J Clin Hepatol Vol.31 No.12 Dec.2015 HBeAg HBeAg clearance HBeAg 30% 45% 2-3 HCC HBeAg HBeAg HBeAg seroconversion HBeAg HBeAg - HBe

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1 R B The guideline of prevention and treatment for chronic hepatitis B a 2015 update Chinese Society of Hepatology and Chinese Society of Infectious Diseases Chinese Medical Association Key words hepatitis B chronic treatment prevention guidelines CHB CHB 2005 A CHB B CHB C CHB 1 2 A B C GRADE HBsAg inactive HBsAg carrier 1 HBsAg HBeAg HBV DNA 1 HBV chronic HBV infection HBsAg HBV DNA ALT HAI < 4 chronic hepatitis B CHB HBV HBeAg CHB HBeAg CHB HBeAg HBeAg positive CHB HBeAg HBeAg negative CHB HBsAg HBeAg HBV DNA ALT reactivation of hepatitis B HBV DNA doi /j. issn jlhou@ smu. edu. cn weilai@ pkuph. edu. cn 1 resolved hepatitis B CHB HBsAg HBs - HBc HBV DNA ALT HBsAg HBeAg HBV DNA ALT acute exacerbation or flare of hepatitis B ALT ULN 10 HBV DNA 2 log 10 IU /ml HBV DNA 100 IU /ml HBV DNA HBV DNA IU /ml ALT HBsAg

2 J Clin Hepatol Vol.31 No.12 Dec.2015 HBeAg HBeAg clearance HBeAg 30% 45% 2-3 HCC HBeAg HBeAg HBeAg seroconversion HBeAg HBeAg - HBe HBeAg HBeAg reversion HBeAg - HBe HBeAg histological response HBsAg 7. 18% Metavir HBV 9300 CHB complete response HBsAg 1 ~4 5 ~14 15 ~29 HBsAg - HBs clinical cure HBsAg - HBs ALT HBsAg HBV DNA primary nonresponse nucleos t ide analogs NAs 12 HBV DNA < 1 log 10 IU /ml 24 HBV DNA < 2 log 10 IU /ml suboptimal or partial virological response NAs 24 HBV HBV DNA >2 log 10 IU/ml HBIG 10 virological response HBV DNA virological breakthrough NAs HBV HBV DNA 1 log 1 ALT viral relapse 9 1 HBV DNA > 2000 IU /ml clinical relapse ALT > 2 ULN ALT sustained off - treatment virological response HBV DNA drug resistance NAs HBV HBsAg genotypic resistance phenotypic resistance cross resistance NAs 1 24 h multidrug resistance HBV HBV 20 HBsAg 24 h HBV 2. 4 HBV 1 HBV 60% 80% 4 HBV HBV HBeAg CHB ~ 59 CDC 1 ~ % 0. 94% 4. 38% HBV 9 HBV 10 HBV HBV HBV HBV % h HBIG 100 IU 65 HBV 10 μg 1 6 HCC 2 HCC HBV 2 3

3 h HBIG HBsAg 10 HBV DNA HBV 13 HBV DNA > 10 6 IU /ml HBsAg HBV DNA HBsAg 24 h HBsAg 10 μg 10 μg A1 10 μg 20 μg 2 Chinese hamster ovary CHO 10 μg 20 μg CHO 3 20 μg 20 μg CHO A h HBIG 60 μg 3 HBsAg B μg 3 20 μg ~ 2 - HBs 60 μg μg 60 μg 3 20 μg 2 1 ~ 2 - HBs HBs 1 60μg A1 - HBs - HBs < 10 miu /ml kb DNA HBsAg HBeAg HBV HBcAg DNA HBx HBV 1 HBV DNA HBsAg - HBs HBeAg - HBe - HBc sodium taurocholate cotransporting polypeptide NTCP HBs HBV 20 HBV - HBs < 10 miu /L - HBs HBIG 200 ~ 400 IU DNA cccd μg 1 6 NA cccdna mrna μg HBsAg HBV 9 A ~ J 21 B C HBsAg - HBc - HBs HBV α IFNα C B HBV HCC HBeAg IFNα HBV DNA ALT AST B C A D HBeAg HBV HBsAg 4 HBsAg 12 h HBIG 100 IU 3 HBV DNA hepadnaviridae h 10 min HBV HBV - - HBV DNA DNA RNA HBV cccdna HBV HBV HBV 90%

4 J Clin Hepatol Vol.31 No.12 Dec % ~ 30% 5 5% ~ 4. 2 CHB 10% 28 HBV HBV HBV 4 CHB HCC HBV 29 HBsAg HBeAg HBV DNA ALT Toll - Toll - like receptors TLRs 30 HBV DNA > 2000 IU /ml ALT mdc pdc mdc pdc IFNα HBeAg - HBe HBV DNA ALT HBeAg HBV HBV HCC 5% ~ 15% IFNγ HBeAg - HBe HBV DNA > 2000 IU /ml ALT HBeAg CHB 31 HBeAg HBV 4 53 HBV 5 HBeAg 5. 1 HBV HBV HBsAg - 2% ~ 15% < 40 ALT HBV A 29 B 32 HBeAg 0. 5% ~ 1. 0% HBsAg 33 HBsAg 10 14% cccdna 34 HBsAg > 50 HCV HBc IgG HBV HDV HCC 35 HBeAg CHB CHB 2% ~ 10% 36 HBeAg > 40 HBsAg 37 ALT 38 9 HBV DNA > 2000 IU /ml HBeAg 39 C HCV HDV HIV 5. 2 HBV DNA HBV DNA HBV 3% ~ 5% 5 14% ~ 35% 36 HBV HCC 0. 5% ~ 1. 0% 36 HCC 3% ~ 6% HCC PCR2 HCC HBsAg 3 36 HCC HBsAg 5. 3 HBV HBeAg ALT AST HBV DNA < 2000 IU /ml B C HBV HBsAg HBsAg 1000 IU /ml HCC HBV HBV HBeAg HBx retinoic acid inducible gene - I RIG - I CHB HBV T 51 MHC I CD8 + T HBV 52 HBV T T HBV HBs HBeAg - HBe - HBc - HBc - IgMHBsAg HBV - HBs HBV - HBc - IgM CHB - - HBc PegIFN NAs real - time quantitative PCR HBV 1 ALT AST

5 ULN ALT AST CHB ALT < 2 ULN kpa LSM < kpa LSM 9. 4 kpa PT PTA 7. 4 ~ 9. 4 kpa INR LSM kpa LSM 9. 0 kpa γ - GGT GGT LSM < 9. 0 kpa LSM < 6. 0 kpa LSM 6. 0 ~ 9. 0 kpa ALP ALP 7 ALP ALP CHB ALP HCC TBA 7. 1 US US TBA AFP AFP HCC 7. 2 CT AFP ALT AST K - Ⅱ protein induced by vitamin K absence or antagonist - Ⅱ PIVKA - Ⅱ γ des - gamma - carboxyprothrombin DCP HCC AFP CT APRI AST PLT aspartate aminotransferase - to - platelet ratio index APRI APRI > 2 CHB APRI AST /ULN 100 /PLT 10 9 /L FIB - 4 ALT AST PLT FIB - 4 CHB FIB - 4 = AST ALT TE LSM kpa LSM kpa LSM < 7. 4 kpa LSM HCC 7. 3 MRI MR CT US CHB 6. 3 transient elastography TE TE CHB Masson TE significant fibrosis Metavir TE TE F2 advanced fibrosis Metavir ALT TE F3

6 J Clin Hepatol Vol.31 No.12 Dec.2015 ALT AST HAI < 4 HBsAg HBcAg PCR HBV DNA CHB HBV DNA HBV DNA cccdna 73 CHB 20% CHB Metavir collagen proportionate area CPA HBV Metavir HCV 79 histologic activity A * * A < 1% 3% ~ 4% 20% 50% > 60% 3 Metavir Fibrosis F HBV HBV 1 HBeAg HBeAg HBV 9. 1 HBV HBsAg HBeAg HBV DNA ALT AST HBV 9 DNA HBeAg CHB HBsAg HBeAg HBV 2 HBeAg DNA ALT HBeAg CHB HBsAg HBeAg HBV DNA ALT 9. 5 CHB HBsAg - HBs - HBe - HBc HBV DNA - HBc HBV HCC CHB HBsAg ALT HBsAg HBsAg ALT HBeAg HBeAg ALT 3 HBV DNA HBV DNA ALT HBsAg HBsAg HBeAg - HBe HBV DNA < IU /ml HBeAg ALT

7 ~ 6 HBeAg 12 IFNα PegIFNα ALT IFNα PegIFNα IFNα HBV DNA HBeAg HBV DNA IU / ml 10 5 /ml HBeAg HBV DNA 2000 IU /ml 10 4 /ml 2 ALT ALT 2 ULN 24 HBeAg 32% ~ 36% ALT 10 ULN <2 ULN HBV DNA 44. 8% ALT 5 ~10 ULN 61. 1% 24 HBsAg 2. 3% ~ 3% HBeAg 1 2 CHB PegIFNα - 2b HBV DNA 2 A1 2 ALT 1 ULN 2 ULN > 30 11% 88 HBeAg CHB 60% PegIFNα - 2a B2 3 ALT 3 > 30 43% 48 42% HBsAg HCC 24 3% % 80 5 B2 12% 89 PegIFNα 2 4 ALT HBeAg A PegIFNα NAs PegIFNα NAs ALT ALT IFNα PegIFNα CHB CHB PegIFNα IFNα HBeAg HBV DNA 86 HBeAg CHB PegIFNα - 2a 180 μg / 48 ALT 2 ~ 5 ULN 24 HBeAg HBeAg HBsAg 80 3 HBsAg HBV DNA < 2000 IU /ml PegIFNα HBeAg HBsAg 1 HBV HBV HCV 2. ALT

8 J Clin Hepatol Vol.31 No.12 Dec.2015 IFNα PegIFNα G - CSF GM - entecavir ETV HBeAg HBsAg 95 NAs PegIFNα NAs HBeAg HBsAg HBeAg CHB ETV 9 ~ 36 HBV DNA < 1000 /ml HBeAg < 100 PEIU /ml Peg - IFNα - 2a 48 ETV HBeAg 14. 9% vs 6. 1% HBsAg 8. 5% vs 0 97 HBeAg IFNα IFNα NAs lamivudine LAM ETV adefovir dipivoxil ADV 1 ~ 3 HBV DNA < 200 IU /ml HBeAg PegIFNα - 2a 48 HBsAg 16. 2% 12. 5% 98 PegIFN IFNα < IFNα HBeAg CHB PegIFNα HBeAg NAs 4 5 HBV DNA < IU /ml 2 ALT 3 A B 4 HBsAg 5 G2 CHB HBV DNA < 300 /ml 67% HBeAg CHB HBeAg 21% ALT 68% 78 72% 104 HBeAg CHB HBV DNA < 300 /ml 90% ALT 78% PegIFNα HBeAg CHB 24 HBsAg HBV DNA HBV DNA < 300 /ml 94% ALT 78 PegIFNα 24 HBsAg < 1500 IU /ml 48 HBeAg % LAM 24 HBsAg > IU /ml ETV 5 51% 107 PegIFNα 101 NAs HBeAg CHB HBsAg HBV DNA HBsAg HBV DNA < tenofovir disoproxil fumarate TDF Ⅲ log 10 IU /ml PegIFNα 103 NAs IFNα <400 /ml 93% ALT 76% 109 IFNα TDF 5 87% % Ishak /L < /L IFNα IFNα IFNα 10 9 /L < /L 13 NAs ETV Ⅲ ETV 48 HBeAg 70% 105 ETV 5 HBeAg CHB 80% 106 NAs CHB HBeAg ETV ETV 5 88% 55/ % 4/ TDF 48 HBeAg CHB HBV DNA < 400 /ml 76% HBeAg 21% ALT 68% HBeAg CHB HBV DNA 5 74% Ishak ~ 2 8 TDF HBeAg HBV DNA < /L < /L 400 /ml 98% HBeAg 31% HBsAg

9 HBeAg CHB % HBeAg HBV DNA ALT HBsAg 48 ~ 52 PegIFNα - 2a PegIFNα - 2b LAM 16 ~ ~ ~ 72 0 ~ LdT ETV ADV 12 ~ ~ ~ TDF ~ 8 PegIFN LAM LdT ETV ADV TDF HBeAg CHB % HBV DNA ALT HBsAg 48 ~ 52 PegIFNα - 2a LAM 72 ~ ~ LdT ETV ADV 51 ~ ~ TDF ~ 8 PegIFN LAM LdT ETV ADV TDF % HBeAg HBV DNA < 400 / ml 99. 6% TDF HBeAg HBV DNA < 10 7 /ml HBeAg 2. 2% 0. 5 mg /dl 1% LdT 24 HBV DNA < 300 /ml 50 ml /min TDF NAs ~ 4 CK 7. 5% LAM ADV ETV ADV LAM ADV TDF telbivudine LdT Ⅲ ADV HBeAg LdT LAM HBV DNA < 10 9 /ml ALT 2 ULN LdT LAM % LAM 3. 1% 4. 1% IFNα CHB ADV HBV DNA ALT HBeAg

10 J Clin Hepatol Vol.31 No.12 Dec HBV DNA < 1000 /ml 28% 45% 56% 58% HBeAg 12% 29% 43% 48% % 3. 1% 20% HBeAg 5 HBV DNA < 1000 /ml 67% ALT 69% 5 ADV 29% 120 ADV LAM CHB LdT LAM ETV LdT HBV DNA ADV 121 NAs ADV mg/dl 3% CFDA ADV NAs CHB LAM LAM 100 mg 1 /d HBV DNA HBeAg % % 23% 28% 35% 122 CHB NAs LAM HCC 123 ALT HBeAg LAM 124 < % 38% 49% 66% NAs NAs CHB HBV DNA 6 NAs EFFORT LdT 24 HBV DNA < 300 /ml % HBV DNA < 300 /ml HBeAg 41. 3% 5. 5% LdT 24 HBV DNA 300 /ml ADV 2 HBV DNA < 300 /ml 71. 1% ADV LAM ETVTDF 0. 5% 2 LAM /LdT TDFETV + ADV HBV DNA < 300 /ml 76. 7% 2. 7% ADV ETV TDF ADV ETV TDF A181T + ETV + TDFETV + ADV NAs N236T + M204V ALT AST HBV DNA HBsAg HBeAg - HBe HBeAg CHB HBV ALT CK HBeAg CHB 4 5 HBeAg ALT NAs ADV TDF LdT CK NAs ETV TDF PegIFNα 138 LAM LdT 6 NAs TDF ADV 139 ALT HBeAg CHB ~ 6 HBeAg ALT 140

11 ETV TDF PeglFN A1 LAM LdT 24 >300 /ml TDF ADV ADV 24 <2 log 10 IU/ml ETV TDF A1 6 NAs 4 HBV DNA ALT HBeAg B1 7 IFNα PegIFNα 1 24 HBsAg > IU /ml 146 NAs B HCC HBeAg CHB HBeAg HBV 3 ~ 6 8 ETV TDF PeglFN A1 LAM LdT 24 AFP B > 300 /ml TDF ADV ADV 24 HBsAg < 2 log 10 IU/ml ETV TDF A1 HBeAg CHB HCC NAs HBsAg HBV DNA 10 IFNα PegIFNα 1 12 HBsAg HBV DNA < 2 log 10 IU /ml IFNα 103 NAs B1 11 ETV TDF A1 IFNα 149 A HBV HBsAg HBV AFP B B IFN NAs 1 1 ~ HBV DNA HBsAg/ - HBs/HBeAg/ - HBe AFP LSM ~ ~ B CT MRI LdT 3 ~ 6 TDF ADV 3 ~ 6

12 J Clin Hepatol Vol.31 No.12 Dec antiretroviral therapy ART CD4 + T > 500 /μl CHB HCC PegIFNα ADV HBV C1 3 1 ALT 1 ~ 2 ULN HBV HBV DNA 3 1 HBV HBV DNA 1 ALT ART TDF LAMTDF FTC HBV DNA A ART ART HBV DNA AFP ALT HBV NAs PegIFNα C2 HBV DNA 6 1 HBV DNA ALT AFP 3 AFP CT MRI HCC 1 ~ HBsAg HBV IFNα A1 HBsAg C1 PegIFNα NAs A1 NAs HCC HBV HCC A1 ETV TDF HBV HCC HBV DNA HBV HCC % ~ 50% HBV DNA HCC NAs ETV TDF A HBV 152 HBV NAs 153 ETV TDF 154 HBV HBV DNA HBsAg - HBc HBV DNA B1 170 HBV HBsAg HBIG NAs - HBc B ETV TDF HBIG A NAs NAs 6 B HBV NAs 12 NAs A1 A HBV HCV HBV HCV CHB HBV DNA HCV RNA ALT HBV DNA HCV RNA HCV A1 HBV DNA HCV IFN NAs 6 A1 CHB ALT RNA PegIFNα 3 TDF HBV DNA < 2 log 10 IU /ml ETV TDF A HBV HIV B2 CD4 + T 500/μl CHB ART HBeAg HBV B1 DNA NAs A ETV TDF C1 ETV TDF HBIG LdT A1 TDF HCV ETV IFNα

13 B2 NAs CHB ADV TDF B LdT TDF LAM LdT estimated glomerular fil- ETV ADV tration rate egfr TDF LdT CHB LdT ETV A HBV DNA 12 IFNα PegIFNα NAs HBV NAs HBV DNA > IU /ml A1 24 ~ 28 TDF LdT LAM A1 HBsAg - HBc C HBV DNA IFNα ETV TDF HBsAg - HBc 6 NAs B NAs A1 C2 14 HBV HIV CD4 + T HBV 500 /μl CHB ART TDF LAMTDF FTC A1 FDA 15 HBsAg HBV DNA IFNα 2 ~ 17 LAM 2 ~ 17 ADV 12 ~ 17 NAs ETV 2 ~ 17 TDF 12 ~ 17 ETV TDF A1 IFNα 16 HBV DNA HCC NAs IFNα 3 3 ~ 6 MU /m 2 ETV TDF A1 10 MU /m 2 17 HBV DNA HBV IFNα 1 ETV TDF 2 ~ 11 ETV 12 ~ 17 HBIG B1 HBV ETV TDF A1 FDA WHO NAs HBIG ETV TDF HBIG 8 A1 kg mg /d 18 ALT ETV 2 10 ~ > 11 ~ > 14 ~ > 17 ~ > 20 ~ > 23 ~ > 26 ~ > TDF NAs HBV C2 NAs B TDF LdT A1 19 IFNα B2 B LdT TDF LAM ETV ADV TDF LdT A1 20 HBV HBV DNA > IU /ml 24 ~ 28 TDF LdT LAM A ~ 11 / IFNα ETV 12 ~ 17 IFNα ETV TDF A1

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15 Liver Dis LIN CL KAO JH. The clinical implications of hepatitis B virus genotype recent advances J. J Gastroenterol Hepatol Suppl LIVINGSTON SE SIMONETTI JP BULKOW LR et al. Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A B C D and F J. Gastroenterology YU MW YEH SH CHEN PJ et al. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma a prospective study in men J. J Natl Cancer Inst LIM SG CHENG Y GUINDON S et al. Viral quasi - species e- volution during hepatitis Be antigen seroconversion J. Gastroenterology WANG HY CHIEN MH HUANG HP et al. Distinct hepatitis B virus dynamics in the immunotolerant and early immunoclearance phases J. J Virol LIU F CHEN L YU DM et al. Evolutionary patterns of hepatitis B virus quasispecies under different selective pressures correlation with antiviral efficacy J. Gut LAI CL RATZIU V YUEN MF et al. Viral hepatitis B J. Lancet LIAW YF. 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17 VALLET - PICHARD A POL S. Hepatitis B virus treatment beyond the guidelines special populations and consideration of treatment withdrawal J. Therap Adv Gastroenterol TANG CM YAU TO YU J. Management of chronic hepatitis B infection current treatment guidelines challenges and new developments J. World J Gastroenterol ZHAO H KURBANOV F WAN MB et al. Genotype B and younger patient age associated with better response to low - dose therapy a trial with pegylated /nonpegylated interferon - alpha - 2b for hepatitis B e antigen - positive patients with chronic hepatitis B in China J. Clin Infect Dis LIAW YF JIA JD CHAN HL et al. Shorter durations and lower doses of peginterferon alfa - 2a are associated with inferior hepatitis B e antigen seroconversion rates in hepatitis B virus genotypes B or C J. Hepatology BUSTER EH FLINK HJ CAKALOGLU Y et al. Sustained HBeAg and HBsAg loss after long - term follow - up of HBeAg - positive patients treated with peginterferon alpha - 2b J. 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20 J Clin Hepatol Vol.31 No.12 Dec.2015 cleotide / nucleoside analogs on postoperative prognosis of hepatitis B virus - related hepatocellular carcinoma a two - stage longitudinal clinical study J. J Clin Oncol CHOLONGITAS E PAPATHEODORIDIS GV. High genetic barrier nucleos t ide analogue s for prophylaxis from hepatitis B virus recurrence after liver transplantation a systematic review J. Am J Transplant YI NJ CHOI JY SUH KS et al. Post - transplantation sequential entecavir monotherapy following 1 - year combination therapy with hepatitis B immunoglobulin J. J Gastroenterol TEPERMAN LW POORDAD F BZOWEJ N et al. Randomized trial of emtricitabine/ tenofovir disoproxil fumarate after hepatitis B immunoglobulin withdrawal after liver transplantation J. Liver Transpl LAI CL YUEN MF. Prevention of hepatitis B virus - related hepatocellular carcinoma with antiviral therapy J. Hepatology BZOWEJ NH. Optimal management of the hepatitis B patient who desires pregnancy or is pregnant J. Curr Hepat Rep PAN CQ DUAN ZP BHAMIDIMARRI KR et al. An algorithm for risk assessment and intervention of mother to child transmission of hepatitis B virus J. Clin Gastroenterol Hepatol ZHANG H PAN CQ PANG Q et al. Telbivudine or lamivudine use in late pregnancy safely reduces perinatal transmission of hepatitis B virus in real - life practice J. Hepatology GREENUP AJ TAN PK NGUYEN V et al. Efficacy and safety of tenofovir disoproxil fumarate in pregnancy to prevent perinatal transmission of hepatitis B virus J. J Hepatol SARKAR M TERRAULT NA. Ending vertical transmission of hepatitis B the third trimester intervention J. Hepatology DELLA CORTE C NOBILI V COMPARCOLA D. Management of chronic hepatitis B in children an unresolved issue J. J Gastroenterol Hepatol SAADAH OI SINDI HH BIN - TALIB Y et al. Entecavir treatment of children 2-16 years of age with chronic hepatitis B infection J. Arab J Gastroenterol JONAS MM CHANG MH SOKAL E et al. Randomized controlled trial of entecavir versus placebo in children with hepatitis B envelope antigen - positive chronic hepatitis B J. Hepatology Epub ahead of print Chinese Society of Hepatology and Chinese Society of Infectious Diseases Chinese Medical Association. The guideline of prevention and treatment for chronic hepatitis B a 2015 update J. J Clin Hepatol in Chinese J