Title: NATURAL HISTORY OF HBV
1Dwivedi 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 ?
2Dwivedi 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
3Dwivedi 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
4Dwivedi 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
5Dwivedi 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
6Dwivedi 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
7Dwivedi 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 -
8Dwivedi 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
9Dwivedi 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
10Dwivedi 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
11Dwivedi 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.
12Dwivedi Management of chronic HBV infection
- New immunomodulatory compounds
- 1. Thymosin
- 2. Interleukin-12
- 3. Therapeutic vaccines
- Have not demonstrated sufficient efficacy for
widespread use
13Dwivedi 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
14Dwivedi 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