NATURAL HISTORY OF HBV

1
Dwivedi Management of chronic HBV infection

• NATURAL HISTORY OF HBV
• Interplay between host immune response viral
  replication
• 4 Phases of HBV INF
• -Perinatal-HBeAg,? HBV DNA, ALT-N
• -Childhood - HBeAg ?HBV DNA, ALT ?
• -Carrier - no HBeAg, no HBV-DNA, ALT-N
• -HBe-Ve CHB-no HBeAG, ? HBV-DNA-ALT ?

2
Dwivedi Management of chronic HBV infection

• Aims of treatment
• Suppress viral replication induce remission of
  liver disease
• Eliminate virus improve survival
• Sustained hbv dna suppression
• ALT normalization
• Stable HBeAg seroconversion persistence of
  anti - HBeAg
• ? necroinflammation on liver bx

3
Dwivedi Management of chronic HBV infection

• Evaluation
• History, physical exam
• Lab invest -LFT
• -Markers of HBV replication
• -Serial testing-AST/ALT HBeAg, HBV-DNA
• -Co-infect with C,D, HIV
• Liver bx -With intermittent or persistent ALT
• Counseling to prevent transmission
• Discuss natural history and progression
• Careful balance treatment options
• Vaccination of sexual / household contacts

4
Dwivedi Management of chronic HBV infection

• Antiviral therapeutic agents
• Immunomodulators interferon side effect
• Nucleoside analogues drug resistance
• Antiviral therapy indicated
• NIH guidelines
• HBV DNA serove detectable by non-amplified
  assays
• ALT gt twice normal
• Factors predicting virological response to IFN in
  HBeAg hepatitis
• HBV DNA lt 200 pg/ml
• ALT gt 100 iu/l
• HAI high score

5
Dwivedi Management of chronic HBV infection

• Responses to treatment
• Biochemical normal ALT
• Virological HBV-Undetectable in non-amplified
  SS HBeAg loss
• Histological HAI by 2 points pre-treatment
• Hbeagve CHB
• IFN treatment
• Response obtained in 25-40 with ?ALT
• Spontaneous loss in 10-15 in controls
• Re-activation in 10-20
• Lok as. Gastroenterology 2001 Wong dk.Ann Intern
  Med 1993
• 11 yr FU101 pts (taiwan) Improvement in
  survival in development of HCC (p.01) in IFN
  group Lin hepatology 1999
• 20 yr FU (Hongkong) No ? in liver failure/
  HCCYuen hepatology 2001

6
Dwivedi Management of chronic HBV infection

• HBeAg hepatitis factors predicting response to
  lamivudine
• High baseline ALT
• High baseline HAI
• Antiviral efficacy 1 yr lamivudine (100mg) HBeAg
  hepatitis
• Lai, 1998 Dienstag,1999
• Lam 143 Pla 73 Lam 66 Pla 71
• Hbe seroconversion 16 4 17 6
• Undectectable HBVDNA 96 23 98 33
• Sustained normalized ALT 72 24 41 7

7
Dwivedi Management of chronic HBV infection

• Treatment with lamivudine
• At 1 yr 55 improvement in histology
• 29 normalization of ALT
• Response 20 --- 1yrs
• 35 --- 2yrs
• 44 --- 3yrs
• 66 --- 4yrs
  Tassopoules NC. Hepatology 99
• Continue treatment for at least 3 yrs
• Trial of 12-18 mths
• Reactivation is the rule when therapy stopped
• Continue treatment indefinitely with fibrosis st
  II

8
Dwivedi Management of chronic HBV infection

• Effect of lamivudineresistant mutations
• Exacerbation of hepatitis
• Decreased rate of seroconversion
• Rapid reinfection of liver graft
• Rapid disease progression after liver
  transplant
• Severe hepatitis HBV / HIV coinfection
• Transmission of drug resistance
• YMDD mutants
• Not detected in immunocompetent pts before 6 mths
  Rx
• After 1 yr 23 after 2 yr 40 (asians
  detected by sensitive PCR methods) after 3 yr
  60
• In these pts also ALT, HBV-DNA was much lt pre-Rx
  values
• Variants are not as replication competent
• Adefovir has activity against mutants, may be
  used in combination with L.
• Gibbs, J. Hepatol 1998

9
Dwivedi Management of chronic HBV infection

• Combination therapy for CHB
• LAM followed by IFN
• Combination of FAM LAM
• 9-L ALONE 150mg/d
• 12-LF 500mg TID x 12 Wks.
• 5-fold diff in viral suppression
• Lau Hepatology 2000
• Advantages of combination therapy
• Less development of mutants
• Minimizes toxicity
• Cell-culture, animal models-useful
• To assess efficacy of combination

10
Dwivedi Management of chronic HBV infection

• New HHV antivirals
• 1. Adefovir dipivoxil
• 2. Entecavir
• 3 Emtricitabine appear as potent as
  Lamivudine
• 4. DAPD
• 5. Clevudine
• L has cross-r with Emtricitabine as far as YMDD
  mutants are concerned.
• Adefovir
• Lobucavir Suppress
  both wild type HBV
• DAPD and
  YMDD mutants.
• Possibly clevudine

11
Dwivedi Management of chronic HBV infection

• Adefovir dipivoxil
• Significant Biochemical
• Histological
• Virological activity against HBV -L
  resistant strains in 48 wks of Rx
• Adverse effects in 3 pts transient ? of
  S.Cr
• Marcellin.N Engl. J Med 2003 Abst. Tong M
  Gastroenterology 2003 Abst.

12
Dwivedi Management of chronic HBV infection

• New immunomodulatory compounds
• 1. Thymosin
• 2. Interleukin-12
• 3. Therapeutic vaccines
• Have not demonstrated sufficient efficacy for
  widespread use

13
Dwivedi Management of chronic HBV infection

• TREATMENT OF SPECIAL GROUPS
• Immunosuppressed patients
• Lam effective in post renal
  transplant pts
• Patients on chemotherapy
• Co infection
• HBV HDV Lam not effective --- prolonged IFN
  used
• HBV HIV Lam 97 efficacious dose 150 mg BD
  ---- IFN not promising.
• HBV HCV IFN some promise --- role of LAM not
  clear

14
Dwivedi Management of chronic HBV infection

• Conclusions
• CHB Therapy
• Progress with oral antivirals
• Well tolerated
• Combination therapy
• Newer immunotherapies ? nucleoside efficacy
• Goal of viral eradication - Still elusive for
  most
• Clinical concern - Long term risk of mutations