Rai: Management of HBV related cirrhosis

1
Rai Management of HBV related cirrhosis

• Clinical spectrum of HBV infection- variable
• 15-40 chronically infected persons are
  expected to progress to cirrhosis
• Incidence of developing cirrhosis in
  chronic hepatitis B
• HBeAg ve 10-24
• HBeAg ve 30-40
• J.Med.Virol. 200061362-366
• Hepatology 199930257-264

2
Rai Management of HBV related cirrhosis

• Rate of progression depends on
• Fibrosis stage at presentation
• Severity of necroinflammation at diagnosis
• Recurrent acute exacerbations
• Ongoing replication (ve DNA)
• Genotype C gt B
• Concurrent HDV, HCV or HIV infection
• Concurrent alcohol use (Heavy drinking increases
  risk 6 fold)
• Older age

3
Rai Management of HBV related cirrhosis
Natural history of HBV related cirrhosis Compensa
ted cirrhosis - usually asymptomatic patients
(76) - Difficult to identify - Insidious
progression - 5 years survival
84 Decompensated cirrhosis 5 years cumulative
incidence 16 - 20 5 years survival 14
J Hepatol 1994 21656-666 Liver
1989 9235-241 Gastroenterology 1992
1031630-1635
4

Rai Management of HBV related cirrhosis
Risk of developing decompensation HCC at 5 years
(Fattowich et al) Am J Gastroenterol 2002 97
2886-95
5
Rai Management of HBV related cirrhosis
Survival with and without decompensation in
untreated patients
Cause of death Liver failure 53HCC 35Non
hepatic 12
Fattowich et al, Am J Gastroenterol 2002 97
2886-95
6
Rai Management of HBV related cirrhosis

• Is cirrhosis of the liver reversible ?
• Dynamic process
• Necro inflammation ? fibrosis ? cirrhosis
• persistence of underlying cause

7
Rai Management of HBV related cirrhosis

• Factors influencing the disease progression
• Fibrosis stage at presentation
• Severity of Necroinflammation at diagnosis
• Recurrent acute exacerbations
• Ongoing replication (ve DNA)
• Genotype C gt B
• Concurrent HDV, HCV or HIV infection
• Continued alcohol use (Heavy drinking increases
  risk 6-fold)
• Older age

8
Rai Management of HBV related cirrhosis

• Risk Rate of development cirrhosis
• HBeAg ve/- ve, HBV DNA ve
• Increased risk of progressive liver disease,
  death
• 684 chinese patients (Liaw et al) with chronic
  HBV infection Patients with flares, ve HBeAg or
  ve DNA developed progressive liver disease
• Dutch cohort (De Jongh et al) Loss of HBeAg and
  development of HBeAntibody, with 55 reduction in
  likelihood of death
• Hepatology 19888493-6
• Gastroenterology 19921301630-35

9
Rai Management of HBV related cirrhosis

• Goals of therapy
• To ? viral replication
• ?
• Necroinflammation ? Fibrosis
• To stabilize/improve liver disease severity
• Improve clinical symptoms Quality of life
• Possibly extend survival ?
• Prevent HCC

10
Rai Management of HBV related cirrhosis

• General Medical Management
• Assessment of Severity and prognosis
• Liver disease severity scales in decompensated
  HBV cirrhosis
• Scales Mild Moderate Severe
• CTP score (5 to 15) 5 6 7 9 10 - 15
• MELD score (6 40) 6 10 11 24 25 40
• HBV risk profile (1 50) 1 4 4 7 7 50

11
Rai Management of HBV related cirrhosis

• Assessment of HBV replication
• Decompensated cirrhosis
• ALT surrogate marker
• Mostly HBeAg Ve
• HBV DNA
• - very low levels
• - undetectable
• - fluctuate over the time (recheck every 6 month)
• HBeAg ve/- ve with HBV DNA gt 105 copies
• Unclear whether lt 105/ml HBeAg ve would benefit
  from antiviral therapy

12
Rai Management of HBV related cirrhosis

• Timely referral for liver transplantation
• Advanced irreversible liver failure
• Complications of portal hypertension
• - Ascites
• - Encephalopathy
• - Variceal bleeding
• - CTP score gt 7
• Selected patients with unresectable HCC lt 5cm in
  size

13
Rai Management of HBV related cirrhosis

• Antiviral treatment
• Suppression of HBV replication
• ?
• Decreased hepatic necroinflammation
• ?
• Improvement or stabilization of liver functions
• Can be used only in selected patients
• Interferons
• Neucleoside analogues
• Lamivudine
• Entecavir
• Neucleotide analogues
• Tenofovir
• Adefovir

14
Rai Management of HBV related cirrhosis

• Management of compensated cirrhosis
• IFN - ? Safe effective in selected patients
• Long term studies (Niederau C et al)
• - Improved liver histology
• - ?sed risk of decompensation
• -Lower incidence of HCC
• Improved survival (Lin SM et al)
• Low response rates (20-30)
• Lower risk of hepatic decompensation
• Improved histology
• Survival improved in sustained responders
• NEJM 996 3341422-1427 Hepatology 1999
  29971-975

15
Rai Management of HBV related cirrhosis

• Management of compensated cirrhosis (contd.)
• Lamivudine
• Suppresses S.HBV DNA to undetectable levels in
  90
• Improves ALT levels
• Improves histology
• Flares uncommon
• Well tolerated
• Optimal duration of therapy unknown
• Dienstag etal NEJM 1999 3411256-1263 NEJM
  1998 33961-68

16
Rai Management of HBV related cirrhosis

• Management of decompensated cirrhosis
• IFN - ?
• High incidence of
• -Bacterial infection (28)
• -Hepatitis flare (50)
• Even with low dose (6-15 MU per week ) INF - ?
  therapy is contraindicated in the presence of
• - Ascites
• - Encephalopathy
• - CTP gt 7
• - Neutropenia/Thrombocytopenia
• (Hoofnagle et al) Gastroenterology 1993
  1041116-21

17
Rai Management of HBV related cirrhosis

• Studies of Lamivudine in patients with
  decompensated HBV cirrhosis
• Study No Median Viral
• Childs Follow-up Resistance Survival
  Transplanted B/C (months)
• Uncontrolled, open label
• UCSF 13 0/100 15 7 100 15
• India 18 78/22 18 17 100 0
• Canada 35 28/72 19 13 70 20
• North America 77 NA 26 21 96 61
• Controlled, open label
• UCSF 23 0/100 13 10 100 35
• North America 162 NA 10 11 83 56

18
Rai Management of HBV related cirrhosis
Comparison of survival in lamiudine treated
patients with decompensated HBV cirrhosis and non
contemporaneous, untreated historical
controls. Gut
199132294-98
Hepatology 200133424-432
19
Rai Management of HBV related cirrhosis

• Fontana et al
• 154 patients of HBsAg ve decompensated cirrhosis
• Lamivudine
• 35 lost HBeAg gt80 suppression of 20
  acquired
• HBV DNA with in 8 weeks Anti-Hbe
• Actuarial 3 year survival- 72
• Fontana et al (North America) Gastroenterology
  2002 123719-27

20
Rai Management of HBV related cirrhosis

• Fontana et al
• 309 pts.( HBsAg ve liver transplant candidates )
• 162 147
• (Lamivudine Rx) (No Lamivudine)
• Similar pretransplant transplant free survival
• No apparent effect on liver disease severity in
  transplanted patients.
• In patients without transplant? stabilization or
  improvement in disease severity
• Fontana et al (North America) Liver transplant
  2002. 8433-39

21
Rai Management of HBV related cirrhosis

• Lamivudine
• Well tolerated in decompensated cirrhosis
• Hepatitis flares uncommon
• Low side effect profile
• Optimal duration of therapy unknown
• ? Indefinite
• Clinical effect in slow - gt 6 months
• Lamivudine resistance
• 7-21 annually in decompensated cirrhosis
  
• Usually seen after 6 months of therapy
• Commonly involves YMDD motif
• Mutants may be less replication fit but patients
  
• May experience a flare
• Adefovir may be used in resistant cases Fontana
  et al Liver Transplant 20028433-39

22
Rai Management of HBV related cirrhosis

• Newer agents
• Adefovir dipivoxil
• Nucleotide analogue of AMP, approved by US FDA
  in U.K.
• Trials (Marcellin etal, Hadziannis etal
  Perrillo et al)
• 575 HBeAg ve patients, 185 HBeAg ve patients
  received 10 mg per day for 48 weeks significant
  improvement in histological, biochemical
  virological responses v/s placebo
• In gt100 patients of decompensated cirrhosis with
  lamivudine resistance Decrease in HBV DNA
  levels stabilization and improvement in liver
  disease potential nephrotoxicity (low incidence
  at 10 mg daily dose)
• Can be used as a salvage therapy in Lamivudine
  resistant cases with worsening liver disease
• J Hepatol 2002 36 (Suppl 1)8 J Hepatol 2002
  36 (Suppl 1)4 Hepatology 200032129-34

23
Rai Management of HBV related cirrhosis

• Adefovir dipivoxil ( cont.)
• Recommended daily dose 10mg/day
• Optimal duration unknown probably gt1year
• No resistance reported
• No data available for durability of response
• Adefovir alone is equally effective as compared
  to adefovir Lamivudine
• (Peters M et al Hepatology 2002. 36374)

24
Rai Management of HBV related cirrhosis

• Newer agents
• Entecavir
• Nucleoside analogue
• Active against both wild Lamivudine resistant
  virus
• Preliminary results promising.
• Phase III study on
• Tenofovir
• Nucleotide analogue
• Approved for Rx of HIV injection
• Active against both wild type Lamivudine
  resistant virus
• Further studies needed for both agents before
  recommendation

25
Rai Management of HBV related cirrhosis

• Hepatocellular carcinoma
• In high endemicity areas, incidence of HCC/100
  person year
• 0.1 (asymptomatic carriers)
• 1 (chr. Hepatitis B-untreated)
• 3.8 (comp. Cirrhosis-untreated)
• Majority of patients do not experience
  decompensation before or at diagnosis Liver
  19899235-41
• Relation between risk of HCC and ongoing HBV
  replication
• No difference between HBeAg ve, HBeAg-ve,
  HBeAg-ve DNA ve or HBeAg-ve DNA-ve Fattovich et
  al (European cohort) Am J Gastroenterol
  2002972886-95
• Taiwan study - Relative risk for HCC versus HBsAg
  -Ve men
• -9.6 (HBsAg ve)
• -60.2 (HBeAg ve)Liaw et al, Liver
  19899235-41

26
Rai Management of HBV related cirrhosis

• Risk of development of HCC in cirrhotics
• No.of Patients HCC Incidence
• Authors, Area Type IFN not IFN not RR
  95CI
• treated treated
• Oon et al, Singapore CS, P 518 162 0 6.2 0.03 0.00
  07-0.21
• Mazzella et al, Italy CS,R 34 28 1.4 3.6 0.4 0.03-
  2.8
• Eurohep, Europe CS,R 40 50 1.4 1.7 0.96 0.21-4.37
• International IFN-?, Italy CS,R 49 97 n.a n.a 0.98
  0.33-2.92
• HCC Study Group, Argentina
• Ikeda et al, Japan CS,P 94 219 1.5 3.3 0.45 0.2-0
  .9

27
Rai Management of HBV related cirrhosis

• Liver transplantation
• Excellent patient and graft survival rates with
  use of long term high dose HBIG prophylaxis
• Recurrent HBV infection occurs in 20 40
  patients
• Presence of HBeAg or HBV DNA before transplant
  High likelihood of recurrence
• Suppression of HBV replication prior to
  transplant - May reduce risk of recurrence
• Lamivudine prophylaxis in transplant candidates
• Lamivudine monotherapy can decrease rate of
• Recurrence of HBV infection after transplantation
• Efficacy diminishes with time ? selection of drug
  resistant mutants NEJM 1993 3291842-47

28
Rai Management of HBV related cirrhosis

• HBIG Plus lamivudine prophylaxis
• High rate of breakthrough infection with
  lamivudine alone
• Most transplant centers using combination
  therapy
• Retrospective analysis
• 59 patients High dose HBIG Lamivudine No
  recurrence after 15 months followup
• Low dose HBIG Lam. ? recurrence rate lt 10
• Han SH et alLiver transplant 2000 6 741-48