Types of Viral Hepatitis

1
Types of Viral Hepatitis

• Hepatitis A - enteric
• Hepatitis B - parenteral
• Hepatitis C - parenteral
• Delta hepatitis - parenteral
• Hepatitis E - enteric

2
Prevalence of Hepatitis B Virus Infection

• About 300-350 million chronic carriers worldwide.
• About 75 of all cases occur in Asia.
• An estimated 40 million carriers are in India

3
The Hepatitis B Virus
Lipid Bilayer
HBsAg Protein
Viral DNA
DNA POL
Core HBcAg
4
Complications of Chronic HBV Infection

• Cirrhosis
• Decompensated liver disease
• Hepatocellular carcinoma
• Death

5
Treatment approaches forchronic HBV infection

• Antiviral chemotherapy, especially nucleoside
  analogues.
• Manipulating the immune response
  (immunomodulatory agents, vaccines).
• Gene therapy.

6
Limitations of interferon - ?

• Rate of HBeAg disappearance in unselected
  patients ranges from 20 to 30.
• Individuals who are immunosuppressed and have
  high levels of viral replication or low levels of
  serum aminotransferases are unlikely to respond.
• Interferon-? is also not effective in vertically
  acquired infection, and is a particular problem
  in Asia.
• Administration of interferon- ? is cumbersome,
  costly and limited by side effects.

7
Mode of Action of Lamivudine

• HBV replication requires synthesis of an RNA
  intermediate for reverse transcription.
• The 5 triphosphate derivative of lamivudine
  competitively blocks the reverse transcriptase
  activity of HBV and acts as a chain terminator.
• Importantly, lamivudine does not inhibit
  mitochondrial DNA or marrow progenitor cells, and
  is therefore well-tolerated.

8
THE ASIA HEPATITIS LAMIVUDINE STUDY

• 1-year, double-blind trial of lamivudine in 358
  Chinese patients with chronic hepatitis B
• Patients were randomly assigned to receive 25 mg
  or100 mg of lamivudine, or placebo
• Primary end point -- reduction of at least 2
  points in the Knodell necroinflammatory score
• Secondary efficacy variables included HBeAg and
  HBsAg seroconversion, sustained suppression of
  HBV DNA, and normal ALT values on at least 2
  consecutive occasions
• NEJM 199833961-8

9
The Asia Hepatitis Lamivudine Study
80
Lamivudine, 100 mg
70
60
Lamivudine, 25 mg
50
40
Cumulative Percentage of Patients
with Sustained Response
30
Placebo
20
Cumulative percentage of patients with sustained
alanine aminotransferase responses
10
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Week
No. of patients without response
50
48
47
47
47
47
47
46
46
45
43
43
41
38
Placebo
98
91
87
79
71
56
51
44
40
39
38
36
34
34
25 mg
95
94
91
81
69
58
51
46
41
40
35
12
30
27
100 mg
N Engl J Med 1998 339 61-8.
10
The Asia Hepatitis Lamivudine Study
80
Lamivudine, 100 mg
Lamivudine, 25 mg
Placebo
60
40
Improvement ()
20
0
20
Worsening ()
Necroinflammatory Activity
Fibrosis
40
Improvement or worsening of necroinflammatory
activity and fibrosis in biopsy specimens
obtained before and after treatment with
lamivudine (25 or 100 mg) or placebo.
N Engl J Med 1998 339 61-8.
11
Three year Lamivudine Therapyfor Chronic HBV
Continued increase in Seroconversion

• Even the subset of patients with YMDD variants
  for 2 or more years who remain on treatment,
  continue to have lower HBV DNA and ALT than at
  baseline.

- J Hepatology 1999 30 (Suppl 1) 59
12
Lamivudine reducesprogression to Cirrhosis

• Study Method578 treatment-naive adult patients
  with chronic hepatitis B were enrolled into 3
  controlled trials(2 placebo and 1 interferon-µ )
• Study Period 1 year
• ResultsProgression to cirrhosis

µ
exploratory integrated analysis
- J Hepatology 1999 30 (Suppl 1) 59
13
Lamivudine in Decompensated Liver DiseaseDue to
HBV

• No. of patients 5 Mean
  duration of therapy 59.5 weeks
• Results
• HBV DNA became undetectable in all patients. Lab
  values for all patients are

ALT AST Albumin Pro Time Platelets Bilirubin (U/
L) (U/L) (g/dL) (secs) (/mm3) (mg/dL) Baseline 99
145 3.7 13.4 94 2.36 Aftertreatment 21 36 3.4 13.
4 81 1.38 2 patients with Childs class C
improved to class B. One patient with class A had
complete resolution of troublesome porto-systemic
encephalopathy. -Hepatology 1998 28(4 pt 2) 589A
14
Efficacy in HBV-infected renal transplant
recipients
HBV DNA (log pg/ml) at the beginning (MO), during
(M1),at the end (M6) of lamivudine therapy.
Transplantation 1997 64 1624-7.
15
Efficacy in HBeAg negative / HBV DNApositive
patients (precore mutants), as assessed by loss
of serum HBV DNA and normalisation of ALT
Efficacy of lamivudine versus placebo in precore
mutant HBV infection
Hepatology 1999 29(3) 889-96.
16
Lamivudine Prophylaxis for patients undergoing
Chemotherapy

• Cancer chemotherapy in chronic HBV carries is
  known to promote viral replication.
• When immunosuppressive treatment is stopped, a
  fulminant hepatitis may follow.
• The study by Buhler et al suggests that all
  hepatitis B surface antigen-positive patients
  undergoing chemotherapy would benefit from
  prophylactic lamuvudine therapy.
• - Transplantation 1999 67(4) 630

17
LAMIVUDINE IS EFFECTIVE IN ALL PATIENT GROUPS

• Lamivudine is effective in patients who are
  considered
• poor responders to interferon-?, such as
• Neonatally acquired infection
• Transaminases elevated above 1.3 times normal
• HBeAg negative patients (precore mutant HBV)
• High HBV DNA levels pre-treatment
• Immunosuppressed patients (cancer
  chemotherapy,HIV coinfection, transplant
  recipients)
• Decompensated liver disease
• Ref Clinics in Liver Disease May 993(2)
  365-7
• Drugs July 199958(1)101-41
• Canadian Consensus Guidelines September 1999

18
RECOMMENDATIONS FOR THERAPY WITH LAMIVUDINE

• Patients with ongoing HBV replication, ?ALT/AST,
  histologic evidence of liver injury. Lamivudine
  is now considered first-line therapy, eclipsing
  interferon-?.
• Failure to respond to interferon- ?Unlikely to
  respond to interferon-? -Immunocompromised/perina
  tal infection/AST-ALT normalWill not tolerate
  interferon-? - decompensated liver disease/
  post-transplant
• Clinics in Liver Disease May19993(2)358-9

19
RECOMMENDATIONS FOR THERAPY WITH LAMIVUDINE
(Contd.)

• Monitor HBeAg/Anti-HBe/ALT/HBV DNA monthly
• Discontinue only after repeated assays
  demonstrate HBeAg loss or seroconversion from
  HBeAg to anti-HBe. Closely monitor
  HBeAg/Anti-HBc/ALT/HBV DNA. If reactivation of
  hepatitis occurs, reinstitute therapy promptly.
• YMDD mutants continue therapy
• Ref Clinics in Liver Disease May 19993(2)358-9