Epatite B in Oncologia - dubbi e certezze 31.5.2006

1
Epatite B in Oncologia - dubbi e
certezze31.5.2006

• Prof. Dr. med Andreas Cerny

2
Outline

• Basics HBV infection
• Case Study
• Implications for oncology
• Take home messages

3
Hepatitis B The essentials

• Small (3200 bp), partially double-stranded
  Hepadna virus
• Worldwide 350000000 people affected
• Acute hepatitis B is decreasing in Switzerland
• Highly effective and well tolerated vaccine is
  available.

4
HBV replication cycle
Infectious HBV virion
Infectious HBV virion
HBsAg envelopes
DNA pol
RT
Partially double-stranded DNA
(-)-DNA
Encapsidated pregenomic mRNA
A(n)
mRNA
cccDNA
Lai et al, J Med Virol 2000
5
HBV Immunity
NEJM 35011, 2004
6
(No Transcript)
7
Evolution of hepatitis B is a function of age

8
Spectrum of Disease
Acute HBV infection
90 neonates
2530 children
lt10 adults
2
Chronic infection
1540
Progressive chronic hepatitis
Inactivecarrier state
Fulminant hepatic failure
Cirrhosis
HCC
Death
Decompensated cirrhosis
EASL Consensus Guidelines. J Hepatol 2003 Lok,
McMahon. Hepatology 2004 (AASLD Guidelines)
9
Outline

• Basics HBV infection
• Case Study
• Implications for oncology
• Take home messages

10
Case study

• 35 year old man, history of hypertension
• He was had recently been seen for upper abdominal
  pain lab tests showed elevated transaminases
  (AST 47, ALT 50) gGTalcP normal, LDH 560,
  Quickalbumin normal
• serology
• HBsAg pos
• Anti HBsAg neg
• Anti HBc pos
• HBeAg neg
• Anti HBe pos

11
Your interpretation?

• A. Healthy (HBsAg) carrier (inactive carrier
  state) look for other causes of liver enzyme
  abnormalities (alcohol, drugs, autoimmunity,
  metabolic disease)
• B. Chronic (active) hepatitis B workup
  including virological tests for HBV and consider
  liver biopsy

12
Lee W.M. NEJM 33717331997
13
Workup of our patient...

• 35 year old man, history of hypertension
• He was had recently been seen for upper abdominal
  pain lab tests showed elevated transaminases
  (AST 47, ALT 50) gGTalcP normal, LDH 560,
  Quickalbumin normal
• serology
• HBsAg pos
• Anti HBsAg neg
• Anti HBc pos
• HBeAg neg
• Anti HBe pos
• HBV DNA 240000 copies/ml
• -gt Liver biopsy ?

14
What test should we use to investigate an HBsAg
HBeAg- patient?

• Prospective multicenter study performed in the
  Netherlands
• 123 HBsAg, HBeAg- patients were investigated
  with
• a large panel of liver function and
  hematological tests
• virological tests including quantitation of
  viral DNA
• liver biopsy
• Statistical analysis on the predictive power of
  the tests used to predict the presence of liver
  injury

Borg et al. Lancet 1998 3511914.
15
AST and the probability to find chronic active
hepatitis B on liver biopsy in HBsAg HBeAg-
patients
Borg et al. Lancet 1998 3511914.
16
Chronic active hepatitis with mild to moderate
activity
Staining for HBsAg
17
Negative Positive
Lee W.M. NEJM 33717331997
18

• HBeAg negative, DNA positive Hepatitis
• - 40-80 of cases of chronic hepatitis B in the
  mediterranian region are HBeAg negative
• Hadziannis SJ Viral Hepatitis 199517.
• - 95 of patients in the mediterranian region
  with HBsAg neg hepatitis carry a pre-core
  mutation (variant 1896-gtstop codon)
• Brunetto MR et al. Gastroenterology 1993
  105845.
• Laras A et al. J Viral Hepatitis 19985241

19
What is a pre-core mutation ?
Brunetto MR et al. J Gastroenterol 1989
21151. Carman WF et al. Lancet 1989 2 588.
20
Emergence of the HBeAG-NegativePrecore Mutant
HBeAg
HBeAg / anti-HBe
Anti-HBe
HBV-DNA (mutant)
HBV-DNA (wild)
Transaminases
Chronic moderate to severe hepatitis
Chronic hepatitis mild
Cirrhosis hepato- cellular carcinoma
Continued HBV precore mutant replication
HBV wild-type clearance
HBV tolerance
Years
0
5
10
15
20
Carman WF et al Viral Hepatitis. Scientific
Basis and Clinical Management. NY Churchill
Livingstone 1993121.
21
Diagnostic Criteria Inactive HBsAG carrier state

• HBsAG positive gt6 months
• HBeAG negative anti-HBe positive
• Serum HBV DNA lt105 copies/mL
• Persistently normal ALT/AST levels
• Liver biopsy showing absence of significant
  hepatitis (necroinflammatory score lt4)

22
Diagnostic Criteria Chronic Hepatitis B

• HBsAG positive gt6 months
• Serum HBV DNA gt105 copies/mL
• Persistent or intermittent elevation in ALT/AST
  levels
• Liver biopsy showing chronic hepatitis
  (necroinflammatory score 4)

23
Hepatitis B treatment

• HBeAg-neg chronic hepatitis B (serum HBV DNA gt105
  copies/mL, elevated ALT gt2 uln or moderate/severe
  hepatitis on biopsy)
• Should be considered for treatment.
• Treatment may be initiated with (pegylated)
  IFN-alpha, lamivudine, or adefovir.

Lok, McMahon Hepatology March 2004
24
Case study

• 35 year old man, history of hypertension
• He was had recently been seen for upper abdominal
  pain lab tests showed elevated transaminases
  (AST 47, ALT 50) gGTalcP normal, LDH 560,
  Quickalbumin normal
• Diagnosis HBeAg neg. chronic Hepatitis B
• While evaluating initiation of treatment with
  pegylated IFN he develops night sweats.
• An abdominal CT and a subsequent lymph node bx
  reveals the diagnosis of Hodgkins disease the
  oncologist is anxious to start chemotherapy

25
Outline

• Basics HBV infection
• Case Study
• Implications for oncology
• Take home messages

26
Reactivation of hepatitis B after cytotoxic
therapy in 100 chinese lymphoma patients Lok et
al. (1991) Gastroenterology 100 182-188
27
Reactivation of hepatitis B after bone marrow
transplantation

• 137 consecutive patients who underwent
  hematopoietic cell transplantation
• 23 positive for HBsAg
• 37 positive for anti-HBs
• 77 negative for HBV
• Hepatitis developed in 32 patients (23 percent)
  with a mean onset at 136 days after
  transplantation
• considered to be due to hepatitis B reactivation
  in 13 of the 32 patients.
• Hepatitis due to HBV reactivation was more common
  in HBsAg-positive patients than HBsAg-negative
  patients (11 of 23 versus 2 of 114).
• The most important risk factor for reactivation
  was an HBV DNA level of gt10(5) copies/m.

Lau, GK, Leung, YH, Fong, DY, et al. High
hepatitis B virus (HBV) DNA viral load as the
most important risk factor for HBV reactivation
in patients positive for HBV surface antigen
undergoing autologous hematopoietic cell
transplantation. Blood 2002 992324
28
Reactivation of hepatitis B

• Spontaneous (up to 10 /year)
• Chemotherapy
• Immunosuppression, in particular after decreases
  described for
• for steroids, methotrexate, chloroquin, anti-TNF
  etc.
• Selection of a mutant (anti-HBe DNA Å)
• Superinfection with Delta or another hepatotropic
  virus

29
Recommendations for Hepatitis B Carriers Who
ReceiveImmunosuppressive or Cytotoxic Therapy
HBsAg testing should be performed in persons who
have high risk of HBV infection, prior to
initiation of chemotherapy or immunosuppressive
therapy (III). Prophylactic antiviral therapy
with lamivudine is recommended for HBsAg positive
patients at the onset of cancer chemotherapy or
of a finite course of immunosuppressive therapy,
and maintained for 6 months after completion of
chemotherapy or immunosuppressive therapy
(III). The benefit of preemptive therapy in
patients with serological markers of recovered
HBV infection is less clear. It may be reasonable
to monitor such patients closely and to initiate
treatment when serum HBV DNA level becomes
detectable or when a hepatitis flare is diagnosed.
AASLD guidelines update 2004 Hepatology March 2004
30
Case study follow up

• 35 year old man, history of hypertension and
  chronic hepatitis B
• He underwent chemotherapy for Hodgkins disease
  and is still under treatment with Lamivudine
• The serum aminotransferases are still normal and
  the HBV viremia is suppressed...

31
Occult HBV Infection

• patients who received HBsAg-negative,
  antihepatitis B core antibody (HBcAb)positive
  blood were still at risk of developing
  post-transfusional hepatitis B (N Engl J Med
  1978298 13791383).
• patients with chronic liver disease and with no
  serological markers of HBV infection, could still
  be shown to have HBV DNA present in their serum
  or liver (N Engl J Med 1985312270276).

32
Occult HBV Infection

• HBsAg patients generally have HBV DNA levels of
  104 to 108 viral genomes per ml.
• occult infections, the circulating levels of
  HBV DNA are below 103 viral genomes per ml
  (Hepatology 200134194203), and liver HBV DNA
  levels are also low (Hepatology 200031507512).
• patients with chronic liver disease and with no
  serological markers of HBV infection, could still
  be shown to have HBV DNA present in their serum
  or liver (N Engl J Med 1985312270276).

33
Anti-HBV core only

• are much more likely to have occult HBV DNA
  present than patients with only HBsAb positivity
  or no markers at all (Hepatology 1995222529, J
  Med Virol 199444 293297).
• They are also more likely to be Anti- HCV Ab

34
HBsAg negative infection

• HBsAg-negative infections have been described (J
  Med Virol 199958193195),
• The basis was in some mutations in the S gene
  (Hepatology 19972616581666, J Virol
  19987276927696).
• Mutations in the preS1 sequence have recently
  been reported to be associated with reduced HBsAg
  expression, possibly explaining the
  HBsAg-negative, HBV DNA findings in these
  patients (Hepatology 200032116123).

35
Impact of occult HBV Infection
36
Study population
37
Impact of occult HBV Infection
38
Conclusions

• Viral genomes was detected in 68 of 107 cases of
  HCC (63.5) and in 63 of 192 cases of chronic
  hepatitis (32.8) (P lt 0.0001 odds ratio, 3.6
  95 confidence interval, 2.2 5.9).
• Occult HBV was more common in Anti-HBc pts
  (84), but was seen in 56 (!) of the Anti-HBc
  neg pts.
• The significant association of occult HBV with
  HCC was irrespective of age, sex, and
  contemporary hepatitis C virus infection.

39
Conclusions (2)

• Less than 30 had no other cause for HCC than
  occult HBV infection (NASH not identifyable in
  advanced stages)
• Statistical association is not proof of causation
• In HBV-HCV coinfected and HIV-HCV-HBV coinfected
  patients occult HBV may be a relevant driver of
  carcinogenesis (implications for treatment and
  HCC screening?)
• Check for viral DNA in serum of all patients with
  HBV seromarkers and liver disease?

40
Vaccination in SCT
Bone Marrow Transplantation (2005) 35, 737746
41
Vaccination in SCT
Bone Marrow Transplantation (2005) 35, 737746
42
Outline

• Basics HBV infection
• Case Study
• Implications for oncology
• Take home messages

43
THM

• Check for HBV serostatus
• Evaluate HBV patients for pre-emptive therapy
• Vaccinate against HBV
• Think of occult HBV in cases of unexplained
  Hepatitis

44
(No Transcript)