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