Farmaci biologici e avventi avversi:Epatite B

Giammarco MocciSC di Gastroenterologia

Azienda Ospedaliera G. Brotzu - Cagliari

Biologic agent for Rheumatoid Arthritis MTX- naiveapproval

OPPORTUNISTIC INFECTIONS

World population6 billion

2 billion with evidence of HBV infection

400 million with chronic HBV

>100 million will die of cirrhosis or HCC

25-40%

Global Impact of HBV Infection/Disease at the turn of the new Millennium

Global Impact of HBV Infection/Disease at the turn of the new Millennium

HBsAg+Imunocompetent

HBsAg-/antiHBc+Imunocompromised

HBV infection: prevalence

WHO Summit Conference October 2010 Locarnini S, Journall Hepatol, 2015

350 milioni di persone infette/mondo

REUMATOLOGY

DERMATOLOGYIBDInflammatory

Disease

Lopez-Serrano P, WJH 2015

Prevalence of HBV infection in ID patients

ID PATIENTS ARE NOT A GREAT RISK POPULATION!!

HBsAg-negative

HBsAg-positivi HBsAg-negativiReplicazione Attiva Inattiva

HBeAg Pos o Neg Neg NegAnti-HBc Pos Pos PosAnti-HBe Neg o Pos Pos Neg o Pos

HBV DNA UI/mLsiero

2.000(qHBsAg>1000)

< 2.000(qHBsAg 90% < 90% No^

Stato di Portatore ConclamatoOcculto

(OBI) anti-HBe pos. ; in 1/3 dei casi 2.000-20.000 UI; * in pi del 90% dei veri OBI;

^ in assenza di concause di epatopatia o storia di pregressa epatite B; ^^score necro-infiammatorio > 4 HAI

OBI

Marzano A et al, DLD 2011

HBV Virological Categories

HBV reactivation in immunocompromised

0

100

200

300

400

ALT

HBsAg +CH

++++

HBsAg OBI

+

Asia: ALT and/or DNA x 10 UNVItaly: ALT > UNV; DNA > pos or 2000 IU

Virological status

HBsAg positive active carrier

HBsAg positive inactive carrier

Anti-HBc carrier

Risk stratification for HBV reactivation

Rituximab

MED

IUM

LOW

HIG

HN

ULL

Medium/high-dose prednisone (>7.5 mg/die)

Cyclophosfamide

Calcineurin inhibitors

Leflunomide

TNFa-inhibitors Other biological DMARDs

Methotrexate

Azathioprine

Hydroxychlorochine

6-mercaptopurine

Low-dose prednisone (

HBVr in RA patients undergoing RTX

De Nard F et al, WJH 2015

Indication USNew indication Gastroenterology

1998 1999 2000 2001 2002 2003 2004 20062005 2007

RA: signs and

symptomsLuminal CD maintenance

Early Active RA

Ulcerative Colitis

RA: physical function

Fistulizing CD maintenance

Ankylosing Spondylitis

Psoriatic Arthritis

Moderate - Severe

Psoriasis

RA: joint damageCrohns Disease

US Crohns Disease

EU

CD: 3rd to 2nd line

New indication RheumatologyNew indication Dermatology

Ped CD

Infliximab Indications (1998-2008)

PsA: structural damage

Cellular Immune Responses to HBV

Ganem D, N Engl J Med 2004

Perez Alvarez R et al, Medicine 2011

257 patients with positive HBV markerswho received anti-TNF therapy

- 89 HbsAg carriers

- 168 anti-HBc+

HBV reactivation:- 35 (39%) HbsAg carriers- 9 (5%) anti-HBc+

- > in patients previously treated with immunosuppressive agents(96% vs 70%)

- < in patients who received antiviralprophylaxis (23% vs 62%)

Acute liver failure reported in5 patients (4 died)

IFX was associated with ahigher rate of induced liverdamage compared with ETA

Cantini F, Intern J Rheumatol 2014

Prevalence of reactivation: 3.9% for treatment with ETA and 4.6% for ADA

Gisbert JP et al, APT 2011

HBV reactivation after anti-TNF in CD

HBsAg

HBVDNA

HBcAb

HBeAb

HBeAg

HBsAb

Bessone F et al, WJH 2016

Screening: whom and what to check

Inactive carrier: HBsAg+ ALT nn HBV DNA < 2000 UI

HBVDNA< 2000 UI/ml LAM until 12 mo after IT withdrawal

HBVDNA > 2000 UI/ml or IT > 12 mo ETV/TDF

OBI: HBsAg-/HBcAb+ ALT nn HBV DNA assente

Systematic Prophylaxis: RTX Regimi combinati se:

HBsAb negative HBV DNA monitoring during follow-up not

possible

Lopez Serrano et al, WJH 2015

Prevention of HBVr in ID patients: Algorithm

VACCINATION

Chevaux JB et al, IBD 2010Loras C et al, Am J Gastroenterol 2009Papa A et al, JCC 2013

An anti-HBs concentration of 10 mIUmLmeasured 13 months after administrationof the last dose of the vaccination isconsidered a reliable marker of protectionagainst HBV infection

Periodic (e.g. annual) testing to assessanti-HBs concentrations (and administering booster doses when anti-HBs levels decline to

Gisbert J.P. 2012

Hepatitis B Vaccination in IBD

Gisbert J.P. , AJG 2012

Loras C et al, JCC 2014

Hepatitis B Vaccination in IBD

Kim PS et al , Arthritis Care Res 2012

APC T-cellMHC

TCR

Abatacept

CD28

ABATACEPT & HBV Reativation

TOCILIZUMAB & HBV Reativation

De Nard F et al, WJH 2015

TCZ, if co-administred with pre-emptive NAs, produced favorable outcomes in RA patients and chronic HBV infection

..Periodic monitoring of liver function tests and HBV-DNA: mandatory

IgG1k monoclonal Ab against IL 12/23

Chiu HY et al British J Dermatol 2013

In a placebo-controlled study of normal volunteers, a single 750 mg dose ofvedolizumab did not lower rates of protective immunity to hepatitis B virus involunteers who were vaccinated intramuscularly with 3 doses of recombinanthepatitis B surface antigen.

Wyant et al, Gut 2015

Normal visit day

Mean HBsAb concentration, IU/LHepatitis B surface antibody (HBsAb) Serum IgA response to oral cholera vaccine

Normal visit day

Mean IgA titer, IU/L

Vedolizumab did not affect the protective immunity to HBV

Chart1

BaselineBaseline

Day 18Day 18

Day 32Day 32

Day 60Day 60

Day 74Day 74

Placebo

Vedolizumab

0

0

0

0

0

0

16

16

114.4

129.6

Sheet1

PlaceboVedolizumabSeries 3

Baseline002

Day 18002

Day 32003

Day 6016165

Day 74114.4129.6

To resize chart data range, drag lower right corner of range.

Chart1

BaselineBaseline

Day 18Day 18

Day 32Day 32

Day 60Day 60

Day 74Day 74

Placebo

Vedolizumab

0

0

700

300

3000

750

1000

600

750

500

Sheet1

PlaceboVedolizumabSeries 3

Baseline002

Day 187003002

Day 3230007503

Day 6010006005

Day 74750500

To resize chart data range, drag lower right corner of range.

CONCLUSIONSHBV reactivations are not uncommon in inactive HBV patients treated with

immunosuppressive therapies for ID

Current guidelines highly recommend prophylaxis in case of IS therapies

ETV or TDF are recommended as the optimal agents against HBV reactivations

Patients with occult or resolved HBV precise regularly HBV DNA monitoring during immunosuppressant therapy in order to detect reactivations

There is a paucity of data concerning HBVr among new biological therapies

Diapositiva numero 1Diapositiva numero 2OPPORTUNISTIC INFECTIONSDiapositiva numero 4Diapositiva numero 5Diapositiva numero 6Diapositiva numero 7Diapositiva numero 8Diapositiva numero 9Diapositiva numero 10Diapositiva numero 11Diapositiva numero 12Diapositiva numero 13Diapositiva numero 14Infliximab Indications (1998-2008)Diapositiva numero 16Diapositiva numero 17Diapositiva numero 18Diapositiva numero 19Diapositiva numero 20Diapositiva numero 21Diapositiva numero 22Diapositiva numero 23Diapositiva numero 24Diapositiva numero 25Diapositiva numero 26Diapositiva numero 27Diapositiva numero 28CONCLUSIONS