高雄醫師公會演講
Hepatitis B diagnosis and ideal treatment strategy B型肝炎的診斷與理想的治療策略 高雄長庚胃腸肝膽科 蔡明釗醫師 Jan. 19, 2018
Outlines • • • •
Natural history Hepatitis B diagnosis Overview the benefit of CHB treatment The idea strategies of CHB treatment
Hepatitis B virus replication cycle
Natural history of HBV infection
Liaw YF & Chu CM. Lancet. 2009
REVEAL: HBeAg and risk of HCC
Yang HI, NEJM, 2002
R.E.V.E.A.L: high viral load is associated with increased incidence of cirrhosis Cumulative Incidence of Liver Cirrhosis, All Subjects (n=3,582)
Cumulative incidence of liver cirrhosis (% subjects)
40 36.2%
Baseline HBV DNA level, copies/mL ≥106 (n=602) 105–<106 (n=333)
30
104–<105 (n=628) 300–<104 (n=1,150)
23.5%
<300 (n=869)
20
Log rank test of trend p<0.001
10
9.8% 5.9% 4.5%
0 0
1
2
3
4
5
6
7
8
9
10
11
12
13
Year of follow-up Iloeje UH, et al. Gastroenterology. 2006;130:678-686
R.E.V.E.A.L: high HBV viral load is associated with increased incidence of HCC Cumulative Incidence of HCC: All Subjects (n=3,653)
Cumulative incidence of HCC (%)
16 14.89% Baseline HBV DNA Level, copies/mL ≥106 105–<106 104–<105 300–<104 <300
14 12 10 8
12.17%
6 4
3.57%
2
1.37% 1.30%
0 0
1
2
3
4
5
6
7
8
9
10
11
12
13
Year of follow-up Chen CJ, et al. JAMA. 2006;295:65-73.
Outlines • • • •
Natural history Hepatitis B diagnosis Overview the benefit of CHB treatment The idea strategies of CHB treatment
B型肝炎的病毒標記 • B型肝炎表面抗原 (HBsAg): 表示是B型肝炎帶原者。 • B型肝炎表面抗體 (Anti-HBs): 表示具保護力，不會被B型肝炎感染。 • B型肝炎e抗原 (HBeAg): 表示病毒複製非常活躍，傳染性高。 • B型肝炎e抗體 (Anti-HBe): 表示病毒活性減低，傳染性低。 • B型肝炎核心抗體 (Anti-HBc): 若呈陰性表示不曾感染B型肝炎。若呈陽性表示曾 感染過B型肝炎， 目前帶原或痊癒還須配合表面抗 原與表面抗體判斷。
Acute HBV Infection with Recovery Typical Serologic Course HBeAg Symptoms
anti-HBe
Total anti-HBc
Titer HBsAg
0
4
anti-HBs
IgM anti-HBc
8 12 16 20 24 28 32 36
Weeks after Exposure
52
100
Progression to Chronic HBV Infection Typical Serologic Course Acute (6 months)
Chronic (Years) HBeAg
anti-HBe HBsAg Total anti-HBc
Titer
IgM anti-HBc
0 4 8 12 16 20 24 28 32 36
52
Weeks after Exposure
Years
HBeAg的重要性 HBsAg Anti-HBs HBeAg
+
+
−
−
+
−
Anti-HBe
代表意義
−
高度傳染性的B型肝 炎帶原者病毒活性很 強，傳染力很大肝功 能可能正常也可能升 高需定期追蹤。
+
低傳染性的B型肝炎 帶原者病毒濃度低、 但仍具傳染力若病毒 複製力仍強，病毒濃 度高、GPT值也可能 會上升。需定期追蹤。
越早HBeAg陰轉，越少肝硬化
Chu CM & Liaw YF, JVH, 2007
B型肝炎病毒量(HBV DNA) • 好處: -- 疾病活動性的評估 -- 抗病毒治療的評估和追蹤 -- 抗病毒治療的追蹤和反應
• e抗原陽性病人: HBV DNA > 105 copies/ml 則考慮治療
• e抗原陰性病人: HBV DNA > 104 copies/ml 則考慮治療
Outlines • • • •
Natural history Hepatitis B diagnosis Overview the benefit of CHB treatment The idea strategies of CHB treatment
Clinical goals of CHB therapy
Su and Kao. Expert Rev. Gastroenterol. Hepatol. 2015
Long-term NAs treatment results in regression of liver fibrosis and cirrhosis ETV
TDF Ishak Score (N=3 48)
Ishak score (N=57)
50 40
Missing 6
30
5 4 3
20
Proportion of patients (%)
Number of patients, N
60
2 1
10 0
0
Baseline 48 weeks Long-term (6 years)
The proportion of patients in the cohort demonstrating at least a 1-point improvement in the Ishak fibrosis score is 88% (50/57) after long-term (median=6 years) treatment
Baseline
1yr
5yr
176 (51%) of the 348 had regression of fibrosis ((â&#x2030;Ľ1 unit decrease by Ishak scoring system) at week 240
1. Chang, TT, et al. Hepatology 2010;52:886-93; 2. Marcellin P, Gane E, Buti M, et al. Lancet, 2013, 381(9865):468-475.
Long-term ETV treatment reduces LSM score A total of 855 CHB naïve patients , treated with ETV 0.5 mg up to 8 years, HBeAg (+) vs HBeAg(-) = 381 vs 474
LS value Median kPa Value
12.4
70% 60.5%
9.4
14
Proportion of cirrhosis*
80%
60% 7.1
12
7.2
10
48.8%
50% 40%
8
34.9% 25.6%
30%
6 20%
4 2
10%
0
0% B a se lin e
1y
3y
LSM：liver stiffness measurement
5y
Baseline
1y
3y
5y
*Using cutoff value of 11 kPa for diagnosis of cirrhosis Sang Hoon Ahn, 2016 APASL P-0443
HCC reduction after ETV therapy -Japan experiencePatients with liver cirrhosis
Overall patients
50
40 Log-Rank test: P < 0.001
30
Control (n=316)
20
13.7% 10
7.2% 4.0% 0.7%
0 0
1
10.0% ETV (n=316)
Cumulative incidence of HCC progression (%)
Cumulative incidence of HCC (%)
50
3.7% 1.2% 2.5% 3
40
ETV vs control (P < 0.001 ) ETV vs LAM (P < 0.043 )
28.5%
30
LAM 20.9% 11.4% 12.2%
10
4.8% 4.3%
7.0%
ETV
1
3
5
Treatment period (year)
Treatment period ( year)
Number of patient at risk
Number of patient at risk ETV
7.0%
2.6% 0
7
22.2% 19.7%
20
0
5
Control 38.9%
316
316
264
185
101
44
2
2
Control 316
316
277
246
223
200
187
170
ETV
79
79
72
53
35
17
LAM
49
49
41
35
32
29
Control
85
85
76
65
54
47
Hosaka T, et al. Hepatology, 2013
Cirrhosis Taiwanese EntecAvir Multicenter Study C-TEAM study Entecavir group Compensated CHB-LC pts Treated with ETV 0.5mg, 2006-2014
n=1315
Median follow-up: 4.0 years HCC cases: 119 24 academic centers in Taiwan
Historical untreated group CHB-LC pts at NTUH Followed-up, 1993-2008 n=503
Median follow-up: 6.0 years HCC cases: 121 Su and Kao et al., Liver Int. 2016
Cumulative incidence of HCC (%)
HCC reduction after ETV therapy -Taiwan experience50
Untreated Entecavir Log-rank test P<0.0001
40
HR: 0.40
30 20 10 0 0
Number at risk Untreated 503 Entecavir 1315
1
2
503 1315
464 1274
3 4 5 Years of follow-up 392 1030
320 640
276 246
6
7
8
240 118
193 37
161 4
Su and Kao et al., Liver Int. 2016
NA therapy reduces the risk of HCC recurrence -Taiwan experienceHCC recurrence HCC Cumulative incidence (%)
60
54.6%*
P<0.001
50
45.6%* Untreated cohort
40 30
NA treatment cohort (56% ETV monotherapy)
20 10 0 0
1
2
3
4
5
6
411 19
205 9
Follow-up (years) Number of patients at risk 2697 4051 No treatment 518 246 NA treatment
1685 124
1080 68
667 40
Wu, CY, et al. JAMA, 2012
Outlines • • • •
Natural history Hepatitis B diagnosis Overview the benefit of CHB treatment The idea strategies of CHB treatment
The strategies of CHB treatment
•When to Start Treatment •Which drug or strategy •When to Stop Treatment
上車容易下車難
When to Start When to Stop
乾脆不要下車
Lifelong Therapy
全民健康保險加強慢性B型及C型肝炎治療計畫 106年4月1日
• Liver cirrhosis＊: – HBV DNA >2,000 IU
• CHB with decompensation: – bil-T >= 2 mg/dL or PT prolong 3 sec
• CHB, HBeAg (+): – ALT >200 IU/mL – ALT >80 IU/mL, HBV DNA > 20,000 IU
• CHB, HBeAg (-): – ALT > 80 IU/mL, 2x in half year, HBV DNA > 2,000 IU ＊Echo: cirrhosis with splenomegaly or varices; or biopsy
The strategies of CHB treatment
•When to Start Treatment •Which drug or strategy •When to Stop Treatment
Currently approved therapy for hepatitis B
IFN vs NAs Treatment
IFN
Nucleos(t)ide analogs
Route
Parenteral
Oral
Duration of treatment
Finite duration ~12m
Long duration, yrs to life long
Antiviral activity
Modest, additional immunomodulatory effects
Potent ETV/TDF/LDT>LAM>LDT
HBsAg loss
1-3% after 1yr
Rare, 0-1% after 1 yr
Resistance mutations
None
0-25% after 1 yr LAM>LDT>ADV>ETV/TDF
Side effects
Frequent
Rare Anna Lok, 2016 APASL STC HBV oral
Initial selection of antiviral therapy ETV, TDF or PeglFN is preferably recommended for treatment-naĂŻve CHB patients.
APASL
AASLD
EASL
WHO
1.Papatheodoridis G, Buti M, Cornberg M, et al. EASL clinical practice guidelines: management of chronic hepatitis B virus infection[J]. Journal of Hepatology, 2012, 57(1): 167-185. 2.Sarin S K, Kumar M, Lau G K, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update[J]. Hepatology international, 2015: 1-98. 3.Norah A. Terrault, Natalie H. Bzowej, Kyong-Mi Chang, et al. AASLD Guidelines for Treatment of Chronic Hepatitis B. Hepatology, 2015. 4.Liver diseases branch of Chinese Medical Association, Infectious diseases branch of Chinese Medical Association. The prevention and treatment guideline of chronic hepatitis B (version 2015) Chinese Journal of Hepatology (Electronic Version) 2015; 7(3): 1-18. 5. http://www.who.int/
HBeAg loss and HCC development in ETV and TDF groups HBeAg loss
P=0.933
HCC development
P=0.978
Wu IT & Chen CH, Clin Microbiol Infect. 2017.
TDF vs. ETV in treatment of CHB with severe acute exacerbation Overall mortality
Hung CH, Antimicrob Agents Chemother, 2015.
TDF and ETV in CHB: meta-analysis Forest plot for HBV DNA suppression rates 48 weeks post therapy
No significant differences Favours entecavir | Favours tenofovir
Forest plot for HBeAg seroconversion rates 48 weeks post therapy
Favours entecavir | Favours tenofovir
Ke W. PLoS One. 2014.
TDF decreased renal function in CHB
Tsai MC & Hu TH, Clin Microbiol Infect, 2016
Monitoring renal function during long-term NAs Guideline
Recommendations
• The renal function and bone mineral density shall be monitored during TDF/ADV treatment. 20151 • The renal function shall be monitored during the treatment for patients treated with TDF, which 20153
20124
includes serum creatinine, serum phosphorus, urine protein and urine glucose. • Nucleotide analog treatment: serum creatinine (creatinine clearance rate) and serum phosphorus for all patients shall be monitored. • Nucleoside analog treatment: Only serum creatinine (creatinine clearance rate) for patients who have a high risk of renal impairment shall be monitored. • The renal function shall be tested once a month within 3 months before administration, every 3 months in the first year, and afterward, every 6 months.
1. Sarin S K, Kumar M, Lau G K, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update[J]. Hepatology international, 2015: 1-98. 2. Liver diseases branch of Chinese Medical Association, Infectious diseases branch of Chinese Medical Association. The prevention and treatment guideline of chronic hepatitis B (version 2015) Chinese Journal of Hepatology (Electronic Version) 2015; 7(3): 1-18. 3. Norah A. Terrault, Natalie H. Bzowej, Kyong-Mi Chang, et al. AASLD Guidelines for Treatment of Chronic Hepatitis B. Hepatology, 2015. 4. Papatheodoridis G, Buti M, Cornberg M, et al. EASL clinical practice guidelines: management of chronic hepatitis B virus infection[J]. Journal of Hepatology, 2012, 57(1): 167-185.
Mechanism of Action
Bi
TAF – A Novel Prodrug of Tenofovir GI TRACT
RENAL TUBULAR CELL
TFV OAT 1&3
TFV (tenofovir)
PLASMA
HEPATOCYTE
DIANION
TFV TDF (tenofovir disoproxil fumarate) ESTER
short plasma half-life†
300 mg
TFV
TAF (tenofovir alafenamide)
25 mg
TFV-DP
HBV
longer plasma half-life † - greater plasma stability
~90% LOWER PLASMA TFV
AMIDATE
OAT 1&3
RENAL TUBULAR CELL
TFV
†T 1/2 based on in vitro plasma data - TDF = 0.4 minutes, TAF = 90 minutes. Lee W et. Antimicr Agents Chemo 2005;49(5):1898-1906. Birkus G et al. Antimicr Agents Chemo 2007;51(2):543-550. Babusis D, et al. Mol Pharm 2013;10(2):459-66. Ruane P, et al. J Acquir Immune Defic Syndr 2013; 63:449-5. Sax P, et al. JAIDS 2014. 2014 Sep 1;67(1):52-8. Sax P, et al. Lancet 2015. Jun 27;385(9987):2606-15. GS06; Chan, EASL 2016, Oral GS12
Agarwal K et al. J Hepatology 2015; 62: 533-540; Buti EASL 2016, Oral
40 - GILEAD CONFIDENTIAL AND PROPRIETARY DRAFT. FOR INTERNAL USE ONLY. NOT FOR DISTRIBUTION OR PROMOTION.
40
EASL HBV Clinical Practice Guideline Indications for selecting TAF or ETV over TDF Age >60 years Bone disease • Chronic steroid use or use of other medications that worsen bone density • History of fragility fracture • Osteoporosis Renal alteration* • eGFR <60 mL/min/1.73 m2 • Albuminuria >30mg or moderate dipstick proteinuria • Low phosphate (<2.5mg/dL) • Hemodialysis EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol (2017)
全民健康保險加強慢性B型及C型肝炎治療計畫 106年4月1日
• • • •
Liver cirrhosis: CHB with decompensation: CHB, HBeAg (+): CHB, HBeAg (-): – Lamivudine (100mg) – Entecavir (0.5mg) (1.0mg for decompensation) – Telbivudine (600mg) – Tenofovir (300mg) – Tenofovir Alafenamide (TAF) (2018/7 ?)
The strategies of CHB treatment
•When to Start Treatment •Which drug or strategy •When to Stop Treatment
Guideline recommendations on duration of NAs treatment for CHB patient without cirrhosis Guideline
HBeAg+ After HBeAg seroconversion (Consolidation therapy for 1-3 years)*
20151
HBeAgWhen HBsAg seroconversion is achieved or the total duration of treatment is greater than 3 years, and HBV DNA is undetectable in consecutively 3 semiannual detections.
HBeAg seroconversion (Consolidation therapy for greater than 1 year) * 20152
Drug discontinuation is not recommended
an alternative approach is to treat until HBsAg loss HBeAg seroconversion (Consolidation therapy for greater than 1 year)*
HBsAg seroconversion is achieved
20123
1. Sarin S K, Kumar M, Lau G K, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update[J]. Hepatology international, 2015: 1-98. 2. Norah A. Terrault, Natalie H. Bzowej, Kyong-Mi Chang, et al. AASLD Guidelines for Treatment of Chronic Hepatitis B. Hepatology, 2015. 3. Papatheodoridis G, Buti M, Cornberg M, et al. EASL clinical practice guidelines: management of chronic hepatitis B virus infection[J]. Journal of Hepatology, 2012, 57(1): 167-185.
全民健康保險加強慢性B型及C型肝炎治療計畫 106年4月1日
• Liver cirrhosis: – Life-long treatment
• CHB with decompensation: – By HBeAg status
• CHB, HBeAg (+): – Consolidation for 1 year after HBeAg loss (checked every 3 months) – Keep treatment if HBeAg remains positive (~50%, life-long)
• CHB, HBeAg (-): – Stop till HBV DNA is undetectable in consecutively 3 semiannual detections – Duration: 2~3 years
The durability after discontinuation of 3-yr ETV therapy • HBeAg-positive: – 3rd year: • Virologic relapse: 48.5% • Clinical relapse: 44.5%
• HBeAg-negative: – 3rd year: • Virologic relapse: 64.3% • Clinical relapse: 51.6% Chen CH, Clinical Gastroenterology and Hepatology, 2015
Incidence and predictors of HBV relapse after cessation of NAs in HBeAg-ive with HBsAg <200 IU/mL Predictors: baseline HBV DNA >2x105 IU; EOT HBsAg >50 IU/mL HBV DNA >2x105 HBsAg > 50 IU/mL
HBV DNA <2x105 HBsAg < 50 IU/mL
Yao CC & Chen CH, Sci. Rep. 2017.
全民健康保險加強慢性B型及C型肝炎治療計畫 106年4月1日
• 若若停藥後復復發,得以合併療療法或 tenofovir 單一藥物再治療療,或以干擾素再治療療 1 年年。 • 前述以口服抗病毒藥物治療療之給付療療程依 HBeAg(+)或 HBeAg(-)而定:HBeAg(+)病患 治療療至 e 抗原轉陰並再給付最 多 12 個月;HBeAg(-)病患 治療療至少二年年,治療療期間需檢驗血清 HBV DNA, 並於檢驗血清 HBV DNA 連連續三次,每次間隔 6 個 月,均檢驗不不出 HBV DNA 時停藥,每次療療程至多 給付36 個 月。再次復發時得再接受治療,不限治療 次數。(106/4/1)
Incidence of Resistance in NUC-naĂŻve Patients
EASL HBV Clinical Practice Guideline Management of patients who develop NA resistance Resistance pattern
Recommended rescue strategies
LAM resistance
Switch to TDF or TAF
TBV resistance
Switch to TDF or TAF
ETV resistance
Switch to TDF or TAF
ADV resistance
If LAM-naĂŻve: switch to ETV or TDF or TAF If LAM-resistance: switch to TDF or TAF If HBV DNA plateaus: add ETV*** or switch to ETV
TDF or TAF resistance**
If LAM-naĂŻve: switch to ETV If LAM-resistance: add ETV*
Multidrug resistance
Switch to ETV plus TDF or TAF combination
*The long-term safety of these combinations is unknown **Not seen clinicall so far, do genotyping and phenotyping in an expert laboratory to determine the cross-resistance profile ***Especially in patients with ADV resistant mutations (rA181T/V and/or rN236T) and high viral load, the response to TDF or TAF can be protracted
EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol (2017)
全民健康保險加強慢性B型及C型肝炎治療計畫 106年4月1日
• 經使用 lamivudine 100mg、 entecavir 0.5mg 或 1.0mg、 telbivudine 治療療或預防 B 型 肝炎發作出現抗藥株(指 於治療療中一旦 HBV DNA 從治療療期間之最低值上升超過 一個對數數值 (1 log IU/mL),以下條件擇 一給付: – (1)得以原治療療藥物再加上adefovir 進行行合併救援 治療療(rescue therapy); – (2)改用 entecavir 1.0mg(僅 限於 lamivudine 產生 抗藥 性之病人)單一藥物治療療 – (3)以 Interferon alpha-2a (如 Roferon-A)或 interferon alpha-2b(如 Intron A)或 peginterferon alfa-2a (如 Pegasys)治療療 1 年年。 – (4)改用 tenofovir 300mg 單一 藥物治療療。 – (5)原已接受其他口服抗病毒藥物救援治療療,治療療期 間出現抗藥株,或治療療未達預期之病毒學反應,得改以 tenofovir 單一藥物救援治療療。
全民健康保險慢性B型肝炎治療試辦計畫 口服藥給付規定及流程 106-04-01修訂 • • • •
HBeAg 陽性病患
HBeAg 隂性病患
肝代償不全病患
HBsAg (+) > 6 個月 HBeAg (+) > 3個月 ALT ≥ 5倍 ULN 或 2倍 ≦ALT <5倍 ULN 且HBV DNA ≥ 20,000 IU/mL 或肝組織切片 HBcAg (+ ) （血友病患及類血友病 患得不做切片）
• HBsAg (+) > 6 個月 • HBeAg (-) > 3個月 • ALT ≥ 2倍 ULN (半年有兩次以上,每次間 隔3個月)且HBV DNA ≥ 2,000 IU/mL，或 肝組織切片HBcAg (+ )（血友病患及類血 友病患得不做切片）
HBsAg (+)且已發生 肝代償不全 *已發生肝代償不全 1. PT延長≥3秒 或 2. T-Bil. ≥ 2 mg/dL
Entecavir (0.5 mg)，Tenofovir，Telbivudine，Lamivudine擇一 給付 HBeAg(-)病患治療至少2年，每次療程至多給付36個月 HBeAg (+)患者治療至e抗原轉陰並再多給付最多12個月，無陰轉則繼續服用 (肝代償不全者Entecavir使用1mg)
治療完成後，觀察3 - 6個月，復發且符合治療條件
ETV (0.5 mg)，TDF，LAM，LdT 再次給付，不限次數
全民健康保險慢性B型肝炎治療試辦計畫 口服藥給付規定及流程 長期給予 • HBsAg (+) • 肝硬化病患* • 接受非肝臟器官移 植後或接受癌症化 學治療法中B型肝炎 發作者 • 接受肝臟器官移植 後，持續接受免疫抑 制劑者
預防性使用
預防 B型肝炎發作出現抗藥株 經使用LAM, ETV 0.5 or 1 mg, LdT (指於治療中一旦HBV DNA從治療期間之最 低值上升超過一個對數值 1 log IU/mL)
• HBsAg (+) • 接受肝臟器官移植或 接受癌症化學療法的 病患預防性使用 • 異體造血幹細胞移植， 捐贈者可接受預防性投 藥至HBV DNA偵測不到， 受贈者移植前一週開始 給付，至免疫抑制劑停 用後6個月
106-04-01修訂
• • • •
轉換至TDF單一藥物 ETV 1.0 mg (限LAM-Res) 或原藥物加上ADV 療程依據HBeAg (+)或HBeAg(-)而定
• 若停藥後復發，得以口服抗病毒藥物合併療法 或救援療法再治療 • TDF、ETV(0.5mg)、 • TDF、ETV(0.5mg) • 或以干擾素再治療1年 LdT、LAM 、LdT、LAM等則一 • 原已接受其他抗病毒藥物救援治療者，若出現 • 化療前一週開始給付， 長期給予 抗藥株，或未達預期之病毒學反應，得改以 至結束後6個月 TDF 救援治療。 • 多重抗藥株病患(對LAM、LdT 、ETV或ADV產 生2種藥物以上之之抗藥性) 可給予TDF單一藥 * 肝硬化條件為需同時符合下列二項條件： 物，或ETV 1.0mg及TDF治療。 (一) HBsAg (+)且血清HBV DNA ≥ 2,000 IU/mL者。 (二) 診斷標準：1. 肝組織切片 (Metavir F4或Ishak F5以上，血友病患及類血友病患經照會消化系專科醫師同意後，得不作切 片) 或 2. 超音波診斷為肝硬化併食道或胃靜脈曲張，或肝硬化併脾臟腫大。若患者因其他臨床適應證接受電腦斷層檢 查而被診斷為肝硬化時，可作為診斷依據。
感謝聆聽