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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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