{"id":23818,"date":"2021-12-27T12:15:26","date_gmt":"2021-12-27T09:15:26","guid":{"rendered":"https:\/\/www.klimikdergisi.org\/?p=23818"},"modified":"2021-12-27T12:10:48","modified_gmt":"2021-12-27T09:10:48","slug":"kronik-hepatit-b-de-antiviral-tedavi","status":"publish","type":"post","link":"https:\/\/www.klimikdergisi.org\/tr\/2021\/12\/27\/kronik-hepatit-b-de-antiviral-tedavi\/","title":{"rendered":"Kronik Hepatit B Hastalar\u0131nda Antiviral Tedavi Sonu\u00e7lar\u0131 ve Tedavi Esnas\u0131nda G\u00f6r\u00fclen Yan Etkiler"},"content":{"rendered":"

G\u0130R\u0130\u015e<\/h2>\n

Hepatit B virusu (HBV), karaci\u011fer hastal\u0131klar\u0131n\u0131n ba\u015fl\u0131ca nedeni olup karaci\u011ferin akut veya kronik inflamasyonuna neden olarak, kronik hepatit, siroz ve hepatosel\u00fcler karsinoma (HSK) yol a\u00e7an \u00f6nemli sa\u011fl\u0131k sorunlar\u0131ndan biridir. D\u00fcnya Sa\u011fl\u0131k \u00d6rg\u00fct\u00fc (DS\u00d6) verilerine g\u00f6re 2019\u2019da 296 milyon insan\u0131n KHB infeksiyonu ile ya\u015fad\u0131\u011f\u0131, ayn\u0131 y\u0131l HBV kaynakl\u0131 siroz ve HSK nedeniyle 820 bin \u00f6l\u00fcm\u00fcn ger\u00e7ekle\u015fti\u011fi ve her y\u0131l 1.5 milyon yeni infeksiyon oldu\u011fu tahmin edilmektedir (1).<\/p>\n

Kronik HBV infeksiyonu olan hastalar i\u00e7in tedavinin as\u0131l amac\u0131 hastal\u0131\u011f\u0131n ilerlemesini ve HSK geli\u015fimini \u00f6nleyerek hayatta kalmay\u0131 sa\u011flamak ve ya\u015fam kalitesini iyile\u015ftirmektir. Antiviral tedavinin di\u011fer hedefleri, anneden bebe\u011fe bula\u015fmay\u0131 ve hepatit B\u2019nin yeniden aktivasyonunu \u00f6nlemek, HBV ile ili\u015fkili ekstrahepatik bulgular\u0131 \u00f6nlemek ve tedavi etmektir (2). G\u00fcn\u00fcm\u00fczde, KHB tedavisinde kullan\u0131lan onayl\u0131 ila\u00e7lar; antiviral, antiproliferatif ve imm\u00fcnomod\u00fclat\u00f6r etkili subkutan uygulanan interferon-alfa (IFN-\u03b1) ve PEG-IFN-\u03b1; oral antiviraller olan n\u00fckleoz(t)id analoglar\u0131 (NA), lamivudin (LAM), entekavir (ETV), telbivudin (LdT), adefovir (ADV), tenofovir disoproksil fumarat (TDF) ve tenofovir alafenamid (TAF)\u2019tir. Ancak s\u00f6z konusu ila\u00e7lar, HBV reverse transkriptaz\u0131 inhibe ederek HBV replikasyonunu bask\u0131lamalar\u0131na, karaci\u011ferdeki inflamasyonu azaltmalar\u0131na, hastal\u0131\u011f\u0131n progresyonunu yava\u015flatmalar\u0131na ve karaci\u011fer hastal\u0131\u011f\u0131n\u0131n remisyonunu sa\u011flamalar\u0131na ra\u011fmen KHB i\u00e7in hen\u00fcz virusun eradikasyonunu sa\u011flayacak k\u00fcratif bir tedavi bulunamam\u0131\u015ft\u0131r (3, 4).<\/span><\/p>\n

Bu \u00e7al\u0131\u015fmada, KHB tan\u0131s\u0131 ile en az 6 ay tedavi al\u0131p izlenen hastalar\u0131n kulland\u0131klar\u0131 antiviral ila\u00e7lar\u0131n etkinlik ve yan etkilerinin kar\u015f\u0131la\u015ft\u0131r\u0131larak de\u011ferlendirilmesi ama\u00e7lanm\u0131\u015ft\u0131r.<\/p>\n

Y\u00d6NTEMLER<\/h2>\n

Klini\u011fimizde, Ocak 2005- Kas\u0131m 2017 tarihleri aras\u0131nda KHB tan\u0131s\u0131 ile takip edilen, 6 aydan uzun s\u00fcreli HBsAg pozitifli\u011fi olan, tedavi ba\u015flang\u0131c\u0131nda HBV DNA 104<\/sup> kopya\/ml olan, karaci\u011fer histolojisi Ishak evre \u22652 veya HA\u0130 \u22656 olan, daha \u00f6nce tedavi almam\u0131\u015f (naif) ve en az 6 ayd\u0131r antiviral tedavi alan, 18-80 ya\u015f aral\u0131\u011f\u0131nda 572 hasta retrospektif olarak de\u011ferlendirildi. \u00c7al\u0131\u015fmaya \u00fcniversite etik kurulundan onay al\u0131nd\u0131ktan sonra (2018\/1341 nolu karar) ba\u015fland\u0131. Hastalar\u0131n KHB tan\u0131s\u0131, Avrupa Karaci\u011fer Ara\u015ft\u0131rmalar\u0131 Derne\u011fi (European Association fort he Study of Liver \u2013 EASL)\u2019nin 2017 Klinik Uygulama K\u0131lavuzu kriterlerine uygun olarak serolojik ve patolojik olarak konuldu (2). Hamile, altta yatan imm\u00fcn sistem bozuklu\u011funa yol a\u00e7an kronik bir hastal\u0131\u011fa, malignite veya kolajen doku hastal\u0131\u011f\u0131na sahip, insan imm\u00fcn yetmezlik virusu (HIV) koinfeksiyonu, imm\u00fcns\u00fcpresif veya steroid tedavisi alaca\u011f\u0131 i\u00e7in KHB\u2019ye y\u00f6nelik antiviral profilaksi ba\u015flanm\u0131\u015f, KHB d\u0131\u015f\u0131nda karaci\u011fer hastal\u0131\u011f\u0131na neden olacak hastal\u0131klar\u0131 bulunan (HCV veya HDV pozitifli\u011finin olmas\u0131, otoimm\u00fcn hepatit, vs.), tan\u0131 an\u0131nda HSK\u2019nin e\u015flik etti\u011fi dekompanse karaci\u011fer sirozlu ve KHB tedavisini d\u00fczenli kullanmayan bireyler \u00e7al\u0131\u015fmaya dahil edilmedi. Hepatit B hasta takip dosyalar\u0131 ve hastane otomasyon sisteminde bulunan; cinsiyete, ya\u015fa, antiviral tedavi s\u00fcresine, karaci\u011fer biyopsisinde fibrozis ve HA\u0130 sonu\u00e7lar\u0131na, uygulanan antiviral tedavi t\u00fcr\u00fcne, tedavi \u00f6ncesi aspartat aminotransferaz (AST), alanin aminotransferaz (ALT), trombosit, INR, kreatinin, AFP, HBV DNA, HBsAg, HBeAg d\u00fczeylerine, tedavinin 3. 6. ve 12. aylar\u0131ndaki HBV DNA d\u00fczeylerine ve ila\u00e7 yan etkilerine dair takip bilgileri kaydedildi.<\/span><\/p>\n

\u0130statistiksel analizler i\u00e7in \u201cSAS 9.4 University Edition\u201d (\u201cSAS Institute, Cary, NC\u201d) program\u0131 kullan\u0131ld\u0131. T\u00fcm de\u011fi\u015fkenler i\u00e7in tan\u0131mlay\u0131c\u0131 istatistikler verildi. Kategorik de\u011fi\u015fkenler i\u00e7in frekans ve y\u00fczde de\u011ferleri; say\u0131sal de\u011fi\u015fkenler i\u00e7in ortalama \u00b1 standard sapma veya medyan (Q1-Q3) de\u011ferleri verildi. Kategorik de\u011fi\u015fkenlerin kar\u015f\u0131la\u015ft\u0131r\u0131lmas\u0131nda \u03c7\u00b2 testi, say\u0131sal de\u011fi\u015fkenlerin kar\u015f\u0131la\u015ft\u0131r\u0131lmas\u0131nda Student t testi, ANOVA, Mann-Whitney U ve Kruskal-Wallis testlerinden faydalan\u0131ld\u0131. Tedavi gruplar\u0131nda HBV DNA de\u011fi\u015fiminin kar\u015f\u0131la\u015ft\u0131r\u0131lmas\u0131 i\u00e7in karma etki modeli kullan\u0131ld\u0131. p<\/i><0.05 istatistiksel olarak anlaml\u0131 kabul edildi.<\/p>\n

BULGULAR<\/h2>\n
\"\"<\/a>

Tablo 1.<\/strong> Hastalar\u0131n Demografik ve Ba\u015flang\u0131\u00e7 Verileri<\/p><\/div>\n

Be\u015f y\u00fcz yetmi\u015f iki hastan\u0131n 323 (%56.5)\u2019\u00fc erkek, 249(% 43.5)\u2019u kad\u0131nd\u0131. Hastalar\u0131n ya\u015f ortalamas\u0131 43.4 \u00b112.4 y\u0131ld\u0131. Y\u00fcz elli \u00fc\u00e7 (%26.8) TDF, 134 (%23.4) LdT, 114 (%20) ETV, 92 (%16) LAM, 26 (%4.5) ADV, 27 (%4.7) PEG-IFN-\u03b1, 26 (%4.6) PEG-IFN-\u03b1+NA kullan\u0131m\u0131 mevcuttu. \u00c7al\u0131\u015fmaya al\u0131nan hastalar\u0131n tedavi t\u00fcrlerine g\u00f6re demografik ve ba\u015flang\u0131\u00e7 verileri Tablo 1\u2019de g\u00f6sterilmi\u015ftir. Tedavi t\u00fcrlerine g\u00f6re cinsiyet da\u011f\u0131l\u0131m\u0131n\u0131n benzer oldu\u011fu (p<\/i>=0.77) ancak PEG-IFN-\u03b1 +NA grubunda ya\u015f ortalamas\u0131n\u0131n di\u011ferlerine k\u0131yasla anlaml\u0131 olarak daha d\u00fc\u015f\u00fck oldu\u011fu tespit edildi (p<\/i>=0.0005). T\u00fcm hastalar\u0131n, ba\u015flang\u0131\u00e7 fibrozis skorlar\u0131 ortalamas\u0131 2.3\u00b10.8, HA\u0130 ortalamas\u0131 8.2\u00b12.6 bulundu ve tedavi t\u00fcrleri ile fibrozis skoru ortalamas\u0131 aras\u0131nda istatistiksel olarak anlaml\u0131 fark saptanmad\u0131 (p<\/i>=0.14). Hastalar\u0131n ba\u015flang\u0131\u00e7 ALT ve AST (U\/L) de\u011ferleri medyan olarak s\u0131ras\u0131 ile 39 (23.5-91) ve 31 (22-56) olup ba\u015flang\u0131\u00e7 ALT de\u011feri LdT grubunda di\u011fer tedavi t\u00fcrlerine g\u00f6re anlaml\u0131 olarak d\u00fc\u015f\u00fck bulundu (p<\/i><0.0001); di\u011fer tedaviler aras\u0131nda istatistiksel olarak anlaml\u0131 fark saptanmad\u0131. Hastalar\u0131n ba\u015flang\u0131\u00e7 trombosit de\u011ferleri ortalamas\u0131 226 460\u00b163 840\/mm<\/span>3<\/span>, ba\u015flang\u0131\u00e7 INR de\u011ferleri ortalamas\u0131 1\u00b10.1, ba\u015flang\u0131\u00e7 AFP (IU\/mL) de\u011ferleri medyan 2.2 (1.6-3.5) bulundu. Ya\u015f, cinsiyet, fibrozis skoru, HA\u0130 skoru, ba\u015flang\u0131\u00e7 trombosit, INR, AFP de\u011ferleri a\u00e7\u0131s\u0131ndan tedavi gruplar\u0131 aras\u0131nda istatistiksel anlaml\u0131 fark bulunmad\u0131 (p<\/i>>0.05).<\/span><\/p>\n

\"\"<\/a>

Tablo 2.<\/strong> HBeAg\u2019ye G\u00f6re Tedavi \u00d6ncesi Virolojik ve Biyokimyasal De\u011ferlerin K\u0131yaslanmas\u0131<\/p><\/div>\n

Hastalar\u0131n ba\u015flang\u0131\u00e7 HBV DNA (kopya\/ml) ortalamas\u0131 71 573 590 \u00b1 221 752 936 iken, LdT ve LAM grubunda, ba\u015flang\u0131\u00e7 HBV DNA d\u00fczeyi ortalamas\u0131 ve log10 HBV DNA ortalama d\u00fczeyi di\u011fer tedavilere g\u00f6re istatistiksel anlaml\u0131 olarak d\u00fc\u015f\u00fck bulundu (p<\/i><0.0001). HBeAg durumuna bak\u0131lm\u0131\u015f olan 568 hastan\u0131n 70 (%12.3)\u2019i HBeAg (+), 498 (%87.7)\u2019i HBeAg (-) idi. HBeAg\u2019 ye g\u00f6re tedavi \u00f6ncesi virolojik ve biyokimyasal de\u011ferlerin k\u0131yaslanmas\u0131 Tablo 2\u2019de g\u00f6sterilmi\u015ftir.<\/p>\n

\"\"<\/a>

Tablo 3.<\/strong> Tedavi T\u00fcrlerine G\u00f6re Virolojik Yan\u0131t Oranlar\u0131<\/p><\/div>\n

\"\"<\/a>

\u015eekil 1.<\/strong> Tedavi t\u00fcrlerine g\u00f6re HBV DNA seyri.
A:<\/strong> Adefovir, B:<\/strong> Telbivudin, E:<\/strong> Entekavir, L:<\/strong> Lamivudin, T:<\/strong> Tenofovir
PF:<\/strong> PEG-IFN-\u03b1, XYZC:<\/strong> PEG-IFN-\u03b1+NA<\/p><\/div>\n

Tedavi gruplar\u0131 aras\u0131nda HBV DNA\u2019n\u0131n zaman i\u00e7erisindeki seyrinin farkl\u0131 oldu\u011fu g\u00f6r\u00fcld\u00fc (p<\/i><0.0001).\u00a0 <\/span>En h\u0131zl\u0131 HBV DNA d\u00fc\u015f\u00fc\u015f\u00fcn\u00fcn TDF ve ETV\u2019de oldu\u011fu, ADV grubunda di\u011fer gruplara g\u00f6re HBV DNA\u2019daki d\u00fc\u015f\u00fc\u015f\u00fcn daha ge\u00e7 oldu\u011fu ve PEG-IFN-\u03b1+NA tedavisinde virolojik yan\u0131t\u0131n PEG-IFN-\u03b1 monoterapisine k\u0131yasla daha k\u0131sa s\u00fcre i\u00e7inde oldu\u011fu \u015eekil 1\u2019de; tedavi t\u00fcrlerine g\u00f6re virolojik yan\u0131t oranlar\u0131 Tablo 3\u2019te g\u00f6sterilmi\u015ftir.<\/span><\/p>\n

Ba\u015flang\u0131\u00e7ta HBeAg (+) olan 70 hastan\u0131n 15 (%21.4)\u2019inde takipte HBeAg serokonversiyonu olup en s\u0131k %50 ile PEG-IFN-\u03b1 tespit edildi. TDF\u2019de %14.3 (4\/28), ETV\u2019de %36.3 (8\/22), ADV\u2019de %25 (1\/4) oran\u0131nda HBeAg serokonversiyonu saptand\u0131. PEG-IFN-\u03b1+NA, LdT ve LAM kullanan hastalarda serokonversiyon saptanmad\u0131.<\/p>\n

Hastalar\u0131n takibinde %2.3 (13\/572) HBsAg klirensi olup tamam\u0131 HBeAg (-) idi. PEG-IFN-\u03b1+NA\u2019da %11.5 (3\/26), LAM\u2019da %4.3 (4\/92), PEG- IFN-\u03b1\u2019da %3.7 (1\/27), LdT\u2019de %2.2 (3\/134), ETV\u2019de %0.9 (1\/114), TDF\u2019de %0.7 (1\/153) HBsAg klirensi g\u00f6r\u00fcld\u00fc. Tedavinin 12. ay\u0131 sonunda PEG-IFN-\u03b1+LAM tedavisi alan bir hastada HBsAg klirensi geli\u015fti. PEG-IFN-\u03b1 i\u00e7eren bir tedavi al\u0131rken HBsAg klirensinin ortalama 57. ayda oldu\u011fu, klirensin IFN tedavisi sonland\u0131ktan aylar sonra geli\u015fti\u011fi g\u00f6zlendi.<\/span><\/p>\n

Hastalar\u0131n 136 (%23.8)\u2019s\u0131nda takiplerde tedavi de\u011fi\u015fikli\u011fi olup 103 (%76.3)\u2019\u00fcnde TDF\u2019nin tercih edildi\u011fi g\u00f6r\u00fcld\u00fc. En \u00e7ok tedavi de\u011fi\u015fikli\u011fi yap\u0131lan hasta grubu 48 (%52) hasta ile LAM grubuydu. K\u0131rk (%43.4) LAM, 18 (%13.4) LdT, 8 (%7) ETV, 1 (%0.6) TDF kullanan hastada virolojik k\u0131r\u0131lma d\u00fc\u015f\u00fcn\u00fclerek tedavi de\u011fi\u015fimi yap\u0131ld\u0131. TDF kullan\u0131m\u0131 s\u0131ras\u0131nda virolojik k\u0131r\u0131lma g\u00f6r\u00fclen hasta sorguland\u0131\u011f\u0131nda, ilac\u0131n\u0131 d\u00fczensiz kulland\u0131\u011f\u0131 \u00f6\u011frenildi. Ba\u015flang\u0131\u00e7 HBV DNA d\u00fczeyi \u226510\u2077 <\/span>kopya\/ml, fibrozis skorlar\u0131 \u22654, HA\u0130 skorlar\u0131 \u226514 olan 3 hastada HSK geli\u015fti\u011fi g\u00f6r\u00fcld\u00fc.<\/p>\n

Hastalar\u0131n 169 (%29.5)\u2019unda en az bir yan etki olup, en az yan etki TDF\u2019de %7.8 (12\/153) ve ETV\u2019de %7.9 (9\/114) oran\u0131nda g\u00f6r\u00fcld\u00fc; bu iki grup aras\u0131nda yan etki a\u00e7\u0131s\u0131ndan istatistiksel olarak anlaml\u0131 fark bulunmad\u0131 (p<\/i>>0.05).\u00a0 <\/span>Tedavi esnas\u0131nda en az bir yan etki, PEG-IFN-\u03b1+NA\u2019da %92.3, PEG-IFN-\u03b1\u2019da %77.8, LAM\u2019da %47.8, LdT\u2019de %40.3, ADV\u2019de %19.2 oranlar\u0131nda tespit edildi.<\/p>\n

\u00c7al\u0131\u015fmam\u0131zda yan <\/span>etki g\u00f6r\u00fclme oran\u0131 en y\u00fcksek olan grup PEG-IFN-\u03b1+NA olup en s\u0131k g\u00f6r\u00fclen yan etki %73 ile miyalji, bitkinlik\/halsizlik; %69.2 ile kilo kayb\u0131, sinirlilik, sa\u00e7 d\u00f6k\u00fclmesi; %65.3 ile ate\u015f, artralji, ba\u015f a\u011fr\u0131s\u0131 ve unutkanl\u0131kt\u0131. PEG-IFN-\u03b1 kullanan hastalarda en s\u0131k g\u00f6r\u00fclen yan etkiler %44.5 ile miyalji, ba\u015f a\u011fr\u0131s\u0131, bitkinlik\/halsizlik; %40.7 ile titreme, ate\u015f, artralji, uykusuzluk, ka\u015f\u0131nt\u0131, sa\u00e7 d\u00f6k\u00fclmesi olup yan etki nedeni ile bir hastada tedavi sonland\u0131r\u0131ld\u0131.<\/p>\n

\"\"<\/a>

Tablo 4.<\/strong> N\u00fckleoz(t)id Analo\u011fu Tedavilerinde G\u00f6r\u00fclen Yan Etkiler<\/p><\/div>\n

NA\u2019larla g\u00f6r\u00fclen yan etkiler Tablo 4\u2019te g\u00f6sterilmi\u015ftir. Tedavi \u00f6ncesi kreatinin seviyesi normalin \u00fcst\u00fcnde olan LdT kullanan bir hastan\u0131n takiplerde kreatinin seviyesi normale geriledi. LdT kullananlarda rabdomiyoliz gibi ciddi bir toksisite g\u00f6r\u00fclmedi.<\/p>\n

ADV kullanan bir ve ETV kullanan bir hastada kreatinin art\u0131\u015f\u0131 (serum kreatinin d\u00fczeyi \u22650.5 mg\/dL art\u0131\u015f) olup bu hastalarda LdT tedavisine ge\u00e7ildi. ETV alan bu hastan\u0131n \u00e7oklu ila\u00e7 kullan\u0131m\u0131 olup kreatinin art\u0131\u015f\u0131n\u0131n di\u011fer ila\u00e7lara da ba\u011fl\u0131 olabilece\u011fi d\u00fc\u015f\u00fcn\u00fcld\u00fc.<\/p>\n

TDF kullan\u0131rken kreatinin art\u0131\u015f\u0131 olan iki hastada, halsizlik ve CPK art\u0131\u015f\u0131 olan bir hastada, bulant\u0131-kusma nedeni ile bir hastada ve miyalji \u015fikayeti ile bir hastada ETV tedavisine ge\u00e7ildi. TDF kullanan t\u00fcm hastalarda kalsiyum ve fosfor de\u011ferleri normal s\u0131n\u0131rlardayd\u0131. \u00c7al\u0131\u015fmam\u0131zda hi\u00e7bir hastada laktik asidoz g\u00f6r\u00fclmedi.<\/p>\n

\u0130RDELEME<\/strong><\/h2>\n

G\u00fcn\u00fcm\u00fczde kullan\u0131lan b\u00fct\u00fcn tedavilerin amac\u0131 HBV DNA\u2019n\u0131n bask\u0131lanmas\u0131d\u0131r (2). Literat\u00fcrdeki yay\u0131nlar\u0131n \u00e7o\u011funun, TDF ve ETV\u2019deki virolojik yan\u0131t oranlar\u0131n\u0131 de\u011ferlendirdi\u011fi g\u00f6r\u00fclm\u00fc\u015ft\u00fcr. Cunha-Silva ve arkada\u015flar\u0131 (5) bir y\u0131ll\u0131k tedavi sonunda LAM, ETV ve TDF tedavileri ile negatif viral y\u00fck oranlar\u0131n\u0131 s\u0131ras\u0131yla %56, %75 ve %75; iki y\u0131l\u0131n sonunda %86, %90.6 ve %92.9 oran\u0131nda bulmu\u015ftur. Ba\u015far\u0131r ve arkada\u015flar\u0131 (6) ise bu oranlar\u0131 s\u0131ras\u0131yla %76, %88 ve %75 olarak saptam\u0131\u015f ve \u00fc\u00e7 ila\u00e7 aras\u0131nda virolojik yan\u0131t <\/span>a\u00e7\u0131s\u0131ndan farkl\u0131l\u0131k tespit etmemi\u015ftir. G\u00fczelbulut ve arkada\u015flar\u0131 (7) birinci y\u0131l <\/span>yan\u0131tlar\u0131n\u0131, TDF\u2019de %95, ETV\u2019de %87.5 ile <\/span>y\u00fcksek oranda bulmu\u015fken; Bilge ve arkada\u015flar\u0131 (8) 48 haftal\u0131k tedavi ba\u015far\u0131s\u0131n\u0131 TDF\u2019de %72.3, ETV\u2019de %69 bulmu\u015ftur. \u00c7al\u0131\u015fmam\u0131zda, birinci y\u0131l yan\u0131tlar\u0131n\u0131n en y\u00fcksek oranda LdT\u2019de (%92.5) ve ikinci y\u0131l virolojik yan\u0131t oranlar\u0131n\u0131n LAM\u2019da %95, LdT\u2019de %94.2, ETV\u2019de %93.4, TDF\u2019de %91 oldu\u011fu tespit edilmi\u015f; tedavilerin 3, 4 ve 5. y\u0131l sonu\u00e7lar\u0131nda tedavi de\u011fi\u015fikli\u011fi yap\u0131lmadan TDF, ETV, LdT, ADV ve LAM tedavisi devam eden hastalar\u0131n t\u00fcm\u00fcnde HBV DNA\u2019n\u0131n negatif oldu\u011fu g\u00f6r\u00fclm\u00fc\u015ft\u00fcr.<\/p>\n

KHB tedavisinde, tedaviye yan\u0131t\u0131n izlenmesinde \u00f6nemli parametrelerden biri de HBeAg (+) hastalarda HBeAg\u2019nin kaybolarak anti-HBe geli\u015fmesidir (9). HBeAg serokonversiyonu, literat\u00fcrde %20-40 aras\u0131nda de\u011fi\u015fmektedir (10, 11). \u00c7al\u0131\u015fmam\u0131zda HBeAg serokonversiyonu en y\u00fcksek oranda PEG-IFN-\u03b1 grubunda olup t\u00fcm hastalarda %21.4 oran\u0131nda g\u00f6r\u00fclm\u00fc\u015ft\u00fcr.<\/p>\n

HBsAg serokonversiyonu d\u00fcnya \u00e7ap\u0131nda d\u00fc\u015f\u00fck kalmaktad\u0131r (12, 13). ETV veya TDF tedavisinin ilk y\u0131l\u0131nda HBeAg negatif KHB hastalar\u0131n\u0131n hi\u00e7birinde HBsAg kayb\u0131 olmam\u0131\u015f ve \u00e7ok az say\u0131da hastada (~%1) uzun d\u00f6nem (8 y\u0131l) tedavi s\u0131ras\u0131nda bu sonlan\u0131m noktas\u0131na ula\u015f\u0131labilmi\u015ftir (2). Lok ve arkada\u015flar\u0131n\u0131n (14) \u00e7al\u0131\u015fmas\u0131nda, bir y\u0131ll\u0131k tedavi sonras\u0131 HBsAg kayb\u0131 PEG-IFN ile %3 oran\u0131nda olurken bu oran LAM kullananlarda %1, ADV ve LdT kullananlarda %0, ETV kullananlarda %2, TDF tedavisi alanlarda %3.2 oran\u0131nda bildirilmi\u015ftir. \u00c7al\u0131\u015fmam\u0131zda hastalar\u0131n %2.3\u2019\u00fcnde HBsAg klirensi g\u00f6r\u00fclm\u00fc\u015f olup TDF (%0.7) ve ETV (%0.9)\u2019deki klirens oranlar\u0131n\u0131n literat\u00fcre g\u00f6re d\u00fc\u015f\u00fck oranda oldu\u011fu tespit edilmi\u015ftir. Ancak tedavisi devam eden hastalarda y\u0131llar i\u00e7inde bu oranlar\u0131n y\u00fckselece\u011fi d\u00fc\u015f\u00fcn\u00fclmektedir.<\/p>\n

Kim ve arkada\u015flar\u0131n\u0131n (15) 2016 y\u0131l\u0131nda yay\u0131nlad\u0131\u011f\u0131 2829 hastay\u0131 i\u00e7eren meta-analiz sonu\u00e7lar\u0131nda; HBeAg (+) ve HBeAg (-) hastalarda PEG-IFN-\u03b1+LAM kombinasyon tedavisinde PEG-IFN-\u03b1 monoterapisine k\u0131yasla daha iyi virolojik ve biyokimyasal yan\u0131tlar elde edilmi\u015ftir. \u00c7al\u0131\u015fmam\u0131zda da virolojik yan\u0131t, HBeAg serokonversiyonu ve HBsAg serokonversiyonu oranlar\u0131 PEG-IFN-\u03b1+NA tedavisinde daha y\u00fcksek oranlarda bulunmu\u015ftur.<\/span><\/p>\n

KHB tedavisinin uzun s\u00fcreli ba\u015far\u0131s\u0131 i\u00e7in, antiviral ajanlar\u0131n h\u0131zl\u0131, tam ve kal\u0131c\u0131 viral s\u00fcpresyonu sa\u011flamas\u0131 ve direncin y\u00fcksek bir bariyerine sahip olmas\u0131 gerekir. LAM ile tedavi s\u0131ras\u0131nda erken d\u00f6nemde ila\u00e7 direnci ortaya \u00e7\u0131kar, uzun s\u00fcreli tedavi ile s\u0131kl\u0131\u011f\u0131 artar ve 5 y\u0131l sonra yakla\u015f\u0131k %80\u2019e ula\u015f\u0131r (16). Literat\u00fcrde HBeAg negatif KHB hastalar\u0131nda 5 y\u0131ll\u0131k takipte tedaviye diren\u00e7 oranlar\u0131n\u0131n TDF\u2019de %0, ETV\u2019de <%1, LAM\u2019da %70 oran\u0131nda oldu\u011fu bildirilmi\u015ftir (17). \u00c7al\u0131\u015fmam\u0131zda ila\u00e7 direnci d\u00fc\u015f\u00fcn\u00fclerek tedavi de\u011fi\u015fimi yap\u0131lan hastalar\u0131n oran\u0131 en y\u00fcksek LAM\u2019da (%43.5) bulunmu\u015ftur.\u00a0 <\/span>Takip s\u00fcremiz boyunca LdT\u2019de %13.4, ETV\u2019de %7, TDF\u2019de %0.65 oran\u0131nda virolojik k\u0131r\u0131lma g\u00f6zlenmi\u015f olmakla birlikte genotipik diren\u00e7 \u00e7al\u0131\u015fmas\u0131 yap\u0131lamad\u0131\u011f\u0131 i\u00e7in ger\u00e7ek diren\u00e7 oranlar\u0131 belirlenememi\u015ftir.<\/span><\/p>\n

ETV ve TDF, NA\u2019larla daha \u00f6nce tedavi ba\u015far\u0131s\u0131zl\u0131\u011f\u0131 olan hastalarda tercih edilmektedir (18). \u00c7al\u0131\u015fmam\u0131zda da tedavisi de\u011fi\u015ftirilen hastalarda en \u00e7ok tercih edilen yeni tedaviler ETV ve TDF olmu\u015ftur.<\/span><\/p>\n

IFN\u2019nin zor tolere edilmesi ve belirgin yan etki profili nedeni ile kullan\u0131m\u0131n\u0131n s\u0131n\u0131rl\u0131 kalmas\u0131na ra\u011fmen, oral antiviraller de uzun s\u00fcreli kullan\u0131m\u0131 zorunlu k\u0131lmas\u0131 ve diren\u00e7 ortaya \u00e7\u0131karmas\u0131 nedeniyle dezavantajl\u0131d\u0131r. (19). IFN injeksiyonu, tipik olarak ate\u015f (%20-30), ba\u015f a\u011fr\u0131s\u0131 (%40-50) ve miyaljiyi (%20-30) i\u00e7eren influenza benzeri semptomlara neden olabilir (20). \u00c7al\u0131\u015fmam\u0131zda da PEG-IFN-\u03b1 tedavileri ile en s\u0131k g\u00f6r\u00fclen yan etkiler s\u0131ras\u0131yla miyalji, bitkinlik\/halsizlik, ba\u015f a\u011fr\u0131s\u0131, ate\u015f ve titreme olmu\u015ftur.<\/span><\/p>\n

Uzun s\u00fcreli tedavi i\u00e7in antiviral ila\u00e7lar\u0131n iyi tolere edilmesi gereklidir. Tescil III faz\u0131 \u00e7al\u0131\u015fmalar\u0131 s\u0131ras\u0131nda, NA\u2019lar\u0131n t\u00fcm\u00fc iyi tolere edilebilirlik ve genellikle uygun emniyet profilleri g\u00f6stermi\u015ftir. Bununla birlikte, uzun vadeli tedavide, \u00e7e\u015fitli hematolojik bozukluklar, periferik n\u00f6ropati, iskelet ve kardiyak miyopati, pankreatit, karaci\u011fer yetmezli\u011fi ve laktik asidoz gibi baz\u0131 potansiyel yan etkiler tespit edilmi\u015ftir (21).<\/p>\n

Buti ve arkada\u015flar\u0131n\u0131n (22) \u00e7al\u0131\u015fmas\u0131nda, TDF kullanan 389 hastadan 2 (%0.5)\u2019sinin ila\u00e7 ili\u015fkili yan etki (halsizlik, kar\u0131n a\u011fr\u0131s\u0131, dikkat bozuklu\u011fu, ba\u015f d\u00f6nmesi, osteoporoz, kreatinin art\u0131\u015f\u0131) nedeniyle ilac\u0131 b\u0131rakt\u0131\u011f\u0131; hastalar\u0131n %1.3\u2019\u00fcnde ila\u00e7 ili\u015fkili ciddi yan etkilerin (akut pankreatit, osteopeni, osteoporoz, b\u00f6brek yetmezli\u011fi, ALT art\u0131\u015f\u0131) g\u00f6r\u00fcld\u00fc\u011f\u00fc; %1.5\u2019inde serum kreatinin art\u0131\u015f\u0131 ve %1.3\u2019\u00fcnde fosfat d\u00fczeyinin <2 mg\/dl oldu\u011fu belirtilmi\u015ftir. Marcellin ve arkada\u015flar\u0131n\u0131n (23) \u00e7al\u0131\u015fmas\u0131nda ise 5 y\u0131l TDF alan hastalar\u0131n %1\u2019inde kreatinin art\u0131\u015f\u0131 g\u00f6r\u00fclm\u00fc\u015ft\u00fcr. \u00c7al\u0131\u015fmam\u0131zda TDF alan hastalarda akut pankreatit, b\u00f6brek yetmezli\u011fi, ALT art\u0131\u015f\u0131 g\u00f6r\u00fclmemi\u015ftir. En s\u0131k g\u00f6r\u00fclen yan etki CPK art\u0131\u015f\u0131 (%3.2) ve kreatinin art\u0131\u015f\u0131 (%1.9); en nadir g\u00f6r\u00fclen yan etkiler ise miyalji, halsizlik, bulant\u0131 ve kusma olmu\u015ftur. T\u00fcm hasta takiplerinde kalsiyum ve fosfor d\u00fczeylerinin normal s\u0131n\u0131rlarda oldu\u011fu g\u00f6r\u00fclm\u00fc\u015ft\u00fcr. \u00c7al\u0131\u015fmam\u0131zda TDF kullanan hastalar\u0131n %1.9\u2019unda serum kreatinin d\u00fczeylerinde art\u0131\u015f meydana gelmi\u015f ve bu hastalar\u0131n ikisinde tedavi ETV ile de\u011fi\u015ftirilmi\u015ftir. Ayr\u0131ca yan etki oranlar\u0131 a\u00e7\u0131s\u0131ndan TDF ve ETV aras\u0131nda istatistiksel olarak anlaml\u0131 fark saptanmam\u0131\u015ft\u0131r.<\/p>\n

Hadziyannis ve arkada\u015flar\u0131 (24), ADV alan hastalarda 5 y\u0131ll\u0131k takipte serum kreatinin art\u0131\u015f\u0131n\u0131, plasebo grubuna k\u0131yasla %3-4 aras\u0131nda fazla bulmu\u015ftur. \u00c7al\u0131\u015fmam\u0131zda da ADV\u2019nin bu yan etkisi benzer \u015fekilde %3.8 oran\u0131nda bulunmu\u015ftur.<\/p>\n

LdT\u2019nin, eGFR\u2019yi d\u00fczeltebilece\u011fi ve ADV verilen hastalarda nefrotoksisiteyi \u00f6nleyebilece\u011fi \u015feklinde bir g\u00f6zlem vard\u0131r (25). \u00c7al\u0131\u015fmam\u0131zda bir hastada, tedavi \u00f6ncesi kreatinin seviyesi normalin \u00fcst\u00fcnde iken LdT tedavisi alt\u0131nda kreatinin seviyesinde 0.3 mg\/dL azalma oldu\u011fu g\u00f6r\u00fclm\u00fc\u015ft\u00fcr. KHB tedavisi i\u00e7in kullan\u0131lan t\u00fcm NA\u2019lar b\u00f6brek yoluyla at\u0131ld\u0131\u011f\u0131ndan b\u00f6brek yetmezli\u011fi durumunda doz ayarlamalar\u0131 gereklidir.<\/p>\n

Sonu\u00e7 olarak, \u00e7al\u0131\u015fmam\u0131zda TDF, LdT ve ETV KHB\u2019de en s\u0131k kullan\u0131lan tedaviler olarak tespit edilmi\u015ftir. Birinci y\u0131l sonunda en y\u00fcksek virolojik yan\u0131t oran\u0131 LdT\u2019de bulunmu\u015ftur. LdT y\u00fcksek d\u00fczeyde virolojik yan\u0131t ile ili\u015fkili olmakla birlikte olgu say\u0131s\u0131n\u0131n azl\u0131\u011f\u0131 ve sadece viral y\u00fck\u00fc d\u00fc\u015f\u00fck hastalarda kullan\u0131lm\u0131\u015f olmas\u0131 bu de\u011ferlendirmeyi yapmay\u0131 k\u0131s\u0131tlayan fakt\u00f6rlerdir. Virolojik yan\u0131t oran\u0131 en d\u00fc\u015f\u00fck olan ve en s\u0131k yan etki g\u00f6r\u00fclen ila\u00e7 PEG-IFN-\u03b1 olarak bulunmu\u015f olup kullan\u0131m\u0131 se\u00e7ili hasta gruplar\u0131 ile s\u0131n\u0131rl\u0131 kalmal\u0131d\u0131r. Yan etki g\u00f6r\u00fclme ve diren\u00e7 geli\u015fme oranlar\u0131 en d\u00fc\u015f\u00fck tedaviler TDF ve ETV olarak bulunmu\u015ftur. Ayr\u0131ca, yan etki oranlar\u0131 a\u00e7\u0131s\u0131ndan TDF ve ETV aras\u0131nda anlaml\u0131 fark tespit edilmemi\u015ftir. Y\u00fcksek virolojik yan\u0131t oranlar\u0131 da dikkate al\u0131nd\u0131\u011f\u0131nda KHB tedavisinde TDF ve ETV tercih edilmelidir. T\u00fcm tedaviler de\u011ferlendirildi\u011finde, HBsAg kayb\u0131 ve k\u00fcr oranlar\u0131 yetersizdir. Bu nedenle yeni tedavi stratejileri \u00fczerinde daha \u00e7ok \u00e7al\u0131\u015fma yap\u0131lmas\u0131 gereklidir.<\/p>\n","protected":false},"excerpt":{"rendered":"

G\u0130R\u0130\u015e Hepatit B virusu (HBV), karaci\u011fer hastal\u0131klar\u0131n\u0131n ba\u015fl\u0131ca nedeni olup karaci\u011ferin akut veya kronik inflamasyonuna neden olarak, kronik hepatit, siroz ve hepatosel\u00fcler karsinoma (HSK) yol a\u00e7an \u00f6nemli sa\u011fl\u0131k sorunlar\u0131ndan biridir. D\u00fcnya Sa\u011fl\u0131k \u00d6rg\u00fct\u00fc (DS\u00d6) verilerine g\u00f6re 2019\u2019da 296 milyon insan\u0131n KHB infeksiyonu ile ya\u015fad\u0131\u011f\u0131, ayn\u0131 y\u0131l HBV kaynakl\u0131 siroz ve HSK nedeniyle 820 bin \u00f6l\u00fcm\u00fcn […]<\/p>\n","protected":false},"author":2,"featured_media":24120,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[5129],"tags":[4964,5320,3328,3330,4565,5164],"class_list":["post-23818","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-ozgun-arastirma","tag-entekavir","tag-interferon-2","tag-kronik-hepatit-b","tag-lamivudin","tag-telbivudin","tag-tenofovir-2"],"acf":[],"_links":{"self":[{"href":"https:\/\/www.klimikdergisi.org\/tr\/wp-json\/wp\/v2\/posts\/23818","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.klimikdergisi.org\/tr\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.klimikdergisi.org\/tr\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.klimikdergisi.org\/tr\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.klimikdergisi.org\/tr\/wp-json\/wp\/v2\/comments?post=23818"}],"version-history":[{"count":3,"href":"https:\/\/www.klimikdergisi.org\/tr\/wp-json\/wp\/v2\/posts\/23818\/revisions"}],"predecessor-version":[{"id":24023,"href":"https:\/\/www.klimikdergisi.org\/tr\/wp-json\/wp\/v2\/posts\/23818\/revisions\/24023"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.klimikdergisi.org\/tr\/wp-json\/wp\/v2\/media\/24120"}],"wp:attachment":[{"href":"https:\/\/www.klimikdergisi.org\/tr\/wp-json\/wp\/v2\/media?parent=23818"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.klimikdergisi.org\/tr\/wp-json\/wp\/v2\/categories?post=23818"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.klimikdergisi.org\/tr\/wp-json\/wp\/v2\/tags?post=23818"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}