17 Marzo 2016

I farmaci: Impatto dell’immunodepressione farmacologica, tradizionale e 2.0

Pietro Lampertico

Gastroenterology and Hepatology UnitFondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico

University of Milan

Financial disclosures

Advisory Board/Speaker Bureau for

- BMS, ROCHE, GILEAD SCIENCES, GSK, MSD

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 (<7.5 mg/die)Sulfasalazine

RIS

K Combination therapies

Risk stratification for HBV reactivation

combinedtherapy

HBsAg+

HBsAg+anti-HBc+BMT

SOTs

HIV

Rheum

IBD

BMT

SOTs

HIV

Rheum

IBD

Disease Drugs Virus

Marzano A et al., DLD 2007 (2011)

Outline of the presentation

● Risk of HBV reactivation

● Patients’ management- Universal vs targeted prophylaxis- First vs third generation NUC- Unmet needs and challenges

Biologic or targeted therapies involved in HBV reactivation - Mechanisms of action and indications

Viganò M et al, Expert Opin Biol Ther 2016

Category Drug Mechanism of action Therapeutic indications

Monoclonal Abs Rituximab B-cell depletion NHL, CLL, RA

Anti-TNF alpha Interruption of TNF-α signal RA, UC, CD, psoriasis

Ustekinumab Anti IL-12 and IL-23 Psoriasis

Alemtuzumab Lymphocyte depletion CLL

Ipilimumab Stimulates T cell activation Melanoma

Ofatumumab Inhibition of B-cell activation CLL, NHL, RA

Tocilizumab Anti IL-6 receptor RA

Abatacept Abatacept Prevents T-cells activation RA

Tyrosine Kinase inhibitors

Imatinib Inhibition of tyrosine kinase enzymes CML, GIST

Dasatinib Small-molecule inhibitor CML, ALL Ph+

Proteasome inhibitors BortezomibInhibition of proteasomes and

disruption of cell signaling pathways

MM, mantle cell lymphoma

mTOR inhibitors Everolimus mTOR inhibitorRenal cell carcinoma,

neuroendocrine tumors, breast cancer

Biologic or targeted therapies involved in HBV reactivation – available studies

Viganò M et al, Expert Opin Biol Ther 2016

Category Drug Active carrires Inactive carriers Anti-HBc positive

Monoclonal Abs Rituximab RCT (17,38,58)R (13,15,24,36)

CR (14,18,19,23,26,27,29)RS (28,30,33-35,37-39,43)

RCT (38,58)R (13,24,36)

CR (20-22,25,31,32,43)RS (28,30,33-35, 37,43,54,55)

RCT (48)R (13,24,36)

RS (28,30,35,39,54, 56)CR (51,52) PS (40)

Anti-TNF alpha R (59-61)RS (62,63)PS (65,66)

R (60,61)RS (62,63,66)

PS (65,66)

R (61)RS (63)

PS (66,67)Ustekinumab RS (70,71) No studies RS (71-73)

Alemtuzumab CR (75) No studies CR (74)

Ipilimumab CR (76,77) No studies CR (77)

Ofatumumab FDA alert FDA alert FDA alert

Tocilizumab CR (80-82) No studies RS (83)

Abatacept Abatacept RS (84) RS (84) CR (85,86)

Tyrosine Kinase inhibitors

Imatinib CR (88,92) CR (87,89,90) CR (91)

Dasatinib No studies No studies CR (95)

Proteasomeinhibitors

Bortezomib CR (101)RS (98,100)

No studies CR (97,99)

mTOR inhibitors Everolimus CR (102) CR (103) No studies

Type of study (references): CR=case report; RS=retrospective study; PS=prospective study; R=review; RCT=randomized control study

Biologic or targeted therapies not involved in HBV reactivation

Viganò M et al, Expert Opin Biol Ther 2016

Category Drug

Monoclonal Abs Basiliximab, Belimumab, Bevacizumab, Blinatumomab, Brentuximabvedotin, Canakinumab, Cetuximab, Epratuzumab, Gemtuzumabozogamicin, Ibritumomab, Natalizumab, Nivolumab, Obinutuzumab, Panitumumab, Pertuzumab, Ramucirumab, Ranibizumab, Secukinumab, Sifalimumab, Siltuximab, Tositumomab, Trastuzumab, Vedolizumab

Tyrosine Kinase inhibitors

Afatinib, Axitinib, Bosutinib, Crizotinib, Erlotinib, Gefitinib, Ibrutinib, Lapatinib, Nilotinib, Pazopanib, Sorafenib, Sunitinib

Proteasome inhibitors Carfilzomib

mTOR inhibitors Deforolimus, Sirolimus, Temsirolimus.

RTX in onco-hematological settings

HBV reactivation in HBsAg-positive patients with onco-hematological disease treated with RTX without prophylaxis

Viganò M et al, Expert Opin Biol Ther 2014

7 studies including 100 patients

HBV reactivation in HBsAg-negative/HBcAb-positive patients receiving RTX for lymphoma - A meta-analysis*

Mozessohn L, et al, J Viral Hep 2015

‘preclinical HBV reactivation’

‘Clinical’ HBV reactivation

‘Preclinical’ HBV reactivation

*15 studies including 578 patients

RTX in non onco-hematological settings

Long-term safety of RTX in patients with rheumatic diseases and resolved HBV infection

Mitroulis I et al, Ann Rheum Dis 2013 (Letter)

No HBV reactivation (HBsAg and HBV DNA negative) during 13 months (range: 6–50) in the 12 patients with resolved HBV

infection (anti-HBc only: n=3, anti-HBc+ anti-HBs+: n=9).

Barone M et al, Hepatology 2015

Safety of long-term biologic therapy in rheumatologic patients with resolved HBV infection

Safety of long-term biologic therapy in rheumatologic patients with resolved HBV infection

Barone M et al, Hepatology 2015

No risk of HBV- DNA or

HBsAg seroreversion !

No universal prophylaxisneeded !!

ALT >2xULN: 1%

Low risk of HBV reactivation in HBsAg negative/anti-HBc positive carriers receiving Rituximab for RA

Varisco V et al, J Reumatol 2016

N=33 patients treated with RTX for 34 (0-80) months

Anti-TNF alpha antagonists

Cantini F et al, Int J Rheumat 2014

HBV reactivation among rheumatologic or dermatologic patients treated with anti-TNF alpha – A meta-analysis

Cantini F et al, Int J Rheumat 2014

HBV reactivation among RA patients treated with anti-TNF alpha – A meta-analysis

HBV reactivation among patients treated with EtanerceptA meta-analysis

Cantini F et al, Int J Rheumat 2014

Cantini F et al, Int J Rheumat 2014

HBV reactivation among patients treated with Adalimumab A meta-analysis

Safety of long-term biologic therapy in rheumatologic patients with resolved HBV infection

Barone M et al, Hepatology 2015

No risk of HBV- DNA or

HBsAg seroreversion !

No universal prophylaxisneeded !!

ALT >2xULN: 1%

Drug Year* Indication HBsAg positive HBsAg negative

Active carriers Inactive carriers Anti-HBc positive

Ustekinumab 2009 Severe psoriasisPsoriatic arthritis

RS (70,71) * No studies RS (71-73) *

Alemtuzumab 2001 CLL CR (75) No studies CR (74)

Ipilimumab 2011 Metastaticmelanoma

CR (76,77) No studies CR (77)

Ofatumumab 2009 CLL FDA alert ?? FDA alert ?? FDA alert ??

Tocilizumab 2010 RA CR (80-82) No studies RS (83) **

*Year of approval by Food and Drug AdministrationType of study (references): CR=case report; RS=retrospective study; PS=prospective study; R=review; RCT=randomized control study

Viganò M et al, Expert Opin Biol Ther 2016

HBV reactivation in HBsAg positive or HBsAg negative/anti-HBc positive patients treated with Mabs

*Ustekinumab: HBV reactivation in 2/7 (29%) HBsAg positive and in 0/26 HBsAg neg/anti-HBc pos

** Tocilizumab: HBV reactivation in 2/18 (11%) HBsAg neg/anti-HBc pos

Abatacept for RA patients

Safety and efficacy of Abatacept in eight rheumatoid arthritis patients with overt HBV infection

Kim PS et al, Arthritis Care & Research 2012

* 4 inactive carriers (#1, 2, 4, and 6) did not receive antiviral prophylaxis for HBV and all 4 (100%) had HBV reactivation (>10-fold elevation of HBV DNA) within 10 months (range 3–27).

Safety of Abatacept in rheumatoid arthritis with serological evidence of past or present HBV infection

Padovan M et al, Arthritis Care & Research 2015

Safety of Abatacept in rheumatoid arthritis with serological evidence of past or present HBV infection

Padovan M et al, Arthritis Care & Research 2015

Among 47 inactive carriers and 21 patients with resolved HBV (tot 68):- 38 inactive carriers (81%) received no prophylaxis- 17 occult carriers (81%) received no prophylaxis- 13 patients received LAM prophylaxis

Tyrosine kinase inhibitors (TKI)

Reactivation of resolved infection with HBV immune escape mutant G145R during Dasatinib treatment for CML

Ando T et al, Int J Hematol 2015

Proteasome inhibitors

Drug Year* Indication HBsAg positive HBsAg negative

Active carriers Inactive carriers Anti-HBc positive

Bortezumib 2003 MM and mantlecell lymphoma

CR (101)RS (98,100)

No studies CR (97,99)RS (100)

*Year of approval by Food and Drug AdministrationType of study (references): CR=case report; RS=retrospective study; PS=prospective study; R=review; RCT=randomized control study

Viganò M et al, Expert Opin Biol Ther 2016

HBV reactivation in HBsAg positive or HBsAg neg/anti-HBcpos patients treated with Bortezomib

97) Hussain S, Jhaj R, Ahsan S, Ahsan M, Bloom RE, Jafri S-M R. Bortezomib induced Hepatitis B reactivation. Case Rep Med 2014;2014:964082.

98) Mya DHT, Han ST, Linn YC, Hwang WYK, Goh YT, Tan DCL. Risk of hepatitis B reactivation and the role of novel agents and stem-cell transplantation in multiple myeloma patients with hepatitis B virus (HBV) infection. Ann Oncol 2012;23:421-6.

99) Goldberg R, Smith E, Bell S et al. Bortezomib monotherapy in patients with Multiple Myeloma is associated with reactivation of Hepatitis B. Intern Med J 2013;43:835-6.

100) Li J, Huang B, Li Y, Zheng D, Zhou Z, Liu J. Hepatitis B virus reactivation in patients with multiple myeloma receiving bortezomib-containing regimens followed by autologous stem cell transplant. Leuk Lymphoma 2015;56:1710-7.

101) Tanaka H,Sakuma I,Hashimoto S, et al. Hepatitis B reactivation in a multiple myeloma patient with resolved hepatitis B infection during bortezomib therapy: case report. J Clin Exp Hematop 2012;52:67-9.

HBV reactivation in patients with MM receiving Bortezomibcontaining regimens followed by autologous SCT

Li J et al, Leukemia & Lymphoma 2015

112 HBsAg negative: 31 (28%) HBsAg negative but anti-HBc pos*HBV reactivation among anti-HBc positive: 2/31 (6.4%)

*

N=139 patients

mTOR inhibitors

Mizuno S, et al Clin J Gastroenterol 2013 Sezgin Göksu S, et al. World J Hepatol 2013

HBV reactivation in HBsAg positive inactive carrierstreated with Everolimus for renal cell carcinoma

Death

Death

TDF

TDF

Management of HBV patients

Outline of the presentation

● Risk of HBV reactivation

● Patients’ management- Universal vs targeted prophylaxis- First vs third generation NUC- Unmet needs and challenges

Management of HBV patients undergoingimmunosuppression

Adapted from Lau GKK, et al. Crit Rev Oncol Hematol 1999;31:71-76.

TIME

Acute Hepatitis (transient)

Chronic Hepatitis

Hepatic Failure (FCH)

ALTHBV DNA

Variable time interval to Hepatic Flare

Immune suppression

“silent”

Universal Prophylaxis

FCH = fibrosing cholestatic hepatitis

Adapted from Lau GKK, et al. Crit Rev Oncol Hematol 1999;31:71-76.

TIME

Acute Hepatitis (transient)

Chronic Hepatitis

Hepatic Failure (FCH)

ALTHBV DNA

Variable time interval to Hepatic Flare

Immune suppression

“silent”

Targeted prophylaxisor

Pre‐emptive therapy

FCH = fibrosing cholestatic hepatitis

Management of HBV patients undergoingimmunosuppression

Adapted from Lau GKK, et al. Crit Rev Oncol Hematol 1999;31:71-76.

TIME

Acute Hepatitis (transient)

Chronic Hepatitis

Hepatic Failure (FCH)

ALTHBV DNA

Variable time interval to Hepatic Flare

Immune suppression

“silent”

FCH = fibrosing cholestatic hepatitis

Therapy 

Management of HBV patients undergoingimmunosuppression

Drug Active carriers Inactive carriers Anti-HBc positive

Rituximab

Antiviral therapy Universal prophylaxis

Universal prophylaxis for hematological

malignancies

Targeted prophylaxis in all other settings

BortezomibUniversal prophylaxis

Carfilzomib

TNF-α antagonists

Targeted prophylaxis

Ustekinumab

Alemtuzumab

Bevacizumab

Tocilizumab

Abatacept

Imatinib

Dasatinib

Everolimus

Ipilimumab

Antiviral therapy:ETV or TDF started prior to start biologic therapies and maintained long-term unless HBsAg seroclearance takes place.

Universal prophylaxis: LAM lasting for 12/18 months after completion of biologic therapies. In patients who received RTX-based chemotherapy for onco-hematological disease, if long-term biologic therapy can be anticipated or whenever regular HBV DNA monitoring cannot be implemented ETV or TDF should be preferred instead of LAM.

Targeted prophylaxis:close monitoring of HBsAg and/or HBV DNA every 3/4 months to start anti-HBV drugs following HBV DNA increase and/or HBsAg seroreversion before clinical evidence of hepatitis reactivation.

Management of patients with current or resolved HBV infection undergoing biologic or targeted therapies

Viganò M et al, Expert Opin Biol Ther 2016

● These therapies are widely used in different conditions

● Some of these drugs may cause HBV reactivation

● Literature difficult to interpret

● Screening of all patients

● Treat or universal prophylaxis or monitor (targeted prophylaxis)

● Very safe and effective algorithm: no reactivation, no fatal cases, no viral problems

● …….but a lot of long-term extra work…….

Management of HBV patients under biologic or targeted therapies - Summary

● Screening of all candidates to immunosuppression

● HBsAg positive, inactive carriers: LAM vs ETV/TDF

● Anti-HBc positive: universal prophylaxis (LAM) vs monitoring

● Risk of HBsAg seroreversion in anti-HBs positive isolated ?

● Risk of HBV reactivation without HBsAg (only HBV-DNA )?

● Risk of HBV reactivation after NUC withdrawal in inactive carriers ?

● Duration of NUC prophylaxis…………..

Challenges in the management of HBV patientsunder immunosuppression

Back-up slides

Active carriers

Before starting targeted therapy screen all patients for HBsAg, anti-HBs and anti-HBc

If HBsAg positive, define the virological and clinical profile If HBsAg negative but anti-HBc positive (± anti-HBs)

Start anti-HBV therapy with ETV orTDF before targeted therapy. Maintainanti-HBV therapy until HBsAgseroconversion.

In most patients, start universal anti-HBV prophylaxis withLAM before immunosuppression and continue for 12/18months after completion of therapies.In the subgroup of inactive carriers undergoing RTX-basedchemotherapy for onco-hematological disease, if long-termtargeted therapy can be anticipated, those with serum HBVDNA between 2000 and 20.000 IU/mL or whenever regularHBV DNA monitoring cannot be implemented, prophylaxis withETV or TDF should be preferred.

Inactive carriers High risk targeted therapy for onco-hematological malignancies (RTX,

BOR and Carfilzomib)

Low risk targetedtherapy

Pre-emptive anti-HBV therapy bymonitoring of HBsAg and/or HBV DNAevery 3 months to start antiviral therapy ifHBV DNA becomes detectable and/orHBsAg seroreversion before clinicalevidence of hepatitis reactivation.Whenever regular monitoring cannot beimplemented, LAM prophylaxis should bestarted before targeted therapy.

Viganò M et al, Expert Opin Biol Ther 2016

Reactivation of HBV during targeted therapies for cancer and immune-mediated disorders – an algorithm