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B 型肝炎治療新知

新竹馬偕醫院 肝膽胃腸科張瀚文. B 型肝炎治療新知. The HBV Genome. preS1. preS2. 3174. 2850. 157. Relaxed circular partially double-stranded DNA Approximately 3,219 bps Four overlapping open reading frames. (-). S. (+). 2452. 833. 2309. DR1. DR2. Core. POL. Pol. 1903. 1621. Pre-core. 1376.

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B 型肝炎治療新知

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  1. 新竹馬偕醫院 肝膽胃腸科張瀚文 B型肝炎治療新知

  2. The HBV Genome preS1 preS2 3174 2850 157 • Relaxed circular partially double-stranded DNA • Approximately 3,219 bps • Four overlapping open reading frames (-) S (+) 2452 833 2309 DR1 DR2 Core POL Pol 1903 1621 Pre-core 1376 1816 1838 X Adapted from Lee WM. N. Engl. J. Med. 1997; 337:1733–45

  3. mRNA The Life Cycle of HBV in the Hepatocyte Infectious HBV virion Subviral ParticlesHBsAg Hepatocyte HBeAg ER/Golgi Viral POL converts pgRNA to partially dsDNA Partially dsDNA HBeAg Encapsidated pre-genomic-RNA HBsAg HBcAg Pre-core/Core cccDNA Nucleus Adapted from Lai CL and Yuen MF. J. Med. Virol. 2000; 61:367–73

  4. HBV Infection 15-20% HBsAg carrier in adult Infants Inapparent Disease Recovery (<10%) Chronic Infection (>90%) 30-40% 60-70% Chronic Hepatitis Healthy Carrier 0.8%/year 2%/year Cirrhosis 0.1%/year 3-10%/year HCC

  5. 哪些B型肝炎容易變成肝硬化肝癌

  6. Stage of chronic hepatitis B

  7. HBeAg Positive hepatitis HBeAg Negative hepatitis Stage of chronic hepatitis B

  8. B型肝炎如何致病？ HBV主要的致病機轉並不是直接殺死肝細胞，它是藉 由人體的免疫機轉而導致肝細胞壞死的。人體免疫系 統內的T cell，平常不會攻擊體內的正常細胞，當體內 的正常細胞遭受到病菌感染時，它就會將已受感染的 細胞殺死，目的是為了要除去入侵的病菌。 B型肝炎病毒導致肝炎就是經由這樣的途徑。T cell要 將HBV「驅除出境」，然而HBV是在肝細胞內，所以在Tcell欲除去HBV同時，肝細胞也跟著陪葬了。

  9. Who should be tested for HBV infection

  10. Who should be tested for HBV infection

  11. Recommendations for Infected Persons Regarding Prevention of Transmission of HBV to Others

  12. Evaluation of Patients with Chronic HBV Infection

  13. Suggested follow-up for patients not considered for treatment

  14. Definition of Response to Antiviral Therapy of Chronic Hepatitis B

  15. Definition of Terms Relating to Antiviral Resistance to Nucleoside Analogue(NA) Treatment

  16. Genotype Geographic Distribution A Africa, India, Northern Europe, United States B Asia, United States C Asia, United States D India, Middle East, Southern Europe, United States E West and South Africa F Central and South America G Europe, United States H Central and South America, California in United States Genotypes of HBV and Geographic Distribution Int J Med Sci. 2005; 2(1): 36–40.

  17. 治療慢性B型肝炎的目標 • Stop HBV replication,ideally permanently • Improve hepatitis: normalise ALT, HBeAg seroconversion, improve symptoms • Arrest/reverse hepatic fibrosis: Improve long-term prognosis • Stop progressive liver damage  cirrhosis • Prevent HBV-related hepatocellular carcinoma • Prolong life, or at least improve life quality

  18. 慢性B型肝炎治療之endpoints Biochemical: Normalisation of ALT Virological: • Decrease HBV DNA to <105 copies/mL • Loss of HBeAg Histological: Decrease HAI score by >2 points and to below score of 7 Complete: • Biochemical and virological response plus loss of HBsAg

  19. 治療慢性B型肝炎的藥物 抗病毒 (Antiviral) Interferon Lamivudine(3TC) *Adefovir dipivoxil *Entecavir Telbivudine(L-dT) Emtricitabine (FTC) *Tenofovir *Remofovir *LB80380 *Clevudine (L-FMAU) *L-Fd4C *DAPD 免疫調節(Immunomodulation) Interferon ( PEG-IFN ) Thymosin-1 Steroid withdrawal, IL-12 Therapeutic vaccines 無效或有毒 (Toxic or ineffective) Acyclovir, ganciclovir, levamisole, IL-2, ribavirin, AZT, ddI, ARA-AMP, fialuridine, foscarnet, lobucavir, famciclovir *Effective for YMDD mutants

  20. Endpoints defining efficacy of treatment • Termination of HBV replication • Loss of HBeAg, seroconversion to Anti-HBe • Loss of HBV DNA by hybridization assay • Cessation of chronic liver injury • Normalization of aminotransferases • Decreased symptomatology, if any • Disease-free state • Seroconversion to HBsAg–negative and Anti-HBs–positive status • Absence of HBV DNA from serum and liver tissue by PCR

  21. ? Stage of chronic hepatitis B

  22. Interferon FDA approved Since 1991 Treatment of chronic hepatitis B

  23. Action of the interferons

  24. 干擾素治療慢性B型肝炎的好處 • Short treatment course (4-6 months) • 40% HBeAg seroconversion (less in Asians) • Best predictors: • ALT> 5 ULN • HBV DNA<200 pg/mL • Short duration infection • Alters outcome of chronic liver disease - Wang, NEJM, 1996

  25. 干擾素治療慢性B型肝炎的缺點 Few cases are optimal • Most are neonatally acquired, low ALT • Minimally effective with HBeAg (-) variants Poorly tolerated • Frequent unpleasant side effects • Occasional dangerous side effects • Hazardous for decompensated cirrhosis Poorly accepted • Need for injections • Expensive

  26. N H 2 N H 2 N N O O O O O O N O N O O ( - ) O P O P O P O ( - ) O P O P O P O S ( - ) O ( - ) O ( - ) O ( - ) O ( - ) O ( - ) O O O H Lamivudine Triphosphate (3TCTP) Deoxycytidine Triphosphate (dCTP) Lamivudin (Zeffix)干安能 FDA approved Since 1998 TREATMENT OF CHRONIC HEPATITIS B

  27. Lamivudine Infectious HBV virion Infectious HBV virion HBsAg envelopes DNA pol RT Partially double-stranded DNA (-)-DNA Encapsidated pregenomic mRNA A(n) cccDNA mRNA Antiviral mechanism of lamivudine Lai et al.,J Med Virol 2000

  28. Lamivudine, IFN-與安慰劑副作用的比較 Adverse eventPlaceboLamivudineIFN-n=200n=416n=70 Malaise and fatigue282670Headache212247Viral respiratory infection191937 Nausea and vomiting171634Muscle pain9840Temperature disturbance9743 Arthralgia5623 Depression5413 Feeding problems33 33 Hair loss3323Decreased white cells1126 Integrated data from NUCB3009, NUCA3010, NUCB3010 and NUCAB3011

  29. HBeAg seroconversion (%) Placebo Lamivudine 70 ALT 2–5X ULN ALT < 2X ULN ALT >5X ULN 50 30 10 0 0 8 16 24 32 40 52 0 8 16 24 32 40 52 0 8 16 24 32 40 52 Duration of lamivudine therapy (weeks) 治療前血清ALT值與e抗原陰轉的關係

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