20141015-Resistance & seroreversion of HBV
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CASE DISCUSSION :RESISTANCE & SERO-REVERSION OF HEPATITIS B VIRUS
報告:陳建豪 藥師指導:吳珮君 藥師
DEPARTMENT OF PHARMACY, NTUH
2014.10.15
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如何選定個案 ?HOW THIS CASE TO BE DETERMINED?
CASE
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Family history: An elder brother died from hepatocellular carcinoma
(HCC).
Medical history:
Recent lab data: 2014
CASE
176 cm
51 y/oMale
76 KgHBV carrier
Renal stone
20041/14
Zeffix® 100 mg QD
20146/9
20059/6 11/29
20095/29
20134/8
Zeffix® 100 mg QD
Hepsera® 10 mg QD
Viread®300 mg
QDLAM: lamivudine (Zeffix®) ADV: adefovir (Hepsera®) TDF: tenofovir (Viread®)
2004/1/14AST/ALT=837/1300 IU/L↑HBV bDNA >4800 mEq/mL
2005/6/21AST/ALT=46/75 IU/LHBV DNA >38 KIU/mLGenotype: C2005/8/17L180M+YVDD
2006/10/4AST/ALT=59/111 IU/L75% L180M; 181(-); 236(-)40% YMDD, 20% YVDD, 40% YIDD
2007/5/1590% L180M; 181(-); 236(-)25% YMD, 65% YVDD, 10% YIDD
2009/5/29Add LAM to ADV to reduce the possibility of ADV-resistance
2010/5/25HBeAg=0.97 (-)Anti-HBe=0.33 (-)HBV DNA < 0.108 KIU/mL2012/5/28HBeAg=0.83 (-)Anti-HBe=0.33 (-)HBV DNA < 0.108 KIU/mL
2013/7/29HBeAg=94.108 (+) ↑Anti-HBe=0.08 (-)AST/ALT=19/17 IU/L
2013/9/27HBeAg=1361.544 (+) ↑HBV DNA>17,0000 KIU/mL ↑
Date 3/27 4/30 6/9 6/15 6/27 7/21 9/29
Bil (mg/dL) 0.47 0.95 - 0.52 0.72 0.56 0.52
AST (IU/L) 54 122 - 289 200 82 60
ALT (IU/L) 99 212 - 581 455 181 98
Scr (mg/dL) 1.46 1.27 1.16 - - 1.39 -
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EPIDERMIOLOGY: WORLDWIDE
2 billion people have been infected
HBV350 Million Carriers
Ref: Dienstag JL. N Engl J Med 2008;359:1486-1500.
EPIDERMIOLOGY: TAIWAN
1 Million DEATH annually from cirrhosis, liver failure or HCC
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EPIDERMIOLOGY: TAIWAN
HBV Prevalence: 15-20%1986 HBV vaccination to ALL newborns~2 40,0000 Carrier (2009)Car-
rier13.2
%
Non-car-rier86.7
%2009 HBV Prevalence
144,5000♂♀975000
30-40%Chronic
hepatitis B
2%Cirrhosis
every year
3-10%HCC
every year
Ref: 台灣地區 B型肝炎病毒之血清流行病學研究 , CDC, 2011
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TREATMENT GOALS Sustained viral suppression
Achieve initial response HBsAg seroconversion (+)(-)
HBeAg seroconversion (+)(-)
HBV DNA suppression
ALT normalization
Ensure maintained/sustained response Prevent hepatic decompensation
Reduce/prevent progression to cirrhosis, HCC
Prolong survivalRef: JAMA. 2006; 295(1):65-73.; Gastroenterology. 2006; 130(3):678-86.; Clin Gastroenterol Hepatol. 2007; 5(8):921-31.
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FDA-APPROVED ANTI-HBV AGENTS
1998 Dec.LamivudineZeffix®
2002 Sep.AdefovirHepsera®
2005 Mar.Entecavir Baraclude®
2006 Oct. TelbivudineSebivo®
2008 AugTenofovirViread®
2005 MayPeginterferon α-2aPegasys®
1986 Jun.Interferon α-2bRoferon-A®
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EFFICACYHBV DNA UNDETECTABLE
Year 12345
36-40%39%
20%
NA
NA
Lamivudine
Telbivudine
Tenofovir
Adefovir
Entecavir
Year 12345
13-21%
NA
36%
38%
39%
Year 12345
76%
NA
72%
NA
NA
Year 12345
67-71%
80-83%
83-89%
91%
94%
Year 12345
60%
56%
77%
NA
NA
Adapted from Hepatitis B consensus guidelines from GESA (2009); APASL (2012); EASL (2012)
Lamivudine
Adefovir
EntecavirTelbivudine
Tenofovir
Zeffix®
Sebivo®
Baraclude® 0.5 mg
Viread®
Hepsera®
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EFFICACYHBeAg SEROCONVERSION
Year 12345
15-22%
25-29%
35-40%
46-47%
44%
Lamivudine
Telbivudine
Tenofovir
Adefovir
Entecavir
Year 12345
12-18%
29%
37%
35%
30%
Year 12345
21%
26%
26%
NA
NA
Year 12345
21-22%
31%
44%
NA
NA
Year 12345
23%
30%
37%
NA
NA
Adapted from Hepatitis B consensus guidelines from GESA (2009); APASL (2012); EASL (2012)
Zeffix®
Sebivo®
Baraclude® 0.5 mg
Viread®
Hepsera®
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GENOTYPIC RESISTANCE
Year 12345
12-24%
40-50%
53-71%
67-70%
71%
Lamivudine
Telbivudine
Tenofovir
Adefovir
Entecavir
Year 12345
0%
3%
11%
18%
29%
Year 12345
0%
0%
0%
0%
0%
Year 12345
0-0.2%
0.5%
1.2%
1.2%
1.2%
Year 12345
3-4%
8-21%
NA
NA
NA
Adapted from hepatitis B consensus guidelines from GESA (2009); APASL (2012); EASL (2012)
Zeffix®
Sebivo®
Baraclude® 0.5 mg
Viread®
Hepsera®
0.8-3.3 % in Japan & Hong Kong
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HOW RESISTANCE DEVELOPED
Ref: Hepatitis Web Study.Accessed at 2014/10/04. (http://depts.washington.edu/hepstudy/hepB/mgmt/treatment/discussion.html)
YMDD
L180M
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GENETIC BARRIER
Ref: Lancet Infect Dis 2012;12: 341-54
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SIGNIFICANCE OF MUTATIONHBV Lamivudine Telbivudine Entecavir Adefovir Tenofovir
Wild type 1 1 1 1 1
M204I >100 4 1 <1-8 <1
L180M + M204V >100 NA 5-6 <1-4 3-6
A181T/V 1-2 5-6 1-4 1-3 1
N236T 1 3 <1 3 5
I169T+V173L+M250V
>1000 >1000 >700 1 <1
T184G+S202I* >1000 35 >700 2 6
A194T NA NA NA NA 2
* (+L180M+M204I/V); NA: not available; Number expressed in ~fold resistance: 2–9 foldno or low level of resistance; 10–99 foldmedium level of resistance; 100 foldhigh level of resistance.
Ref: Hepatology. 2007;46: 254-65.
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CROSS RESISTANCE
Ref: Heptol Int 2012; 6;531-561Hepatitis Web Study.Accessed at 2014/10/04.
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BACK TO THE CASE
2006/10/3 (Adefovir M13, HBV DNA 7.04 KIU/mL)75% L180M; 181(-); 236(-)
2007/5/15 (Adefovir M21, HBV DNA 0.682 KIU/mL)90% L180M; 181(-); 236(-)
Sub-optimal virological response
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BACK TO THE CASE
Transition to another drug?
Entecavir 1 mgIn LAM-resistant
Year 12345
6%15%
36%
46%
51%
Adefovir onlyIn LAM-resistant
Year 12345
5%
20%
16%
NA
NA
Adefovir + lamivudineIn LAM-resistant
Year 12345
0%
0%
0%
0%
NA
Ref: J Gastroenterol and Hep. 2010; 25: 1374-1380 Chronic Hepatitis B Recommendations. GESA, 2nd Edition 2010.
Entecavir
Adefovir+lamivudine
Adefovir
Entecavir Adefovir+lamivudineAdefovir
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WHEN TO STOP ANTI-HBV MEDS
HBeAg (+) At least 12 months consolidation HBeAg seroconversion
with undetectable HBV DNA
HBeAg ( -- )Could be considered after emergency of undetectable
HBV DNA for 2 years
Cirrhosis Indefinite regardless status of HBeAg*
Ref: Heptol Int 2012; 6;531-561; * Referenced from NEJM 2008
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健保給付規定
→Interferon α-2b or
Peg-interferon α-2a1 year
+ Adefovir3 year
Resistance
[HBV DNA↑10 X]
→Entecavir 1 mg
3 year
If HBeAg seroconversion, oral
agents 1 year
HBsAg (+) > 6 month
HBeAg (+) > 3 month
ALT > 5X 5X > ALT > 2X
HBV DNA > 20000
Lamivudine3 year
Entecavir 0.5 mg3 year
Telbivudine3 year
Tenofovir3 year
Interferon α-2b orPeg-interferon α-2a
6 month
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Factors affecting different sero-reverion ratePatient characteristics
Observing period
Sero-reversion markers Virological
Biological
WHEN TO STOP ANTI-HBV MEDS
Ref: J Clin Gastroenterol 2012; 46(10);865-870
Continued “Indefinite” therapy (49)
Cosolidation therapy (39)
Discontinued therapy (39)
HBeAg (-)anti-Hbe (+)
(88)
Recurrent viremia (35)
90%
Recurrent viremia (0)
Re-initiate antiviral agents
(25)Monitoring (10)
ALT flare (15) 38%
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MONITORING PARAMETERS
Drug adherence
Efficacy: well in naïve, lamivudine- and/or adefovir resistant patientsHBsAg, anti-HBs
HBeAg, anti-HBe
HBV DNA
Side effectsRenal function: case reports of renal failure
Bone density: increased loss of phosphate
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REFERENCES1. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012
Update. Hepatol Int. 2012; 6: 531-561.
2. EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012; 57:167-185.
3. Astralian And New Zealand Chronic Hepatitis B (CHB) Recommendations: Summary & Algorithm. GESA, 2nd Edition 2010.
4. Hepatitis B virus infection. Dienstag JL. N Engl J Med 2008;359:1486-1500.
5. Selecton of chronic hepatitis B therapy with high barrier to resistance. Lancet Infect Dis 2012; 12: 341-354.
6. Hepatits Web Study-University of Washington. http://depts.washington.edu/hepstudy/ (Funded by the Centers for Disease Control and Prevention.) Accessed at 2014/10/04.
7. 台灣地區 B 型肝炎病毒之血清流行病學研究 . 台灣疾病管制局 , 2011.
8. Hepatitis B virus serology: Use and interpretation. SM Shah, SP Singh. Hep B Ann 2007;4(1):39-54.
9. NICE clinical guideline: Hepatitis B (chronic). 2013.
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REFERENCES10. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA
level. JAMA. 2006; 295(1):65-73.
11. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006; 130(3):678-86.
12. Risk and predictors of mortality associated with chronic hepatitis B Infection. Clin Gastroenterol Hepatol. 2007; 5(8):921-31.
13. Antiviral drug-resistant HBV: Standardization of nomenclature and assays and recommendations for Management. Hepatology. 2007; 46(1): 254-265.
14. Rescue therapy for lamivudine-resistant chronic hepatitis B: Comparison between entecavir 1.0 mg monotherapy, adefovir monotherapy and adefovir add-on lamivudine combination therapy. J Gastroenterol and Hepatol. 2010; 25: 1374-1380.
15. High frequency of recurrent viremia after hepatitis B e antigen seroconversion and consolidation therapy. J Clin Gastroenterol. 2012; 46(10): 865-870.
16. Nucleos(t)ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B. Gastroenterology. 2010; 139: 491-498.
17. Tenofovir for the treatment of hepatitis B virus. Pharmacotherapy. 2009; 29(10): 1212-1227.
18. Efficacy of tenofovir disoproxil fumarate in the treatment of adults with chronic HBV infectionwho do not have HIV infection. In UpToDate. Accessed at 2014/06/26.
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