Therapy of chronic hepatitis

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Sarin Selection of patients and monitoring

• Therapy of chronic hepatitis
• Selection of Patients
• e Ag ve, e Ag ve
• Results of therapy
• Monitoring of therapy
• Follow-up

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Sarin Selection of patients and monitoring

• Selection of patients whom to treat
• ALT
• Raised Normal
• ? ? ? ?
• eAg eAb eAg eAb
• ? ? ?
• HBV DNA (quant) watch 6 mo HBV DNA
• ? ? ? ? ? ?
• ve -ve ?ALT nALT ve -ve
• ? ? ?
• Treat as CHB Protocol
• ?
• Lam pulse
• Ind J Gastroenterol 1999, J Viral Hep (In Press)

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Sarin Selection of patients and monitoring

• Selection of Patients
• AVH vs. Reactivation NA rare
• Incidentally Detected HBsAg ve Subject
• (IDAHS) ? ALT Positive
• Chronic Hepatitis B ? ALT Yes
• Cirrhosis ALT ? Yes
• Decompensated cirrhosis ??
• NORMAL ALT ??

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Sarin Selection of patients and monitoring
HBeAg Anti-Hbe ?HBV DNA pg/ml ?ALT u/l
?Lamivudine
500 300 100
1800 900 300
0 20 40 60 Weeks of followup Normal ALT
prednisolone priming
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Sarin Selection of patients and monitoring

• Lam Pulse Therapy
• Normal ALT
• Can convert Non-Treat worthy into Treat
  worthy patients
• Seroconversion in 35 with 24 mo. therapy
  sustained for 4-8 months
• Immune rebound
• J Viral Hep (In Press)

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Sarin Selection of patients and monitoring
ALT levels
Lamivudine x4 weeks
Lamivudine stoppedx2 weeks
Lamivudine restarted
HBV DNA levels
Immune Rebound ? Th-1 cell response enhancement
HBV DNA
Immune Competence induced
ALT
HBV DNA
ALT
Seroconversion
4 weeks
HBeAgve
Lamivudine Pulse therapy in HBeAgve normal ALT
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Anti-HBeve CHB flares (n164)Bonino F et al,
Hepatology, 2003
Sarin Selection of patients and monitoring
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Wong et al, Ann Int Med 1993
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Sarin Selection of patients and monitoring
69
70
66
60
HBeAg seroconversion
53
50
50
YMDD mutation
47
40
38
40
30
27
20
16
14
10
0
52wk Lai
104wk Liaw
156wk Leung
208wk Chang
260wk Guan
Asian Lamivudine Trial
12
Sarin Selection of patients and monitoring
100

91
HBeAg response
Asia
90
Asia
YMDD mutations
80
USA
69
HIV
67
70
60
60
56
50
49
47
50
40
38
40
32
27
30
20
16
14
10
0
1
2
3
4
5
Years on lamivudine therapy
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Sarin Selection of patients and monitoring
Long term Lam in HBeAgve
G.B. Pant Data (n27)
At yr 1
At yr 3
At yr 2
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Sarin Selection of patients and monitoring

• Interferon vs. Lamivudine in HBeAg Chronic
  Hepatitis B (AASLD 2001)
• Interferon Lamivudine
• 12-24 52
• weeks controls weeks controls
• Loss if Serum HBV DNA 37 17
• Loss of HBeAg 33 12 17 6-11
• HBeAg seroconversion Diff. Of 18
  16-18 4-6
• Loss of HBsAg 78 1.8 lt1 00
• Normalization in ALT Diff. Of 23
  41-72 7-24
• Histologic improvement 49-56 23-25

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Sarin Selection of patients and monitoring
Histologic activity index HAI worsened after
initial improvement in patients with YMDD mutants
9 with YMDDm
4 without YMDDm
Baseline 1 3 yr
Baseline 1 3 yr
Asian Study
Leung et al Hepatology 2001
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AdefovirStudy 437 Randomized placebo-controlled
double-blind study of adefovir in patients with
HBeAg positive chronic hepatitis
BMarcellin et al. NEJM 2003
Sarin Selection of patients and monitoring
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Sarin Selection of patients and monitoring
Virological and serological results
p 0,049
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Lok AS, Gastroenterology, 2001
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Response to long term Lamivudine Therapy in
anti-HBe positive patients (G.B. Pant Data, n22)
Sarin Selection of patients and monitoring
At yr 1
At yr 3
At yr 2
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Sarin Selection of patients and monitoring

• Therapy of HBeAg negative HBV Infection
• Lamivudine End of treatment response rate 60-70
  (response after 12 months of treatment )
• Sustained response rate 10-13 (high relapse rate
  at follow up 6 months after end of treatment)
• Long term therapy response rate 40 (response
  after continued treatment for 24 months)
• Problems with lamivudine resistance stick to one
  year

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Sarin Selection of patients and monitoring

• YMDD mutants
• YM539V/IDD mutants
• Developed only in Group II (gt9 mo. therapy)
  patients
• Frequency 5/17 (29) - YMDD - 4, YIDD - 1
• At 12 mo. - 6 (1 of 17)
• At 18 mo. - 29 (5 of 17)
• HBeAgve 3/17 (43)
• HBeAb ve 2/10 (20)
• In 3 of 5 patients YM539V/IDD associated with
  ?ALT
• Kazim et al., JMV 2002

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Sarin Selection of patients and monitoring

• Lamivudine
• e CHB 16 at 1 yr., 50 5 year
• e CHB - 10-13 at 1 yr., 40 at 2 yr.
• Better to stop at 1 yr.
• IFN remains the T/O choice for e-CHB
• Problems with lamivudine
• Drug Resistance
• Durability of response 20-80

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Resistance to Adefovir
Sarin Selection of patients and monitoring
(Angush P et al, Gastroenterology 2003)
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Comparison of three approved treatment of CHB
Sarin Selection of patients and monitoring
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Comparative dynamics among three viruses
Sarin Selection of patients and monitoring

• HBV HBV HIV HCV
• Adefovir Lamivudine Ritonavir IFNa
• Plasma VirusHalf-life 26.4 hr 24 hr 5.8 hr 2.7 -
  7.2 hr
• Daily 2.1 x 1012 1011 101 (1.1 - 12.7) x
  1011production (plasma)
• Infected CellsHalf-life 11 - 30 d 10- 100 d 1.6
  d 2.4 - 4.9 d

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Sarin Selection of patients and monitoring

• New Approach Combination Therapies
• PEG IFN Lam
• PEG IFN GMCSF
• PEG IFN Thymosin
• Lam Adefovir
• LdT Lam
• GB Pant protocols
• HBeAg ve (wild type)
• Naieve Normal ALT Protocol
• ALT - 2-5 times IFN 3-5 MIU/AD
• ALT gt 10 times Lam.100 mg/d
• Non-responder PEG IFN Lam
• Anti HBe ve Raised ALT IFN, Lam 100 mg/d
• Decompensated cirrhosis LAM/adefovir
• YMDD Mutant Adefovir