vaccination and hepatology - belgium

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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


Chronic hepatitis B profilesInactive carrier

Immunotolerant phase

HBsAg + +

HBeAg ‐ +

Anti‐HBe Ab + ‐

ALT normal normal

HBV DNA IU/ml

< 2.000 ≥ 2.106


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Active chronic HBV wild type

HBsAg + + +

HBeAg ‐ + +

Anti‐HBeAb

+ ‐ ‐

ALT normal normal Elevated

HBV DNA IU/ml

< 2.000 ≥ 2.106 ≥ 20.000




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


Was false positive HBcAb: 34-38%



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3. Isolated HBc Abs


HBV DNA

False positive HBcAb: 34-38%

Occult HBV: 4%



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


• 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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• 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


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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HBsAg + + ‐

HBc Ab + + +

HBV DNA + neg +

Status Active

HBV

Inactive carrier

Occult HBV

TO DO ETV

Tenof

Lamivudine?


Premptive tt

Lamivudine?

A S L


HBsAg + + ‐ ‐

HBc Ab + + + +

HBV DNA + neg + neg

Status Active

HBV

Inactive carrier

Occult HBV “Cured”

HBV ???

TO DO ETV

Tenof

Lamivudine?


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


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 +

vaccination and hepatology - belgium

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