1. 내과스텝강의
국내 만성B형간염의 현황과 치료 전략

2. There Is A Cat In This Photo

3. Chronic hepatitis B is a viral infection
Hepatic complications
- Acute or chronic hepatitis
- Liver cirrhosis
- Hepatic failure
- Liver cancer (HCC, CC)
- Co-infection with HDV
Non-hepatic complications
- Pancreatic cancer
- Chronic kidney diseases (GN)
- Cryoglobulinemia
Illustration by Sarah L. Williamson, MA

4. The interplay between virus and the hosts (human)
Virus and host (human)
The interplay between virus and the hosts (human)

5. B형간염바이러스(HBV)
600년 전 조선시대 미이라
150만명 추정

6. 150만명 중 12%에서 ALT 상승

7. REVEAL study cohort Incidence rate of HCC by group of patients with hepatitis B virus from REVEAL study
Subjects N
Age
F/U
(year)
No of HCC
Incidence rate (per 100,000 person-years) (95% CI)
Annual incidence rate
Inactive HBV carrier*
1,932
47±10
13.1 16
64/100,000
0.06%
Inactive HBV carrier with undetectable HBV DNA (<300)
837 6
56/100,000
0.056%
Inactive HBV carrier with HBV DNA (300 – 10,000 copies/mL)
1095 10
71/100,000
0.07%
All low normal (ALT<30 U/L)
1621
46±10
19,810 20
101
0.1%
Ever high normal (ALT: 30 ~ 45 U/L)
570
7,054 13
184
0.18%
Transient abnormal (ALT > 45 U/L, < 50%)
452
5,557 21
378
0.38%
Persistent abnormal (ALT > 45 U/L, > 50%)
191
2,226 23
1033
1.1%
Cohort 환자 중 51%는 위험군!
23%는 (643/2,834) ALT 상승자  Candidates for antiviral therapy
*Inactive HBV carrier: serum ALT < 45 U/L, HBV DNA < 10,000 copies/mL (1900 IU/mL)
Among a total of 3,931 participants with HBsAg (+): 49% (1932/3931)
Chen CF, Gastroenterology 2011;141:1240
Chen JD, Gastroenterology 2010:138:1747

8. 2011년 경구 B형간염치료제 현황 국내 B형간염보유자 150만명 중 20%를 고위험군으로 가정하면 30만명이 치료가 필요
총 150,425 명 추정
국내 B형간염보유자 150만명 중 20%를 고위험군으로 가정하면 30만명이 치료가 필요

9. 국민건강영양조사 3~5기 분석 21.4% B형간염 인지자 48 50 45 32 47 315 대상자 222 123 235 263
207
194
226
1470

10. 미국의 치료 현황
Cohen C, Holmberg SD, McMahon BJ, et al. Is chronic hepatitis B being undertreated in the United States? Journal of Viral Hepatitis. 2011; 18(6):
Cohen C, Holmberg SD, McMahon BJ, et al. Journal of Viral Hepatitis. 2011

11. Hepatitis B virus N Engl J Med 2008;359:1486
Covalently closed circular DNA (cccDNA)
Integration into the host genome
N Engl J Med 2008;359:1486

12. Natural course of chronic HBV Infection
54th AASLD Annual Meeting - SHOW
10/27/03
Natural course of chronic HBV Infection
Replicative phase
(Relatively) non-replicative phase
HBeAg
Anti-HBe
HBV DNA
ALT
Immune clearance HBeAg-positive chronic hepatitis
Reactivation HBeAg-negative chronic hepatitis
Immune tolerant
Inactive carrier state
Yrs
Yim HJ, et al. Hepatology. 2006;43:S173-S181.
Satellite Symposium - Boston, MA

13. 면역 관용기 + + HBV-DNA HBeAg anti-HBe (-) HBsAg anti-HBs (-)
ALT
HBeAg anti-HBe (-)
HBsAg anti-HBs (-) + +
Immune tolerant phase

14. 면역 반응기 + + HBV-DNA ALT HBeAg anti-HBe (-) HBsAg anti-HBs (-)
Immune reactive phase
HBeAg (+) 만성B형간염

15. Inactive HBV carrier state
HBV-DNA
ALT
HBV DNA (PCR) < 2,000 IU/mL
Persistently normal ALT
Anti-HBe seroconversion
HBeAg anti-HBe
HBsAg anti-HBs (-) - + +
Inactive HBV carrier state

16. HBeAg (-) chronic hepatitis B
HBV-DNA
ALT
HBeAg anti-HBe
HBsAg anti-HBs (-) - + +
HBeAg (-) chronic hepatitis B

17. HBsAg 소실기 - + - HBV-DNA ALT HBsAg anti-HBs (±) HBsAg clearance phase
HBeAg anti-HBe
HBsAg anti-HBs (±) - + -
HBsAg clearance phase

18. Inactive HBV carrier state CHB, chronic hepatitis B
Natural course of chronic hepatitis B
HBV-DNA
HBV-DNA
ALT
HBV-DNA
HBeAg anti-HBe
HBsAg anti-HBs
ALT + +
ALT
Immune tolerant phase
HBeAg anti-HBe
HBsAg anti-HBs - +
HBeAg anti-HBe
HBsAg anti-HBs
HBV-DNA + + +
HBeAg negative CHB
Immune reactive phase
ALT
HBeAg positive CHB
HBeAg anti-HBe
HBsAg anti-HBs
HBV-DNA - + +
Inactive HBV carrier state
ALT
HBV DNA (PCR) < 2,000 IU/mL
Persistently normal ALT
Anti-HBe seroconversion
HBeAg anti-HBe
HBsAg anti-HBs - + - - +
CHB, chronic hepatitis B
HBsAg-negative phase

19. Virus and host interaction
HBsAg (+)
Anti-HBs Ab(+)
Titer or level
HBV DNA
ALT
Time

20. Chronic infection: virus and host interaction
HBV DNA 20 30 40 50 60
Age

21. Current status of chronic HBV infection (assumption from REVEAL data)
Neonatal infection
Adulthood infection
Immune clearance
Inactive HBV carrier state
Immune tolerant phase
Immune clearance
Reactivation
48%
Yang HI et al. J Clin Oncol 2010; 28: , Chen CJ, Yang HI, Su J, et al.JAMA. 2006; 295:
HBsAg negative
HBeAg (+/-) CHB
Immune clearance
52%
Antiviral therapy
Yang HI et al. J Clin Oncol 2010; 28: , Chen CJ, Yang HI, Su J, et al.JAMA. 2006; 295:

22. 만성B형간염 환자에서 간암 발생률 - HBV DNA 수치에 따라 위험도가 증가
1.152% / year
0.962% / year
0.297% / year
0.111% / year
0.108% / year
Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study. A total of 89 293 individuals aged 30 to 65 years, who were living in 7 townships in Taiwan, were invited to participate in the study. From 1991 to 1992, 23 820 individuals agreed to participate
A total of 4155 participants who were seropositive for HBsAg and free of hepatocellular carcinoma at study entry examination were followed up with abdominal ultrasonography and serological tests until June 30, Serum samples that had been collected and frozen at study entry were adequate for HBV DNA testing in 3851 participants. Among them, 3653 were seronegative for anti-HCV and were included in this study. This study was approved by the institutional review board of the College of Public Health, National Taiwan University in Taipei.
Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study. in 7 townships in Taiwan (1991 to 1992) 23 820 individuals agreed to participate
3653 were included
JAMA. 2006;295:65-73

23. Changes in Serum Levels of HBV DNA and Alanine Aminotransferase
Determine Risk for Hepatocellular Carcinoma
GASTROENTEROLOGY 2011;141:1240–1248

24. Incidence of HCC in chronic HBV infection (REVEAL study)
1,152
1,000
962
900
800
700
600
Rate (per 100,000 person-years)
500
400
297
300
200
104
100 64
Chen JD, et al. Gastroenterology. 2010
Lee MH, et al. Hepatology. 2013 15
HBsAg negative1
HBV DNA < 1900 IU/mL2
ALT < 45 U/L & HBV DNA < 1900 IU/mL1
HBV DNA 2,000 – 20,000 IU/mL4
HBV DNA 20,000 – 200,000 IU/mL4
HBV DNA > 200,000 IU/mL4
Chen JD, et al. Gastroenterology. 2010
Lee MH, et al. Hepatology. 2013
3. Iloeje UH et al. Clin Gastroenterol Hepatol. 2007
4. Chen JC, et al. JAMA 2006

25. Rate (per 100,000 person-years)
Rate of incidence and mortality from HCC in chronic HBV infection (REVEAL study)
Incidence
Mortality
104
100 90 80 70 64 59 60
Rate (per 100,000 person-years) 50 40 ? 30 20 15 14
Chen JD, et al. Gastroenterology. 2010
Lee MH, et al. Hepatology. 2013 10
HBsAg negative1
HBsAg negative3
HBV DNA < 1900 IU/mL2
HBV DNA < 1900 IU/mL3
ALT < 45 U/L & HBV DNA < 1900 IU/mL1
ALT < 40 U/L & HBV DNA < 1900 IU/mL
Chen JD, et al. Gastroenterology. 2010
Lee MH, et al. Hepatology. 2013
3. Iloeje UH et al. Clin Gastroenterol Hepatol. 2007

26. Rate (per 100,000 person-years)
Rate of incidence and mortality from LC in chronic HBV infection (1NHANES 2-4REVEAL study)
Incidence
Mortality
429
400
377
338
300
200
Rate (per 100,000 person-years)
100 80 60 57 48
1. Ruhl CE, Everhart JE. Gastroenterology. 2005
2. Iloeje UH, et al. Gastroenterology. 2006
3. Lee MH, et al. Hepatology. 2013
4. Iloeje UH et al. Clin Gastroenterol Hepatol. 2007
Chen JD, et al. Gastroenterology. 2010
Lee MH, et al. Hepatology. 2013 40 20 17 9
HBsAg negative1
HBsAg negative4
HBV DNA < 1900 IU/mL3
HBV DNA = undetectable2
HBV DNA = 50 ~ 2000 IU/mL2
HBV DNA = undetectable4
HBV DNA = 50 ~ 2000 IU/mL4
1. Ruhl CE, Everhart JE. Gastroenterology. 2005
2. Iloeje UH, et al. Gastroenterology. 2006
3. Lee MH, et al. Hepatology. 2013
4. Iloeje UH et al. Clin Gastroenterol Hepatol. 2007

27. 적절한 치료 대상은? <2,000 IU/mL <30-33 U/L (M), <19-25 U/L (F)
Active viral replication
Active necroinflammation
Risk of decompensation
<2,000 IU/mL
<30-33 U/L (M),
<19-25 U/L (F)
HBV-DNA
ALT
HBeAg anti-HBe + -
Bilirubin
Albumin
Platelets
HBsAg
High BMI
Diet, DM, …
Male
Smoking
Alcohol
Old age
Family history

28. 치료 대상 – Chronic HBV infection
이상적(ideal)
대한간학회(2011)
국민건강보험공단
EASL (2012)
Most HBsAg (+)
(> 1,000 IU/mL)
ALT > 2 x ULN+
- Liver Bx (1~2 x ULN)
HBV-DNA
HBeAg (+) >20,000 IU/mL
HBeAg (-) >2,000 IU/mL
Cirrhosis (LC)
HBV-DNA > 2,000 IU/mL, ALT: no limit
HBeAg (+)
- AST or ALT > 80 U/L
- HBV DNA > 20,000 IU/mL
(105 copies/ml)
HBeAg (-)
- HBV DNA > 2,000 IU/mL
(104 copies/ml)
LC, HCC:
HBV DNA> 2,000 IU/mL
AST or ALT > ULN
ALT > ULN+
HBV-DNA
>2,000 IU/mL
Liver Bx
HBV DNA 2,000 ~ 20,000 IU/mL, ALT < ULN
이것을 표로 정리해 보면 다음과 같습니다.
EASL 2012
HBV-DNA > 2,000 IU/mL
ALT > ULN
AASLD 2009
HBV-DNA > 20,000 IU/mL
ALT > 2 x ULN
+ULN: 정상 상한치, 30 U/L for men, 19 U/L for women

29. 치료는 언제 시작하는가? When to start treatments?
Necroinflammation (ALT) ↑
Viral replication (HBV-DNA)↑
Risk for LC or HCC
Alcohol
Family Hx
Fibrosis
Smoking DM 3 2 1
Time
Duration of hepatitis B

30. Current status of CHB in Korea 만성B형간염 치료 대상자 비율
5기 국민건강영양조사 ( ) 40세 이상 HBsAg 양성자 420명 분석 4
약 4 만명
약 48 만명
약 14 만명

31. 만성B형간염 치료제 Entecavir (Barclude®,BMS) Tenofovir (Viread®,Glead/유한)
많은 약제 중에서 ETV, TDF를 왜 사용해야 되고 사용하면 어떤 효과가 있는지를 검토해 보겠습니다.
Peg-IFN-α2a (Pegasys®,Roche)
Peg-IFN-α2b
(Peg-intron®,MSD)
Lamivudine (Zeffix®,GSK)

32. 치료 목표 Goal of therapy 삶의 질 개선 생존율 향상 간경화 진행 억제, 간세포암 발생 억제
간경화 진행 억제, 간세포암 발생 억제
Suppression of viral replication
HBV-DNA
HBV-DNA
치료 목표는 모든 가이드라인이 공통적으로 제시하는 것이 생존율의 향상과 삶의 질의 개선입니다.
복수, 황달, 간부전, 감염증 등의 간경화 합병증이 발생하지 않고 특히 간암을 예방하여 생존율을 향상하는 것이 B형간염의 치료 목표가 되겠습니다.
ALT
ALT
HBeAg anti-HBe
HBsAg anti-HBs
Restoration of decreased viral control of host immunity
HBeAg anti-HBe
HBsAg anti-HBs + - + + - - +
Immune reactive phase
HBsAg-negative phase

33. 최근 10년간 국내 간질환 및 간암 사망자수

34. Long-term outcomes of chronic hepatitis B virus infection in the era of antiviral therapy in Korea
간경화 발생률: 연간 5%  1%
간세포암 발생률: 연간 1%  0.53%
Between 2001 and 2005, treatment-naïve 360 Korean CHB patients without cirrhosis 
LAM (71%)
J Gastroenterol Hepatol. 2013 Dec 10. doi: /jgh [Epub ahead of print]
Long-term outcomes of chronic hepatitis B virus infection in the era of antiviral therapy in Korea.
Park YH, Kim BK, Kim JK, Kim HC, Kim DY, Park JY, Han KH, Kim SU, Shin SH, Hahn KY, Ahn SH.
Author information
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
Abstract
BACKGROUND&AIMS:
Chronic hepatitis B (CHB) can progress to cirrhosis, hepatocellular carcinoma (HCC), and ultimately liver-related deaths. Recently, owing to potent antiviral therapy with minimal side effects, sustained suppression of hepatitis B virus replication can be achieved, thereby preventing such complications. We aimed to reappraise clinical courses regarding disease progression in the era of antiviral therapy.
METHODS:
Between 2001 and 2005, treatment-naïve Korean CHB patients without cirrhosis were enrolled and follow-up for at least 5 years. During follow-up, antiviral therapy was commenced according to Korean Association for the Study of the Liver guidelines, if eligible, and ultrasonography and laboratory and clinical assessment were performed regularly. Primary endpoints were development of cirrhosis, hepatic decompensation, HCC, orliver-related deaths.
RESULTS:
Of 360 patients, 323 (89.7%) received antiviral therapy such as lamivudine (70.6%), entecavir (8.7%), or telbivudine (6.5%). During follow-up, cirrhosis developed in 29 (8.1%), hepatic decompensation in 4 (1.1%), and HCC in 15 (4.2%) patients. Annual incidences of cirrhosis, hepatic decompensation, and HCC were 1.05%, 0.14%, and 0.53% per person-year, respectively. Age was an independent predictor for developing cirrhosis(hazard ratio [HR] 1.075, 95% confidence interval [CI] ; p<0.001), whereas age (HR 1.060, 95% CI ; p=0.014) and cirrhosis(HR , 95% CI ; p<0.001) were those for developing HCC.
CONCLUSIONS:
In the era of antiviral therapy, overall clinical courses have been much improved since introduction of lamivudine in However, patients with older age or cirrhosis are still subject to HCC development despite appropriate antiviral therapy, necessitating cautious surveillance.
This article is protected by copyright. All rights reserved.
KEYWORDS:
antiviral therapy, chronic hepatitis B, cirrhosis, decompensation, hepatocellular carcinoma, prognosis
PMID:   [PubMed - as supplied by publisher]
J Gastroenterol Hepatol Dec 10.

35. 간섬유화, 간경변 진행이 차단 422 days J Gastroenterol. 2011 Nov;46(11):1324-34.
J Gastroenterol. 2011 Nov;46(11): doi: /s Epub 2011 Aug 6.
Reduction of liver stiffness by antiviral therapy in chronic hepatitis B.
Osakabe K, Ichino N, Nishikawa T, Sugiyama H, Kato M, Kitahara S, Hashimoto S, Kawabe N, Harata M, Nitta Y, Murao M, Nakano T, Shimazaki H, Arima Y,Suzuki K, Yoshioka K.
Author information
Abstract
BACKGROUND:
Liver stiffness (LS) has been reported to correlate with fibrosis stage (F). The correlation between LS and fibrosis stage and the reduction of LS by antiviral therapy were examined in patients with hepatitis B infection.
METHODS:
LS was measured by FibroScan in 212 patients infected with hepatitis B virus. Liver biopsies were done in 51 patients. Changes of LS were assessed in 29 patients treated with nucleotide or nucleoside analogs and 52 patients without antiviral therapy.
RESULTS:
LS was significantly correlated with fibrosis stage (ρ = 0.686, P < ). The optimal cut-off values of LS were 7.1 kPa for F ≥ 2, 10.7 kPa for F ≥ 3, and 16.0 kPa for F4. LS was significantly reduced by antiviral therapy, from 12.9 (range ) kPa to 6.6 ( ) kPa measured at an interval of 512 (range ) days (P < ). Eleven of 19 (58%) patients with baseline fibrosis stages of F3-4 deduced from LS had 2-point or greater reductions of deduced stage at the last LS measurement. The change ratio of hyaluronic acid (P = ) was associated with a 2-point or greater reduction of deduced fibrosis stage. Without antiviral therapy, LS tended to increase, increasing from 6.1 (range ) kPa to 6.3 (range ) kPa at an interval of 422 (range ) days (P = ).
CONCLUSIONS:
LS was significantly correlated with fibrosis stage in patients with chronic hepatitis B. The reduction of LS by antiviral therapy was significantly correlated with the reduction of hyaluronic acid. Thus, we conclude that LS can be useful to assess the progression and regression ofliver fibrosis stage noninvasively.
PMID:   [PubMed - indexed for MEDLINE]
J Gastroenterol. 2011 Nov;46(11):

36. Percent collagen area decreased by
Studies 102/103
Morphometric Assessment of Liver Biopsies
An example of liver biopsies in a TDF-treated subject with histological
regression of cirrhosis at Week 240
shows a marked decrease in PCA
over time
Percent collagen area decreased by
79% from Baseline to Week 240
This patient had regression of histologic cirrhosis at Week 240
Week 48 Ishak score was unchanged from baseline
No slide was available at Week 48, but PCA decreased by 79% from baseline to Week 240
Baseline
21.5%
Week 240
4.6%
Goodman Z, et al. AASLD Washington, DC. #820.

37. Morphometric Assessment of Liver Biopsies
Studies 102/103
Morphometric Assessment of Liver Biopsies
Percent collagen area (PCA) measurement in liver biopsies at Baseline, Week 48 and Week 240 in subjects treated with TDF1
Change in PCA*
Biopsy slides were stained with Sirius red:
• Digital image analysis used to calculate
relative collagen content of each biopsy 35 30
P<0.005
P<0.001
Slides with < 5 mm2 tissue and slides with < 3% collagen at baseline were excluded 25 20
Mean PCA decreased over time:
• 7.1% at Baseline
• 5.3% at Week 48
• 3.9% at Week 240
Collagen (%) 15 10
Among 344 subjects with biopsies, 71/96 had histologic regression of cirrhosis by Week 2401 under TDF treatment
There was a statistically significant reduction in mean quantitative collagen at Week 48, which significantly decreased further by Week 240
Mean PCA was 7.1% at baseline, 5.3% at Week 48, and 3.9% at Week 240. Relative reductions at Week 48 and 240 were 25% and 45%, respectively 5
Baseline
Week48
Week240
*PCA, % collagen area
1.Histology described previously: Marcellin P, et al. The Lancet 2013;381(9865): ; Goodman Z, et al. AASLD Washington, DC. #820.

38. Change From Baseline in Fibrosis Score
간경화의 호전 – 경구 항바이러스제 장기 치료 효과
Change From Baseline in Fibrosis Score
n=24
n=1
n=15
n=41
n=14 -5 -4 -3 -2 -1 +1 +2 +3 +4 +5
최근 B형간염치료제를 장기간 사용하면서 장기치료 효과를 보여주는 연구 결과들이 나오고 있습니다.
우리가 최근 경험하고 있듯이 만성B형간염의 악화로 간경화 및 합병증이 발생하는 사례가 이제 많이 감소하고 있습니다.
최근 연구 결과 tenofovir 5년 사용 시 약 74%의 환자에서 간경화의 호전을 볼 수 있었습니다.
96 patients with cirrhosis (Ishak fibrosis score ≥5) had paired BL and Year 5 biopsies
74% (n=71) of patients had cirrhosis reversed (Ishak fibrosis score <5) at Year 5
1% (3/252) of non-cirrhotics (Ishak score ≤4) progressed to cirrhosis at Year 5 (P <0.001, McNemar’s test)
Marcellin, et al. Lancet 2013; 381: 468–75.

39. 간세포암의 예방 – 경구 항바이러스제 장기 치료 효과
Hosaka T, Suzuki F, Kobayashi M, et al. Hepatology. 2013; 58:

40. 간세포암의 예방 – 경구 항바이러스제 장기 치료 효과20
Predicted
Observed 15
Patients (%) 10
SIR = 0.55
(95% CI = ) 5
올해 유럽과 우리나라에서 발표된 연구로
테노포비어 7년 사용한 데이터를 분석한 결과 예상되는 간세포암 발생률보다 약 절반 정도로 발병 위험을 낮추는 것으로 나왔습니다.
W.R. Kim EASL 2013 Amsterdam
641 TDF therapy for 6 years, 13 cases of HCC , 48 96
144
192
240
288
336
641 TDF therapy for 6 years, 13 cases of HCC
REACH-B prediction model
W.R. Kim EASL 2013

41. Figure 4. The cumulative incidence of HCC development after institution of long-term (>12 months) oral antiviral therapy.
207명의 환자 중 적어도 12개월 이상 항바이러스제 치료를 받고 F/U이 된 171명에서 치료 개시 12개월 이후 HCC의 누적 발생률은 다음과 같습니다.
평균 31개월의 추적 기간 중 누적 발생률은 8.8% 였으며 년간 HCC 발생률은 3.4%였습니다.
8.8% / 31 months
심재준, 2013 대한소화기학회 구연

42. 경희대학교병원 간암위험도 판정 프로그램

43. 경구 항바이러스 제제의 종류 Nucleosides Nucleotides Adefovir Lamivudine
Telbivudine
Clevudine
Entecavir
Tenofovir
Nucleosides
Nucleotides

44. 약제별 내성바이러스 발생률 HBV Resistance to in Naïve Patients
*Each bar represents 1 year 80
1st generation 24 38 49 67 70 60
2nd generation
Patients (%) 40 3 11 18 29
3rd generation 20 4 17 ?
또한 이 약물들은 5~6년까지 내성 발생률이 매우 낮은 것으로 나왔고.
0.2
0.5
1.2
LAM
ADV
LDT
ETV
TDF
Collation of currently available data – not from head-to-head studies
Adapted from EASL HBV Guidelines, J Hepatol 2012.

45. 높은 항바이러스 효과 – 경구 항바이러스제
Patients with undetectable HBV DNA by entecavir (ETV) and tenofovir (TDF)
ETV Italian Real World Cohort Results (n=418)
TDF European Real World Cohort Results (n=302) 20 40 60 80
100 6
67%
Patients %
85% 12
405
391
Patients
on F/U
95%
344
Months 24
96%
288 36
98%
188 48
100% 81 54
100
95%
90%
91%
84% 80
65% 60
% Patients 40 20
그러나 최근 나온 경구항바이러스제는 매우 높은 항바이러스 효과를 보이며 실제 임상 데이터를 보면 95% 이상의 환자에서 바이러스를 미검출 수준까지 억제시킬 수 있는 것으로 알려져 있습니다. 6 12 24 30 36
Months
Patients on F/U
271
273
240
175
103
Lampertico P, et al. EASL 2012; Poster #522, #525

46. 장기치료 후 혈청학적 반응 – 경구 항바이러스제
Serologic responses with ETV or TDF in HBeAg + patients
49%
40% 50
HBeAg Loss
ETV-022
ETV Long-term Cohort (ETV-022/-901)
94% 45
HBeAg Seroconversion
91%
100
89% 40
HBsAg Loss
83% 35 80
67% 30
Patients (%) 60
55%
HBeAg Seroconversion 25
Patients %
HBsAg Loss 20 40 15
31%
11%
23% 10 20
페그인터페론에 비해 혈청학적 반응이 낮다고 알려져 있었지만 최근의 5년 치료 결과를 보면 약 40%에서 HBeAg 혈청전환을 유도할 수 있는 것으로 나와
상당히 고무적인 결과를 보여 주었습니다. 다만 이 약제를 5년 10년 이상 사용하였을 때 체내에 미치는 영향에 대해서는 아직 자료가 불충분합니다.
N=238명Study 103 HBeAg+ CHB patients
354명 중 146명이 장기 치료, 110명 + 추가로 33명이 혈청전환, 최종적으로 약 40%에서 seroconversion 있었다고 볼 수 있음. 5 5%
1.3% 12 12 24 36 48 54 12 48
168
240
Months
Patients
236/354
80/146
116/140
116/131
98/108
88/94
Study Week
On-Treatment Analysis (Observed; missing = excluded/addition of FTC = included)
HEPATOLOGY 2010;51:
Marcellin, et al AASLD, Poster 1375.

47. Sustained off-therapy durability
Target
Sustained off-therapy durability
ALT normal
HBV-DNA < 2,000 IU/mL
HBeAg (-), or HBsAg (-)
HBV-DNA
HBV-DNA
ALT
ALT
HBeAg anti-HBe
HBsAg anti-HBs
HBeAg anti-HBe
HBsAg anti-HBs + - + + - - +

48. 약물은 언제까지 사용해야 하는지? Sustained off-therapy durability HBeAg(+) CHB
At 12 months after HBeAg loss or seroconversion
HBsAg loss or seroconversion
HBeAg(-) CHB
6개월 이상 간격, 3회 이상 HBV DNA undetectable

49. HBeAg(+) CHB discontinued 12 months after anti-HBe seroconversion.
J Clin Gastroenterol Nov-Dec;46(10):865-70
J Clin Gastroenterol Nov-Dec;46(10):865-70

50. HBeAg(-) CHB discontinued if undetectable HBV-DNA has been documented on three occasions 6 months apart.
45.3% 재발 (1년)
HEPATOLOGY 2013;58:
HEPATOLOGY 2013;58:

51. HBV DNA는 미검출 수준까지 낮춰야… VR, virological response HBV DNA < 80 IU/mL
Virological response to entecavir is associated with a better clinical outcome in chronic hepatitis B patients with cirrhosis
The cumulative probability of achieving VR was 68% at week 48, 87% at week 96 and 93% at week 144 of ETV treatment.
VR, virological response HBV DNA < 80 IU/mL
Event: decompensation, HCC, or death
Gut. 2013 May;62(5):760-5

52. 학회 권고안과 보험 기준 학회 권고안 보험 기준: 3년 기간 제한 폐지됨  평생 사용 가능
HBeAg(+) CHB: 12 months after HBeAg loss or seroconversion  불충분 (90% 이상 재발)
HBeAg(-) CHB: 6개월 이상 간격, 3회 이상 HBV DNA undetectable  절반에서 재발
HBsAg loss or seroconversion  약물 중단 가능하지만 달성이 어려움
High risk: liver cirrhosis

53. Summary 만성B형간염 환자의 치료 치료 효과는 확실하나… B형간염바이러스(HBV)의 증식을 지속적으로 강력하게 억제해야
목표: “HBV DNA titer (RT-PCR) = undetectable”
약제 중단 시 재발 가능성이 높아 장기간 치료해야
치료 효과는 확실하나…
간경화(LC)는 거의 대부분(99%) 예방이 가능
간세포암(HCC)은 절반 정도의 효과(특히 LC 환자는 매우 위험)
6개월마다 초음파검사와 AFP 검사 필요

54. 열심히 B형간염약을 먹었는데…
62세 남성, 만성B형간염, 간경변

55. 만성 간염

56. 만성 간염
무증상 환자
쉽고 빠른 검사
정확한 진단
높은 치료 효과
낮은 부작용
낮은 비용
간경화
간세포암

57. 경청해 주셔서 감사합니다.

58. Answer