762/1764)ೀԖँᡂ ޣǴ҂ٰԖၨଯᑡ஻طᕎޑ॥ᓀ[26]Ƕ

ୃᇻӦ୔ۚ҇ϷξӦໂচՐ҇܌ۚϐӦǴ೯தҬ೯࣬྽όߡǴ൩ᙴၡ೼Ͽ߾

ኧΜϩដǴӭ߾ኧλਔǴᙌξຫᔂ܈ࢂݽξੋН܈ࢂམᐒ४ಭޑ࣮ੰՉࣁǴჹд ॺٰᇥࢂ࣬྽ੁ຤ਔ໔Ъ઼ᇤ࿶ᔮғౢޑ٣Ǵ೯தيᡏр౜ᝄख़ੱރω཮ᑈཱུ൩ ບǶԶط᠌೭ኬ؇ᓨޑᏔ۔Ǵջ٬ᑡ஻طੰ೯த೿ؒԖੱރǴ৒ܰᡣΓᇸ۹ΑѬǴ ۳۳طᕎ҃යр౜ੱރω൩ᙴǴႣࡕᆶӸࢲ౗೿ࡐৡǶӢԜჹܭيᡏคੱރޑ B

ࠠطݹ஥চޣǴᕵ٬ޕၰځᑡ஻طᕎޑᐒ཮К҅தΓଯǴૈۓය଺ܜՈϷဎ೽ຬ

ॣݢᔠٰࢗᜢЈόภό᝚ޑطݹੰΓǴჴӧԖ୺Չ΢ޑ֚ᜤǶ

όӕӦୱ܄ᆶ௼ဂ܄ޑৡ౦ǴନΑᙴᕍၗྍၨ೦Юǵғࢲಞᄍᆶᙴᕍྣៈϩ թό֡ޑӢનϐѦǴࢂցᗋԖځдޑӢન཮ቹៜځύޑৡ౦Ǵ࣬྽ॶளࣴز௖૸Ƕ ӧᏢೌࣴزޑӕਔǴനख़ाޑࢂૈᙖԜගٮୃᇻӦ୔ B ࠠطݹ஻ޣֹ᏾ޑطੰᔠ

ࢗǴЍජᙴᕍ೦ЮޑୃᇻӦ୔Ǵගܹӄ୯ӚӦ൩ᙴё߈܄(accessibility)Ǵ٠ࡌҥֹ

᏾ޑ B ࠠطݹၗ਑ᔞǴёගٮ҂ٰࡹ۬࣬ᜢൂՏࡌҥطੰྣៈᆛ๎ϐୖԵ٩ᏵǴ

ಃΒ࿯Ǻ

ࠠطݹੰࢥϐ୷Ӣࠠܭόӕ௼ဂϐϩթ

Bࠠطݹੰࢥ୷ӢࠠЬाԖ AǵBǵCǵDǵEǵFǵGǵHǵIǵJ ฻ 10 ᅿǴӄ ౚӚӦୱ܌౰Չޑੰࢥ୷ӢࠠԖ܌όӕǴѠ᡼Ϸܿ٥а୷Ӣࠠ B ᆶ C ۚӭǴεഌ ߏԢача୷Ӣࠠ C ࣁЬǴߏԢаࠄа୷Ӣࠠ B ࣁЬǴ܌ᛥߐဂ৞а୷Ӣࠠ C ᆶ DࣁЬ[17, 36-37]Ƕ

Ѡ᡼ޑ B ࠠطݹੰࢥ୷ӢࠠЬाࢂ B ᆶ C നதـǴB ࠠطݹ஥চޣӭࢂࠟޔ གࢉ܈ 2 ྃ߻ޑགࢉǴځύ΋૓ਈՈ௼ဂޑ୷Ӣࠠ B ऊ՞ 80%ǶӆޣࣴزΨว౜

Ծ 1945 ԃಃΒԛШࣚεᏯࡕǴҗεഌࠄБᎂ౽ٰѠۓۚޑΓȐӵǺӭۚՐӧዋ෫ ᑜǵߎߐᑜᆶೱԢᑜ฻ӦȑǴऩࣁ B ࠠطݹ஻ޣǴځ୷Ӣࠠ C К౗཮ၨଯ[6, 16, 19, 35, 41]Ƕ

ӭϡϯޑѠ᡼ޗ཮ǴϩࣁѤε௼ဂǴځύ׳ёᘜᜪচՐ҇ᆶߚচՐ҇ٿঁ௼

ဂǴӢࣁӧΓᜪᏢ΢ٿޣឦܭ࣬྽όӕޑٰྍǶߚচՐ҇хࡴǺѠ᡼መࠄΓǵ࠼

ৎΓϷѦ࣪ΓǴځ઒ӃӭٰԾܭύ୯εഌǹԶѠ᡼চՐ҇߾ឦܭȨࠄ৞ᇟ௼ȩǴ

ࢂࡰᅇΓ౽ۚѠ᡼߻നԐܢၲѠ᡼ۓۚޑ௼ဂǶ

଼நፓࢗύว౜চՐ҇ϐᄌ܄طݹ܈طฯϯԝΫ౗೿ଯܭߚচՐ҇Ǵՠࢂط ᕎޑԝΫ౗ࠅեܭߚচՐ҇ǹࣴزΞளޕ B ࠠطݹੰࢥޑ୷Ӣࠠ཮ቹៜطᕎϷط ฯϯޑᑡ஻॥ᓀǴЪطᕎӸࢲ౗ޑӦ୔܄ৡ౦ǴӢԜ௖૸ߚচՐ҇ᆶচՐ҇௼ဂ ϐ໔ǴB ࠠطݹੰࢥޑ୷ӢࠠϩթࢂցӸӧৡ౦Ǵ׳ૈΑှ೷ԋୃᇻӦ୔ϷচՐ҇

طੰᝄख़ࡋޑচӢǶ

ќѦǴࠄ৞ᇟ௼ӧϼѳࢩᆶӑࡋࢩޑᎂ౽ၡ৩ǴࣁΓᜪЎܴว৖ў΢࣬྽ख़

ाޑ٣ҹϐ΋Ǵځᎂழၡ৩ޑଷᇥࡐӭǴՠҞ߻ۘค΋ঁዴۓޑှញଷᇥǶ߈ԃ

ၨࣁ౰ՉޑᇥݤࢂѠ᡼ࢂࠄ৞҇௼ޑଆྍӦǴсᡉΑѠ᡼ӧࠄ৞҇௼ᎂழၸำύ ޑख़ाӦՏǶѠ᡼চՐ҇௼ဂ໔ B ࠠطݹੰࢥ୷Ӣࠠϩթϐ࣬ᜢࣴزǴҭёගٮ ࠄ৞ᇟ௼ᎂழᄽϯޑୖԵ٩ᏵǶ

ಃΟകǵࣴزޑଷᇥᆶ੝ۓҞޑ

࿶җ΢ॊёޕǴBࠠطݹޑ౰Չ౗ǵᄌ܄طݹǵطฯϯᆶطᕎ኱ྗϯԝΫ౗Ϸ طᕎޑӸࢲ౗ǴӧѠ᡼ӸӧܴᡉޑӦୱ܄ǵόӕ௼ဂ໔ᆶচՐ҇௼ဂ໔ޑৡ౦Ƕ ќѦࣴزΞளޕBࠠطݹ஻ޣϐၨεԃសǵALT౦தǵHBeAg໚܄ǵੰࢥໆၨଯǵ

ੰࢥ୷ӢࠠCޣǴᑡ஻طฯϯϷطᕎޑ॥ᓀၨଯǶ

ӢԜךॺଷ೛ǴѠ᡼চՐ҇ϐᄌ܄طݹ܈طฯϯԝΫ౗೿ଯܭߚচՐ҇Ǵՠ

ࢂطᕎޑԝΫ౗ࠅեܭߚচՐ҇ϐচӢǴёૈᆶВҁᏢޣӧؑᛣᑜ܌ࣴز࣬՟ǺB

ࠠطݹଯ౰ՉӦ୔ՠځطᕎԝΫ౗ࠅၨեǴচӢࢂੰࢥ୷ӢࠠЬाࣁᑡ஻طᕎ॥

ᓀၨեϐ୷ӢࠠB[54]Ƕ

ќѦǴӕࣁୃᇻӦ୔চՐ҇ᆶߚচՐ҇ϐBࠠطݹ஻ޣǴځBࠠطݹੰࢥޑ୷ ӢࠠǵੰࢥໆϩթϷHBeAg໚܄౗฻ӢનǴӧ௼ဂϐ໔ᔈ၀཮Ӹӧৡ౦܄Զቹៜ طੰޑԝΫ౗Ƕҁࣴز׆ఈૈ௖૸ନΑᙴᕍᕉნǵғࢲಞᄍᆶޗ࿶ӦՏޑቹៜϐ ѦǴBࠠطݹ୷Ӣࠠ฻ӢનǴࢂցΨӸӧӦୱ܄܈௼ဂ܄ৡ౦ǴԶቹៜ҂ٰᑡ஻ط ᕎϐ॥ᓀǴගٮ҂ٰᙴᕍྣៈᆶፁғࡹ฼ϐୖԵǶ

Զࠄ৞ᇟ௼ӧϼѳࢩᆶӑࡋࢩޑᎂ౽ၡ৩ǴࣁΓᜪЎܴว৖ў΢࣬྽ख़ाޑ ٣ҹϐ΋Ǵ߈ԃၨࣁ౰ՉޑᇥݤࢂѠ᡼ࢂࠄ৞҇௼ޑଆྍӦǴсᡉΑѠ᡼ӧࠄ৞

҇௼ᎂழၸำύޑख़ाӦՏǶԶۚՐܭѠ᡼Ӧ୔ޑࠄ৞ᇟ௼໔ǴҗआՈౚלচ߄

౜ࠠ฻ᒪ໺Ꮲࣴز௢ፕѠ᡼চՐ҇ࢂόӕޑԃжٰډѠ᡼ǴԶЪϕό೯ஆǶӢԜ ךॺӆଷ೛ǴBࠠطݹੰࢥޑ୷ӢࠠޑϩթǴӧόӕ௼ဂ໔ᔈӸӧځৡ౦܄ǶԶԜ ৡ౦܄҂ٰёૈගٮࠄ৞ᇟ௼ᎂழၡ৩ϐୖԵǴচӢࢂѠ᡼Bࠠطݹ໺ࢉ೼৩ӭࣁ

҆໺ηϐࠟޔ໺ࢉǴԜᜪ՟ܭаಈጕᡏDNAբࣁࣴزᚒ׷Ƕ

ࣴ

ࣴزБݤᆶ׷਑

ಃ΋കǺڙ၂ޣᒧ᏷኱ྗ

ࣴزीฝӧڙ၂ޣᒧ᏷΢ǴЬा่ӝٿεٰྍǺ

1. җ଄იݤΓطੰٛݯᏢೌ୷ߎ཮ 10 ӭԃٰǴଞჹѠ᡼҇୯ 74 ԃ 01 Д 01 В߻

рғǴԾᜫ߻ٰ଺طੰᑔᔠ҇౲ύǴᑔᔠࣁ B ࠠطݹ߄य़לচȐHBsAgȑ໚܄ϐ

஻ޣǹ

2. ӚӦ୔ፁғ܌ଞჹӚໂᙼ҇౲଺ӄय़܄᏾ӝԄᑔᔠ฻ࢲ୏ύǴ೏ፁғൂՏӈᆅ

ଓᙫޑ܌Ԗ B ࠠطݹ஥চޣȐHBsAg ࣁ໚܄ȑǶ܈྽Ӧᙴᕍଣ܌ϐӈᆅଓᙫ B ࠠ طݹ஥চޣȐHBsAg ࣁ໚܄ȑǶ

ࢲ୏߻ঁձ೯ޕ B ط஻ޣǴࢲ୏྽Ϻ຾ՉୢڔǵܜՈϷဎ೽ຬॣݢᔠࢗǴڙ ၂ޣٰྍϩթܭѠ᡼чǵύǵࠄǵܿϷᚆ৞ӚӦǴх֖܌Ԗ௼ဂǴتζόܥǴᙍ

཰όज़Ƕ

ঁਢٰྍӦ୔Ǵх֖Ǻϣࡹ೽܌Ϧ֋ϐୃᇻӦ୔ȐۓကǺΓαஏࡋեܭӄ୯ ѳ֡Γαஏࡋϖϩϐ΋ϐໂȐᙼǵѱȑǴ܈ຯᚆޔᗄѱǵᑜȐѱȑࡹ۬܌ӧӦ 7.5 Ϧٚа΢ϐᚆ৞ȑǴ܈ՉࡹଣࣴԵ཮ϦѲୃᇻำࡋၨଯޑໂᙼ฻Ƕ

܌Ԗڙ၂ޣȐх֖ߚচՐ҇ᆶচՐ҇ȑӧ၁ᅰ֋ޕࣴزၸำࡕǴѸ໪ӕཀୖ

ᆶҁࣴزǴ٠ܭڙ၂ޣӕཀਜȐܭ҇୯ 97 ԃ 3 Д 3 В࿶Ѡεᙴଣࣴزউ౛ہ঩཮

ቩਡ೯ၸᖏ׉၂ᡍࣴزीฝጓဦǺProtocol ID: 200801059RȐClinicalTrials.gov ID:

NCT00946010ȑǴࣴزਔ໔ԾӕཀਡഢВଆԿ҇୯ 100 ԃ 1 Д 31 ВЗȑ΢ᛝӜЪ ຏܴВයȐߕҹ 1ȑǶ

ಃΒകǺࣴز೛ीᆶࢬำ

ಃ΋࿯Ǻࣴزࢲ୏೛ी

Bࠠطݹੰ஻ӜൂዴۓϐࡕǴаѠ᡼ӚӦ୔ϐ፾྽൑ӦǴҗطੰٛݯᏢೌ୷ߎ

཮஑཰Γ঩ᆶ྽ӦፁғϷՉࡹπբΓ঩ଛӝǴᡣς૽ግؼӳϐπբΓ঩຾Չੰ஻

ୢڔ኱ྗϯޑፓࢗȐхࡴǺڙ၂ޣϷځР҆ᒃϐрғӦǵۚՐӦǵࢂցڀԖচՐ

҇ব΋௼ϐيϩǵࢂցڀԖ࠼ৎΓيҽǵࢂցම࿶ௗڙᒡՈǵ໒ΘЋೌǵڈߙ܈

ऀᡏࢰǵᆶдΓӅҔଞᓐϷࢂցԖ໯ଚಞᄍ฻Ȑკ 5ȑǵ୷ҁၗ਑༤ቪᆶෳໆȐх

ࡴǺԃសǵ܄ձǵيଯǵᡏख़Ϸဈൎ฻ȑǵᔠᡏ௦໣Ϸဎ೽ຬॣݢᔠࢗϐ୺ՉǶ

҅ዴဈൎෳໆࢂਥᏵ୯଼҇நֽޑࡌ᝼Ǵ໪Ӄନѐဈ೽ᙟᇂޑՊނǴᡣੰ஻

ᇸ᚞ઠҥǴᚈЋԾฅΠࠟǴаҜЁᙅၸဈ೽Ǵፓ᏾ଯࡋ٬ૈ೯ၸѰѓٿୁဉମ΢

ጔԿԻମΠጔޑύ໔ᗺǴӕਔҜЁѸ໪ᆶӦय़ߥ࡭НѳǴ٠ᆙຠԶόᔒᓸҜጥǴ ᆢ࡭҅தڥ֎Ǵӧӗ਻่״ਔǴໆڗځဈൎǶ

ಃΒ࿯Ǻࣴزࢲ୏ࢬำ

җطੰٛݯᏢೌ୷ߎ཮ᆶ྽ӦፁғϷՉࡹπբΓ঩΋ӕӝբǴଞჹࢲ୏ࢬำ

຾ՉೕჄᆶ୺ՉǴᔠᡍ൑ӦӅϩࣁѤઠȐკ 6ȑǴϩձࣁǺ

ಃ΋ઠȋሦڗ୷ҁၗ਑߄Ϸୢڔ٠уа༤ቪ

ಃΒઠȋሦڗຠԖጓဦޑ၂ᆅ٠җៈ౛Γ঩຾ՉܜՈऊ 10c.c.

ಃΟઠȋෳໆيଯȐcmȑǵᡏख़ȐKgȑϷဈൎȐcmȑ

ಃѤઠȋᙴৣ຾Չဎ೽ຬॣݢᔠࢗǴϐࡕҗ஑཰ៈ౛ৣ຾Չঁձطੰᒌ၌Ƕ ࡑᔠᡍൔ֋ֹԋࡕǴೱӕ B ࠠطݹፁ௲Ћн஌ଌԿೱ๎Ӧ֟Ǵ٠๏ϒႝ၉ǵ ᆛၡϷߞҹ฻ᒌ၌ᆅၰǴӕਔஒӜൂҬϒ࣬ᜢፁғൂՏ଺ഌុۓයଓᙫǶଞჹԖ

੝ਸሡᆙ࡚ೀ౛ੰݩϐ஻ޣǴӼ௨஑཰ៈ౛ৣ๏ϒ፾྽ϐᙯບ୍ܺᆶᙴᕍྣៈǶ

ಃΟ࿯Ǻᔠᡏϩ݋Бݤ

ԏ໣ϐ HBsAg ໚܄ᔠᡏ໻ߕԖጓဦǴό֖ҺՖڙ၂ޣϐ୷ҁၗ਑Ǵ୷ܭჹڙ ၂ޣϐᗦد៾ߥஏচ߾Ǵ٩Ѡεᙴଣࣴزউ౛ہ঩཮ೕۓǴڙ၂ޣޑҺՖၗ਑֡

ό཮଺ҺՖڀӜว߄Ƕ

ᔠᡏԏ໣ࡕ຾ՉᚆЈǴ٠ஒᚆЈࡕϐՈమᔠᡏܫ࿼-70ʚӇጃߥӸǶڗ 500͓

ᔠᡏǴճҔՈమϯᏢԾ୏ϩ݋ሺȐserum chemistry autoanalyzerȑ຾ՉՈమϐ AST ȐAspartate AminotransferaseȑϷ ALTȐAlanine Aminotransferaseȑᔠᡍǵӆа୘Ҕ ၂ᏊȐcommercially available kitsȑམଛሇનխࣝϩ݋ݤȐELISAȑᔠᡍϩ݋Ոమύ ϐ AFPȐalpha-fetoproteinȑǵHBeAg Ϸ anti-HBe ኧॶǶ

Bࠠطݹੰࢥໆޑϩ݋Ǵࢂڗ 200λ ᔠᡏՈమа୘Ҕ၂ᏊȐQIAamp DNA Mini Kit, Qiagen Inc.ȑ๧ڗрੰࢥϐ DNAǴڗрϐ HBV DNA ᐚᕭన࿼ܭᑻӀۓໆᆫӝ ሇન᜘ᙹϸᔈȐPCRȑᐒᏔȐABI Prism® 7300ȑύǴаջਔᆫӝ䁙᜘ϸᔈݤ ȐReal-Time polymerase chain reaction, Real-Time PCRȑמೌӃ຾Չ B ࠠطݹੰࢥ ໆȐHBV DNA levelȑޑᔠෳǶPCR চ౛ࣁǺ

(1)ᡂ܄ϸᔈ (denaturizing)Ǵ٬ DNA ޑٿިϩᚆǶ

(2)጗հଛჹϸᔈ (annealing)Ǵ٬ЇηȐprimerȑᆶҞ኱ DNA ଛჹǶ (3)ۯߏϸᔈ (extension)Ǵӝԋཥޑ DNA ިǶ

࣬ӕ؁ᡯൻᕉӭԛࡕǴёளډεໆϐ DNAǶځЇη੝ਸТࢤࣁբҔܭ preS2/S ȐNC003977ȑǴׇӈࣁ[55]Ǻ

5’-AGTGGGCCTCAGTCCGTTT-3’ȐforwardȑϷ 5’-AGCCCTACGAACCACTGGAACA-3’ȐreverseȑǴ

ׇӈТࢤޑᑻӀ௖ᓐׇӈࣁǺ

(FAM)-5’-TCCTGGCTCAGTTTACTAGTGCCA-3’-ȐTAMRA)Ǵ

ୀෳጄൎࣁ 50ɴ2x10⁹IU/mlǴ؂ԛ่݀ޑ኱ྗԔጕਠٰ҅Ծܭ Macrometrix ኱ྗ

నǴ٠ᆶځд Amplicor assayȐRocheȑਠ҅Ǵளډղۓ߯ኧ R²=0.98-1.0Ƕ

Bࠠطݹੰࢥϐ୷ӢࠠᔠෳǴڗ๧ڗӳޑ HBV DNAǴӃаணԄᆫӝ䁙᜘ϸᔈ

ݤ(nested polymerase chain reaction, nested PCR) ܫε HBV DNA ޑໆǴځЇηࣁǺ HBV-2821F and HBV-2437RȐ߄ 1ȑǹӆٰуΕόӕ੝ۓ୷ӢࠠޑЇηȐ߄ 1ȑǴ ӭख़ᆫӝሇન᜘ᙹϸᔈȐmultiplex-polymerase chain reaction, multiplex-PCRȑמೌ

຾Չϩ݋ǴPCR 45 ঁൻᕉࡕǴௗ๱າ 2%ࢩ๼ጤႝݚǶନ࿶ၸӭԛख़ፄϩ݋Ǵа ᔠۓ୷Ӣࠠϐ҅ዴ܄ѦǴ٠ӆଌۓׇȐsequencingȑϩ݋[56-58]Ƕ

ࣁዴۓ୷Ӣࠠϐ҅ዴ܄Ǵᒧڗځύኧঁᔠᡏ຾Չੰࢥӄߏ୷Ӣᡏکԛ୷Ӣᡏ ޑቚ൯ᆶۓׇǶፓ᏾Αቺ୯ Gýnther ฻೛ीрٰޑЇη[59]Ǵӧ HBV Ѧᕉ୷Ӣᡏ ޑલα(nick)ٿୁ೛ी΋ჹЇη P1(X+S)F Ϸ P2(X+S)RȐ߄ 2ȑа຾Չᆫӝ䁙ೱᙹ ϸᔈǴ٬ҔڀԖਠ҅фૈޑᆫӝ䁙(KOD-Plus DNA polymeraseǴTOYOBO CO., LTD)ǴPCR ൻᕉ 35 ԛǴௗ๱຾Չ 1%ࢩ๼ጤႝݚǴӆаѱ୧પϯ঺ಔ(GFXš

Polymerase Chain Reaction DNA and Gel Band Purification KitǴAmersham

BiosciencesǴGE HealthcareǴUSA)ஒ PCR પϯளډౢނǶௗ๱٬ҔԾ୏ۓׇሺ٠ ٩ᏹբЋн຾ՉۓׇπբǴճҔ 1 ঁϸӛۓׇЇηک 5 ঁ҅ӛۓׇЇηȐ߄ 2ȑஒ ೭٤ PCR ౢނуаۓׇǶ࿶җ 6 ಔۓׇϸᔈёளډ೽ϩख़᠄ޑਡ㧿ለׇӈǴճҔ DNA STAR Lasergene¯ v8.0 SeqMan Pro Ԝ೬ᡏКჹׇӈ٠ಔӝԋֹ᏾ޑੰࢥӄߏ

ׇӈǶ܌ளϐ B ࠠطݹੰࢥϐӄߏ୷Ӣᡏۓׇϩ݋Ǵځ୷Ӣ่ࠠ݀ᆶ PCR ܌ளϐ

ੰࢥ୷Ӣ่ࠠ݀֡࣬ӕǶ

ಃΟകǺ಍ीБݤ

ஒԏ໣ϐڙ၂ޣ୷ҁၗ਑ǵୢڔǵ୷Ӣࠠǵဎ೽ຬॣݢൔ֋฻ၗ਑Ǵа Excel

܈ STATA ܈ SAS ฻಍ी೬ᡏբ΋૓ϩթ܄಍ी฻ϩ݋ǴхࡴǺԃសǵ܄ձǵي ଯǵᡏख़ǵဈൎǵрғӦǵۚՐӦǵ௼ဂϩթǵР҆ᒃϐрғӦǵۚՐӦǵ௼ဂ ϩթǵௗڙᒡՈᆶցǵ໒ΘЋೌᆶցǵڈߙ܈ऀᡏࢰᆶցǵӅҔଞᓐᆶցǵ࿶த

໯ଚಞᄍȐ؂Ϻ܈ 2-3 Ϻസ΋ԛȑǵHBV ୷ӢࠠϩթǵASLǵALTǵHBeAg ໚܄

౗ǵanti-HBe ໚܄౗ǵિެطᆶցȐطჴ፦ᆶѓ๝Ҝ፦໔ߝࡋჹКࢂցቚуȑϷط ฯϯᆶցȐࢂցԖطჴ፦દ౛ǵ่࿯ރϐѰୁط᠌߄य़аϷόೕ߾੟ઞϐѓطᓉ

ેȑ฻Ǵ߃؁ᔠຎځ࣬ᜢ܄Ƕ

ASTޑ኱ྗॶुࣁǺت<37ǵζ<31 U/LǹALT ޑ኱ྗॶुࣁǺت<41ǵζ<31 U/LǴځϪΕᗺȐcut pointȑ೛ࣁຬၸ 40 U/L ࣁ౦தǴբࣁ಍ीϩ݋ǹB ࠠطݹੰ

ࢥໆޑ cut pointǴ೛ӧऍ୯طੰᏢ཮ȐAASLDȑϷ٥ϼطੰࣴز཮ȐAPASLȑ2008 ԃϦѲϐᄌ܄ B ࠠطݹݯᕍྗ߾ϐࡌ᝼ݯᕍ:྽ ALT εܭ 2 ७а΢Ǵe לচ഍܄ޣ Ъځ HBV DNA ॶ>2, 000 ܈ࢂ e לচ໚܄ޣЪځ HBV DNA ॶ>20,000 IU/mlǶр ғӦᆶۚՐӦεठϩࣁǺч(୷ໜǵѠчǵਲ༜ǵཥԮ)ǵύ(भਪǵѠύǵࠄ׫ǵ ᄆϯǵ໦݅)ǵࠄ(჏ကǵѠࠄǵଯ໢ǵࡀܿ)ǵܿ(ەើǵ޸ጪǵѠܿǵើᔁ)ǵᚆ৞

(ዋ෫ǵߎߐǵೱԢᑜǵᅽࡌ)ǵځд(ύ୯ǵੀ୯ǵຫࠄǵࢍ঵ჵǵӑѭ฻)ǶচՐ

҇Ξ୔ϩࣁ 4 εᇟسǶ

നࡕஒ܌Ԗޑڙ၂ޣǴ٩ྣځ௼ဂϐόӕ୔ϩࣁচՐ҇ᆶߚচՐ҇ٿε௼ဂ ǴКၨځ໔ϐৡձǹڗځύԖ୷Ӣࠠၗ਑่݀ϐڙ၂ޣǴ୔ϩࣁ୷Ӣࠠ B Ϸ C ٿ ဂǴКၨځ໔ϐৡձǶ຾΋؁٩ྣځ e לচ໚܄܈഍܄ǴКၨচՐ҇ᆶߚচՐ҇

໔܈όӕ௼ձচՐ҇ϐ୷Ӣࠠ B К౗Ƕа͞²test܈ t-test ܈ Fisher's exact test ฻ϩ

݋όӕӦ୔܈όӕ௼ဂϐ໔ӚӢηޑᜢ߯Ǵ٠а logistic regression ܈ linear

regressionӧᕖ҅ԃសǵ܄ձǵALT ฻ၗ਑ΠǴᔠຎӚಔ໔ځ୷Ӣࠠ܈ੰࢥໆᆶځ дӢηࢂցԖ܌ৡ౦Ϸځ࣬ᜢ܄Ƕ

ࣴ

ࣴز่݀

ಃ΋കǺ୷ҁၗ਑ϷܜՈၗ਑่݀ϩ݋

ҁࣴزᕴӅԏ໣Α 3,488 ՏٰԾܭୃᇻӦ୔ޑ B ࠠطݹ஻ޣǴЬा 42 ঁໂᙼ хࡴǺч೽ȐѠчᑜਜ਼ٰໂǵਲ༜ᑜൺᑫໂȑǵύ೽Ȑ໦݅ᑜ߁׀ᙼǵࠄ׫ᑜߞ ကໂǵࠄ׫ᑜϘངໂǵभਪᑜੀӼᑜǵε෫ໂȑǵࠄ೽ȐࡀܿᑜΟӦߐໂǵًࠤ ໂǵࡡࡾໂǵأϏໂǵྰηໂǵ੥ౚໂǵଯᐋໂǵ჏ကᑜߓٚξໂȑǵܿ೽ȐѠ

ܿᑜੇᆄໂǵၲϘໂǵεݓໂǵܿݞໂǵۯѳໂǵើᔁໂǵߎঢ়ໂǵڒࠄໂǵߏ ᔭໂǵᆘ৞ໂǵᜢξᙼǵϼഞٚໂǵജഁໂǵԣ΢ໂǵەើᑜࠄᐞໂǵεӕໂǵ

޸ጪᑜذ݅ໂǵ࿤ᄪໂǵڑྛໂȑϷᚆ৞ȐೱԢᑜࠄंໂǵчंໂǵܿЇໂǵܿ

ಶໂǵՋಶໂǵዋ෫ᑜ෫ՋᑜǵଭϦᑜǵқ؅ᑜȑǶ

ڙ၂ޣࣣԖᛝ࿿ڙ၂ޣӕཀਜǵ༤ቪၗҁၗ਑٠ԏ໣ᔠᡏǴځύ 2,663 Տڙ ၂ޣҭֹԋဎ೽ຬॣݢᔠࢗǶ

ڙ၂ޣ୷ҁၗ਑Бय़Ǻت/ζΓኧКऊࣁ 1Ȑ1,720 Γ/1,768 ΓȑǴѳ֡ԃសࣁ 50.7ྃǴѳ֡ BMIȐᡏख़ϦА/يଯϦЁѳБǴൂՏ Kg/m²ȑࣁ 26.1 Kg/m²Ƕ

ܜՈၗ਑Бय़Ǻѳ֡ AST ࣁ 34 U/LǴѳ֡ ALT ࣁ 39 U/LǴe לচ໚܄౗ࣁ 8%Ȑ280 Γ/3,488 ΓȑǴҘᅿजٽೈқ౦தޣȐAFP >20 ng/mlȑࣁ 0.6%Ȑ22 Γ/3,488 ΓȑǶѳ֡ HBV DNA ࣁ 25,340,981 IU/mlǴ29%Ȑ1,012 Γ/3,488 Γȑڙ၂ޣᔠෳ

όډՈύੰࢥໆǴλܭ 2,000 IU/ml ޣ 67.4%Ȑ2,349 Γ/3,488 ΓȑǴεܭ 2,000 IU/ml ޣ 32.6%Ȑ1,139 Γ/3,488 ΓȑǴεܭ 20,000 IU/ml ޣ 17.8%Ȑ621 Γ/3,488 ΓȑǶ

ڗځύ 1,178 ΓԖֹ᏾ޑੰࢥໆǵALTǵe לচϷୢڔ฻ၗ਑ޣǴа linear regressionঁձϩ݋ੰࢥໆଯեᆶԃសǵ܄ձǵિެطǵطᠼᆢϯ܈طฯϯǵe ל চ໚܄ǵASTǵALTǵ୷ӢࠠǵBMIǵ໯ଚǵচՐ҇ᆶցǵම࿶ᒡՈǵ໒Θǵڈߙ ǵӅҔଞᓐ฻ӢηǴࢂցԖᜢೱ܄Ƕ่݀ว౜ੰࢥໆଯեᆶԃសǵe לচ໚܄ǵ୷

ӢࠠϷচՐ҇ᆶցǴ೭ 4 ঁӢηԖ಍ी΢ᡉ๱ᜢ߯Ƕӧᕖ҅ԃសᆶ܄ձޑӢનΠ ǴӆӅӕϩ݋Ԝ 4 ঁӢηว౜Ǵ໻ e לচ໚܄ޣȐ͊ॶǺ0.271Ǵp-value<0.001ȑ ᆶ୷Ӣࠠ C ޣȐ͊ॶǺ0.175Ǵp-value<0.001ȑ཮٬ੰࢥໆቚଯǶ

ୢڔБय़Ǻ56.2%Ȑ1,961 Γ/3,488 Γȑڙ၂ޣҁيࣁߚচՐ҇ǴҁيࣁচՐ

҇ϐ௨᡼ᇟسΓኧനӭȐ42%ȑǴੀ໡ᇟسԛϐȐ35.2%ȑǴၽ௼ᇟسӆԛϐȐ22.4%

ȑǴЃϏᇟسനϿȐ0.3%ȑǶрғӦӧࠄ೽നӭȐ31.5%ȑǴځԛࣁύ೽Ȑ24.8%

ȑǵܿ೽Ȑ18.9%ȑǵᚆ৞Ȑ18.0%ȑǵч೽Ȑ5.5%ȑǵځдȐ1.3%ȑǴځۚՐӦ ΨکрғӦԖ࣬ӕᖿ༈Ƕම࿶ᒡՈޣ 14.7%Ȑ502 Γ/3,413 ΓȑǴම࿶໒ΘЋೌޣ 49.2%Ȑ1,694 Γ/3,446 ΓȑǴම࿶ڈߙ܈ऀᡏࢰޣ 29.2%Ȑ1,003 Γ/3,435 ΓȑǴ ම࿶ӅҔଞᓐޣ 7.0%Ȑ239 Γ/3,421 ΓȑǴԖ࿶த໯ଚಞᄍޣऊ 27.9%Ƕ

ဎ೽ຬॣݢᔠࢗБय़ǺԖિެطޣ 52%ǵԖطฯϯޣ 2.9%Ƕ

ஒڙ၂ޣϩࣁচՐ҇Ȑ1,527 ΓȑᆶߚচՐ҇Ȑ1,961 Γȑٿε௼ဂǴচՐ҇

ѝाР҆ځ΋ԖচՐ҇Ո಍൩ᘜΕǴځύԖٿঁ௼ဂคڙᔠΓኧǴջǹᖻহ௼Ϸ Ꮪᅦើ௼ǶߚচՐ҇ޑ೽ҽǴхࡴǺመࠄΓǵ࠼ৎΓϷѦ࣪Γ 3 Ӛ௼ဂǶ୷ҁၗ

਑ᆶܜՈၗ਑ᡉҢȐ߄ 3ȑǺ

1. ߚচՐ҇ت/ζΓኧКଯܭচՐ҇Ȑ1.2 vs. 0.8ȑǹe לচ໚܄౗ߚচՐ҇ҭ ଯܭচՐ҇Ȑ10.2% vs. 5.3%ȑǹߚচՐ҇ϐѳ֡ HBV DNA ॶᆶ HBV DNA>2, 000 IU/mlК౗Ȑ36.7% vs. 27.4%ȑ֡ଯܭচՐ҇Ƕ ԜѤঁᡂ໨࿶ၸ͞²܈ t-test ϩ݋

Ǵp-value ࣣλܭ 0.0001Ǵၲډ಍ी΢ᡉ๱ৡ౦Ƕ

2. ѳ֡ AST ॶচՐ҇ଯܭߚচՐ҇Ȑ37.6 vs. 31.6 U/LȑǹԖ࿶த໯ଚಞᄍޣ К౗ǴচՐ҇߾ᇻଯܭߚচՐ҇Ȑ40.0% vs. 19.3%ȑǶԜٿঁᡂ໨࿶ၸ͞²܈ t-test ϩ݋Ǵp-value ࣣλܭ 0.0001Ǵၲډ಍ी΢ᡉ๱ৡ౦Ƕ

3. ٿޣѳ֡ԃសऊ 50 ྃѰѓǹٿޣѳ֡ ALT ࣁ 39 U/LǴ಍ी΢٠คৡձǶ

ќѦǴဎ೽ຬॣݢᔠࢗ೽ϩǺচՐ҇ޑિެطК౗ၨߚচՐ҇ౣଯȐ55.2% vs.

50.3%Ǵp-value=0.017ȑǹԶٿޣӧطჴ፦ੰᡂ܈طฯϯޑКٯ࣬ӕ 29%Ƕ

ಃΒകǺ୷Ӣࠠ B Ϸ C ϐ่݀ϩ݋

ӧ 3,488 ঁᔠᡏჴᡍύ PCR Ԗளډ୷Ӣ่ࠠ݀ޑᔠᡏӅ 1,335 ΓȐ38.3%ȑǴ Ӆᔠᡍр 6 ᅿ୷ӢࠠރݩǴхࡴǺ୷Ӣࠠ BǵCǵDǵB+CǵB+DǵB+C+DȐკ 7 ȑǴ܌՞К౗ϩձǺ୷Ӣࠠ BǺ75.6% (1009 Γ)ǵ୷Ӣࠠ CǺ17.7% (236 Γ)ǵ୷Ӣ

ࠠ DǺ1.0% (13 Γ)ǵ୷Ӣࠠ B+CǺ4.9% (66 Γ)ǵ୷Ӣࠠ B+DǺ0.7% (10 Γ)ǵ୷ Ӣࠠ B+C+DǺ0.1% (1 ΓȑǶӧѝԵቾ୷Ӣࠠ B ܈ C చҹΠǴ୷Ӣࠠ B ޑ౰Չ౗

ࣁ 80.6%ǹՠӧԌନᚆ৞Ӧ୔ȐೱԢᑜ 41.7%Ȑ70 Γ/168 Γȑᆶዋ෫ᑜ 34.2%Ȑ13 Γ/38 ΓȑȑࡕǴ୷Ӣࠠ B ޑ౰Չ౗ࣁ 89.1%ǹऩаӦ୔ٰ࣮Ǵ୷Ӣࠠ B ޑК౗ࣁ Ǻܿ೽Ȑ92.7%ȑ>ύ೽Ȑ91.22%ȑ>ч೽Ȑ90.2%ȑ>ࠄ೽Ȑ82.0%ȑ>ᚆ৞Ȑ40.3%

ȑǶ

ӧёளډ୷Ӣࠠޑ 1,335 ΓύǴᑔᒧрӕਔԖ e לচ໚܄܈഍܄ၗ਑ޣ 1,185 ΓǴӆஒ೭٤Γϩࣁ୷Ӣࠠ B Ϸ C ٿಔ຾Չϩ݋Ǵ୷ҁၗ਑ᆶܜՈၗ਑ᡉҢǺ୷ Ӣࠠ B ޣѳ֡ԃសၨ୷Ӣࠠ C ޣεȐ50.3 vs. 48.1 ྃȑǹ୷Ӣࠠ B ޣځ e לচ໚܄

౗ၨ୷Ӣࠠ C ޣեȐ10.3% vs. 37.4%ȑǹ୷Ӣࠠ B ޣځѳ֡ ALT Ϸ౦த ALT Ψ

ၨեȐ44 vs. 54 U/Lǵ35.7% vs. 43%ȑǹ୷Ӣࠠ B ޣځѳ֡ HBV DNA ॶᆶ HBV DNA>2, 000 IU/mlΨၨեǶԜѤঁᡂ໨࿶ၸ͞²܈ t-test ϩ݋Ǵp-value ࣣλܭ 0.05 Ǵၲډ಍ी΢ᡉ๱ৡ౦Ȑ߄ 4ȑǶ

а logistic regression ٰᔠᡍቹៜԋࣁ୷Ӣࠠ B ޑ࣬ᜢӢηǴளډϐ่݀ࣁǺ ԃសၨεޣȐodds ratio [OR]= 1.014Ǵ95% confidence interval [CI]= 1.003-1.025Ǵ p-value=0.0161ȑǵۚՐӧߚᚆ৞Ӧ୔ǵচՐ҇ȐЀځࢂၽ௼നଯ, ځ OR=24.026, 95%CI=3.315-174.143, p-value=0.0017ȑǵALT եǵੰࢥໆեǵe לᡏ໚܄ޣȐodds

ratio [OR]=5.691Ǵ95% confidence interval [CI]= 3.899-8.306Ǵ p-value<0.0001ȑǴ คطᠼᆢϯ܈طฯϯޣǴႣෳځ஥Ԗ୷Ӣࠠ B ޑᐒ཮ၨଯǶ

ಃΟകǺߚচՐ҇ᆶচՐ҇௼ဂ໔୷Ӣࠠ B Ϸ C ϐ่݀ϩ݋

ڗځύ 1,178 ΓԖֹ᏾୷Ӣࠠ B ܈ C ᆶ e לচ໚܄܈഍܄ၗ਑ޑڙ၂ޣǴஒ ೭٤ΓϩࣁߚচՐ҇ᆶচՐ҇ٿಔ຾Չϩ݋ᡉҢǺচՐ҇୷Ӣࠠ B К౗ࣁ 92.7%

ଯܭߚচՐ҇ࣁ 72.7% ȐऩԌନೱԢᑜࣁ 82.2%ǴऩԌନዋ෫ᑜࣁ 74.9%Ǵऩӕ ਔԌନೱԢᑜᆶዋ෫ᑜࣁ 85.6%ȑǴࣣၲ಍ी΢ᡉ๱࣬ᜢȐp-value<0.05ȑǶӆஒ e לচϩࣁ໚܄ᆶ഍܄ٿಔǴe לচ໚܄ޣύȐ188 ΓȑǴߚচՐ҇ޑ୷Ӣࠠ B ౰Չ

౗ၨեȐ44.5% vs 83.3%ȑǹe לচ഍܄ޣύȐ990 ΓȑǴߚচՐ҇ޑ୷Ӣࠠ B ౰ Չ౗ၨեȐ80.0% vs 93.7%ȑǴЪ࿶ၸ͞²ϩ݋Ǵp-value ࣣλܭ 0.0001Ǵၲډ಍ी

΢ᡉ๱ৡ౦Ȑ߄ 5ȑǶ

Ԗֹ᏾୷Ӣࠠ B ܈ C ᆶ e לচ໚܄܈഍܄ၗ਑ޑ 467 ՏচՐ҇ڙ၂ޣǴ٩ྣ

ځ܌ឦᇟسόӕϩࣁ 4 ಔǴхࡴǺੀ໡ᇟسǵ௨᡼ᇟسǵၽ௼ᇟسǵЃϏᇟسȐค Ԝᇟسϐڙ၂ޣȑǴϩ݋่݀ᡉҢǺၽ௼ᇟسϐ୷Ӣࠠ B ޑК౗നଯ 97.8%Ǵځ ԛࣁ௨᡼ᇟس 96.4%Ǵӆޣࣁੀ໡ᇟس 88.1%Ǵՠ٠҂ၲډ಍ी΢ᡉ๱࣬ᜢ

Ȑp-value=0.182ȑǶӆஒ e לচϩࣁ໚܄ᆶ഍܄ٿಔǴe לচ໚܄ޣύȐ42 ΓȑǴ ၽ௼ᇟسϐ୷Ӣࠠ B ౰Չ౗നଯȐ100%ȑǴځԛࣁ௨᡼ᇟسȐ89.5%ȑϷੀ໡ᇟ سȐ66.7%ȑǴՠ 3 ಔ໔٠҂ၲډ಍ी΢ᡉ๱࣬ᜢȐp-value=0.0775ȑǹe לচ഍܄

ޣύȐ425 ΓȑǴၽ௼ᇟسϐ୷Ӣࠠ B ౰Չ౗നଯȐ97.9%ȑǴځԛࣁ௨᡼ᇟسȐ97.1%ȑ ᆶੀ໡ᇟسȐ89.7%ȑǴЪ࿶ၸ͞²ϩ݋Ǵp-value ࣁ 0.0054Ȑ<0.05ȑǴၲډ಍ी΢

ᡉ๱ৡ౦Ȑ߄ 6ȑǶ

ऩаԃសϩቫٰ࣮ߚচՐ҇ᆶচՐ҇ϐ໔ޑᜢ߯Ǵ಍ीว౜চՐ҇௼ဂ୷Ӣ

চՐ҇௼ဂǴவ 40 ྃ໒ۈ୷Ӣࠠ B ౰Չ౗ջ໒ۈᡉ๱ගଯǴ࿶ၸ Fisher's exact test

܈͞²testϩ݋ࣣᡉҢٿޣ໔Ԗ಍ी΢ᡉ๱ৡ౦Ȑp-value <0.05ȑȐკ 8ȑǶ

ಃѤകǺ୷Ӣࠠ D ϐ่݀ϩ݋୷ҁၗ਑ϷܜՈၗ਑่݀ϩ݋

ࣴزύว౜ 13 ٯӧѠ᡼࣬྽شـޑ୷Ӣࠠ D ڙ၂ޣǴځتζКࣁ 0.86Ǵѳ֡

ԃសࣁ 49.3 ྃȐت/ζǺ54.5/44.9 ྃȑǴځѳ֡ԃសᆶ୷Ӣࠠ B ܈ C ޣ҂Ԗܴᡉৡ ౦Ƕ

ܜՈၗ਑ᡉҢѳ֡ AST ࣁ 67 U/LǴѳ֡ ALT ࣁ 43 U/LǴҘᅿजٽೈқѳ֡

ॶࣁ 11 ng/mlǴځॶ౦தޣ 16.7%Ǵe לচ໚܄౗ 15.4%Ǵѳ֡ HBV DNA ॶ 10,309,203 IU/mLǴHBV DNA ॶ>2,000 IU/ml ࣁ 100%Ƕ

ځрғӦϷۚՐӦӭ໣ύܭࡀܿᑜȐ12 ՏȑǴѝԖ 1 Տӧ჏ကᑜǶ೭ 13 Տڙ ၂ޣԖ 12 ՏԖচՐ҇يϩǴځύа௨᡼௼നӭȐ10 ΓȑǴځд 3 ΓϩձࢂᎹഩ௼ǵ ၽ௼ϷߚচՐ҇ǶୢڔύᡉҢ 13 Տڙ၂ޣύԖ 2 Տ(15.4%)ම࿶ௗڙၸᒡՈǵ6 Տ Ȑ46.1%ȑම࿶ௗڙ໒ΘЋೌǴԖ 5 Տ(38.5%)ම࿶ڈߙ܈ऀᡏࢰǴคΓම࿶ӅҔଞ ᓐȐ߄ 7ȑǶ

૸

૸ፕ

ҁࣴزว౜ӧѠ᡼ୃᇻӦ୔ۚ҇ϷচՐ҇ϐ B ࠠطݹ஻ޣύǴቹៜᑡ஻طᕎ

॥ᓀޑӢηǴচՐ҇೿ၨߚচՐ҇௼ဂࣁեǴӵǺե e לচ໚܄౗Ȑ5.3% vs. 10.2%Ǵ p-value<0.0001ȑǴၨեѳ֡ੰࢥໆЪ HBV DNA>2,000 IU/ml ޣК౗ၨեȐ27.4% vs.

36.7%Ǵp-value<0.0001ȑϷҺՖԃសቫϐ୷Ӣࠠ B/C ౰Չ౗ࣣၨଯȐ92.7% vs.

72.7%Ǵp-value<0.05ȑǴЪ֡ၲ಍ी΢ᡉ๱ৡ౦ǶќѦǴᚆ৞Ӧ୔ޑ B ࠠطݹ஻ޣ а୷Ӣࠠ C ࣁЬȐ60%ȑǴҁ৞Ӧ୔а୷Ӣࠠ B ࣁЬȐ89%ȑǴচՐ҇ϐ୷Ӣࠠ B К౗ᡉ๱ଯܭߚচՐ҇Ǵځύаၽ௼ᇟسᆶ௨᡼ᇟسϐ୷Ӣࠠ B ޑК౗നଯऊ

97%Ƕӆޣࣴزύว౜ӧѠ᡼࣬྽شـޑ୷Ӣࠠ DǴЬा໣ύܭࡀܿᑜǴа྽Ӧ௨

᡼௼ۚӭǴځੰࢥໆၨଯȐHBV DNA >2,000 IU/mlȑǴЪୢڔၗ਑ᡉҢᗨԖ೽ϩੰ

஻ම࿶ௗڙᒡՈǵ໒Θǵڈߙ܈ऀᡏࢰǴՠคΓමӅҔଞᓐǶ

୯ϣᏢޣࣴزว౜ B ࠠطݹ஻ޣύǴаت܄ǵԃសၨεǵALT ౦தǵHBeAg

໚܄ǵԖطฯϯǵੰࢥໆၨଯǵ୷Ӣࠠ Cǵprecore1896 ೀคँᡂϷ BCP (1762/1764)

ೀԖँᡂޣǴ҂ٰԖၨଯᑡ஻طᕎޑ॥ᓀ[26]ǶҁࣴزᡉҢѠ᡼ୃᇻӦ୔ۚ҇ύǴ คੱރޑ B ࠠطݹ஥চޣǴe לচ໚܄౗ࣁ 8%ǴЪߚচՐ҇ e לচ໚܄౗ଯܭচ Ր҇Ȑ10.2% vs. 5.3%Ǵp-value<0.0001ȑǴࣣᇻեܭځдᏢޣࣴزϐ B طৎ௼ύޑ คੱރ B ࠠطݹ஥চޣȐ20%ȑ[60]ǶߚচՐ҇ᆶচՐ҇໔ϐѳ֡ ALT ٠คᡉ๱

ৡ౦ǴՠࢂচՐ҇ϐѳ֡ AST ᆶ࿶த໯ଚಞᄍК౗ࠅଯܭߚচՐ҇Ǵ௢ፕԜёૈ

ࢂ໯ଚಞᄍ೷ԋ AST ୃଯޑރᄊǶќѦǴԖ 29%ޑ B ࠠطݹ஥চޣՈύᔠෳόډ

ੰࢥໆǴHBV DNA ଯܭ 2,000 IU/ml ޣଯၲ 32.7%ǴԶߚচՐ҇ϐѳ֡ੰࢥໆ܈

HBV DNA ଯ ܭ 2,000 IU/ml ޣ К ౗ ೿ ଯ ܭ চ Ր ҇ Ȑ 36.7% vs. 27.4% Ǵ

p-value<0.0001ȑǹќѦҁࣴزΨว౜ǴѝԖ e לচ໚܄ᆶ୷Ӣࠠ C ೭ٿঁӢηǴᆶ

ቚуੰࢥໆԖᜢ߯ǶЪόፕ e לচ഍܄܈໚܄ǴচՐ҇஥Ԗ୷Ӣࠠ B ޑК౗֡ᇻ

93.7% vs. 80.0%Ǵp-value<0.0001ȑǴЪόᆅব΋ঁԃសቫচՐ҇୷Ӣࠠ B ϐ౰Չ౗

ࣣଯܭߚচՐ҇Ƕᕴ่΢ॊǴቹៜᑡ஻طᕎ॥ᓀޑӢηǴচՐ҇೿ၨߚচՐ҇௼

ဂࣁեǴ௢ፕឦܭࠄ৞ᇟ௼ޑѠ᡼চՐ҇Ǵځᡏϣޑխࣝس಍܈Ϻғᒪ໺୷Ӣ฻

ӢηᆶߚচՐ҇௼ဂԖ܌όӕǴёૈቚமځჹ B ࠠطݹੰࢥޑܢלΚ

୯ϣѦࣴزளޕ B ࠠطݹ஻ޣӧ҂ٰёૈᑡ஻طฯϯϷطᕎޑ॥ᓀ೿ၨଯǴ Ъࣁ׎ԋطᕎޑЬाচӢ[1, 61]Ǵӧፁғ࿿಍ीύΨว౜ᄌ܄طੰϷطฯϯϐ኱ྗ

ϯԝΫ౗ǴচՐ҇ၨӄ୯Γ҇ࣁଯǴѳ֡ტڮၨߚচՐ҇อȐ0 ྃѳ֡Ꭹڮ 68.5 vs.

77.9ȑǴЪ 25-44 ྃϐচՐ҇ЬाԝӢಃ΋Տࣁᄌ܄طੰϷطฯϯǴՠطᕎϐ኱ྗ

ϯԝΫ౗চՐ҇ࠅၨե[7, 14]Ƕӆу΢ҁࣴزว౜Ǵᑡ஻ B ࠠطݹϐচՐ҇Ǵቹៜ ځᑡ஻طᕎϐӒᓀӢη೿ၨߚচՐ҇ࣁեǴѳ֡ AST ॶᆶ࿶த໯ଚК౗Ȑ40%ȑ

ၨଯǴ܌аளޕǴ೷ԋচՐ҇ᄌ܄طੰϷطฯϯԝΫ౗ଯϐЬाচӢ٠ߚ B ࠠط ݹ܌ठǴᔈࣁଚᆒ܄طݹ฻ځдচӢǶӆу΢চՐ҇௼ဂۚೀܭୃᇻӦ୔Ҭ೯ό ߡǴᙴᕍၗྍၨ೦ЮǴᙴᕍྣៈس಍ၨৡǴ೭٤طݹ஻ޣӧੰำۘ҂ว৖Կطᕎ ਔǴ൩ς࿶ԝΫΑǴ܌аচՐ҇ϐطᕎԝΫ౗ω཮ၨߚচՐ҇եǶ

ӢԜǴӵՖӧϦӅፁғࡹ฼Бय़լܺୃᇻӦ୔҇౲൩ᙴόߡޑ֚ᜤǵׯ๓ط

ੰᙴᕍྣៈس಍Ȑගܹޗ୔ᙴᏢᆶ୷ቫᙴᕍߥ଼ޑϖε੝፦Ȑ2A3CȑǴхࡴǺё߈

܄ Ȑ accessibility ȑǵ ڬ ӄ ܄ ޑ ྣ ៝ Ȑ comprehensiveness ȑǵ ڐ ፓ ܄ ޑ ྣ ៝ Ȑcoordinationȑǵ࡭ុ܄ޑྣ៝Ȑcontinuity)Ϸॄೢ܄ޑྣ៝Ȑaccountability)ȑ٠ ႴᓰיଚǴႣයஒёεεफ़եୃᇻӦ୔ϷচՐ҇ϐطੰᝄख़ࡋǶ

୷Ӣࠠϩ݋ࣴزว౜ǴӧᔠෳޑډӚᅿ୷Ӣࠠޑڙ၂ޣύǴ୷Ӣࠠ B ޑК౗

ࣁ 75.6%Ǵऩѝൂપीᆉ୷Ӣࠠ B ܈ CǴ߾୷Ӣࠠ B ޑ౰Չ౗ࣁ 80.6%Ǵᆶϐ߻୯ ϣᏢޣࣴزፓࢗϐ 80%࣬ӕǹՠӧԌନᚆ৞Ӧ୔ȐೱԢᑜᆶዋ෫ᑜȑࡕǴ୷Ӣࠠ B ޑ౰Չ౗߾ගଯࣁ 89.1%Ǵ߾ᇻଯܭ 80%[35]Ƕӧᚆ৞Ӧ୔Ьा 59.7%ࣁ୷Ӣࠠ C ȐೱԢᑜ 58.3%ᆶዋ෫ᑜ 65.8%ȑǴѠ᡼ҁ৞Ьाࣁ୷Ӣࠠ BȐܿ೽Ȑ92.7%ȑ>ύ

೽Ȑ91.22%ȑ>ч೽Ȑ90.2%ȑ>ࠄ೽Ȑ82.0%ȑȑǶԜ่݀Ѝ࡭୯ϣᏢޣॺޑࣴز่

݀ǴջಃΒԛШࣚεᏯࡕҗεഌᎂழٰѠۓۚޑΓǴځ୷Ӣࠠ C К౗ၨଯ[19]Ƕ

௼ ဂ ೽ ϩ চ Ր ҇ ୷ Ӣ ࠠ B К ౗ ࣁ 92.7% ଯ ܭ ߚ চ Ր ҇ ࣁ 72.7%

Ȑp-value<0.05ȑǴЪ؂ঁԃសቫচՐ҇ϐ୷Ӣࠠ B ౰Չ౗ࣣଯܭߚচՐ҇ǴԶԾ

40ྃଆٿޣϐ୷Ӣࠠ B ౰Չ౗೿໒ۈ೴ྃගଯǴԜᔈੰݩၨܰൾϯ܈ၨԐౢғط

ᕎϐ B ࠠطݹੰࢥ୷Ӣࠠ C ޣǴᒿ๱ԃសቚу೿ၨ୷Ӣࠠ B ޣගԐԝΫǴ੮Πޑ

௼ဂࣁϺ᏷ࡕੰݩၨӳޑ୷Ӣࠠ B ޣǴ܌а୷Ӣࠠ B ϐ౰Չ౗ω཮೴ྃගଯǶќ ѦǴҁࣴزΨว౜Ⴃෳ B ࠠطݹੰࢥ୷Ӣࠠࣁ B ޑ࣬ᜢӢηԖǺԃសၨεޣǵۚ

ՐӧѠ᡼ҁ৞Ӧ୔ǵচՐ҇ǵALT եǵੰࢥໆեǵe לᡏ໚܄ޣǵคطᠼᆢϯ܈ط ฯϯޣǴځ஥Ԗ୷Ӣࠠ B ޑᐒ཮ၨଯǶ

ऩӆϩࣁ e לচ໚܄ᆶ഍܄ٿಔǴচՐ҇௼ဂϐ୷Ӣࠠ B К౗ϝၨଯȐ83.3%

Ϸ 93.7%ȑǹচՐ҇௼ဂύΞаၽ௼ᇟسϐ୷Ӣࠠ B ޑК౗നଯ 97.8%Ǵځԛࣁ௨

᡼ᇟس 96.4%Ǵӆޣࣁੀ໡ᇟس 88.1%Ǵՠ 3 ಔ໔҂ၲ಍ी΢ᡉ๱࣬ᜢ܄ǶԶচՐ

҇௼ဂϐ୷Ӣࠠ B ޑК౗ଯၲ 92.7%Ǵ௢ፕӧࠄ৞ᇟ௼ᎂழਔǴѠ᡼চՐ҇௼ဂ ᆶۚՐӧεഌܿࠄБޑࠄ৞ᇟ௼ޑᜢ߯ǴКځѬӦ୔ޑࠄ৞ᇟ௼׳ࣁஏϪǴ܌а

୷Ӣࠠ B ޑК౗ၨଯǹځύၽ௼ᇟسȐၽ௼ᆶᎹഩ௼ȑ୷Ӣࠠ B ޑК౗ΞനଯǴ Р҆ᚈБ֡ࣁӕ΋௼ဂޣଯၲ 95.6%Ǵ௢ፕёૈځᎂழٰѠࡕӦೀୃᇻǴεӭࣁ௼

ϣ೯ஆࣁЬǶ

ୖᆶࣴزϐ 42 ঁໂᙼڙ၂ޣύǴว౜Ԗ 13 ՏࣁѠ᡼࣬྽شـޑ B ࠠطݹੰ

ࢥ୷Ӣࠠ DǴԜ୷Ӣࠠ D தـܭኻࢪǵࠄ٥Ȑӑࡋȑǵ܌ᛥߐဂ৞฻ӦǴԶѠ᡼

ߚதีϿǶځѳ֡ԃសࣁ 49.3 ྃȐت܄ऊεܭζ܄ 10 ྃȑǶܜՈၗ਑ᡉҢѳ֡

ASTᆶ ALT ั༾౦தୃଯǴΨԖၨଯޑ e לচ໚܄౗ 15.4%Ǵѳ֡ HBV DNA ॶ ϟܭ୷Ӣࠠ B ᆶ C ޣѳ֡ॶϐ໔ǴЪ܌ԖΓ HBV DNA ॶ֡>2,000 IU/mlǶќѦځ

ϩੰ஻ම࿶ௗڙᒡՈǵ໒Θǵڈߙ܈ऀᡏࢰǴՠคΓමӅҔଞᓐǶऩӆу΢ځд ᆶ୷Ӣࠠ B ܈ C ӝٳགࢉޣǴ߾ऊԖ 1.8%ޑѠ᡼ୃᇻӦ୔ᆶচՐ҇ B ࠠطݹ஻

ޣǴځᡏϣ஥ԖѠ᡼ၨشـޑ B ࠠطݹੰࢥ୷Ӣࠠ DǶࢌ٤Ӧ୔ဂᆫѠ᡼ၨࣁش ـϐ B ࠠطݹੰࢥ୷Ӣࠠ DǴځགࢉ೼৩ᆶ໺ኞБԄǴߚதॶள҂ٰుΕޗ୔଺

ҖഁፓࢗǶ

҂

҂ٰ৖ఈ

ҁࣴز׫Ε࣬྽ᚳεޑΓΚǵނၗᆶޗ཮ངЈ฻ၗྍڐΚֹԋǴ٠ࡌҥ΋

ঁගܹ୷ቫᙴᕍ2A3C ੝ՅޑطੰྣៈኳԄǴҞޑࢂૈගٮࡹ۬࣬ᜢൂՏܭϦӅ ፁғࡹ฼ϐୖԵ٩ᏵǴӢࣁҁࣴزޑ௼ဂֹӄٰԾܭӄѠӚӦޑޗ୔௼ဂȐЀ ࣁѠ᡼ୃᇻӦ୔ᆶচՐ҇Ӧ୔ȑǴԶߚ୺Չࣴز܌ӧޑᙴଣ௼ဂǴ׳ૈ੿ჴϸ ᔈޗ୔ੰ஻ޑ౜ݩǴᗨฅؒԖၲډࣴزᒿᐒܜኬޑ኱ྗǴՠҗߚচՐ҇ᆶচՐ

҇ϐѳ֡ ALT ॶ࣬߈Ъ҂ຬၸ኱ྗॶٰ࣮ǴϝࢂԖځж߄܄ޑཀကӸӧǶ

ࣴزว౜ୃᇻӦ୔চՐ҇ک୷Ӣࠠ C ၨଯޑᚆ৞Ӧ୔ۚ҇ǴԖ๱ଯܭߚচ Ր҇܈೿཮୔ۚ҇ޑطੰԝΫ౗ǴନΑ B ࠠطݹੰࢥޑቹៜѦǴགࢉ C ࠠطݹ

ੰࢥǵ໯ଚ೷ԋଚᆒ܄طੰǵӦೀୃᇻ൩ᙴҬ೯όߡᆶᙴᕍྣៈ೦Ю฻ୢᚒǴ

׳ࢂୃᇻӦ୔ϷচՐ҇طੰٛݯޑќ΋ঁख़ाፐᚒǴॶள୯Γ׫ΕЈΚѐֹ

ԋǶќѦǴ୯Γᄌ܄طੰϷطฯϯޑԝΫচӢ಍ीǴ҂ٰᔈሡ຾΋؁ϩ݋೷ԋ ԝΫޑচӢࣁǺੰࢥ܄طݹǵଚᆒ܄طݹ܈ᛰނ฻Ǵ଺׳ಒ೽ޑԝӢᘜᜪǴω

ૈᙶమ೷ԋচՐ҇ଯطੰԝΫ౗ޑ੿҅ϡӁǶ

Ѡ᡼চՐ҇ B ࠠطݹ஻ޣǴࣴزᡉҢځЬाੰࢥ୷Ӣࠠࣁ B Ъଯၲ9ԋа

΢Ǵӧ B ࠠطݹޑੰำว৖ᆶݯᕍ΢࣬ჹԶق೿ឦܭႣࡕၨ٫ޣǴќѦځѬ཮

ቹៜ҂ٰᑡ஻طᕎޑӒᓀӢનǴচՐ҇௼ဂΨၨߚচՐ҇௼ဂեǴࢂցځᡏϣ խࣝΚ܈ӃϺঁᡏ୷Ӣৡ౦฻ԖձܭߚচՐ҇ǴӵǺΓᜪқՈౚಔᙃלচ(human leukocyte antigen: HLA-DPA1Ϸ HLA-DPB1฻)ǵࢥఠ܄ T ಒझȐCytotoxic T Cell, CTLȑǵmicroRNAsȐmiRNA)܈ Small interfering RNAȐsiRNAȑ฻όӕǴࢂ҂

ٰॶள຾΋؁ࣴزޑፐᚒǶ

Ѡ᡼চՐ҇௼ဂ΋ޔࢂࣴزሦୱύǴᏢޣԖᑫ፪௖૸ޑࠄ৞ᇟ௼ǴдॺӧΓ ᜪᏢޑว৖ў΢׳Ԗځόё܈લޑख़ाӦՏǶԶѠ᡼চՐ҇܌஥Ԗޑ୷ӢࠠBᆶШ

ӵǺКၨBطৎ௼҆η໔܈л׌ۊۂ໔ੰࢥ୷Ӣޑᡂ౦ࡋϷᄽϯำࡋǴКၨѠ᡼চ Ր҇ᆶځд୯ৎϐࠄ৞ᇟ௼ੰࢥ୷Ӣޑᡂ౦ࡋᆶ࣬՟ࡋ฻Ǵ҂ٰߚதॶள଺຾΋

؁ుΕ௖૸Ƕλλय़ᑈޑѠ᡼ǴᑼӝΑ೚ӭޑ௼ဂǴନΑճҔЎϯǵᇟقǵғࢲ ಞᄍǵԵђǵᐕўǵዿԯ܈३ᑴ܈ᘓ཯܈፜฻ғނӭኬ܄БԄٰ௖૸௼ဂޑόӕǴ

௢ፕࠄ৞ᇟ௼ޑᎂழၡ৩ᆶᄽϯϐѦǴ܈೚ΨёаόӕӦ୔Bࠠطݹੰࢥϐ୷Ӣᡏ ৡ౦ޑفࡋǴٰӅӕ௖૸ࠄ৞ᇟ௼ޑᎂழᐕўǴᡣѠ᡼ޑᙴᏢΓᜪᏢϣ৒׳ڀᙦ

൤ЪӭϡϯǶ

ӆޣࣴزΨว౜ࢌ٤Ӧ୔ဂᆫѠ᡼ၨࣁشـϐ B ࠠطݹੰࢥ୷Ӣࠠ DǴд ॺޑགࢉ೼৩ᆶ໺ኞБԄǴ҂ٰΨ࣬྽ॶள଺຾΋؁ҖഁፓࢗᆶࣴزǴӵǺ຾

Չঁձ܈ৎ௼ೖፋǴΑှࢂցԖӅӕགࢉޑਥྍȐӵǺᒃឦᜢ߯ǵᛰ᠅ݙ৔ǵ ڈߙǵऀᡏࢰϷѺଞЎϯ฻ȑǴ٠Αှ྽Ӧ௨᡼௼ޑᐕўసྍࢂցԖձܭځд

௼ဂޑᎂழ೼৩฻ǴќѦΨёӧ೭ኬ੝ਸطੰӦ୔ೕჄֹ๓ޑطੰྣៈس಍Ǵ ߏයଓᙫࢂցёӢԜफ़եځطੰԝΫ౗Ƕ

Ѡ᡼طੰޑٛݯǴନΑ B ࠠطݹϐѦǴC ࠠطݹǵଚᆒ܄طੰϷિެط฻

طੰǴΨ೿ࢂख़ाޑፐᚒǶ҂ٰයఈૈࡌҥҁࣴزύڙ၂ޣϐطੰྣៈኳԄᆶ

ঁਢଓᙫᆅ౛س಍Ǵ٠ஒԜኳԄ௢ቶԿ C ࠠطݹ฻طੰϐٛݯǴගٮШࣚፁғ ಔᙃطੰٛݯϐୖԵ٩ᏵǶ

म

मЎፕЎᙁॊ

INTRODUCTION Background

Section I: The Importance of Hepatitis B in Taiwanese aborigines and non-aborigines

There are an estimated 400 million people with hepatitis B virus (HBV) infection

worldwide, of which 15-40% suffer from liver cirrhosis, hepatic failure or

hepatocellular carcinoma (HCC). Every year, approximately 500,000 people die of

HCC [1-4].

In Taiwan, there are approximately 5,000 people who die of chronic liver disease

and liver cirrhosis, and another 7,700 people die of HCC annually. It is the second most

common cancer death overall and the most common cancer death amongst the male

population. HCC in Taiwan is primarily caused by HBV infection, followed by hepatitis

C virus (HCV) infection and other liver diseases [5-7].

Research surveys show that about 15-20% of adults in Taiwan are HBV carriers [6,

8]. Since the government made neonatal hepatitis B vaccine injection mandatory in

1984, HBV carrier rate has dropped to about 1%, and the percentage of children

suffering from HCC has been reduced significantly [9-10].

Higher mortality rates of chronic liver diseases and lower survival rates of HCC are

observed in rural areas. In addition, there is a higher survival rate in the northern region

compared to central and southern regions, and in urban areas compared to rural areas

[7-8, 11].

In terms of ethnic groups, HBV prevalence within Taiwanese aboriginal

populations is higher than Taiwan's other ethnic groups, such as the Atayal tribe. Even

within the aboriginal communities, significant differences exist. Higher standardized

mortality rate of chronic liver diseases and liver cirrhosis is noted in Taiwanese

aborigines who have lower standardized mortality rate of HCC. Moreover, the major

causes of death in 25-44 age group are chronic liver diseases and liver cirrhosis [14]. In

summary, male Taiwanese aborigines, aborigines in mountain areas, the Atayal tribe

and the Bunun tribe are high-risk groups for chronic liver diseases, liver cirrhosis and

HCC mortality [12-14].

Recent studies indicate that many factors could increase the risk of developing into

HCC in HBV carriers. These factors include: whether hepatitis B virus e-antigen

(HBeAg) is positive or not; the HBV DNA viral load level; alanine aminotransferase

(ALT) values; HBV genotypes, whether HBV mutates in its basal core promoter (BCP)

or precore region; age; gender; etc [15-26]. Male, people with older age, and those with

abnormal ALT, HBeAg-positive, cirrhosis, high HBV DNA, genotype C, precore 1896

location free of mutation and mutations at BCP (1762/1764) are at a higher risk. The

HBV virus load can be reduced by lowering the amount of virus in blood via drug

treatments, as they reduce the incidence of HCC [26].

Section II: Introduction to Hepatitis B Virus

Hepatitis B surface antigen (HBsAg) was first discovered in the serum of

Australian aborigines by Dr. Blumberg in 1965. Hepatitis B virus is a part of the

Hepadnaviridae family of viruses. The virus is a spherical double-layered particle with a

diameter of 42 nm. The virus is composed of 3 parts--an outer envelope which contains

surface protein, an inner nucleocapsid shell composed of core proteins, and the core

particle surrounds the partially double-stranded, relaxed circular deoxyribose nucleic

acid (DNA) and the polymerase [28-29] (Figure 1).

The viral DNA structure consists of one complete negative sense strand and one

partial positive sense strand. The locations prone to mutation in viral replication process

are precore 1896, basal core promoter, BCP T1762/A1764, and genetic defect at per-S.

The annual mutation rate at these gene locations is about 1.4 ~ 3.2x10 ^-5 per one site.

virology, such as the formation of many different types of genotypes, sub-genotype,

gene point mutations or defects, recombinant, and so on. Studies have found that these

changes interplay the risk of patients with HBV infection developing into liver cirrhosis

and HCC [28, 32] (Figure 2).

Section III: Hepatitis B Virus Genotype Distribution and its Pathology

Just as the members of the human race have different genes, traits, and geographic

distribution, HBV likewise has various characteristics. As far as we know, up to this day

there are mainly 10 types of Hepatitis B virus genotypes --A, B, C, D, E, F, G, H, I and

J--listed according to the time they were identified (Figure 3).

Regional viral genotype prevalence is different around the world. In Taiwan and

East Asia, genotypes B and C are most common--Genotype C is prevalent in the north

of the Yangtze River while genotype B is prevalent in the south of the Yangtze River. In

the Solomon Islands, there are mainly genotypes C and D. In Europe and South Asia,

there are mostly genotypes A and D. In the United States and Australia, the genotype is

more diverse, including A, B, C, and D. Low-incidence genotype E is mainly

distributed in West Africa, F and H in Central and South America, G in the United

States and Europe, and I and J in South East Asia and Japan.

In recent years, the percentage of genotypes B and C started to rise in the United

States and Australia as the Asian immigrants have increased [17, 33-37].

The routes of infection may reflect HBV genotype distribution. In the regions (e.g.

Taiwan) where the vertical transmission is the primary method of transmission,

genotypes B and C are more common. On the other hand, in those regions where

horizontal transmission (such as sexual contact, intravenous drug uses, etc.) is the

primary method of transmission, genotypes A and D seem to be more common. To date,

the direct correlation between the transmission pathway and the virus genotype

distribution is still unclear [20, 35, 38].

In Taiwan, HBV genotypes are mostly B and C, in which genotype B is more

common. In addition, the study also found that since the end of World War II in 1945,

the settlers from the mainland are more probable to have higher prevalence of genotype

C [16, 19, 41]. Based on statistical data collected from blood donors, the ratio of

genotype B and genotype C is about 80% / 20% for hepatitis B patients. It is about 70%

/ 30% for asymptomatic carriers, and 60% / 40% for patients with chronic HBV

infection. Once liver cirrhosis has developed, this ratio drops to 35% / 65%.

In the case of patients with HCC, the ratio is about 55% / 45% [35, 38]. As

genotype C. Even though HBV genotype C is not as common in Taiwan, the prognosis

of HBV genotype C infection deteriorated faster, and the risk of developing into

cirrhosis and HCC is relatively higher. In addition, its success rate of interferon

treatment is lower and it has a higher HBV relapse rate post Lamivudine treatment [16,

27, 41-43].

Section IV: Different ethnic groups in Taiwan

Taiwan has had a long history of immigration, and is said to be the place of origin

of many Austronesian groups. Currently there are four main ethnic groups in Taiwan:

native Taiwanese (Hō-Lóh-Lang), the Hakka people, the mainlanders (those who came

to Taiwan after 1945 and their descendants) and the aborigines that belong to the

Austronesian language groups [44]. The Austronesians are widely distributed in the

world, from the Easter Island (east) to Madagascar (west), and from New Zealand

(south) to Taiwan (north) [49-51] (Figure 4).

Native Taiwanese, the Hakka people and the mainlanders are non-aborigines and

have different cultures and ancestors, who immigrated from the mainland China at

different time periods, dating back to the 15th century. These immigrants also

intermarried with the aboriginal populations. .

Currently there are about 0.5 million aborigines in Taiwan, about 2% of the total

population. So far 14 tribes have been recognized by the government and they are

divided into four main language groups: Atayal (Atayal, Truku and Sediq tribe); Paiwan

(Amis, Paiwan, Puyuma, Bunun, Saisiyat, Thao, Kavalan and Sakizaya tribe); Tsou

(Tsou and Rukai tribe); Bataan (Yami tribe). Each tribe has its own distinct language,

culture, traditions, customs and social structure. Most of the aboriginal population lives

in the eastern part of Taiwan, in Hualien County and Taitung County and some live in

Pingtung County [14].

Objective

As discussed in the background, in Taiwan there are clear regional and ethnic

differences in terms of prevalence of HBV infection, standardized mortality rate of liver

cirrhosis and HCC, and survival rate of HCC. Furthermore, some studies show that

those with certain characteristics run a higher risk of developing liver cirrhosis and

HCC: people with HBV infection and ALT abnormalities; HBeAg-positive; people with

a higher HBV DNA, older age; those who have HBV genotype C.

Therefore, the following hypothesis is proposed, that the cause for the Taiwanese

aborigines to have higher standardized mortality rate of chronic liver diseases and liver

cirrhosis and lower standardized mortality rate of HCC may be similar to the Japanese

study in Okinawa. The reason for the lower mortality rate of HCC in high HBV

epidemic area is that the mainly HBV genotype is B that has the lower risk of HCC

[54].

We then assume that within the same community in rural areas, Taiwanese

aborigines and non-aborigines would have different HBV genotypes, HBV DNA,

HBeAg-positive rate, etc. In order to provide a reference for future medical care and

public health policy in Taiwan, this thesis explores the impact of regional and ethnic

differences on the risk of HCC. In addition, the impact of medical environment, medical

care system, living habits, and socio-economic status have also been studied.

The migration path of Austronesian language in the Pacific and the Indian oceans

is very important for the development of human civilization in world history. A recent

popular hypothesis is that Taiwan is the origin of all Austronesian languages,

highlighting the importance of Taiwan in the Austronesian migration path. From a

genetics perspective, the red blood cell antigen phenotype suggests that some Taiwanese

aborigines (Austronesians) came to Taiwan in a different era without interracial

marriage [52-53]. We could then hypothesize that HBV genotype distribution is

different among different ethnic groups. This difference may be the important

information in Austronesian’s migration path because the main infectious root of HBV

in Taiwan is vertical transmission that is similar to study of mitochondrial DNA.

METHODS

Chapter I: Interviewee Selection Criteria

There are two main sources of patients with HBV infection:

1. Screened HBsAg-positive patients from the voluntary population in the Liver

Disease Prevention and Treatment Research Foundation in the past 10 years who

were born before January 1, 1985.

2. Listed HBV carriers (HBsAg-positive) by the health agencies from the

comprehensive health screening activities at district health clinics or local

medical institutions.

HBV carriers include people in the northern, central, southern, eastern and outlying

islands of the rural areas in Taiwan and from various ethnic groups. Gender and

occupation were not forcefully selected. All of the interviewees who were thoroughly

informed about the study processes must agree to participate in the study, sign and date

the consent form (approved by National Taiwan University Hospital Research Ethics

Committee on March 3, 2008, Clinical trials research project No: Protocol ID:

200801059R (ClinicalTrials.gov ID: NCT00946010) with study completion date on

January 31, 2011) (Appendix 1).

Chapter II: Research Design and Process

Section I: Activity Design and Procedure

Coordinated between the professionals of the Liver Disease Prevention and

Treatment Research Foundation and the staff of the local health administrative

department, the well-trained interviewers conducted standardized surveys to collect

basic background information (Figure 5) such as body height (cm), body weight (kg),

waist circumference (cm) measurements, specimen samples and abdominal ultrasound

examination. These interviewers also provide liver disease consultation (Figure 6).

The standard procedure to measure the waist circumference is based on the

recommendations of the National Health Council. The examinee must remove the

clothing covering the waist, relax and stand with arms naturally down. The examiner

will take the measure using the measuring tape around the examinee’s waist at the

mid-point between the lowest rib and the top of the iliac crest at the end of the

examinee’s exhale. Meanwhile, the measuring tape must be maintained horizontally,

and is not too tight or too loose on the skin.

Once the examination is completed, the participant will receive their own reports, a

HBV infection education manual by surface mail and contact information for