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Vaccination and Hepatology
Isabelle Colle, MD, PhD
Dept of Hepatology and Gastroenterology
Ghent University Hospital
Program
• Introduction hep B serology
• Propositions of vaccinations
• Hep B vaccination in chronic liver disease
• Isolated anti HBc Abs: management
• Prevention of hep B reactivation
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Introduction in HBV serology
After resolution HBV infection: HBcAb persists lifelong; HBsAb may decline and become undetecable
Chronic hepatitis B profiles
“Cured”HBV
HBsAg ‐
Anti‐HBsAb +
HBeAg ‐
Anti‐HBe Ab +
Anti HBc Ab +
ALT normal
HBV DNA IU/ml 0
Lok ASF & McMahon BJ. Hepatology. 2007; 45:507-39.
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Chronic hepatitis B profiles
Inactive carrier
HBsAg +
HBeAg ‐
Anti‐HBe Ab +
ALT normal
HBV DNA IU/ml
< 2.000
Lok ASF & McMahon BJ. Hepatology. 2007; 45:507-39.
Chronic hepatitis B profilesInactive carrier
Immunotolerant phase
HBsAg + +
HBeAg ‐ +
Anti‐HBe Ab + ‐
ALT normal normal
HBV DNA IU/ml
< 2.000 ≥ 2.106
Lok ASF & McMahon BJ. Hepatology. 2007; 45:507-39.
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Chronic hepatitis B profilesInactive carrier
Immunotolerant phase
Active chronic HBV wild type
HBsAg + + +
HBeAg ‐ + +
Anti‐HBeAb
+ ‐ ‐
ALT normal normal Elevated
HBV DNA IU/ml
< 2.000 ≥ 2.106 ≥ 20.000
Lok ASF & McMahon BJ. Hepatology. 2007; 45:507-39.
Chronic hepatitis B profilesInactive carrier
Immunotolerant phase
Active chronic HBV wild type
Active chronic HBV precore mutant
HBsAg + + + +
HBeAg ‐ + + ‐
Anti‐HBeAb
+ ‐ ‐ +
ALT normal normal Elevated elevated
HBV DNA IU/ml
< 2.000 ≥ 20.000 ≥ 20.000 ≥ 2.000 ‐20.000Lok ASF & McMahon BJ. Hepatology. 2007; 45:507-39.
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1. Advised vaccinations
Recent guidelines: No booster anymore in immune competent persons
Measle, bof rubella
Advised vaccinations
KINDEREN VOLWASSENEN
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Advised vaccinationsKINDEREN
VOLWASSENEN
2. Hepatitis A and B vaccination in chronic liver disease CLD
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2. Hepatitis A and B vaccination in chronic liver disease CLD
• Acute hepatitis A /B infection in CLD: ↑ morbidity and mortality
• Lower inherent immunity for HAV in younger pts
Keeffe E. Am J Med 2005; 118:21S-27S
2. Hepatitis A and B vaccination in CLD
• Acute hepatitis A /B infection in CLD: ↑ morbidity -mortality• Co-infection hep B with hep C or delta: ↑ natural history, cirrhosis and
HCC• Hep A and B vaccination is safe and effective in mild/moderate CLD,
less effective in cirrhosis and decompensated cirrhosis (+ LTx list)- Hep A vaccination: 98% seroconversion vs 66% in advanced
CLD/LTx list
- Hep B vaccination efficacy:
- mild alcoholic LD: 93-100% seroconversion- alcoholic cirrhosis: 18-75%- mild/moderate HCV CLD: 90-100%- HCV cirrhosis: 42-54%
- cirrhotic pts on waiting LTx list: 30%
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2. Hepatitis A vaccination in CLD
Keeffe E. Am J Med 2005; 118:21S-27S. I. Rowe et al. Hepatology 2012; 56: 501
Vaccination: yes or too expensive in HCV pts?
2. Hepatitis B vaccination in CLDKeeffe E. Am J Med 2005; 118:21S-27SSeto et al. J Clin Gastroenterol 2012; 46:725
Normal:Recombinant HBV vaccine 20µg IM: 0, 1, 6m
Enhancing response: High dose: 40µg IM or 20+20µg IDAccelerated: 0, 1,2, 6mBooster of 80µgHelipsav (immunostimulatory DNA seq => Th1↑)Fendrix 20µg (GSK) or HBVax Pro 40µg (Sanofi Pasteur)
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After resolution HBV infection: HBcAb persists lifelong; HBsAb may decline and become undetecable
3. Isolated HBc Abs: management
3. Isolated HBc Abs: management
• Definition: anti‐HBc Ab + without HBsAg, anti HBsAb• Prevalence: 0.1% ‐ 20% (Mc Mahon et al. Gastroenterol 1992: 103:590) :
low endemic zone: 0.1%‐4%high endemic zone: 15‐20%
• Possible situations:‐ acute hepatitis B in window phase: clearance of HBsAg and
appearance of HBsAb => unlikely with sensitive HBsAg assays‐ resolved HBV infection with disappearance of HBsAb =>
anamnestic response = anti‐HBs ≥ 10 IU/L 4w after first vaccination (95% > 10 IU/ml)
‐ Chronic HBV with HBsAg absence due to low levels or mutation in HBs protein => undetectable: occult HBV infection, HBV DNA will be + (low levels) => no response to vaccination
‐ False positive anti‐HBc Ab => N response to vaccination
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3. Isolated HBc Abs
K. Al-Mekhaizeem et al. CMAJ 2001; 165: 1063-4.Su et al. Vaccine 2012; 30: 4034-39A Silva et al. Clin Infect Dis 1998; 26: 895-7.
Anamnestic response = anti-HBs ≥ 10 IU/L4w after first vaccination
Resolved HBV: +/-60%
3. Isolated HBc Abs
K. Al-Mekhaizeem et al. CMAJ 2001; 165: 1063-4.Su et al. Vaccine 2012; 30: 4034-39A Silva et al. Clin Infect Dis 1998; 26: 895-7.
Was false positive HBcAb: 34-38%
Anamnestic response = anti-HBs ≥ 10 IU/L4w after first vaccination
Resolved HBV: +/-60%
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3. Isolated HBc Abs
K. Al-Mekhaizeem et al. CMAJ 2001; 165: 1063-4.Su et al. Vaccine 2012; 30: 4034-39A Silva et al. Clin Infect Dis 1998; 26: 895-7.
HBV DNA
False positive HBcAb: 34-38%
Occult HBV: 4%
Anamnestic response = anti-HBs ≥ 10 IU/L4w after first vaccination
Resolved HBV: +/-60%
3. Isolated HBc Abs
R Ghandhi et al. JID 2005; 191: 1435-41.
HIV + pts with isolated anti HBc: 16% anamnestic response2.4% occult infection
HCV-HIV coinfection: lower anti-HBs titers after 3 vaccines
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4. Prevention of HBV reactivation under immune suppression
• Prevalence of reactivation depends on
‐ HBsAg +: 100%‐48%
‐ HBsAg neg, anti‐HBc+: 8‐25% (In rheumatic pts: 1.7% Lee 2012)
‐ kidney TX pts with resolved HBV: 6.5% (UCL)(J Clin Virol 2012; 55:233)
• Risk for reactivation:
‐male
‐ high HBV DNA
‐ Asian and black
‐ Degree of IS: hematological disorders, steroids, rituximab (CMdose > 3005mg/m²)
‐Marginal zone and Mantle cell lymphomas: risk
‐ preparative therapy for BMTx or SCTx
4. Prevention of HBV reactivation under immune suppression
• Prevalence of reactivation depends on
‐ HBsAg +: 100%‐48%
‐ HBsAg neg, anti‐HBc+: 8‐25% (In rheumatic pts: 1.7% Lee 2012)
‐ kidney TX pts with resolved HBV: 6.5% (UCL)(J Clin Virol 2012; 55:233)
• Risk for reactivation:
‐male
‐ high HBV DNA
‐ Asian and black
‐ Degree of IS: hematological disorders, steroids, rituximab (CMdose > 3005mg/m²)
‐Marginal zone and Mantle cell lymphomas: risk
‐ preparative therapy for BMTx or SCTx
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4. Prevention of HBV reactivation under immune suppression
• Which IS/chemotherapeutic agents leads to flare: ANY !
‐ corticosteroids (sometimes 4‐6w after abrupt withdrawal)
‐ Rituximab
‐ Anti‐TNF, MTX
‐multi thyrosine kinase inhibitors
‐ ustekinumab (psoriasis)(anti‐IL12,23)
‐ immune reconstitution with HAART in HIV
‐ all IS agents
EASL practice guidelines HBV. J Hepatol 2012; 57: 167-185BASL guidelines HBV. Acta GE Belgica 2007; LXX: 389
Recommendations to prevent HBV reactivation in immunosuppressed patients
-All patients who are candidates for chemo- or immunosuppressivetherapy should be screened for HBV markers and all naïve patientsshould be immunized against HBV as soon as possible (A1).
-Patients who are HBsAg positive should be offered pre-emptive treatment regardless of their HBeAg or HBV DNA status. In these patients, treatment should be started at least 1 week before initiation of chemotherapy and should be continued for at least 12 months after discontinuation of chemotherapy (A1).
If low HBV DNA: lamivudine can be startedIf high HBV DNA: entecavir or tenofovir
A S L
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Prevention HBV reactivation
HBsAg +
HBc Ab +
HBV DNA +
Status Active
HBV
TO DO ETV
Tenof
A S L
Prevention HBV reactivation
HBsAg + +
HBc Ab + +
HBV DNA + neg
Status Active
HBV
Inactive carrier
TO DO ETV
Tenof
Lamivudine?
1w before –12m after
A S L
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Prevention HBV reactivation
HBsAg + + ‐
HBc Ab + + +
HBV DNA + neg +
Status Active
HBV
Inactive carrier
Occult HBV
TO DO ETV
Tenof
Lamivudine?
1w before –12m after
Premptive tt
Lamivudine?
A S L
Prevention HBV reactivation
HBsAg + + ‐ ‐
HBc Ab + + + +
HBV DNA + neg + neg
Status Active
HBV
Inactive carrier
Occult HBV “Cured”
HBV ???
TO DO ETV
Tenof
Lamivudine?
1w before –12m after
Premptive tt
Lamivudine?
Follow every 4w
Untill 12m after chemott
For rituximab tt, BMTx or SCTx => lamivudine? EASL 2012
Anti HBc+ liver graft to HBsAg neg recipient: lamivudine life long
A S L
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Recommendations to prevent HBV reactivation in immunosuppressed patients
- In case of pre-chemotherapy HBV DNA ≥ 2000 IU/ml, immunosuppressive chemotherapy should be preferably started when viral load has declined under 2000 IU/ml and NA should be continued for at least 1 year.
-Patients who are HBsAg negative but positive for anti-HBc alonewith HBV DNA detectable (occult HBV infection) should be treated similarly as patients positive for HBs Ag (C1).
-Patients who are HBsAg negative, anti-HBc positive, anti-HBs Positive, DNA neg (resolved infection) should not be treated pre-emptively ut should be monitored for ALT elevation and HBV DNA rise (every 2 or 4 weeks) during chemotherapy and 3 to 6 months after stopping immunosuppressive therapy. Treatment should be started before ALT rise
A S L
• Results:• all‐cause mortality in prophylaxis group = 21%
no antivirals = 72%
• Reduce also cancer related mortality because
of interruptions of chemoTx
• Screening all patients = cost effective and most
effective in 1y survival
Prevention HBV reactivation
EASL practice guidelines HBV. J Hepatol 2012; 57: 167-185BASL guidelines HBV. Acta GE Belgica 2007; LXX: 389
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Take home messages
• Before starting immune suppression, chemotherapy or anti‐TNF => check always HBV status (HBsAg, anti HBc Ab, anti HBs Ab)
• Vaccination for HAV and HBV in chronic liver diseases: as soon as possible, before cirrhosis or on waiting list
• Isolated anti‐HBc ABs: give 1‐3 vaccinations => determine: resolved HBV, occult HBV (DNA+), false +