Title: Epatite B in Oncologia - dubbi e certezze 31.5.2006
1Epatite B in Oncologia - dubbi e
certezze31.5.2006
- Prof. Dr. med Andreas Cerny
2Outline
- Basics HBV infection
- Case Study
- Implications for oncology
- Take home messages
3Hepatitis 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
5HBV Immunity
NEJM 35011, 2004
6(No Transcript)
7Evolution of hepatitis B is a function of age
8Spectrum 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)
9Outline
- Basics HBV infection
- Case Study
- Implications for oncology
- Take home messages
10Case 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
11Your 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
12Lee W.M. NEJM 33717331997
13Workup 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 ?
14What 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.
15AST and the probability to find chronic active
hepatitis B on liver biopsy in HBsAg HBeAg-
patients
Borg et al. Lancet 1998 3511914.
16Chronic active hepatitis with mild to moderate
activity
Staining for HBsAg
17Negative 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
19What is a pre-core mutation ?
Brunetto MR et al. J Gastroenterol 1989
21151. Carman WF et al. Lancet 1989 2 588.
20Emergence 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.
21Diagnostic 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)
22Diagnostic 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)
23Hepatitis 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
24Case 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
25Outline
- Basics HBV infection
- Case Study
- Implications for oncology
- Take home messages
26Reactivation of hepatitis B after cytotoxic
therapy in 100 chinese lymphoma patients Lok et
al. (1991) Gastroenterology 100 182-188
27Reactivation 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
28Reactivation 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
29Recommendations 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
30Case 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...
31Occult 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).
32Occult 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).
33Anti-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
34HBsAg 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).
35Impact of occult HBV Infection
36Study population
37Impact of occult HBV Infection
38Conclusions
- 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.
39Conclusions (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?
40Vaccination in SCT
Bone Marrow Transplantation (2005) 35, 737746
41Vaccination in SCT
Bone Marrow Transplantation (2005) 35, 737746
42Outline
- Basics HBV infection
- Case Study
- Implications for oncology
- Take home messages
43THM
- 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)