Use of Tumor Necrosis Factor- Patients with Chronic Hepatitis B Infection

THERAPY
Use of Tumor Necrosis Factor-␣ Inhibitors in
Patients with Chronic Hepatitis B Infection
Matthew B. Carroll, MD, FACP, and Michael I. Bond, DO
Objective: Tumor necrosis factor-␣ (TNF-␣) inhibitors have emerged as a potent treatment for
rheumatoid arthritis (RA), but not without significant risks. In chronic hepatitis B viral infection
TNF-␣ is readily produced, and viral clearance is dependent on the amount bioavailable. Limited
data suggest that TNF-␣ inhibitors may facilitate uncontrolled hepatitis B viral replication. The
purpose of this article was to provide a detailed review of the role of TNF-␣ in controlling hepatitis
B viral infection and the clinical impact blockade might have on viral control.
Methods: We describe a patient with chronic hepatitis B viral infection and RA treated with
etanercept. We then review case reports, expert opinion, and manufacturer recommendations
regarding hepatitis B viral infection, TNF-␣, and TNF-␣ inhibitors.
Results: To date, 13 patients with chronic hepatitis B infection treated with TNF-␣ inhibitors
have been reported: 11 with infliximab and 2 with etanercept. Some patients received antiviral
therapy for hepatitis B (specifically lamivudine) before, during, or after TNF-␣ inhibitors were
started. Clinically apparent reactivation of hepatitis B virus typically occurred 1 month after the
3rd dose of infliximab. Etanercept was not associated with a similar reactivation. The difference
between infliximab and etanercept in viral reactivation may be linked to the pharmacologic
difference of each medication.
Conclusions: TNF-␣ inhibitors in general should be used cautiously in chronic hepatitis B viral
infection. But if necessary, when deciding which agent to use, the clinician should consider the
mechanism by which the body clears TNF-␣.
Published by Elsevier Inc. Semin Arthritis Rheum 38:208-217
Keywords: tumor necrosis factor alpha, hepatitis B, etanercept, infliximab, adalimumab
R
heumatoid arthritis (RA) is a systemic disorder
characterized by the chronically inflamed synovium, which leads to gradual degradation and destruction of the joint. Underlying bone is affected, with
periarticular erosive changes and diffuse cortical thinning
found on radiographs. The systemic inflammation seen in
RA is due in part to aberrant production of cytokines,
compounds that normally help fight infection or respond
to injury through modulation of the immune system.
One such cytokine is tumor necrosis factor alpha (TNF␣). TNF-␣ is a pro-inflammatory cytokine that plays a
San Antonio Uniformed Services Health Education Consortium (SAUSHEC), Wilford Hall Medical Center, Lackland Air Force Base, Lackland, Texas.
The authors received neither financial support nor had any affiliation with organizations outside of their respective institutions. Dr. Carroll is a shareholder of Abbott
Pharmaceuticals (adalimumab—Humira ®), Amgen/Wyeth (etanercept—Enbrel ®),
and Gilead Sciences (adefovir dipivoxil—Hepsera ®).
Address reprint requests to Matthew B. Carroll, MD, FACP, 301 Fisher Street,
Keesler AFB, MS 39564. E-mail: [email protected].
208
0049-0172/08/$-see front matter Published by Elsevier Inc.
doi:10.1016/j.semarthrit.2007.10.011
key role in the host response to various types of infection
(1) or other stimuli (2). In RA, continuous production of
TNF-␣ in the joint space sustains inflammation, promotes osteoclast formation, and leads to the characteristic
bone and cartilage destruction seen in advancing disease
(3). Given such effects, TNF-␣ inhibitors (TNF-␣I) have
greatly impacted how RA is currently managed. Despite their
effectiveness, TNF-␣I have side effects, such as the reactivation of tuberculosis in patients given infliximab (4). At
the present time it is not well known whether TNF-␣I
allow reactivation of other chronic infections.
Hepatitis B virus (HBV) is one such infection causing
chronic disease in about 5% of individuals infected, or nearly
350 million people worldwide (5,6). A large body of evidence supports a role for TNF-␣ in the host antiviral response. Animal models demonstrate an impaired antiviral
response when antibodies to TNF-␣ are administered (7).
Neutralization of TNF-␣ or an imbalance with another cytokine, specifically interferon-␥ (IFN-␥), impairs viral clear-
M.B. Carroll and M.I. Bond
209
ance and promotes chronic infection (8,9). A similar imbalance has been found to occur in other chronic infectious
diseases, such as disseminated mycobacterial infection (10).
To date, a handful of case reports suggest that TNF-␣ inhibition facilitates HBV reactivation and replication, with fulminant hepatic failure (11,12) or fatal outcomes reported
(13). Our patient with chronic HBV infection and RA tolerated etanercept without evidence of increased HBV replication. Based on this discrepancy, we undertook this review
of the literature to clarify the role of TNF-␣ in HBV infection, to identify which TNF-␣I may facilitate HBV reactivation, and assist clinicians to prevent reactivation of HBV
infection in their patients.
METHODS
A review of the published English literature was performed
using Medline® and Healthstar databases through Ovid
web gateway (http://gateway.ovid.com) and the New England Journal of Medicine (http://content.nejm.org). The
search screened articles from 1950 (Medline®), 1966
(Healthstar), or full-text articles since 1993 (New England
Journal of Medicine) to January 2007 for the keywords “tumor necrosis factor alpha,” “hepatitis B,” “etanercept,” “infliximab,” and “adalimumab.” Articles on TNF-␣ and hepatitis B were selected if a review of the title and/or abstract
suggested it discussed the basic science or immunology of
these areas. Articles on etanercept (Immunex, Thousand
Oaks, CA), infliximab (Centocor, Horsham, PA), and adalimumab (Abbott, Abbott Park, IL) were selected if they reviewed the pharmacologic properties of these agents or if
they were associated with liver toxicity or hepatitis B infection. Articles from the New England Journal of Medicine database were chosen if they were review articles or clinical
practice/therapeutics. Additional articles of interest were selected from the bibliographies of the published literature.
CASE REPORT
A 73-year-old Hispanic man was followed in our clinic for
seropositive, deforming RA previously complicated by
rheumatoid vasculitis. He was infected with HBV from a
blood transfusion and developed biochemical evidence of
chronic infection by the mid to late 1990s. He had the
following antibody profile: HBs Ag⫹, HBc IgM⫺, HBc
IgG⫹, HBe Ag⫹, HBe Ab⫺, and HBs Ab⫺. His RA was
refractory to d-penicillamine, hydroxychloroquine, sulfasalazine, and moderate dose prednisone. Higher doses
of prednisone used during the episode of vasculitis triggered a flare of HBV infection. Methotrexate and leflonamide were not used because of possible hepatic toxicity. In March 1999, etanercept (Enbrel®) monotherapy
at 25 mg subcutaneously twice a week was started for RA
with marked improvement in articular symptoms. Liver
biopsy done in July 1999 revealed mild to moderate histologic activity and grade 2 (of 4) fibrosis. Lamivudine
(Epivir-HBV®) 100 mg daily was begun in July 1999
because of the results of his liver biopsy and markedly
elevated levels of HBV DNA. Lamivudine therapy resulted in a decline in HBV DNA levels to undetectable
and normalization of serum transaminases, as shown in
Table 1. The trend in his HBV DNA levels is shown in
Fig. 1. Lamivudine was stopped in mid 2001 due to development of the YMDD mutant but etanercept therapy
was continued. In February 2003, adefovir dipivoxil
(Hepsera®) 10 mg daily was initiated, but 8 months later
stopped due to an increase in serum creatinine. He has not
had any other antiviral treatments since then. In October
Table 1 Serum Transaminase Levels and HBV DNA Levels for our Patient with Rheumatoid Arthritis and Chronic
HBV Infection
Date
ALT* (IU/L)†
Log10 HBV DNA (copies/mL)
Jan 1999
Mar 1999
42
28
8.75
9.65
Nov 1999
Dec 1999
May 2000
Jun 2000
Aug 2000
Sep 2000
Dec 2000
May 2001
Aug 2002
Jun 2003
Aug 2004
May 2005
42
ND
12
14
39
ND
55
32
ND
36
36
125
6.84
5.24
Undetectable
Undetectable
Undetectable
Undetectable
Undetectable
8.19
9.06
6.71
9.40
9.40
Clinical Intervention
Mar 1999: etanercept started
Jul 1999: lamivudine started
Jun 2002: lamivudine stopped
Feb 2003 to Oct 2003: brief trial of adefovir diprovil
ND, not done.
Undetectable ⫽ Value less than 5 copies per milliliter on quantitative polymerase chain reaction (PCR).
*Alanine aminotransferase.
†Normal range for alanine aminotransferase is 0 to 40 international units per liter (IU/L).
TNF-␣ inhibitors in chronic hepatitis B infection
210
12
10
Etanercept started
Lamivudine started
Adefovir started
log HBV DNA
8
6
4
2
0
05
nJa
4
l-0
Ju
04
nJa
3
l-0
Ju
03
nJa
2
l-0
Ju
02
nJa
1
l-0
Ju
01
nJa
0
l-0
Ju
00
nJa
9
l-9
Ju
99
nJa
Figure 1 Plot of the log HBV DNA versus time (month/year)
for our patient with rheumatoid arthritis and chronic HBV
infection. Etanercept monotherapy was started in March
1999, with our patient on this therapy as of the publication
of this article. (Color version of figure is available online.)
2004, liver biopsy was repeated, which revealed stable
histologic activity and grade 1 (of 4) fibrosis. Some portal
regions had a mild chronic lymphocytic inflammatory
infiltrate. Although serum HBV DNA levels remain elevated and serum transaminases mildly elevated, he remains on etanercept monotherapy with no antiviral therapy and his RA continues to be remission.
RESULTS
All 5 keywords were entered into the Ovid web gateway
databases but were limited to “English language” and “humans.” This retrieved 219 articles for hepatitis B and
TNF␣, 20 articles for hepatitis B and infliximab, 6 articles
for hepatitis B and etanercept, and 4 articles for hepatitis
B and adalimumab. Two hundred articles were retrieved
when TNF-␣ was crossed with etanercept, infliximab,
and adalimumab. Our search of the New England Journal
of Medicine database retrieved 173 articles for hepatitis B
and 131 for TNF-␣.
LITERATURE REVIEW
Thirteen patients with HBV infection prescribed TNF-␣I
were identified from 9 articles in our literature search
(1,11-18) The first cases were published in 2003 (12,14).
Table 2 summarizes the course of 11 patients who received infliximab (1,11-18), while Table 3 summarizes
the course of 2 patients who received etanercept (1). Nine
of the 13 patients were men and 4 were women. Eight
patients had traditional rheumatic conditions with 3 of
these concomitantly prescribed the disease-modifying antirheumatic drug (DMARD) methotrexate (1,14,16). Although methotrexate can cause changes in serum aminotransaminases and potentially affect HBV viral
reactivation and replication, the patients reported had stable or normal serologic tests before the initiation of
TNF-␣I. Three of 5 patients with Crohn’s disease were
concomitantly treated with azathioprine (11,13). At
present, no case reports have been published involving
sole use of adalimumab. One patient died from variceal
bleeding (13) and 1 patient required liver transplantation
(12); both of these patients were treated with infliximab.
In those patients who received infliximab, HBV reactivation seemed most likely to occur between 30 and 60
days after the 3rd infusion. Another group of authors
commented in their review that HBV reactivation occurred 2 to 3 months after infliximab withdrawal (13). Of
note, 1 patient with RA treated with infliximab and not
given an antiviral medication experienced rapid (within 2
weeks) clearance of HBV DNA but later developed a persistent mild elevation of alanine aminotransferase (18).
The majority of patients had HBV reactivation despite
treatment with low (3 mg/kg) to moderate (5 mg/kg)
doses. Treatment with lamuvidine 100 to 150 mg daily
around the start of infliximab prevented liver function test
abnormalities. Treatment with lamuvidine up to several
months after starting infliximab also helped resolve liver
function abnormalities and control HBV viral load, although 1 patient died from fulminant liver failure waiting
for liver transplantation (12). In the 2 patients reported by
Roux and coworkers who received etanercept, 1 was
treated with lamivudine at the start of etanercept therapy
and the other 20 months into therapy (1). Only 1 patient
was on concomitant methotrexate (1). Regardless of when
lamivudine was started in relationship to etanercept,
HBV DNA viral load remained either the same or improved and serum aminotransferases remained stable (1).
DISCUSSION
What Is TNF-␣?
First identified over 30 years ago by Carswell and colleagues (19), the spectrum of TNF-␣ bioactivity has yet to
be completely understood. TNF-␣ is a homotrimer composed of three 17-kDa units (20,21) and is considered the
main “upstream” link in the cytokine network (3,21).
Rapid release of TNF-␣ can be triggered by diverse infectious (viral, bacterial, or parasitic) (22), physical, chemical, and immunological stimuli (2). Serum levels of
TNF-␣ are detected about 30 minutes after a stimulus
(2). Early amounts come from preformed stores cleaved
from membrane bound TNF-␣ on macrophages (called
soluble TNF-␣) and the release of cytoplasmic granules
by mast cells and eosinophils (2). Subsequent release is
due to new synthesis of TNF-␣ inserted into the cell
membrane and then cleaved (23).
TNF-␣ exerts numerous effects on the immune system
and can amplify its own synthesis (23,24). It can also exist in
either a membrane-bound or a soluble form. Soluble TNF-␣
increases the expression of adhesion molecules, stimulates
the release of other cytokines like interleukin-1 (IL-1) and
interleukin-6 (IL-6) (23), and can induce apoptosis (24).
Membrane-bound TNF-␣ participates in cell-to-cell interactions, activating other effector cells such as neutrophils or
M.B. Carroll and M.I. Bond
macrophages involved in an immune response (25). It may
also play a role with its receptor to down-regulate an immune
response after a pathogen has been cleared (25). The vast
majority of TNF-␣ synthesis (between 70 and 90%) is by
cells of the monocyte/macrophage lineage (2,3,9,22,26).
Under various circumstances, other cells contribute to
TNF-␣ production, including neutrophils, mast cells, endothelial cells, hepatocytes (1), and T-lymphocytes (2,3,22). In
RA, cells containing TNF-␣ are found in the synovial lining,
in deeper parts of the interstitium, in blood vessels, and at the
cartilage–pannus junction (3). For this reason, levels of
TNF-␣ are much higher in the joint space than in the serum
(20). Local production of TNF-␣ directly stimulates osteoclast formation and leads to bone resorption (3).
The gene for TNF-␣ (TNFA) is found on chromosome 6 in the class III region of the major histocompatibility complex (MHC) between human leukocyte antigen
(HLA)-B and HLA-DR (8,27). Expression of the TNFA
gene is tightly controlled at both transcriptional and posttranscriptional levels, yet rapid expression is still possible
(8,27). In response to stimulation by lipopolysaccharide,
macrophage TNFA gene transcription increases 3-fold,
with TNFA mRNA increasing 50- to 100-fold and
TNF-␣ protein secretion increasing 10,000-fold (27). In
nonmonocyte/macrophage cell lines, the constitutive activity of the TNFA gene promoter is absent; thus, it can
only be induced in response to a stimulus (22). Gene
promoter polymorphisms do exist, and these impact transcriptional activity (8,27,28). The best characterized
TNFA gene promoter polymorphisms are those at positions ⫺308 and ⫺238 (8,28). Substitution of adenine (A)
for guanine (G) at position ⫺308 is associated with
higher constitutive and inducible production of TNF-␣
(8,27). Those who are guanine homozygotes (G/G genotype) at position ⫺308 of the TNFA gene produce lower
levels of TNF-␣ (29).
The physiologic effects of TNF-␣ are exerted through
2 receptors (TNF-R), TNF-R-p55 (CD120a) and TNFR-p75 (CD120b) (30). Both receptors are trimeric in
structure (10) and are expressed on the membrane of most
cells, giving TNF-␣ diverse biologic effects (24). As with
TNF-␣, the 2 TNF-R exist in either a membrane-bound
or cleaved (soluble) form (20,26). Binding of TNF-␣ to
the membrane bound receptor activates nuclear factor-␬B
(NF-␬B), triggering the release of inflammatory cytokines
(31). Soluble receptor forms attenuate the bioactivity of
TNF-␣ (32). The effects of TNF-␣ binding with its receptor are regulated in a variety of ways. Constitutive
TNF-␣ synthesis is restricted to a small subset of immune
cells (24). The relative expression of each TNF-R on a cell
surface varies among tissues, implicating this as a distinct
regulatory mechanism (26). The amount of TNF-␣ available to interact with its receptor also regulates biologic
effects (26). Increased expression of both the membrane
bound and the soluble forms of TNF-R can be found in
response to various inflammatory disease states (26,30).
211
TNF-␣ and the Hepatitis B Virus
Failure to secrete adequate amounts of TNF-␣ due to
TNFA gene promoter polymorphisms has been shown to
adversely influence the outcome of acute HBV infection
(8,28). Depending on the population studied, either
polymorphism (positions ⫺308 and ⫺238) may influence HBV clearance (28). In a White German population, only those with the ⫺238A allele were more likely to
develop chronic HBV infection (8,33). In a Korean population, the ⫺308G/⫺238G haplotype demonstrated a
higher risk of HBV persistence (28). Lower levels of
TNF-␣ likely has 2 important effects. First, the cytokine
cascade initiated by TNF-␣ is not as robust (30). Second,
an imbalance with IFN-␥ (8,11) could impair clearance of
the virus (9). Thus, not only the amount of TNF-␣
present, but its balance with IFN-␥, is important. This
has been demonstrated in vitro (29), in animal studies (6),
and in vivo (34). In a trial assessing the efficacy of recombinant TNF-␣, Sheron and coworkers evaluated 6 patients with untreated chronic HBV infection. Those
given lower doses (10-15 ␮g/m2) demonstrated a decline
in serum HBV DNA, whereas those given higher doses
(over 30 ␮g/m2) had enhanced viral replication (29,34).
None of these patients, however, demonstrated serologic
evidence of viral eradication, and disease progression in 1
required liver transplantation (30,34).
On initial hepatocyte infection, viral replication leads
to the production of various proteins, to include surface,
core, polymerase, and X proteins (35). These foreign proteins undergo intracellular processing and are presented
by the HLA class I pathway. Cytotoxic (CD8⫹) T-lymphocytes bind to the HLA class I complex and with appropriate costimulation initiate a robust immune response to the virus (36). This response can inhibit HBV
replication and leave the hepatocyte intact through secretion of IFN-␥ or trigger hepatocyte apoptosis through the
Fas/Fas ligand pathway (36). Both responses had been
observed during resolution of acute HBV infection, and
the latter response may be mediated through recruitment
of other nonspecific inflammatory cells or the secretion of
TNF-␣ (5,6,36). If viral replication eludes this pathway,
virions that are assembled and released into the circulation
may be processed by antigen-presenting cells such as macrophages (5). These foreign proteins are then presented via the
HLA class II pathway to CD4⫹ T-lymphocytes. Once activated, these cells recruit other T-lymphocytes, which induce
cytokine secretion (to include TNF-␣) and activate B-lymphocytes for antibody production (5). As demonstrated in
an animal model, the response of the CD8⫹ T-lymphocytes to HBV infection is more important in virus eradication compared with the other cells of the host immune
system (37). Selective elimination of CD8⫹ T-lymphocytes responding to acute HBV infection leads to persistent viral infection with a delay in DNA clearance and
prolonged hepatocyte destruction (37). When eradication of HBV is incomplete, chronic infection becomes
TNF-␣ inhibitors in chronic hepatitis B infection
212
Table 2 Published Cases of Patients with Rheumatic or Gastrointestinal Disease and Chronic HBV Infection Treated with
TNF-␣I
Year
Reference
2003
[12]
Adult-onset Still’s disease
28/乆
None
[14]
Rheumatoid arthritis
49/么
Methotrexate 10 mg/wk, prednisone
[15]
Ankylosing spondylitis
32/么
None
[13]
Crohn’s disease
34/么
None
Crohn’s disease
Crohn’s disease
38/么
26/么
Azathioprine
Azathioprine
[16]
Spondyloarthritis
35/乆
Methotrexate 15 mg/wk
[17]
Crohn’s disease
28/乆
None
[18]
Rheumatoid arthritis
36/乆
None
[11]
Crohn’s disease
50/么
Azathioprine
[1]
Spondyloarthritis
49/么
None
2004
2005
2006
Diagnosis
Age/Sex
Concomitant Immunosuppressive
NR, not reported.
*“Infliximab treatment” refers to the number of doses administered before hepatitis B reactivation occurred.
†“Days after treatment” refers to the time after the last infliximab dose was given when hepatitis B reactivation occurred.
established with host immunity reaching a balance between virus-specific CD8⫹ T-lymphocytes and small
amounts of replicating virus (38). The same cytokines
that contribute to initial viral clearance, specifically
IFN-␥ and to a lesser extent TNF-␣, are important in
maintaining this balance (36). The amounts secreted depend on the potency of these virus-specific CD8⫹ T-
lymphocytes after recovery from acute infection as well as
during the life of the host (36). Their concentration in the
blood and liver may also be important (36). While secretion of TNF-␣ can be associated with hepatocyte injury or
death, in chronic infection it can also serve to decrease
transcriptional activity of the HBV core promoter gene
and HBV gene expression, without causing hepatocyte
Table 3 Published Cases of Patients with Rheumatic Disease and Chronic HBV Infection Treated with Etanercept
Year
Reference
Diagnosis
Age/Sex
Other Immunosuppressive
Etanercept Dose
2006
[1]
Rheumatoid
arthritis
54/么
Methotrexate 15 mg/wk
25 mg twice a
week
Rheumatoid
arthritis
53/么
None
25 mg twice a
week
NR, not reported.
Outcome
Lamivudine started at
same time as
etanercept with no
biochemical liver
abnormalities;
etanercept later
changed to
adalimumab 40 mg
every 2 weeks
Lamivudine started
about 20 months
after etanercept; no
biochemical liver
abnormalities but
decreased HBV
DNA reported
M.B. Carroll and M.I. Bond
213
Table 2 Continued
Infliximab Dose
Infliximab Treatment*
Days after Treatment†
Outcome
5 mg/kg
2nd
10
6 mg/kg
12th
NR
NR
—
-
5 mg/kg
4th
60
NR
NR
3rd
NR
90
NR
5 mg/kg
Around 3rd
NR
5 mg/kg
1st
14
3 mg/kg
—
-
5 mg/kg
3rd
3 to 30
NR
NR
NR
Fulminant hepatitis; lamivudine started days
before liver transplant
Hepatitis due to flare of HBV, treated successfully
with lamivudine
Pretreated with lamivudine; no biochemical liver
abnormalities
Spontaneous resolution of biochemical liver
abnormalities
Death from variceal bleeding
Pretreated with lamivudine; no biochemical liver
abnormalities
Resolution of biochemical liver abnormalities
when treated with lamivudine
Spontaneous resolution of biochemical liver
abnormalities but persistence of HBV DNA in
serum
Abnormal alanine transaminase values noted 16
weeks after starting infliximab but clearance of
HBV DNA in serum
Spontaneous resolution of biochemical liver
abnormalities after 1 month
Concomitant start of lamivudine with infliximab
with no biochemical liver abnormalities
death (7,8,23,28,29,36,39). Thus, the cytokine profile of
CD8⫹ T-lymphocytes impacts viral clearance in acute
infection and contains viral replication in chronic infection (36-38).
Not all TNF-␣I Are Created Equal
As a class, TNF-␣I exhibit a high affinity for TNF-␣ and
are effective in the treatment of a variety of inflammatory
disorders. Each medication, however, is biochemically
distinct and thus exerts different effects on TNF-␣. Infliximab (Remicade®), the first of 3 TNF-␣I marketed in
the United States, is a chimeric monoclonal antibody to
TNF-␣ that consists of a mix of human constant and
murine variable regions (3). It is about 66% human to
minimize immunogenicity and is administered intravenously (20,40). Infliximab can neutralize either soluble or
membrane-bound TNF-␣, and as a result, cells bearing
TNF-␣ can be destroyed through complement fixation or
cytotoxic killing (2,3,21,32,40). This destruction of
TNF-␣-bearing cells by infliximab has been demonstrated in vivo (41). Adalimumab (Humira®), a newer
monoclonal antibody, is similar to infliximab in that it
also serves as an antibody to TNF-␣ but is a fully human
IgG1 molecule administered subcutaneously (3). Like infliximab, it can neutralize either soluble or membranebound TNF-␣, resulting in cell death through similar
mechanisms (3,32). Etanercept, although administered
subcutaneously like adalimumab, is distinct from the other
TNF-␣I. It is a recombinant, covalently bound dimer of
soluble p75 TNF-R fused to the Fc portion of IgG1 (2,40).
It binds to soluble TNF-␣ longer than the naturally occurring soluble p75 TNF-R, yet has no effect on membranebound TNF-␣ (3,20). In vitro etanercept has been shown to
be less avid for TNF-␣ than infliximab, with etanercept dissociating from both soluble and membrane-bound TNF-␣
much more quickly than infliximab (42).
In addition to the unique ways in which the TNF-␣I
interact with TNF-␣, other differences in the mechanism
of action have been noted. Infliximab, given on an every
other month basis, may cause a “cytokine washout,”
whereas etanercept, administered more frequently and in
smaller doses, may lack such an effect (2). It has been
noted that infliximab blood levels reach well over 100
␮g/mL, whereas etanercept reaches a steady state of 3
␮g/mL (2). Greater immunogenicity with infliximab
leads to higher autoantibody production (2). In patients
with ankylosing spondylitis, in vitro data suggest that infliximab down-regulates Th1 cytokine expression on both
CD4⫹ and CD8⫹ T-lymphocytes (which includes IFN␥), while etanercept up-regulates such expression (43-45).
Statistically significant changes in Th1 cytokine expression with both agents were noted as early as 6 weeks into
TNF-␣I therapy and affected antigen-specific and nonspecific responses (44,45). From a hepatic standpoint,
other differences in the effects of TNF-␣I are noted. In
postmarketing surveillance, infliximab is associated with
214
acute hepatic reactions such as elevated liver enzymes with
jaundice, autoimmune hepatitis, and liver failure, which
in some cases these reactions have been fatal (46,47). A
patient with severe psoriasis who developed an elevated
alanine aminotransferase after 2 doses of infliximab
switched to etanercept and methotrexate and did not experience a similar reaction (48). In patients infected with
hepatitis C virus (HCV), etanercept has been shown not
to affect liver function or HCV viral loads (49). Etanercept has been tested as an adjunct to interferon and ribavirin therapy in HCV with improvement in virologic response noted after 24 weeks (50). Finally, it has been
noted that etanercept increases peripheral T-lymphocyte
reactivity to several microbial antigens and results in a
significant increase in IFN-␥ production (1,10).
TNF-␣I in Patients with Chronic
Hepatitis B Infection
It is intriguing to consider why infliximab has been more
likely to allow HBV reactivation compared with etanercept (and to date adalimumab). The trend of infliximab
causing more reactivation and dissemination of chronic
infections is not unique to HBV. Based on postmarketing
reports, it has been reported that infliximab was associated
with more cases of Mycobacterium tuberculosis infection
compared with etanercept (4) and adalimumab (24). The
risk of reactivation of tuberculosis is almost 10-fold higher
in patients treated with infliximab when compared with
etanercept (10). A similar trend is noted with other opportunistic infections such as histoplasmosis, listeriosis,
cryptococcal infection, systemic candidiasis, and Pneumocystis carinii (24). Although postmarketing surveillance
data do have inherent limitations, the rates of these infections in infliximab patients were higher when compared
with background rates (4). Also of interest, reactivation of
such infections typically occurs around the third dose of
infliximab (4,24). Histoplasmosis infection was seen with
infliximab doses between 3 and 5 mg/kg (24), similar to
that in patients listed in Table 2.
Pharmacologic and biochemical differences between
infliximab and etanercept may explain why this agent is
more likely to facilitate HBV reactivation. Etanercept has
a shorter half-life than infliximab, and this may ensure
rapid clearance once the agent is stopped (51). As previously noted, infliximab binds both membrane-bound and
soluble TNF-␣ and is much more avid for TNF-␣. Infliximab cannot be dissociated from membrane-bound
TNF-␣ in the presence of soluble monomeric TNF-Rp55, whereas etanercept nearly completely dissociates in
vitro (42). The avidity of infliximab for either form of
TNF-␣ likely causes widespread depletion of macrophages. This has been noted in an animal model of infection with parainfluenza type 1 (Sendai) virus (52). Bronchoalveolar lavage specimens from rats treated with
soluble TNF-R-p55 IgG demonstrated significant reduc-
TNF-␣ inhibitors in chronic hepatitis B infection
tions in the number of macrophages and lymphocytes but
higher pulmonary viral titers (52). The authors concluded
that inhibition of TNF-␣ decreased the cellular inflammatory response to viral infection, allowed prolonged viral replication, and prevented destruction of infected epithelial cells (52). This could be what occurs in chronic
HBV infection with infliximab treatment.
On cessation of infliximab therapy, macrophages and
T-lymphocytes may reconstitute in greater numbers, generating a brisk response to replicating virus and potentially causing fulminant hepatic injury. In their hepatitis
B animal study, Thimme and coworkers noted that depletion of CD8⫹ T-lymphocytes led to an unexpected
rebound of these cells to baseline levels several months
later (37). This was associated with a surge in liver enzymes and increased clearance of viral DNA without the
production of anti-hepatitis B surface neutralizing antibodies (37). Their results suggested that viral clearance
was due to the reconstitution of previously eradicated
CD8⫹ T-lymphocytes (37). In an animal model of latent
tuberculosis, infliximab caused a marked increase in the
number of immune cells, out of proportion to the bacillary load (4). Also of interest, concomitant use of methotrexate with infliximab may reduce clearance of intrahepatic HBV specific CD8⫹ T-lymphocytes (53). This
increases the risk of exacerbating HBV infection as infliximab is gradually cleared and these surviving CD8⫹ Tlymphocytes respond to viral replication that was previously kept in check by the inhibitory effects of TNF-␣
(53). Finally, the degree of depletion of TNF-␣ may play
a role. As discussed earlier, it has been postulated that the
balance of IFN-␥ with TNF-␣ presented to infected
hepatocytes helps drive viral clearance with or without
hepatocyte destruction (9). Since TNF-␣ clearance is
more pronounced with infliximab compared with etanercept, it could more dramatically shift such a balance toward hepatocyte destruction.
In our patient, the use of etanercept did not cause an
immediate rise of his HBV viral load or serum transaminases. When started on lamivudine several months later,
the HBV viral load became undetectable and the alanine
aminotransferase normalized. It was not until the HBV
viral load rose again that the YMDD mutant was detected
and lamuvidine was stopped. Adefovir dipivoxil was given
for several months in 2003 but stopped due to a mild
increase in serum creatinine. To this day, the patient remains on etanercept with an elevated HBV viral load and
persistent mild serum transaminitis, but without histologic progression on biopsy and without clinical or biochemical evidence of hepatic decompensation.
Current Recommendations
No consensus currently exists about whether or not
TNF-␣I can be safely used in patients with chronic HBV
infection. In 2004 Centocor, Inc. and the Food and Drug
Administration updated the infliximab label to include a
M.B. Carroll and M.I. Bond
comment that use had been associated with reactivation of
HBV and chronic carriers should be evaluated and monitored before and during treatment (46). The current package insert for infliximab states that prescribers “should
exercise caution in prescribing TNF blockers, including
Remicade®, for patients identified as carriers of HBV”
(47). The package inserts for etanercept and adalimumab
do not provide any specific comments about the reactivation of HBV infection (54,55). Given the immunosuppressive nature of this class of medications and postmarketing problems encountered with reactivation of other
latent infections, a conservative approach would be to
consider not using TNF-␣I in this population (40,56).
From the case reports reviewed in this article, this may be
most applicable when considering whether or not to use
infliximab. One fatal outcome due to a variceal bleed (13)
and 1 patient who developed fulminant hepatic failure
which required liver transplantation (12) have been reported with infliximab in chronic HBV infection. Use of
etanercept may be relatively safer since HBV viral loads
and serum transaminases did not worsen in either our
patient or the 1 reported by Roux and coworkers before
institution of antiviral therapy (1).
For patients who need a TNF-␣I due to severe rheumatologic or autoimmune disease, no guidelines currently exist on which antiviral medication to use or how
long to use it to prevent reactivation of HBV (35). Although the current literature exclusively reflects experiences with lamivudine, no antiviral agent can be assumed
to be better than another. Chronic use of lamivudine may
lead to development of the YMDD mutant. Guidelines
from the European Association for the Study of the Liver
International Consensus Conference on hepatitis B state
that “antiviral therapy should be given 2 to 4 weeks before
the initiation of immunosuppressive therapy or if hepatitis develops in this group of patients” (57). Antiviral therapy should be continued for 3 to 6 months after completion of TNF-␣I therapy and close monitoring of serum
transaminases and HBV viral loads are extremely important (57). The New Zealand MEDSAFE guidelines issued
in 2006 do not recommend a particular antiviral agent
but do state that “patients who are carriers of HBV and
require treatment with anti-TNF agents should be closely
monitored for signs and symptoms” of reactivation during therapy and several months afterward (58).
Finally, no guidelines have been established regarding
who to screen for chronic HBV infection before starting
TNF-␣I (35). It is our routine practice to screen all patients for chronic HBV infection before initiating therapy. The New Zealand MEDSAFE bulletin in November
2006 recommended that patients at risk for HBV infection “should be evaluated for evidence of prior HBV infection before anti-TNF therapy is initiated” (58). In
their discussion on this issue, Calabrese and coworkers
have recommended a potential way to risk-stratify patients with chronic HBV infection before starting
TNF-␣I (35).
215
Although TNF-␣I are effective agents in the treatment
of various rheumatologic and autoimmune conditions,
they have been associated with the reactivation of latent
infections. Reactivation of HBV infection in patients
started on TNF-␣I is currently limited to a handful of case
reports, but the TNF-␣I used could make a difference.
Infliximab, because of its effect on membrane-bound and
soluble TNF-␣, may more potently suppress the cellular
immune response compared with etanercept and adalimumab. This suppression may lead to a disproportionate
immune response on reconstitution. No guidelines currently exist that help formulate a treatment plan for a
patient with chronic HBV infection who may need a
TNF-␣I to ease the symptoms of a rheumatic illness.
Studies exploring the optimal way to screen and treat
patients with chronic HBV infection requiring TNF-␣I
are greatly needed.
ACKNOWLEDGMENTS
We are indebted to Michelle Bond and Jennifer Carroll
for insightful review and grammatical revision of this
manuscript.
REFERENCES
1. Roux CH, Brocq O, Breuil V, Albert C, Euller-Ziegler L. Safety of
anti-TNF-␣ therapy in rheumatoid arthritis and spondyloarthropathies with concurrent B or C chronic hepatitis. Rheumatology 2006;45:1294-7.
2. Feldmann M, Ravinder NM. Anti-TNF␣ therapy of rheumatoid
arthritis: what have we learned? Annu Rev Immunol 2001;19:
163-96.
3. Weaver AL. Differentiating the new rheumatoid arthritis biologic
therapies. J Clin Rheumatol 2003;9:99-114.
4. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J,
Schwieterman WD, et al. Tuberculosis associated with infliximab,
a tumor necrosis factor ␣-neutralizing agent. N Engl J Med 2001;
345:1098-103.
5. Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337:
1733-45.
6. Chisari FV, Ferrari C. Hepatitis B virus immunopathogenesis.
Annu Rev Immunol 1995;13:29-60.
7. Ganem D, Prince AM. Hepatitis B virus infection—natural history and clinical consequences. N Engl J Med 2004;350:1118-29.
8. Höhler T, Kruger A, Gerken G, Schneider PM, Meyer Zum
Büschenfelde KH, Rittner C. A tumour necrosis factor-alpha
(TNF-␣) promoter polymorphism is associated with chronic hepatitis B infection. Clin Exp Immunol 1998;111:579-82.
9. Su F, Schneider RJ. Hepatitis B virus HBx protein sensitizes cells
to apoptotic killing by tumor necrosis factor ␣. Proc Natl Acad Sci
USA 1997;94:8744-9.
10. Saliu OY, Sofer C, Stein D, Schwander SK, Wallis RS. Tumornecrosis-factor blockers: differential effects on mycobacterial immunity. J Infect Dis 2006;194:486-92.
11. Millonig G, Kern M, Ludwiczek O, Nachbaur K, Vogel W. Subfulminant hepatitis B after infliximab in Crohn’s disease: need for
HBV-screening? World J Gastroenterol 2006;12:974-6.
12. Michel M, Duvoux C, Hezode C, Cherqui D. Fulminant hepatitis after infliximab in a patient with hepatitis B virus treated for an
adult onset Still’s disease. J Rheumatol 2003;30:1624-5.
13. Esteve M, Saro C, González-Huix F, Suarez F, Forné M, Viver
JM. Chronic hepatitis B reactivation following infliximab therapy
TNF-␣ inhibitors in chronic hepatitis B infection
216
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
in Crohn’s disease patients: need for primary prophylaxis. Gut
2004;53:1363-5.
Ostuni P, Botsios C, Punzi L, Sfriso P, Todesco S. Hepatitis B
reactivation in a chronic hepatitis B surface antigen carrier with
rheumatoid arthritis treated with infliximab and low dose methotrexate. Ann Rheum Dis 2003;62:686-7.
Oniankitan O, Duvous C, Challine D, Mallat A, Chevalier X,
Pawlotsky JM, et al. Infliximab therapy for rheumatic diseases in
patients with chronic hepatitis B or C. J Rheumatol 2004;31:107-9.
Wendling D, Auge B, Bettinger D, Lohse A, Le Huede G, Bresson-Hadni S, et al. Reactivation of a latent precore mutant hepatitis B virus related chronic hepatitis during infliximab treatment
for severe spondyloarthropathy. Ann Rheum Dis 2005;64:788-9.
Ueno Y, Tanaka S, Shimamoto M, Miyanaka Y, Hiyama T, Ito
M, et al. Infliximab therapy for Crohn’s disease in patient with
chronic hepatitis B. Dig Dis Sci 2005;50:163-6.
Anelli MG, Torres DD, Manno C, Scioscia C, Iannone F, Covelli
M, et al. Improvement of renal function and disappearance of
hepatitis B virus DNA in a patient with rheumatoid arthritis and
renal amyloidosis following treatment with infliximab. Arthritis
Rheum 2005;52:2519-20.
Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B.
An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 1975;72:3666-70.
Case JP. Old and new drugs used in rheumatoid arthritis: part 2.
Am J Therapeut 2001;8:163-79.
Penn H. Biologic therapies in autoimmune diseases. Clin Med
2006;6:105-8.
González-Amaro R, García-Monzón C, García-Buey L, MorenoOtero R, Alonso JL, Yagüe E, et al. Induction of tumor necrosis
factor ␣ production by human hepatocytes in chronic viral hepatitis. J Exp Med 1994;179:841-8.
Choy EHS, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001;344:907-16.
Giles JT, Bathon JM. Serious infections associated with anticytokine therapies in the rheumatic diseases. J Intensive Care Med
2004;19:320-34.
Kroesen S, Widmer AF, Tyndall A, Hasler P. Serious bacterial
infections in patients with rheumatoid arthritis under antiTNF-␣ therapy. Rheumatology 2003;42:617-21.
Marinos G, Naoumov NV, Rossol S, Torre F, Wong PYN, Gallati
H, et al. Tumor necrosis factor receptors in patients with chronic
hepatitis B virus infection. Gastroenterology 1995;108:1453-63.
Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff
GW. Effects of a polymorphism in the human tumor necrosis
factor ␣ promoter on transcriptional activation. Proc Natl Acad
Sci USA 1997;94:3195-9.
Cheong JY, Cho SW, Hwang IL, Yoon SK, Lee JH, Park CS, et al.
Association between chronic hepatitis B virus infection and interleukin-10, tumor necrosis factor-␣ gene promoter polymorphisms. J Gastroenterol Hepatol 2006;21:1163-9.
Ben-Ari Z, Mor E, Papo O, Kfir B, Sulkes J, Tambur AR, et al.
Cytokine gene polymorphisms in patients infected with hepatitis
B virus. Am J Gastroenterol 2003;98:144-50.
Fang JWS, Shen WW, Meager A, Lau JYN. Activations of the
tumor necrosis factor-␣ system in the liver in chronic hepatitis B
virus infection. Am J Gastroenterol 1996;91:748-53.
Karin M. Nuclear factor-␬B in cancer development and progression. Nature 2006;441:431-6.
Olsen NJ, Stein CM. New drugs for rheumatoid arthritis. N Engl
J Med 2004;350:2167-79.
Thio CL, Thomas DL, Carrington M. Chronic viral hepatitis and
the human genome. Hepatology 2000;31:819-27.
Sheron N, Lau JYN, Daniels HM, Webster J, Eddleston ALWF,
Alexander GJM, et al. Tumour necrosis factor to treat chronic
hepatitis B virus infection. Lancet 1990;336:321-2.
Calabrese LH, Zein NN, Vassilopoulos D. Hepatitis B virus
(HBV) reactivation with immunosuppressive therapy in rheu-
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
matic diseases: assessment and preventive strategies. Ann Rheum
Dis 2006;65:983-9.
Rehermann B. Intrahepatic T cells in hepatitis B: viral control
versus liver cell injury. J Exp Med 2000;191:1263-8.
Thimme R, Wieland S, Steiger C, Ghrayeb J, Reimann KA, Purcell RH, et al. CD8⫹ T cells mediate viral clearance and disease
pathogenesis during acute hepatitis B virus infection. J Virol
2003;77:68-76.
Maini MK, Boni C, Lee CK, Larrubia JR, Reignat S, Ogg GS,
et al. The role of virus-specific CD8⫹ cells in liver damage and
viral control during persistent hepatitis B virus infection. J Exp
Med 2000;191:1269-81.
Schlaak JF, Tully G, Löhr HF, Gerken G, Meyer Zum Büschenfelde KH. HBV-specific immune defect in chronic hepatitis B
(CHB) is correlated with a dysregulation of pro- and anti-inflammatory cytokines. Clin Exp Immunol 1999;115:508-14.
Scott DL, Kingsley MB. Tumor necrosis factor inhibitors for
rheumatoid arthritis. N Engl J Med 2006;355:704-12.
Lorenz HM, Antoni C, Valerius T, Repp R, Grunke M, Schwerdtner N, et al. In vivo blockade of TNF-alpha by intravenous
infusion of a chimeric monoclonal TNF-alpha antibody in patients with rheumatoid arthritis. Short term cellular and molecular effects. J Immunol 1996;156:1646-53.
Scallon B, Cai A, Shealy D, Solowski N, Song X, Wagner C. New
comparisons of two types of TNF␣ antagonists approved for
rheumatoid arthritis. Arthritis Rheum 2000;43(Suppl.):S226.
Keller C, Webb A, Davis J. Cytokines in the seronegative spondyloarthropathies and their modification by TNF blockade: a
brief report and literature review. Ann Rheum Dis 2003;
62:1128-32.
Zou J, Rudwaleit M, Brandt J, Thiel A, Braun J, Sieper J. Up
regulation of the production of tumour necrosis factor ␣ and
interferon ␥ by T cells in ankylosing spondylitis during treatment
with etanercept. Ann Rheum Dis 2003;62:561-4.
Zou J, Rudwaleit M, Brandt J, Thiel A, Braun J, Sieper J. Downregulation of the nonspecific and antigen-specific t cell cytokine
response in ankylosing spondylitis during treatment with infliximab. Arthritis Rheum 2003;48:780-90.
Food and Drug Administration Medwatch. Important Drug
Warning: Remicade® (infliximab). Internet Document, December 2004. Available from: URL: http://www.fda.gov/medwatch/
SAFETY/2004/safety04.htm#remicade2.
Infliximab package insert (revised September 2006).
Wahie S, Alexandroff A, Reynolds NJ. Hepatitis: a rare, but important, complication of infliximab therapy for psoriasis. Clin
Exp Dermatol 2006;31:460-1.
Peterson JR, Hsu FC, Simkin PA, Wener MH. Effect of tumour
necrosis factor ␣ antagonists on serum transaminases and viraemia
in patients with rheumatoid arthritis and chronic hepatitis C infection. Ann Rheum Dis 2003;62:1078-82.
Zein NN. Etanercept as an adjuvant to interferon and ribavirin in
treatment-naïve patients with chronic hepatitis C virus infection:
a phase 2 randomized, double-blind, placebo-controlled study.
J Hepatol 2005;42:315-22.
Fleishmann RM. Safety of anakinra, a recombinant interleukin-1
receptor antagonist (r-met-HuIL-1ra), inpatients with rheumatoid arthritis and comparison to anti-TNF- agents. Clin Exp
Rheumatol 2002;20(Suppl. 27):S35-41.
Uhl EW, Moldawer LL, Busse WW, Jack TJ, Castleman WL.
Increased tumor necrosis factor-␣ (TNF-␣) gene expression in
parainfluenze type 1 (Sendai) virus-induced bronchiolar fibrosis.
Am J Pathol 1998;152:513-22.
Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, MacFarlane JD, et al. Therapeutic efficacy of multiple intravenous
infusions of anti-tumor necrosis factor ␣ monoclonal antibody
combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41:1552-63.
Etanercept package insert (issue date December 1, 2006).
M.B. Carroll and M.I. Bond
55. Adalimumab package insert (revised July 2006).
56. Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR,
Bijlsma JWJ, et al. Updated consensus statement on biological
agents, specifically tumour necrosis factor ␣ (TNF␣) blocking agents
and interleukin-1 receptor antagonist (IL-1ra), for the treatment of
rheumatic diseases, 2005. Ann Rheum Dis 2005;64:iv2-14.
57. Calabrese LH, Zein N, Vassilopoulos D. Safety of antitumour
217
necrosis factor (anti-TNF) therapy in patients with chronic viral
infections: hepatitis C, hepatitis B, and HIV infection. Ann
Rheum Dis 2004;63(Suppl. II):ii18-24.
58. Medsafe. Hepatitis B reactivation associated with the auto-TNF
products Enbrel® (etanercept), Humira® (adalimumab), and
Remicade® (infliximab). Internet Document: [2 pages], 8 Nov
2006. Available from: URL: http://www.medsafe.govt.nz.